AGING

new biology THE AGING Theories and Potential Therapies Joseph Panno. Ph.D. .

Longevity.6’7—dc22 2003025469 Facts On File books are available at special discounts when purchased in bulk quantities for businesses. cm.com Text desig n by Erika K.AGING: Theories and Potential Therapies Copyright © 2005 by Joseph Panno. . Ph. including photocopying. Inc. Title. p. Joseph. No part of this book may be reproduced or utilized in any for m or by any means. Aging. institutions.P33 2004 612. Arroyo Cover design by Pehrsson Design Illustrations by Richard Ga rratt and Joseph Panno Printed in the United States of America MP FOF 10 9 8 7 6 5 4 3 2 1 This book is printed on acid-free paper. 2. recording. electronic or mechanical. or by any information storage or retrieval systems. without permission in writin g from the publisher. 132 West 31st Street New York NY 10001 Library of Congress Cataloging-in-Publication Data Pan no. Please call our Spe cial Sales Department in New York at (212) 967-8800 or (800) 322-8755. associations. Al l rights reserved. QP86. — (The new biology) Includes bibliographical references and index. ISBN 0-8160-4951-3 1 . I. You can f ind Facts On File on the World Wide Web at http://www.factsonfile. For information contact: Facts On File. or sales promotions. Aging: theories and potential therapies / Joseph Panno.D.

Diana.For my wife. who worked with me in the lab for many years. and for my dau ghter Eleanor. who knew about cells before she could read or write. V .

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CONTENTS V Preface Acknowledgments Introduction xi xiii xv 1 The Quest for Immortality One Hour upon the Stage Growing Younger The Road Ahead 1 2 7 7 2 Aging Theories Error Catastrophe Theory Genes and Programmed Aging Telomeres Rate-of-Living The ory Free Radicals Hormonal Imbalance Theory Concluding Remarks 9 9 10 11 13 14 14 21 3 Age-Related Diseases Alzheimer’s Disease Arthritis Cancer Cardiovascular Disease Diabetes Osteoporosis 24 24 32 33 34 35 36 .

4 Antiaging Medicine Hormone Therapy Antioxidants Caloric Restriction Gene Therapy 38 39 41 41 42 5 The History of Gerontology The Early Years DNA Structure Inspires New Theories Recombinant Technology Revol utionizes the Field The Postgenomic Era 43 43 45 46 52 6 The Search for Longevity Genes Yeast Nematode Fruit Fly Mouse Human Summary 54 55 58 59 62 62 63 7 Geriatrics Our Aging Society Evaluating the Geriatric Patient Managing Age-Related Disorder s Drug Therapy Nursing Homes Ethical Issues 65 66 67 68 71 72 73 8 Resource Center Eukaryote Cell Primer Recombinant DNA Primer 75 75 95 .

Gene Therapy Primer The Human Genome Project Glossary Further Reading Index 106 110 115 141 147 .

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against the danger of burying—and thereby losing—young stud ents under a mountain of detail. Biotech nology was specifically designed for studying cells. Animal Clon ing. Gene Therapy. but it is also appropriate for firs t-year university students and the general public. since that time it has become clear that the advent of biotechnology was only t he first step toward a new biology. and stem cell therapy. xi . The set is intended pr imarily for middle and high school students. and using those techniques. I have t ried to balance the need for a comprehensive presentation of the material. scientists gained insights into cell structure and function that came with unpr ecedented detail. However. a biology that now includes nuclear transfer technology (animal cloning). biology was la rgely a descriptive science in danger of going adrift. In writing this set. but there was still no way to study the function of a gene or the cell as a whole. The term new biology was coined in the 1970s with the introductio n of recombinant DNA technology (or biotechnology). cover ing many complex fields. All these tec hnologies are covered in the six volumes of this set. At that time.PREFACE V The New Biology set consists of the following six volumes: The Cell. Cancer. and Aging. and biologists in the 1960 s had cracked the genetic code. Thus the use of lengthy discussions and profess ional jargon has been kept to a minimum. A large number of drawings are provided throughout the series to illustrate the s ubject matter. The cell is at the very he art of the new biology and thus figures prominently in this book series. Stem Cell Research. Microbiologists at the tu rn of the century had found cures for a few diseases. Biotechnology changed all that. and scientist s of the period referred to it as the new technique or the new biology. and every attempt has been made to ensu re that this be done without sacrificing the important elements of each topic. gene therapy.

the reader may read the set in the order he or she pre fers. a severed spinal cord. Although it is recommended that The Ce ll be read first. and develop therapies for. on the cell and other new biol ogy topics. followed by animal cloning. That is. that reflects the natural progression of the discipline. These technologies were then used to expand our knowledge of.xii Aging As knowledge of the cell grew. st em cell therapy. indicated pr eviously. the second wave of technologies— animal cloning. located in the final chapter. Is a cloned animal a freak that we are creating for ou r entertainment. or use the technology to re-create a loved one? Is th e use of human embryonic stem cells to save a patient dying from leukemia a form of high-tech cannibalism? These and many other questions are discussed througho ut the series. stem cell therapy. . Th ese procedures are also being used to enhance food crops and the physical charac teristics of dairy cows and to create genetically modified sheep that produce im portant pharmaceuticals. cancer and aging. know ledge of the cell came first. and gene therapy—began to appear throughout the 1980s and 1990s. this is not essential. and gene therapy. Consequently. The technologies and therapies of the new biology are now being used to treat a wide variety of medical disorders. While the technologies of the new biology have produced some wonder ful results. some of the procedures are very controversial. The last application alone could save millions of lives every year. The New Biology set is laid out in a specific order. and perhaps even reverse the aging process. Volumes 2 through 6 contain extensive b ackground material. and someday they may be used to repair a dama ged heart. The ability to clone an animal or genetically engineer a plant raises a host of ethical questions an d environmental concerns. or is there a valid medical reason for producing such animals? Should we clone ourselves.

the late Dr. Karun Nair. and later by Frank Darmstadt. Kit Moser. for the support and encouragement that all writ ers need and are eternally grateful for.ACKNOWLEDGMENTS V I would first like to thank my friend and mentor. for h elping me understand some of the intricacies of the biological world and for enc ouraging me to seek that knowledge by looking beyond the narrow confines of any one discipline. Finally. The clarity and accuracy of the initial manuscript for this book was greatly improved by reviews and comments from Diana Dowsley and Michael Pan no. Dorothy Cummings. xiii . I am also indebted to Ray Spangenburg. Executive Editor. I would like to thank my wife and daughter. and Diana Dowsley for their help in locating photograp hs for the New Biology set. Copy Editor. to whom this book is dedicated. Project Ed itor. and Anthony Sacramone. Sharon O’Brien.

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think as fast. a Galápagos tortoise and a s turgeon can live for 200 years. On a cosmic scale. we have a reasonab ly good immune system. There are those who think a human life span of 85 years is long enou gh. we have a group of enzymes that monitor and repair our DNA. however. a dog is lucky to see 15 summers. it is a life form that has been alive for 3 bil lion years. On the other hand. we heal well after being hurt. There appears to be neither rhyme nor r eason to it. and the poor housefly is bo rn and dead of old age in 30 days. our cells have pl enty of energy to take care of themselves from day to day. Moreover.INTRODUCTION V Everybody keeps getting older. It has been this way since multicellular creature s crawled out of the oceans more than 500 million years ago. despite all that . the difference in li fe span between a housefly and a sturgeon is puny. If we think of those ance stors as being a single lineage. “I will do what I can to get you up to your reproductive years. as long as we eat well. and besides. many animals that have a shorter life span than we do: A h orse has 20 years. have an indefinite life span. but compared with 3 billion years. the comparison b egs the question of why we age in the first place. Yet. for our unicellular ancestors. to be sure. After all. It is almost as though Mother Nature is saying. Some scientists think aging is due to evolutionary neglect: that na tural selection was so busy finding ways to make us successful in the short term that it forgot to cover us in our old age. T here are. we get old with monotonous regularity. or fight off infectious d iseases nearly as well as they did when they were young. mortality a nd multicellularity seem to go hand in hand. and. it truly is the short end of the stick. The elderly cannot run as far. but after that you are on your own. so you can have offspring. one’s physical appearance xv .” Being on our own has mea nt that our bodies begin to break down soon after our peak reproductive years ha ve past. Indeed. the protozoans and bacteria.

involving such a complex system. muscle mass declines. The recent trend in gerontology. the shoulders become broader. The therapies that are available are designed to tre at diseases that are associated with aging. they are providing many valuable insights into th e cellular mechanisms of aging that may lead to the development of truly effecti ng antiaging therapies. particul arly since the completion of the human genome project. m en and women approaching their 80s converge on a common physical appearance. and although the manipulation of these genes do es not stop the aging process. men become more feminine and women become more masculine. Many such genes have been identified.. organs. and the skin becomes thin and wrinkled. the ea rs get bigger. Some evidence suggests th at the brain may be an aging-clock that determines the rate at which the whole b ody ages. Researchers have studied age-related changes in v irtually all tissues. which then acts like an aging-clock for the rest of the body. Gerontologis ts (scientists who study gerontology. such as cancer and arthritis. is to search for genes th at have a demonstrable effect on life span. the endocrine system. in noting these changes. have generated a large number of theories b ut few practical therapies. or are all organs breaking down simultaneously? Answering this question has pro ved to be extremely difficult. th e voice huskier. have pondered one of the most difficult questio ns pertaining to the aging process: Is aging caused by the degenerative changes in a single organ. this trend become s apparent as the shoulders get narrower. the beard thinner. another in the New Biology set. or the mechanisms involved in the aging pr ocess). but do not reverse the aging process itself. At a more subtle level. In men. In women. describes the field of gerontology and the many theories that scientists have developed over the years to explain the age-related changes that occur in virtually all . Consequently. and organ systems (e. con sisting of many hormone-producing glands) of the body. and hair begins to grow on the chin and upper lip.xvi Aging changes dramatically with age: The hair turns gray. but the results of many other studies suggests that the rate at which an animal ages may be the sum of age-related changes occurring simultaneously in all parts of the body. the so-called longevity genes. This book.g. a nd the voice develops a higher pitch. the hips broader. the attempts to understand the aging proce ss.

Introduction xvii animals. and aging therapies (antiaging medicine). The first four chapters discuss the range of animal life spans relative to the human life span. and the field of geriatrics. diseases that are associated with the a ging process. The final chapter provides backgr ound material on cell biology. which uses our growing knowledge of the aging process t o improve the quality of life for the elderly. the ongoing effort to find longevity genes. Subsequent chapters disc uss the history of gerontology. recombinant DNA technology. aging theories. and other topics that are relevant to gerontology. .

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living 4. prepared one of their own for burial. the q uest for immortality has shifted from the spiritual to the physical. the dead. Egyptian pharaohs were buried with all their worldly possessions and even a little food to see them on their way. it did not assume its present form until the 20th century. but many people still believe in the eternal life of chosen spirits. Cro-Magnons were drawn to a quest for immort ality. and in their sorrow. Although th e origins of the scientific method can be traced back to the time of the Cro-Mag nons. and his sister. and the appearance of powerful medical therapies. W ith the rise of science. According to their mythology. The accomplishments of Louis Pasteur and other microbiologists at th e turn of the last century and the explosive growth in biological 1 . carried on the same traditi on but on a colossal scale. Amunet. The pract ice of burying the dead with all their belongings disappeared down through the m illennia. but one that dealt with the soul rather than the body. the first Homo sapiens. if accepted. In grieving for their lost loved ones. Indeed. Cro-Magnon funera ls are taken as evidence by anthropologists that those people thought like us.000 years when Cro-Magnons. Amun-Ra. Distant relatives of the Cro-Magnons.I 1I THE QUEST FOR IMMORTALITY Concerns about human mortality date back at least 20. possibly thinking they would be of use in a spiritual afterlife. they adorned the corpse with prized p ossessions.000 years ago in Egypt. T hey knew about death. where they would live for eternity. could pass to the spirit world of the sun god . histori ans have noted that 90 percent of all scientists who have ever lived are still a live today.

As it is. employing everything from a sh ift in lifestyle to specific hormone supplements. One such concoction. As our science matures. Life spans vary considerably within the animal kingdom. often with disastrous results. but their use was abandone d when Curie and other scientists working with radioisotopes began having seriou s medical problems. he was being very generous. Antiaging creams are still wit h us. One Hour upon the Stage When William Shakespeare in his play Richard III compared the human life span to one hour on the stage. If protozoans ca n live millions of years. we may be able to reverse some effe cts of age. These triumphs have given us reason to h ope that someday we will be able to reverse the effects of age. our life span. only now the active ingredient is retinoic acid (vitamin A) instead of rad ium. popular in the 19 20s. The fruit fly. a new wave of antiaging therapies have been developed. two radioisotopes discovered by the great French physicist Marie Curie. We are only beginn ing to understand the tremendous complexities of the cell and the way an organis m changes with time. is but a wink of a n eye. but the fai lures so far are like the first tentative steps of a toddler. potions. while large animals bearin g few offspring live much longer. was ThoRadia. tiny animals bearing many offspring have short life spans. and smallpox. but whether this leads to physical immortality is a hotly debated to pic at the present time. Drosophila . Many such attempts date back to the turn of the early 1900s and involved the use of concoctions. More recently. The radioactive material was supposed to have an antiaging effect on the skin. to name but a few. a skin cream containing thorium and radium. all from overexposure to radioactive materials. polio. and a fata l leukemia. Whether any of these treatments will be successful is in doubt.2 Aging research since then have provided cures for many terrible diseases: diphtheria. and even radioactive cocktails. why not the human body? But so far. Madame Curie developed cataracts. kidney failure. we would live 125 mi llion years. all attempts at ph ysical rejuvenation have failed. In general. on a 24hour time scale. If our life span were indeed 1/24 of the 3 billion years that microbes have been alive.

It is also much s tudied by the expense of the individual. Mutant flies. With reduced pressure from predators. spend a great deal of time rearing and caring for their young. is an example of a small animal with a short life span. all the biocommonly found around spoiled fruit. gerontologists and geneticists around F lies have many predators.) long before their bi ological time was up. the more things they learn. In a survival of the fruit fly Drosophila melanogaster.The Quest for Immortality 3 melanogaster. but most of them are dead in two weeks. adaptations to increase their life span make a lot of sense . during which time the larvae met amorphose into the adult form. In this case. The females mate within 24 hours. and the ent ire genome has their life span would be useless. with defects in adaptatio ns that could lengthen any of several thousand genes. logical adaptations have focused and is an example o f a very short-lived on preservation of the species at animal. (David M. been sequenced.Scanning electron micrograph (SEM) s ands of offspring. Drosophila have a maximum life span of 40 days. Consequently. and through out their short lives produce tens of thou. and the world. during which time the adults teach them how best to deal with the ir environment. Elephants are mammals and. since the flies would be eaten Phillips/Photo Researchers. is strategy such as this. the young can afford a leisurely develop mental period. are large animals with few p redators that produce a single offspring every five years. The longer the adults live. Elephants. This little insect is about 3 mm long. Inc. like all mammals. on the other hand. are available. and the more they can pass on to their offspring. Th ese animals are called holometabolous insects because the eggs hatch into wormli ke larvae that feed for a time before pupating. The newly emerged males and females waste no time in producing the next generation. these animals have a rel atively long life .

As lo ng as a sturgeon keeps growing. The sturgeon is an extreme ly ancient fish that has existed for more than 200. and y et they are no more intelligent than any other fish. Sturgeon eggs. like m ost fish. its longevity is regulated by external forces. The sturgeon’s strategy for longevity is simply to keep growing. In general. s uch as accidents African elephants (Loxodonta africana) in the Amboseli National Park. They have hit upon a rule of nature that states that happy cells are dividing cells. the most notabl e of which are the sturgeon and the Galápagos tortoise. and Asia. The se large.4 Aging span of 75 to 100 years. Europe. but there are some exceptions. seas. are considered t o be a great delicacy in many parts of the world. Kenya. They live in the oceans. have thousands of offspring each year and spend no time taking care of them. very similar to that of humans. (Martin Harvey/Photo Researchers. similar to that of humans.000 years. long-lived anima ls tend to be rather intelligent. called caviar. sometimes reaching 300 years or more. and rivers of North America. The sturgeon is possibly the l ongest-lived animal that we know of. Inc.) . predating the rise of the dinosaurs during the Jurassic period. where they often grow to a length of 20 feet and weigh a ton or more. intelligent animals have a maximum life span of about 100 years. sturgeons. Moreover.

Inc. which can live a thousand years or more. In fact. not by cellular senescence. ( Jeffrey Greenburg/Photo Resear chers. Galápagos tortoises li ve on a group of islands off the coast of South America. They are not highly intellig ent animals. at least not as mammals understand intelligence. They are large animals. Being a poikilotherm (coldblooded ani mal) reinforces the sturgeon’s continuous-growth strategy because it minimizes the growth rate and activity level of the animal. such as the California redwoo d or the oak tree. T he female lays the eggs in the sand.The Quest for Immortality 5 Giant tortoise from the Galápagos Islands (Santa Cruz Island). These animals have very long life spans that may exceed 200 years. and the rest is left to M other Nature and a bit of luck. covers them over. nor do they spend any time taking care of their young. they dig their way to the surface. When the young hatch. Continuous growth is a strategy t hat also explains the longevity of certain plants. and . sometimes weighing more than 500 pounds that can live for 200 to 250 years and usually give birth to a dozen offspring every year. a feat that takes a month to accomplish.) and predators. a tortoise never sees its young.

6 Aging A sculpture of an elderly couple in their 80s showing the general effects of age and the age-related convergence of physical characteristics described in the in troduction. (Dr. Joseph Panno) make straight for the water, which is usually 10 to 20 yards away. The dash for the water is made through a predator gauntlet, and many of the young tortoises a re caught by seagulls along the way. Those that make it to the water are preyed upon by fish in the sea, and the few that survive to adulthood return to the bea ches of their birth, where they live out the rest of their lives. The tortoise, unlike the sturgeon, reaches a standard adult size, so most of the cells in the adult’s body become postmitotic, as occurs in mammals. The unusual longevity of th is animal is believed to be due to its very low growth rate and, as it is a poik ilotherm like the sturgeon, its low metabolic rate and activity level. Humans ha ve a maximum life span of more than 100 years. The longest-lived human on record was Jeanne Calment, a woman from Arles, France, who died in 1997 at the age of 122. As impressive as this is, it is a short life span indeed when compared with the record holder

The Quest for Immortality 7 from the plant kingdom. This goes to Methuselah, a 4,600-year-old pine that live s on a mountainside in Arizona. Growing Younger Many gerontologists have claimed that it is impossible for individual humans to grow younger, because it would be too difficult to rejuvenate all the cells and organs of the body. Such claims need to be taken with a large grain of salt; it should be remembered that just five years before the first sheep was cloned, mos t scientists thought that cloning a mammal was biologically impossible. In addit ion, what we have learned about animal cloning and stem cells since 1996 suggest s it may indeed be possible to produce a therapy that will allow an individual t o grow younger. Growing younger, at the cellular level, is analogous to the dedi fferentiation of a cloned cell nucleus: Both are a matter of converting a cell f rom an aged phenotype (the physical expression of an organism’s genes) to a youthf ul phenotype. In a sense, the cloning of a cell nucleus is the most successful a ttempt at rejuvenation that has yet been accomplished. In a cloning experiment, the cytoplasm of the recipient oocyte converts the donor nucleus from an aged ph enotype to one that is capable of supporting full embryonic development. At the organismic level, this is equivalent to converting an adult to an embryo. If it can be done in one cell, it could be done in many. And if all the nuclei in an o ld person’s body could be reprogrammed to a youthful phenotype, it would lead to t he complete rejuvenation of all the cells in the body. If that happened, the ind ividual would grow younger. The Road Ahead In 1900 life expectancy for the average North American was only 45 years. This h as increased to the current expectancy of 80 years primarily because of a dramat ic reduction in infant mortality, cures for various diseases, better hygiene, an d better living conditions. This increase occurred despite the enormous number o f deaths per year from cigarette smoking. A further increase of 20 to 30 years i s expected if cures are found for cancer and cardiovascular disease. Beyond that , advances in life

8 Aging expectancy will have to wait for an improvement in our understanding of the basi c mechanisms of cellular senescence. Developing therapies that will reverse the aging process, allowing individuals to grow younger, is theoretically possible, but the realization of that goal will likely turn out to be the most difficult c hallenge that biologists have ever faced. The production of aging therapies will require a fusion of animal cloning, gene therapy, and stem cell technologies. B ut even these technologies, as powerful as they are, will not be enough. Gaining a deep understanding of the basic mechanisms of aging will require detailed inf ormation about every gene in our bodies and about what those genes are doing as we grow old. This information is only now being made available, but over the nex t few years, we should see real gains being made in the field of gerontology.

and telomeres. either for enzymes or structural materials. and the health of mitochondria. a third step. mRNA. programmed senescence. For cells that are actively dividing. occ urs in a two-step process: transcription of the gene to produce mRNA. the rate of living. and the way these properties change with time. first proposed in the 1960s. RNA and proteins have to be synthesized on a regular basis to maintain and run the cell’s machinery (see chapter 8 for a cell primer). precedes the other two. the number of errors build up to a catastrophic level leading t o the death of the cell and. Production of proteins. Genetic theori es deal with speculations regarding the identity of aging genes. Soon after this theo ry was proposed. the entire organism. generation of free radicals. biochemical. defective genes. The error catastrophe theory. accumulation of errors in the genetic machinery. followed b y translation of the message to produce the protein. replication of the DNA. possibly. and physiological properties of a typical organism. suggests that over time. Physiological theories deal almost entirely with the endocrine system and the role of hormones in regulating the rate of cellular senescence. when they do. Biochemi cal theories are concerned with energy metabolism. Error Catastrophe Theory Running a cell is a complex affair.I 2I AGING THEORIES Aging theories cover the genetic. and proteins a re produced. Errors can occur all along the way. Bacteria were grown on a medium containing 9 . many scientists conducted experiments that attempted to force a buildup of errors to see how the cells would cope with it.

Somehow the cells were able to avoid an error catastrophe. vigor. cells avoid an error catastrophe at the translationa l level because they can always try again with a fresh mRNA from a good gene. these experiments had no effect on the bacteria’s or animal’s health. In its original formulation. To everyone’s surprise. Today we understand why those experiments failed: Cells have elaborate repair systems and strategie s that detect and destroy defective molecules. Bu t if the genes themselves are damaged. as their protozoan ancestors have done. which apparently can tolerate a high erro r frequency. Consequently. Genes and Programmed Aging Are we programmed to get old? If we are. it is quickly broken down and replaced with a normal copy. they would liv e for millions of years.10 Aging defective amino acids to maximize the error frequency of protein synthesis. many scientists began to wonder if errors in the geno me. the outcome would be a gradual decline in cell vigor and the eventual death of the organism . If a defective protein is synthes ized. After all. However life spans evolved. one animal lives two weeks. the other 80 years. or programmed for senescence. might be responsible for th e aging process. The genes in a multicellular organism appear to be regu lating life span for the good of the cell community as a whole. it is c lear that our genes have the final say in how long we are going to be on the sta ge. Simi lar experiments were conducted on fruit flies (Drosophila) and mice. is it like the program that guides our development from a single fertilized egg to a multicellular organism? Or is agin g the unfortunate side effect of adaptations that make it possible for us to hav e and protect our offspring? Many gerontologists believe that aging is a matter of evolutionary neglect. The size of the . Even though flies and humans are constructed from the same kinds of cells (e ukaryotes). or possibly a defective regulation of the genes. both of whi ch were given food containing defective amino acids. Only in cases w here the repair systems have been damaged would an error catastrophe occur (see Werner’s syndrome in chapter 5). If those eukaryotes had remained free-living. the error catastroph e theory focused on protein synthesis. rather than design. or life span .

The final l ife span seems to be a balance of all these forces and. the organism. and the pressure th e animal experiences from its predators. There is a very strong correlation between longevity and the weight of the brain: Smart animals live longer than dumb animals (with two exceptions.Aging Theories 11 community. Scientists might try producing a fly that could live that long. With the genome project now complete (se e chapter 8). there is a genetic element called a telomere that clearly regulates the . given these forces. There would be no point to nature’s pr oducing a fruit fly that could live a thousand years. but many experiments have failed to establish a role for genetic (or somatic) mutations in cell senescence. Damage at the gene level re-invokes the error catastrop he theory. but what in the world would an animal with that level of intelli gence do for all that time? This is not just a whimsical point. they are turning on or off at the wrong time) or through a mutation that eventually dama ges the protein product. many genes are directly responsible for an animal’s life span. These genes may be exerting their effects through inappropriate behavior (that is. Telomeres Although we have not identified the genes controlling our life span. and those rep air systems remain intact long after the animal shows visible signs of age. it will soon be possible to screen for the expression of all human genes. in every tissue and organ of the body. may be the best deal the organism can hope for. because their predators ea t them all in a matter of days. The goa l of gerontologists is to try to get a better understanding of the covenant betw een the genes. Whether intended by evolution or not. This is because the cell can detect and r epair DNA damage as easily as it deals with errors in translation. the number of offspring. and the environment. the animal’s intelligence. When this job is complete (and it will be as big a job as the genome project itself) we will finally have an idea of which genes are responsible for our life span. The inappropriate expression of certain genes as a major cause of aging is only now being addressed in a comprehensive way. noted in chapter 1). are all taken into account.

that while telomeras e can block replicative senescence in cultured cells. per manently blocking the ability of the cell to divide. but they are needed for the proper duplication of the chromos omes in dividing cells. on the other hand. Experiments since have shown. DNA polymerase preserves a safe distance from the end of th e DNA so it does not slip off the end. Cancer cells. Indeed some animals with long life spans have short telomeres and negligible telomerase activity. the cell is said to have reached replicative senescence. the telomeres shrink a bit. while other animals wit h short life spans have long telomeres and active telomerase. DNA polymerase s talls automatically whenever it gets too close to the end of the chromosome. and from them scientists isolated an enzyme call ed telomerase that restores the telomeres after each cell division. it has little to do with t he life span of the animal as a whole. located at the tips of each chromosome. can divide indefinitely. The telomeres in human fibrobla sts are long enough to permit about 50 rounds of DNA replication. after Leonard Hayflick. however. This is not surpri sing if we keep in mind that most cells in . If the telom erase gene is added to normal fibroblasts. Telomeres also provide a guarantee that g enes close to the ends of the chromosomes have been replicated. This occurs because the enzyme that duplicates the DNA (DNA polymerase) has to have some portion of the chromosome out ahead of it. Each time the chromosomes are duplicated. Telome res are not genes. That is. the c ell can divide about 50 times in culture. This is often referred to as the Hayfl ick limit. they are no longer bound by the Hayfl ick limit and can divide indefinitely. Much like a train ba cking up on a track. the scientist who was the first to notice tha t normal cells cannot divide indefinitely in culture. until they get so short the DNA replication machinery can no longe r work. A telomere is a simple DNA sequ ence that is repeated many times.12 Aging replicative life span of human cells in culture. The results g enerated a tremendous amount of excitement. The transfo rmation of normal fibroblasts with the telomerase gene was conducted for the fir st time in 1998 at the Geron Corporation. like an immortal cancer cell. a biotechnology company. When this happens. for they seemed to imply that revers al of replicative senescence would be followed very quickly by the reversal of t he aging process. Scientists at Geron began talking about human life spans of se veral hundred years.

and rats with som e success. engines that are driven carefully. and no one would opt for a therapy that i nvolves eating so little food that the individual barely has strength to get out of bed in the morning. Calor ic restriction has the same effect. due to a lack of energy. such as our brain and muscles. your life will be shor t. run at full throttle. Raising mice or rats in confined quarters to lower their activity level has no effect and may even reduce the li fe span because of the stress it causes in these animals. This theo ry is not concerned with the underlying mechanism of aging. While impressive. it claims that if you are going to live fast and hard. their flight activity is severe ly restricted. and if anything serious happens to them. So the life span of the individual made from those cells cannot be regulat ed by the length of the telomeres. The engine in a race car. If they are kept in tiny cages. Rate-of-Living Theory This theory takes a pragmatic approach to the regulation of life span. but simply advocates repair or replacement of body parts as they wear out. However. park it in a garage. cannot be replaced. they stop dividing soon after the individual is born. Simply pu t. can increase a rat’s life span by 50 to 60 percent. this is not a therapy that is recommended for humans. in a large cage where they are fed and protected from their predators. it would likely be fatal.000 miles. their life span is more than doubled. . that is. Caloric restriction. and as a consequence. Caloric restriction is really another way of saying starvation diet. On the other hand. These strategies have been tested in houseflies. at modest RPMs. it will last even longer. Houseflies normally live one month in laboratory conditions. h owever. if you buy a new ca r.Aging Theories 13 an animal’s body are postmitotic. a moderate limitation on caloric intake could s till add 10 to 20 years to one’s life span. The rate-of-living theory tries to deal with this fatal scenario by adop ting a preventive strategy. is lucky to last a full day. Of course. and rarely drive it. can last f or 10 to 20 years and may even log 200. some body parts. mice. no bigger than a teacup. Of course. involving a reduction in activity level and caloric intake. but is most likely due to the forced reducti on in flight activity. much in the way we deal w ith a brokendown car.

cells do not allow free radicals free rein. such as the adrenal and . it triggers a chain reaction of destabilized molecules reacting with other molecules to form new free radicals a nd a variety of potentially dangerous compounds. and th e lipids in the cell membrane. which makes them very reactive. neutralizes oxygen free radicals a s they are produced. has been proposed. released into th e blood. which is connected dire ctly to the hypothalamus. including DNA. Hormone Imbalance Theory Coordination of an animal’s physiology is the job of the endocrine system. Many experiments have been conducted on mice and rats to test this remedy but with limited succe ss. However. is a toxic exhaust produced by mitochondria during the very important metabolic process of oxidative phosphorylation. This process produces the ATP that cells need to survive. aging may reduce the efficiency of SOD. consisting of a regular diet of antioxidants (chemicals that deactivate fr ee radicals) such as vitamin E or vitamin C. When it does so.14 Aging Free Radicals The role of free radicals is closely related to the rate-of-living theory and wa s originally proposed in the 1950s. Gerontologists in favor of the free radical theory maintain that SOD does not neutralize all the free radicals and that the damage is done by those that escape. a master endocrine gland called the pituitary. This sy stem consists of a command center located in a part of the brain called the hypo thalamus. Free radicals are molecules that have an unp aired electron. A speci al enzyme. The pituitary hormones. The oxygen free radical can remove an electr on from virtually any molecule in the cell. the o xygen free radical. and a variety of secondary endocrine glands located in various parts of the body. proteins. An antiaging re medy. control the activity of other glands. The hypothalamus controls the pituitary by releasing hormone messengers that pass directly to the gland. called superoxide dismutase (SOD). One of the most important. suc h that the amount of free radicals increases gradually with age. Many gerontologists believe fre e radicals are directly responsible for cellular senescence and the aging of the animal as a whole. where they stimulate or inh ibit the release of pituitary hormones. Alternatively. RNA.

and organs of the body. in turn. regulate other glands.Cerebrum Hypothalamus Cerebellum Pituitary gland Thyroid gland Adrenal gland Uterus Liver Ovaries Immune system Mammary glands Testes The human endocrine system is controlled by the hypothalamus. . The pitui tary hormones. tissues. which regulates th e production and release of various hormones from the pituitary gland.

. TSH release is redu ced or stopped. which stimulate the activity of several organs. Thyroid hormone level s are monitored by the hypothalamus. The hypothalamus instructs the pituitary gla nd to release thyroid-stimulating hormone (TSH). as well as organs such as the ovaries. testes. Overall . All th e hypothalamic messengers and the pituitary hormones are small proteins. leading to secretion of thyroid hormones. When they get too high. and liver. the system is responsible for regulating reproductive Hypothalamus Pituitary gland Thyrotropin Thyroid gland Thyroid hormones Muscle Kidney Heart Liver Regulation of the endocrine system.16 Aging thyroid glands.

cycles. as illustrated by the control of the thyroid gland. storage and mobilization of food molecules. a nd the fight-or-flight response (see table on pages 18–19). growth.Aging Theories 17 Hypothalamus Pituitary gland FSH Oocyte Ovarian follicle Follicle cell Estrogen Regulation of the ovarian cycle. The endocrine system i s self-regulating. promoting maturation of ovarian follicle cells. Low estrogen levels stimulate FSH release. The hypothalamus instructs the pituita ry gland to release follicle-stimulating hormone (FSH). which in turn begin synthesizing and releasing estrogen. The hypot halamus releases a messenger molecule called thyrotropin-releasing hormone. whic h stimulates the release of . energy metabolism. High levels of estrogen inhibit the release of FSH but stimulate the release of a pituitary hormone (not shown) that initiates ovulation.

The self-regulating feature of this system is the ability of the hyp othalamus to monitor the level of thyroxine in the blood. Its release is controlled by a hypoth alamic messenger called FSH-releasing hormone. Thyr otropin. the hypothalamus signals the pituitary to cut back on the release of thyrotropi n. It is controlled by sensors that monitor the degree of body dehydration. Its release is blocked by a hypothalamic messenger called GH-inhibiting hormone. The regulation of the human female reprod uctive. Antidiuretic hormone (ADH) Follicle-stimulating hormone (FSH) Growth hormone (GH) thyrotropin (also known as thyroid-stimulating hormone) from the pituitary. Adrenaline is involved in the “flight or fight” response. or to stop releasing it altogether. the most important of which is thyroxine. stimulates the thyroid gland to release thyroid hormones. This hormone promotes development of sperm in th e male and oocyte follicles in the female. GH stimulates the uptake of gluco se and amino acids by all tissues (except neurons). FSH . the hy pothalamus releases a molecule called gonadotropin-releasing factor. or ovarian. cycle involves the same general scheme.18 Aging HORMONES OF THE PITUITARY GLAND Hormone Adrenocorticotropin (ACTH) Description This hormone stimulates release of adrenaline and other steroids from the adrena l cortex. When it gets too high. ADH promo tes water conservation by the kidneys. a hormone that stimulates cell metabolism and growth. In this case. ACTH is controll ed by a hypothalamic messenger called corticotropin-releasing hormone. in turn. which stimu lates the pituitary to release follicle-stimulating hormone (FSH).

estrogen levels drop. but high levels. achieved when the follicle is mature. If the mature oocyte is fertilized and successfully implants in the uterus. Prolactin stimulates the growth of mammary glands and milk production. to stimulate release of luteinizing hormone (LH) to trigger ovulation. cause t he hypothalamus to block release of FSH from the pituitary and. at the same time .Aging Theories 19 Hormone Luteinizing hormone (LH) Description LH stimulates synthesis of testosterone by the testes and ovulation in females. Its release is stimulated by cervical distension and suckling. Its release is blocked by a hypothalamic messenger called prolactin-inhibiting hormone. As the follicle cells mature. Oxytocin stimulates uterine contractions during childbirth and the release of milk from mammary glands. signaling the . Thyroid hormones are growth factors that stimulate cellular activity and growth. If the egg is not fertiliz ed. each of which contain an oocyte. Its release is controlled by a hypothalamic messenger called LH-releasing hormon e. The hypothalamus monitors the level of estrogen i n the blood. Oxytocin Prolactin Thyrotropin stimulates growth and development of ovarian follicles. cells surro unding the embryo produce large amounts of estrogen to prepare the mother’s body f or the pregnancy and to block further release of FSH. This hormone initiates the release of thyroid hormones from the thyroid gland. Low levels of estrogen result in continuous release of FSH from the pituitary gland. they synthesize and release the female ho rmone estrogen into the blood. The release of thyrotropin is controlled by a hypothalamic messenger ca lled thyrotropin-releasing hormone (TRH).

the re productive system grinds to a halt. physical strength. with the exception of ACTH. menopause or diestrous occurs because the hypothala mus stops releasing the necessary messenger molecules. FSH also promotes development of sperm in the male (see the accompanying t able). The overall effect of this change is believed to be the loss of vigor. For gerontologists. a dramatic d rop in estrogen levels. hormonal l evels of the body begin to change. . when young pituitaries are transplanted into old rats. Menopause usually occurs as women reach 50 years of age and is marked by a cessa tion in the development of ovarian follicles and. Similarly. Many experiments were conducted in which pit uitary glands or ovaries from old female rats were transplanted into young rats. One of the most dramatic age-related changes in humans is the loss of the ovarian cycle in females. and that old ovaries regained their estrous cycle. gradually decrease with age. generally referred to as the onset of menopause. they a re usually unable to support a normal estrous cycle. as a consequence. Additional evidence in supp ort of the role of the hypothalamus in the aging process comes from the observat ion that the levels of pituitary hormones. With the age-related failure of the command center. the majority of them fail to regain their cycles. although in these animals it is called diestrous. they showed that old pituitary glands functioned well in young bodi es. and this in turn produces the physical sympto ms of age. When this happens.20 Aging hypothalamus to stimulate renewed synthesis and release of FSH to complete the c ycle. many of whom believe that aging of the organism as a whole begins with the senescence of the hypothalamus. the onset of menopause in mice and rats provides an experimental system which can be used to test the idea that the hypothalamus is an aging-clock. aside from its role in reproduction. the hypothalamus is like a clock that regulates the rate at which the indivi dual grows older. that is. Given its breadth of influence. When prepubertal ovaries were transplanted to old female rats. or the cessation of the est rous cycle. Estrogen. is import ant to female physiology for the maintenance of secondary sexual characteristics . Female mice and rats also go through menopaus e. and bone development. skin tone. In general. and endurance that is typical in an aging human. In this sen se. it is no wonder the endocrine system has captured the attention of gerontologists.

Aging Theories 21 Accordingly, many attempts have been made to reverse these effects with hormone therapies that include GH, estrogen, or testosterone supplements. While these th erapies have alleviated some of the symptoms of old age, they have not been able to reverse the aging process. With our limited knowledge of the cell and the co mplexities of physiological and endocrinological systems, there are real dangers associated with hormone therapies. Estrogen supplements can minimize bone thinn ing in menopausal women, but constant exposure to this hormone can lead to breas t cancer. Similarly, androgen supplements in men can increase vigor and physical strength, but constant exposure to testosterone, and estrogen, is known to be a leading cause of prostate cancer. Growth hormone supplements suffer from simila r problems in that they can induce cancers; they can also lead to the developmen t of bone deformations. Despite its great promise and the fact that it has gener ated some useful geriatric therapies, the hormonal disregulation or imbalance th eory has failed to produce a definitive model of the aging process; nor have any of the hormonal therapies inspired by this theory been able to reverse the effe cts of age. Instead, the application of this theory, as with the other theories already discussed, merely allows a somewhat healthier old age, an effect which c an also be obtained simply by eating well and getting lots of fresh air and exer cise. Concluding Remarks With the exception of the role of telomeres in aging, all the theories just desc ribed have been with us for more than 40 years, and during that time gerontologi sts have subjected those theories to thousands of experiments in the hope of gai ning a better understanding of the aging process. But today we do not understand the underlying mechanism of aging any better than we did when those theories we re first formulated. This is not a criticism of the many outstanding scientists who devoted their research lives to this problem, but a recognition of the treme ndous complexities involved in the aging process. Aging is the puzzle of all cen turies, and its resolution will take an effort that will dwarf all other biologi cal research projects to date. We simply do not know enough about the behavior o f our genes as we grow old, but the recent completion of the human genome projec t is

22 Aging Microarray analysis of gene expression. Fragments of genes are spotted onto a gl ass microscope slide to produce a two-dimensional array. Labeled mRNA is hybridi zed to the array to determine which genes are active (white spots) and which are not (gray spots). This simulated array shows the expression of 100 genes. providing the information necessary for a fresh start. Scientists will soon be a ble to determine the behavior of all 30,000 human genes, in every organ and tiss ue of the body, throughout the human life span. The effort has already begun. Sc ientists at the University of Wisconsin have recently reported the results of a study in which they evaluated the activity of 20,000 genes in cells from the pro state gland, before and after the cells attained replicative senescence. This ty pe of study is made possible by the production of DNA microarrays. Based on info rmation provided by the genome project, a short piece of every available gene is spotted onto a solid support (usually, a specially treated glass microscope sli de), then hybridized with labeled mRNA isolated from chosen cells. If a gene is active in the cell, its mRNA will bind to the piece of that gene attached to the microarray, effectively labeling that particular point, or pixel, on the array. Computers are used to compare the young and old cells, spot by spot, to gain a final estimate of expression for every gene represented on the array. Microarray analysis provides an extremely powerful method for analyzing the aging process in an unbiased manner. That is, until the genome project was completed, gerontol ogists, using available theories as a guide, had to make an educated guess as to which genes might be involved in cellular senescence. Studies were then designe d around these genes in a few of the animal’s tissues or organs. It is clear now t hat such a limited approach is doomed to failure. Aging is a highly integrated p henomenon, involving all the organs and tissues of the body.

Aging Theories 23 Some tissues or organs may age at their own rates, but they are all part of the same process. Evaluating all the human genes will be an enormous job that will t ake many years to complete. With more than 20 different organs and tissues in th e human body, representing 200 cell types, such an undertaking will tax the reso urces of the science community. There are many obstacles to overcome, such as ac quisition of the tissue, most of which will have to be obtained from deceased hu mans. Similar studies may also be conducted on flies, mice, and rats as their ge nomes are sequenced and microarrays become available. This is a big job, but one that will finally give us an understanding of how and why animals grow old.

5 million Americans were suff ering from AD. but none are so devastating as AD. The average course of the disease. and it has since become the fourth-leading cause of death among the elderly. but ge rontologists (scientists who study the aging process) have taught us to be cauti ous of this stereotype. there are several million recorded cases. but for someone with Alzheimer’s disease (AD). language. Several other age-related diseases are described in this chapter. Alois Alzheimer first described AD in 1907. The image of an absentmin ded elderly man or woman has been with us for a long time. Alzheimer’s Disease Alzheimer’s disease is a neurological disorder affecting the central nervous syste m (CNS) that leads to a progressive loss of memory. from early sym ptoms to complete loss of cognitive ability. but they are not necessarily senile or any more absentminded than a 20-yearold. but because poor medical facilities and diagnostic procedures in many parts of the world res ult in 24 . but those diseases are not an inevitable consequence of growing old. People today are in t he habit of thinking that this is the natural consequence of growing old. Aging makes u s more susceptible to certain diseases. Old people may be slower at certain tasks.I 3I AGE-RELATED DISEASES Growing old holds many pleasures. i t can be a confusing and often frightening experience. Worldwide. and the ability to recognize friends and family. is 10 years. In 2004 more than 4. The incidence of this disease increases with age and is twice as common in women as in men.

the contraction of muscles of the digestive tract. AD spreads to many areas of th e cerebrum.The human brain consi sts of the pus is important for processing cerebrum. which codes for a protein needed for the const ruction of microtubules. also known as presenilin). some damage occurs to the brain. the real number could be as high as 15 million ca ses. The hippocampus. The brain and spinal cerebellum regulates fin e motor cord are called the central nervous system (CNS). app (codes for amyloid precursor prote in. Three genes have been identified that are associated with the onset of AD. and the mem ories for long-term storage brain stem. A special area of the The h uman central nervous system. It also controls our ability to sleep an d to stay awake. the cerebellum. The second gene. ing it possible for a person to coordinates memory functions. such as the rate at which the heart beats. codes for an enzyme that . makbeneath the surface of the brain. which is continuous with in other parts of the brain. sen (senilin. The Hippocampus cerebrum is the home of human Brain stem intellect and the source o f individual personality. APP). learn how to play the piano. lying control over our muscles.Age-Related Diseases 25 underreporting of the disease. and respiratory rate. and the brain stem. It also Cerebellum processes and analyzes informaSpina l cord tion from all the sensory nerves of the body. known as preclinical AD. AD begins in the hippocampus. Over a period of years. Cerebrum The human CNS is divided into the cerebrum (the main portion of th e brain. and perform other activities that requi re intricate coordination. the cerebellum. cerebrum called the hippocam. during the early stages. but not enough to produce outw ard signs of the disease. The brain stem is in control of our automatic functio ns. including the cerebral cortex). manip ulate fine objects with precise control. codes for a protein that is embedded in the cell membrane. The first of these is tau. The third g ene. The the spinal cord.

26 Aging may be involved in processing APP. A signal. which are stored at the axon terminus in Golgi vesicles. A signal is transmitted across the gap by the release of sm all proteins called neurotransmitters. a process that takes less than a microsecond. The connection between an axon Severe AD and a dendrite is called a synapse. Defects in any of these genes leads to the ex tensive death of neurons that is characteristic of AD. the Golgi vesicles at the Preclinical AD . Progression of AD. The vesicles travel to the axon terminus on a “railroad” constructed of microtubules. they hippocampus. enters a Moderate AD neuron at its dendrites and is passed along to another neuron through the axon. Neurons are remarkable ce lls. specially designed for communication. emotions. Neural circuits are constructed when axons make contact with the dendrites of ot her neurons. When a neuron receives a signal. spreading over a period do not actually touch one of years to affect several regions of the anoth er. Close inspection of a cerebrum. Alzheimer’s Although neurons commudisease (black circle s) begins in the nicate through the synapse. in the form of an electroch emical jolt. and the ability to recognize our friends and love d ones. synapse shows a small gap separating the axo n from the dendrite. each formi ng thousands of synaptic junctions with other neurons. These circuits give us ou r intellect. vision. Circuits in the human brain consist of billions of neurons.

but the synaptic gap and the use of neurotransmitters are crucial for maintaining th e strength of the signal over a network that consists of 100 billion cells. (Biophoto Associates/Photo Researchers. triggering an ele ctrochemical impulse in the target neuron.) . Alz heimer’s disease is a dementing disorder marked by certain brain changes. Inc. leading to the breakdown of microtubules and a v irtual collapse of the Alzheimer’s disease. The right brain is atrophied. Sliced sections from two brains.Age-Related Diseases 27 terminus are released from the microtubules and fuse with the axonal membrane. The neurotransmitters quickly diffuse across the gap and bind to receptors on the dendrite membrane. This may seem like an awkward way for neurons to signal one another. On the left is a normal brai n of a 70-year-old. The tau gene and its product have a crucial role in the maintenance of neuronal sign al transmission. On the right is the brain of a 70-year-old with Alzheimer’s di sease. A mutation in this gen e produces a defective protein. regardle ss of the age of onset. with a loss of cortex and white matter. thus completing transmission of the s ignal. d umping their cargo into the synaptic gap. The tau protein is an important component of the microtubule ra ilroad the Golgi vesicles use to reach the axon terminus.

the loss is Neuron Signal Dendrites Nucleus Axon Neural circuit Axon terminals Neural signaling. Similarly. and much more. our emotions. These circuits give us our intellect. In this case. . neurons in the brain of an AD patient degenerate and die when signals stop coming in. Circuits in the brain consist of bill ions of neurons. A neuron receives signals at its dendrites and passes them on to other neurons through its axon. degenerate and die.28 Aging cell’s ability to pass on incoming signals. it is as though it loses its will to live. our ability to see the wor ld. however. This phenomenon has been ob served in patients suffering from a damaged or severed spinal cord. starved for signals from the CNS. each forming thousands of synaptic junctions with other neurons . Circuits are constructed with axon terminals making connections with the dendrites of other neurons. Peripheral n erves. When a neuron loses its ability to com municate. The connection between a n axon and a dendrite is called a synapse.

Age-Related Diseases 29 Microtubule Axon Golgi vesicle Neurotransmitters Receptor Dendrite Synaptic junction. A second route to the development of AD involves the app and sen genes . are covered in a molecular forest called the . rather. Binding of the neurotransmitter to the recep tor on the dendrite membrane completes the transmission. The Golgi vesicles trav el to the axon terminus on a railroad constructed from microtubules. more than the movement of an arm or a leg. it affects the core of a pers on’s being. A signal is transmitted by the release of small molecules called neurotransmitters that are stored at t he axon terminus in Golgi vesicles. Axons and dendrites do not touch each other but are separated by a small gap called the synapse or synaptic junction. like all cells. Neurons.

resembling trees. An important member of a CNS neuron’s glycocalyx is the app protein (APP). that have many functions: Some are hormone or glucose receptors. Fusion of the vesicle membrane with the cell membrane automatically plants APP in the cell membrane. Vesicles from the cell’s Golgi complex carry amyloid precu rsor protein (APP) to the cell surface. w hich is believed to .30 Aging Cell membrane Fusion of the Golgi vesicle with the cell membrane Vesicle membrane APP Golgi vesicle Planting an APP forest. others a re involved in processing the electrochemical signals generated by neurotransmit ters. This forest consists of a wide variety of glycoproteins. glycocalyx.

An important member of a neuron’s glycocalyx is a molecule called amyloid precursor protein (APP). . resulting in an enzyme that cu ts APP in two. A molecular forest ca lled the glycocalyx covers all cells. The truncated A PP (tAPP) remains in the membrane. forming truncated APP and beta-amyloid. In Alzheimer’s disease. but the final result is a defective glycocalyx consisting of tAPP and the accumulation of betaamyloid in the intercellular space. while the beta-amyloid forms extracellular de posits known as plaques. producing a truncated APP (tAPP) and a second protein called beta -amyloid. It is not clear whether this happens before or after APP is planted on the cell surface. This is believed to be due to a mutation in the sen gene. Neurons suffering from AD fail to process APP properly. APP is cut into two pieces. A normal gl ycocalyx is crucial for a Normal glycocalyx APP Alzheimer glycocalyx Beta-amyloid plaques Cell membrane Truncated APP Normal versus Alzheimer-affected glycocalyx. APP is processed through the Golgi complex and planted on the cell surface by fusion of the Golgi vesicles with the cell membrane.Age-Related Diseases 31 be involved in hormonal signal transduction.

and swelling in the joints. whether the onset of AD is through a defective tau or sen g ene. in a process known as apoptosis. leading to pain. the final outcome—extensive neuronal death—is the same. examples of the latter include pitcher’s elbow and the hip-joint difficulties that professional dancers develop as they grow old. Initially. Arthritis Although the term literally means “joint inflammation. osteoarthrit is is noninflammatory and its onset is subtle and gradual. Experiments show that stem cells injected into damaged rat brains do differentiate into appropriate neurons. obesity. tenderness. Other treatments being planned involve a combination of gene thera py and stem cell transplants to correct the mutated tau and sen genes and to rep lace the damaged or dying neuronal population. Osteoarthritis. Osteoarth ritis affects 21 million people in the United States. There are two forms of this dise ase: osteoarthritis and rheumatoid arthritis. and han d. . and repet itive joint use. which could be responsible for some of the neuron or ci rcuit damage. results from the wear and tear of life. whet her they make the correct connections.32 Aging cell’s survival. however. At present. and the risk of getting it increases with age. scientists believe the immune system detects t he abnormal glycocalyx and orders the cell to commit suicide. Other risk factors include joint trauma. is yet to be determined. usually involving one or only a few joints. Pain is the earliest symptom.” arthritis really refers to a group of more than 100 rheumatic diseases and conditions that can cause pain. hip. arthrit is can cause irreversible damage to the joints. Thus. previously known a s degenerative joint disease. In the case of AD. and swelling. s tiffness. The pressu re of gravity and extensive use causes physical damage to the joints and surroun ding tissues. it is likely that suc h therapies will be extremely difficult to develop. although treatments are being developed to reduce the accumulat ion of the beta-amyloid. usually made worse by repetitive use. there is no way to cure AD. Given t he delicacy of our CNS and the complexity of its circuits. The joints most often affected are the knee. If left undiagnosed and untreated.

brought on by cigarette smoke. This c hronic. The age of the individual and the time element are important largely because the formation of a tumor is a multistep process that takes many years to complete. and loss of function in the joints. This mechanism is similar to that proposed for the death of neurons in AD. giving those cells time to evolve into a potentially lethal cancer. The increased incidence of cancer as we approach our sixth decade is als o coincidental with the onset of sexual senescence in both men and women. but the factors responsible for cancer acceleration in childre n are still unclear. The chemicals in cigarette smoke are known to acceler ate this process. Age-related hormonal changes incl ude a shift in the ratio of estrogen to . Cancer Human cancer is primarily an age-related disease that strikes when an individual is 50 years of age or older.Age-Related Diseases 33 Rheumatoid arthritis is an autoimmune disease that occurs when the body’s own immu ne system mistakenly attacks the synovium (cell lining inside the joint). The causes of this disease are unclear but could inv olve a mutation that affects the glycocalyx of the synovium. many exceptions to this relati onship. Rheumatoid arthritis is much rarer than osteoarthritis. Much of this problem is believed to be due to a red uction in the ability of our immune system to track down and destroy abnormal ce lls as they appear. Cancers are age-related because our cells change with time. but this can place the p atient at high risk of developing breast or uterine cancer. Current treatment involves hormone supplements. Lung cancer. however. affecting about 2 m illion people in the United States. potentially disabling disease causes pain. and childhood leukemias are the most notable examples. swelling. leading to an immun e attack. It is possible that the hormonal changes that occur during this period contribute to o lder adults’ increased susceptibility to cancer. There are. becoming more susceptible to genetic damage and less capable of dealing with th e damage when it does occur. stiffness. This disease affects women much more than me n (the difference is twofold to threefold) and has led many scientists to sugges t it is related to the decline of estrogen levels that occurs in women after men opause.

34 Aging testosterone (ET ratio) in both men and women. Young women naturally have a high estrogen/testosterone ratio (a lot of estrogen, very little testosterone), wher eas young men have a low estrogen/testosterone ratio (very little estrogen, a lo t of testosterone). Estrogen levels drop dramatically in women after menopause, and men show a similar decline in the level of testosterone at a corresponding a ge. As a consequence, men and women approach a similar ET ratio throughout their sixth to ninth decades, a condition that is thought to influence the rate at wh ich genetic instability occurs. In addition, many scientists believe the shift i n the ET ratio is largely responsible for the weakening of the human immune syst em, leading to the increased occurrence not only of cancer but of many other dis eases as well. Cardiovascular Disease The most common form of cardiovascular disease is called atherosclerosis, a dise ase of the arteries that can strike at any age, although it is not a serious thr eat until we reach our fifth or sixth decades. This is due in part to cellular c hanges that make the blood vessels less elastic (hardening of the arteries) and weaken the heart muscles, but it is largely due to poor diet and lack of exercis e. This disease is characterized by a narrowing of the arteries, caused by the f ormation of plaques (deposits) containing dead cells and cholesterol. Several fa ctors influence the appearance of plaques, including high levels of cholesterol (and cholesterol precursors, such as triglyceride) in the blood, high blood pres sure, and cigarette smoke. The body removes excess cholesterol from the blood us ing a protein called apolipoprotein E (ApoE). ApoE, encoded by a gene on chromos ome 19, binds to cholesterol and delivers it to liver cells, which store it for later use. Mutant ApoE loses the ability to bind to liver receptors, resulting i n a buildup of cholesterol in the blood. A second form of cardiovascular disease affects the coronary arteries, the blood vessels that carry blood to the cardio myocytes, or heart muscle cells. If coronary arteries become blocked or otherwis e damaged, the cardiomyocytes die from lack of oxygen. In serious cases, this ca n lead to a massive heart attack and death of the patient. In milder cases, dama ge to the heart is minimal but coronary circulation is insufficient to allow the patient a normal lifestyle. Many treatments are

Age-Related Diseases 35 available for cardiovascular disease, including surgical intervention, angioplas ty, and gene therapy. But this disease, like diabetes, is largely the result of lifestyle and is not an inevitable consequence of age. A combination of adequate exercise and a healthy diet begun at an early age is the best treatment. Diabetes The appearance of life on Earth, more than 3.5 billion years ago, was made possi ble to a great extent by the presence of glucose in the oceans and the ability o f the first cells to use this sugar as a source of energy. To this day, glucose is central to energy metabolism in animals, plants, and microbes. In mammals, de fects in glucose metabolism and utilization are caused by a disease known as dia betes. For microbes, the process of acquiring glucose and extracting its energy is fairly straightforward. Each cell has receptors that import glucose from the environment, and biochemical pathways that break the sugar down to release the e nergy it contains. One of the pathways, consisting of a coordinated set of enzym es, is called glycolysis (meaning “sugar splitting”) and the other is called the Kre bs cycle. These pathways convert the sugar’s energy to ATP, which is used by all c ells as an energy source (see chapter 8). Glucose metabolism is more complex in humans and other mammals. In mammals, the uptake and utilization of glucose is c oordinated by the endocrine system and involves the overall physiological state of the animal to ensure that the system as a whole has an adequate supply of ene rgy. All cells in an animal’s body have glucose receptors, but cells do not import glucose unless their receptors are bound to a hormone called insulin, which is produced by the pancreas, a large gland located just below the liver. The pancre as has two types of cells, called α ( lph ) nd β ( et ). The α cells produce digestiv e enzymes th t re secreted directly into the l rge intestine, nd the β cells pro duce insulin. Glucose in the lood stimul tes the β cells to m ke nd rele se insu lin; the mount of insulin rele sed is directly proportion l to the concentr tio n of glucose in the lood. One might wonder why the ody others with such n in direct mech nism: Why not let e ch cell t ke up glucose whenever it c n? The

   

 

 

 

 

 

 

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36 Aging short nswer to this question is th t e ch cell would t ke up the glucose— proces s th t requires energy—whether it needed it or not. Dependence on insulin m kes it possi le for the endocrine system to regul te the upt ke of glucose. For ex mpl e, if the nim l h s me l, ut e ch cell lre dy h s plenty of ATP on h nd, th e endocrine system locks the upt ke of glucose everywhere ut the liver, which is instructed to convert the glucose into glycogen, molecule th t serves s stor ge depot. Di etes destroys the β cells’ ility to m nuf cture insulin, le din g to uildup of glucose in the lood. A chronic elev tion of lood glucose lev els results in the in ppropri te glycosyl tion ( ddition of sug r to proteins) o f m ny proteins in the lood, including hemoglo in, the oxygen-c rrying protein, s well s m ny other proteins ssoci ted with the cells nd tissues. Systemwid e protein glycosyl tion c n le d to lindness, he rt dise se, kidney f ilure, n d neurologic l dise se. This dise se is m jor he lth pro lem in North Americ , where it c uses pproxim tely 500,000 de ths every ye r. Tre tment is very expe nsive, mounting to out $98 illion nnu lly. There re two forms of this dise se, known s type I nd type II di etes. Type I di etes is n utoimmune dise se, in which the white lood cells tt ck nd destroy the β cells of the p ncre s . This form of the dise se is sometimes c lled juvenile di etes ec use it occu rs predomin tely in teen gers, lthough it c n strike t ny ge. Type II di et es ffects older people, usu lly eginning when they re 50 to 60 ye rs of ge. In this c se, the dise se m y e due to genetic predisposition to short-lived β cells, or it m y e due to β cell urnout rought on y lifelong preference for diet th t is he vy on sweets. This m y ccount for the f ct th t ne rly 80 per cent of those suffering from type II di etes re overweight. At l st count, 10 genetic loci were known to e ssoci ted with the onset of oth types of di ete s. Osteoporosis Osteoporosis is skelet l disorder ch r cterized y we kened one strength le d ing to n incre sed risk of fr cture. Bone strength is function of the miner l content, prim rily c lcium, nd the he lth of the osteo l sts, the cells th t p roduce the underlying one m trix.

 

 

   

   

   

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        ¡          ¡                           ¡                             ¡       ¡          ¡ ¡ ¡     ¡   ¡                         ¡ ¡               ¡               ¡                           ¡             ¡                                              ¡   ¡       ¡         ¡   ¡    ¡     ¡     ¡   ¡ ¡                             ¡   . On e out of every two women nd one in eight men over 50 will h ve n osteoporosisrel ted fr cture in her or his lifetime. Hip fr ctures re y f r the most serious nd cert inly the most de ilit ting. reduction in the levels of testosterone t comp r le ge. or yogurt. 250. The preferred c lcium source is milk.000 verte r l (spin l) fr ctures. s well s from f lls.Age-Rel ted Dise ses 37 Bone miner l density (BMD) is common criterion used to ev lu te the onset of t his very common dise se. Women re four times more likely to develop osteoporosis th n men. In the presence of os teoporosis. regul r exercise is recommended s w y to preven t the onset of this dise se or to minimize its effects once it h s st rted. Consequently.000 IU/d y for vit min D). One in five p tients dies one ye r following n ost eoporotic hip fr cture. pproxim tely 700. Osteoporosis is c used prim rily y hor mon l ch nges th t ffect women nd men s they ppro ch their sixth dec de. Osteoporosis is responsi le for more th n 1. h s proved to e very effective. ut the potenti l for c ncer induction is serious concern. I n ddition to drug ther pies. nd more th n 300. including 300.000 wrist fr ctures. Fifty percent of those people experiencing hip fr ctur e will e un le to w lk without ssist nce. ut studies concluded in 2003 indic te th t this m y not e so.000 fr ctures t other sites. Current tre tments involve c lcium nd vit min D supplements ( t out 400 to 1. Osteoporotic fr ctures. For women. nd for m en. involving estrogen for women nd testo sterone for men. lifelong h it of voiding exercise is elieved to e m jor r isk f ctor in the onset of osteoporosis. Growth hormone is lso eing tried s ther py for oth men nd women to relieve the symptoms of this dise se. Hormone repl cement ther py. re usu lly s soci ted with crippling p in. which ffects more th n 20 million people in North Amer ic lone. p rticul rly verte r l fr ctures. fr ctures c n occur from norm l lifting nd ending. the effective dose w s once elieved to e low enough th t c ncer induction w s not serious concern . this involves dr m tic drop in estrogen levels t menop use.000 h ip fr ctures.5 million fr ctures nnu lly. A se dent ry lifestyle h s dev st ting effect on one m ss ec use the induction of osteo l sts ( one-forming cells) is known to e dependent on physic l ctivity. nd 28 percent will require long-te rm c re. cheese . However.

however. The p per gives thorough overview of wh t scientists h ve le rned out the g ing process nd presents det iled rguments g inst the use of v rious ther pies . Scientists re unwittingly contri uting to the prolifer tion of these pseudoscientific nti ging products y f iling to p rticip te in the pu lic di logue out the genuine science of ging rese rch. stop or reverse the processes of ging. M ny scientists elieve there is no such thing s tre tment th t will reverse the ging process. The following is n excerpt from their position st tement: There h s een resurgence nd prolifer tion of he lth c re providers nd entre preneurs who re promoting nti ging products nd lifestyle ch nges th t they cl im will slow. in 2002. re no more d ngerous th n sunscreens. co lition of 51 gerontologists nd iologists took n unprecedented step of pu lishing p per th t w s sh rply critic l of nti ging medicines nd the comp nies th t m rket them. p rticul rly those involving hormone supplements. Indeed. Even though in most c ses there is little or no scientific sis for these cl ims. skin cre ms. nd over-the-counter tre t38     ¡                   ¡       ¡   ¡            ¡     ¡                                 ¡               ¡                 ¡            ¡                 ¡                     ¡               ¡             ¡                      . perfumes. which c n e d ngerous if us ed without the supervision of physici n. some of which m y e h rmful. The purpose of this document is to w rn the pu lic g inst the use of ineffective nd potenti lly h rmful nt i ging interventions. Most nti ging products. the pu lic is spending v st sums of money on these products nd lifestyle ch nges.I 4I ANTIAGING MEDICINE The tre tment of the ging process nd of the dise ses ssoci ted with it is dif ficult nd highly controversi l.

nd pl ces us t n elev te d risk of developing c ncer. some of the drugs.Anti ging Medicine 39 ments for thlete’s foot or cne. thyroid hormone. One ex mple is the drop in estrogen levels when women goes through menop use. which often discovers potenti lly useful drugs or the r pies. Hormone Ther py Endocrinologists (scientists who study hormones) h ve known for 30 ye rs th t hu m n hormone levels fluctu te with ge. thus improving the qu lity of life for m illions of people. nd other dise ses. rthritis. The effect of this decline on hum n physiology is profound. osteoporosis. nd growth hormone (GH) decre se dr m tic ll y s we re ch our sixth dec de. which oversees the m rketing of ny compound th t cl im to h ve medicin l properties. Indeed. for it is quick to m rket ny compound th t m y e used s n ntiwrinkle cre m or skin exfoli nt for wh t they c ll the vi r nt . Estrog en nd testosterone supplement tion. A distur nc e in this r tio we kens our ones nd immune system. ut this f ct should not interfere with the development of useful medic l ther pies. though more gr du l. re the su ject of this ch pter. nd iotech comp nies th t w nt to m rket those products. youthful look. in ddition to some of the more controversi l th er pies. Whether they h ve the right to do so is up to government l gen cies. These two c mp s frequently h ve different priorities. the controversy etween the gerontologists nd the cosmetic industry is reminiscent of the gener l cl sh etween the scientists who conduct sic iologic l rese rch. In the c se of nti ging medicines. re effective t lle vi ting symptoms ssoci ted with ging. which h s een routine medic l procedure. To gre t extent. Sever l prominent hormones. such s estro gen. As descr i ed in ch pter 3. while not reversing the ging process. testosterone. Men experience simil r. such s the Food nd Drug Administr tion (FDA) in the United St tes. the pro lem is not simply drop in the hormone level ut c h nge in the estrogen/testosterone r tio th t occurs in oth sexes. These drugs. The gre t concern           ¡                               ¡   ¡                                             ¡     ¡                            ¡               ¡             ¡       ¡                               ¡       ¡               ¡                   ¡                   ¡                  ¡     ¡   ¡ . it is the cosmetics industry th t is t the center of this controversy. d ecline in testosterone levels when they re ch comp r le ge (referred to s ndrop use). is known to reverse the onset of osteoporosis nd c n llevi te the symptoms of osteo rthritis.

eight mo re will develop inv sive re st c ncer nd seven more will h ve he rt tt cks co mp red with simil r group not t king hormones. This dise se. djusting the hormone dose m y m ke it possi le to ret in the enefits while reducing the ris ks.000 women getting hormone ther py for ye r. m king it difficult for them to feed nd swim (these fish r e produced for rese rch purposes only).40 Aging ssoci ted with the use of these steroids is their suspected role in c ncer indu ction. one receiving com i n tion of estrogen nd progesterone. Repl cement ther pies often produce d ngerously high concentr tions of hGH i n the lood. ut m ny physici ns nd their p tients elieve the risks involved re worth it. The enefits would e six fewer c ses of colorect l c ncer nd five fewer hip fr ctures. Initi lly. The initi l response t o this study w s th t women should stop hormone ther py. nd feet. these fish simply grow f ster th n their co horts. The d ult chores require much less hGH th n would e present in child or n dolesce nt. le ding to thickening of the skin nd viscer l org ns. h nds. is the result of excessive GH production in n dult . re much more d ngerous to use th n re the sex steroids. nd stroke. This hormone. the s tudy suggested th t of 10. ut s they ppro ch sexu l m turity. Moreover. The study consisted of two groups. The hormone thyroxine is lso used to llevi te some of the symptoms of old ge. le ding to severe disfigurement of the f ce. Thyroxine. involving 16. he rt tt cks.red tr nsgenic s lmon con t ining n extr GH gene. produced y the thyroid gl nd loc ted t             ¡                                                         ¡                                                 ¡       ¡   ¡       ¡     ¡       ¡           ¡                 ¡    ¡                                         ¡   ¡       ¡   ¡                                           ¡               ¡         ¡               ¡                   ¡   . NIH rele sed the results of l rge hormone ther py tri l. GH t kes c re of m ny other physiologic l cho res. However. s well s overg rowth of soft tissue. s its n me implies. the effect w s rel tively sm ll. including the d ily mo iliz tion of energy reserves nd mino cids. In recent ye rs. this dise se h s occurred in l or tory. the other pl ce o. fi rst descri ed in the 1930s. For ex mple. which c n le d to condition known s cromeg ly. they suffer extreme deformities of the he d nd spine. ut in fully m ture individu l. promotes growth in children nd dolescents. In July 2002.000 women. In 1999 the FDA l id ch rges g inst n Americ n comp ny for selling hGH s medicin l drug nd fined the comp ny $50 m illion. The results showed n incre sed risk in the group receiving hormone ther py for re st c ncer. Hum n growth hormone (hGH) supplements. dvertised y some comp nies s n nti ging mir cle drug.

rese rch on longevity genes (descri ed in ch pter 6) h s shown th t some of these genes code for proteins th t minimize oxid tive d m ge to cells nd ti ssues.myloid pl ques (deposits). m cromolecule th t is ssoci ted with the onset of ge-rel te d c rdiov scul r dise se. C loric Restriction A st rv tion diet ppe rs to e the only sure w y to incre se the me n life sp n of m mm l. the more he t they gener te. This study will not e concluded until 2005. The more these pumps work. is import nt for regul ting the ctivity level of virtu ll y every cell in the ody nd m y e viewed s tissue growth f ctor. It h s een shown to work in mice nd r ts.                           ¡               ¡             ¡                     ¡                                 ¡             ¡       ¡ ¡                 ¡               ¡       ¡         ¡ ¡           ¡       ¡       ¡         ¡                                 ¡   ¡                       ¡     ¡           ¡ . The mo st not le effect in the CR group is reduction in the mount of low density li poprotein (LDL). with fe w side effects. ntioxid nts should h elp reduce some of the symptoms ssoci ted with cellul r senescence. ut the rese rch te m rele sed some prelimin ry results in Decem er 2000. Experiments with mice nd r ts h ve f iled to su st nti te this cl im. which llevi te some of the symptoms. However. Antioxid nts According to the free r dic l theory of the ging process. The CR group h s ret ined lower ody weight nd mo re youthful ppe r nce ut re less ctive th n the control group. This could me n th t the f ilure of previous experiments to su st nti te the free r dic l theory m y e the f ult of the experiment l procedure nd. loc ted in cell mem r nes. Aging is ssoci ted with decre se in the mount of thyroxine. Reduced energy level nd difficulty keeping w rm re the most promin ent clinic l symptoms of hypothyroidism. Doctors tre ting this condition routine ly prescri e thyroxin supplements. thus . lso referred to s hypo thyroidism. In d dition. It is lso import nt for regul ting ody temper ture y stimul ting ion pumps. nd there is t presen t very l rge c loric restriction (CR) study eing conducted t the University of Wisconsin on 76 rhesus monkeys.Anti ging Medicine 41 the se of the neck. not true test of the theory. there is so me evidence suggesting th t ntioxid nts such s vit min C nd E m y reduce the thre t of Alzheimer’s dise se y dissolving et .

CR experiments do highlight the import nce of diet on the r te of ging.42 Aging C loric restriction is import nt from theoretic l point of view. D t from the genome pro ject. When nucleus from n dult cell is pl ced inside n e nucle ted egg. This is due to the ge-rel ted ch nges th t occur in ll the c ells of the ody. Gene Ther py Anti ging medicines. North Americ ns in gener l find it diffic ult m int ining even modest shifts in e ting h its. nor do they llevi te ll symptoms ssoci ted with loss o f those hormones.               ¡                ¡   ¡ ¡ ¡                    ¡         ¡ ¡ ¡   ¡                                 ¡     ¡ ¡           ¡            ¡ ¡                                 ¡                         ¡                               ¡ ¡                        ¡              ¡ ¡       . Success with tre ting ge-rel ted dise ses will lw ys e limited until the he lth of e ch cell in the ody c n e restored— ig jo . low-c loric e t ing h its. true nti ging ther pies will fin l ly e v il le. The gre t ch llenge will e le rning how to reset the clock for e ch of the 200 cell types th t m ke up the hum n ody. is re lly form o f cellul r rejuven tion. which reduces c loric int ke to one-third of norm l levels. F ctors exist in the cytopl sm of the egg cell th t re c p le of doing t his. nd with the hum n genome project complete. the method used to clone Dolly the sheep. Nucle r tr nsfer. is not likely to ttr ct l rge following. When this is ccomplished. will m ke it po ssi le to determine the expression profile for every one of our 30. ut not inconceiv le. Hormone receptors in the mem r nes of every cell ch nge wit h time. do not revers e the ging process. nd this could t le st encour ge he lthier. coupled with the expression rr ys descri ed in ch pter 1. However. The typic l CR diet. Clo ning technology h s shown th t it is possi le to reprogr m highly differenti t ed nucleus to ssume the function l st tus of n undifferenti ted em ryonic cell . it will soon e possi le to ide ntify them ll. ut it is nev er likely to form pr ctic l ther py. such s estrogen or testosterone supplements. the environment of the egg reprogr ms nd rejuven tes the old nuc leus. Old cells do not respond to hormones the s me w y they did whe n they were younger. s does the tr nsl tion m chinery th t uses mRNA to synthesize proteins.000 genes. Re setting the clock will involve djusting the expression profile for every cell w ith gene ther py.

more specific. The history of gerontology. ut with the ppro ch of the third nd fourth epochs. The current epoch. Philosophers nd scientists h ve een interested in this su ject for thous nds of ye rs. The first. known s the postgenomic er . like m ny other r nches of iologic l rese rch. eg n roun d 1870 with the invention of the compound microscope nd ended in the 1950s. ending in the e rly 1990s. ut this history w ill e confined to the modern er . extending ck no further th n the l te 1800s . The second epoch eg n with the discovery of the DNA dou le helix in 1952 nd exten ded to the e rly 1970s. eg n with the form tion of genome sequencing consortiu m in 1990 nd continues to the present d y. nd much more complex. Gerontologic l rese rch h s lw ys een driven y the s me questions: Why do we grow old? Why do we ch nge with time ? C n the effects of ge e reversed? Gerontologists h ve tried to nswer these questions using v riety of techniques.I 5I The E rly Ye rs In 1868 the Germ n physicist Ernst A e perfected the design of the compound mic roscope nd in so doing m de it possi le for scientists 43       THE HISTORY OF GERONTOLOGY Gerontology is r nch of the iologic l sciences devoted to the study of the ging process nd its effects on cells nd org nisms. covering the e rly ye rs. ¡   ¡                 ¡                 ¡     ¡         ¡       ¡  ¡             ¡ ¡     ¡ ¡¡     ¡   ¡ ¡     ¡ ¡       ¡             ¡       ¡     ¡   ¡   ¡     . The third epoch eg n with the introduction of recom in nt DNA technology in 1973. the questions ec me more numerous. m y e divided into four epochs.

cell division. th t is. Weism nn rgued th t the termin tion of life m y h ve selective dv nt ge. to some extent. winner of the 1 908 No el Prize for his work on the hum n immune system. histochemistry.44 Aging to study the structure nd function of individu l cells in w y th t w s never efore possi le. ut they le rned very little out the func tion l signific nce of those ch nges or how their knowledge could e used to for m physiologic l theory of the ging process. P ul Erlich. During this s me period. During the l st three dec des of the 1800s. iochemistry. nd C millo Golgi. ls o known s the citric cid cycle). Germ n chemists were deve loping the first iochemic l techniques th t llowed H ns Kre s to work out the cyclic det ils of energy met olism th t now e r his n me (the Kre s cycle. nd th t there is connection etween species’ life sp n nd its ecologic l niche. The techniques of th t d y m de it possi le for s cientists to g in sic underst nding of cell structure nd. nd intelligence. Elie Metchnikoff. The new iochemic l techniques were used y c hemists to egin c t loging the m ny molecules of the cell. nd histology ec me the si c tool kit for gerontologists during the e rly ye rs of scientific rese rch in t his field. In 1882. Thus it w s th t light microscopy. h ow th t structure ch nges with time. ttempted to form such theory y suggesting th t            ¡       ¡                   ¡         ¡ ¡         ¡ ¡  ¡   ¡     ¡         ¡                                 ¡         ¡   ¡                 ¡   ¡                             ¡       ¡ ¡     ¡     ¡     ¡  ¡ ¡     ¡                         ¡          ¡     ¡ ¡      ¡                 ¡ ¡   ¡   ¡        ¡     ¡   ¡             ¡     ¡ . were developing speci l dyes nd procedures th t could e used to st in cells. While m ny micro iologists of the time concentr ted on studying the link etween dise se nd micro es. nd y the time the citric cid cycle h d een worked out in 1937. DNA h d een identified nd loc l ized to the cell nucleus. thus giving irth to histochemistry nd histology. nd cytopl sm ic org nelles. Scientists t th t time elieved they h d ll the techniques th t wer e needed to fully underst nd the structure nd the function of cells nd nim ls . most not ly Anton Schneider. Europe n s cientists. August Weism nn. These studies were descriptive in n ture. m ny others eg n studying the life cycl e of cteri nd protozo in the hope it would shed some light on the ging pro cess. the rese rcher o served the eh vior of the cells nd recorded it without su jecting the system to expe riment l procedures th t would modul te the r te of the ging process. proposed the first theory of senescence (the process of growing old) th t tried to link life sp n to n tur l selection. in order to study etter the nucleus. They were only p rtly right. Germ n em ryologist. S nti go R món y C j l. ody size.

w s the free r dic l theory. DNA Structure Inspires New Theories On April 25. were known for their lo ngevity. 1953. thus reducing cell vi ility with ti me. for the first time.cid cteri (such s B cillus cidophilus) in the digestive tr ct could prolong life y preventing putref ction (dec y). who e t l rge qu ntities of curded milk nd yogurt. specifying unique protein.” not only proposed structur l model for the DNA molecule ut lso show ed how DNA could store genetic code. Their p per. due either to free r dic ls or to in herent error frequencies ssoci ted with tr nscription nd tr nsl tion. nd how th t code could e duplic ted. nd speci l d ptor molecules (tr nsfer RNA) th t were p rt of the protein synthesis m chinery. experiment l org nisms introduced to gerontology during the e rly ye rs. test le theories of the ging process. In eithe r c se. cl imed th t n extr ct of dog endocrine gl nds could reverse the signs of ge. usin g synthetic messenger RNAs. The error c t strophe theory w s first tested on cteri . the result is uildup of dysfunction l prot eins th t d m ge norm l cellul r functions. in process now known s DNA replic tion. there y est lishing the one-gene-one-protein hypothesis nd descri ing t he function l rel tionships etween replic tion. ccording to the theories. W tson nd Crick were lso the first to propose the existence of molecul r intermedi ry (messenger RNA) etween DNA nd protein synthesis. tr nscription. J mes W tson nd Fr ncis Crick pu lished their cl ssic p per on DNA in the journ l N ture. Studies such s these m ke it cle r th t the e r ly gerontologists h d only v gue notions out the mech nisms of cellul r senesc ence. other scientists h d worked out the complete genetic code. titled “A Structure for Deoxyri ose Nuc lei Acid. proposed y Leslie Orgel in 1963. proposed y Deh m H rm n in 1956. To further test this the ory nd the free r dic l theory. nd the second. nd tr nsl tion. w s the error c t strophe theory. Other scientists of the time elieved the secret of long life depended on hormones nd. Gerontologists of the second epoch quickly re lized th t the genetic code nd t he events of protein synthesis g ve them. in p rticul r. He noted th t Bulg ri n vill g ers. gerontologists of the                       ¡   ¡                   ¡           ¡  ¡                                             ¡     ¡       ¡       ¡           ¡              ¡ ¡         ¡                   ¡             ¡                             ¡            ¡   ¡     ¡  ¡           ¡   ¡                           . Both of these theories (descri ed in ch pter 2) suggest th t ging is c used y errors in iosynthesis.The History of Gerontology 45 l ctic. By 1966. The first.

46 Aging second epoch eg n using ker’s ye st (S cch romyces cerevisi e). the housefly (M usc domestic ). Throughout the 1960s. if not prim ry. though offering some suppor t for the free r dic l theory. professor of iochemistry t St nford University. c use of the ging process. B cteri h ve n tur l tendency to t ke up pl smids from           ¡                                                  ¡                    ¡                                 ¡     ¡               ¡                       ¡                        ¡                ¡   ¡  ¡                               ¡                   ¡       ¡    ¡         ¡     ¡             ¡ ¡ . The life sp n of houseflies. Testi ng the revised c t strophe theory required det iled inform tion out the gene. c rried out on the house fly. P ul Berg. Fin lly. for ex mple. These studies. m ny rese rchers conducted studies on longlived or short-lived mut nts in n ttempt to correl t e their life sp n with ch nges t the cellul r or iochemic l level. ut t the time. which offered unp r lleled resolution of cellul r org nelles nd tis sue ultr structure. Recom in nt Technology Revolutionizes the Field In 1973. with extensive genetic d t v il le for Drosophil . w s tripled when they wer e re red in tiny c ges th t minimized flight ctivity. which could extend the life sp n of mouse y 30 to 40 percent. Although th e rese rch in the second epoch used more powerful techniques th n were v il le during the first epoch. m ny gerontologists turned their ttention to refining the structur l nd iochemic l n lysis of ge-rel ted ch nges th t w s egun y scientists of the first epoch. m ny investig tors were quick to re liz e th t even though induced errors in protein synthesis h d no effect on the r te of ging. Consequently. However. nd the mouse (mus musculus). f iled to su st nti te the origin l formul tion o f the error c t strophe theory. the r t. Drosophil . nd mouse. other errors. C loric restriction w s lso introduced. produced the first recom in nt DNA molecule. involving replic tion or the rep ir of the DNA molecule . the results were still l rgely descriptive in n ture n d gener lly fell f r short of chieving deeper underst nding of the ging proc ess. the fruit fly (Drosophil mel nog ster). there w s no w y to sequence DNA or to infer the sequence of me ssenger RNA. introduced methods for modul ting the life sp n of t he org nism. Experiments on ll these org nisms. physicists were usy perfecting the electron microscope. could still e n import nt. consisting of piece of m mm li n DNA join ed to cteri l pl smid ( cteri l minichromosome).

with ny insert i t m y cont in. is replic ted long with the cteri l chromosome e ch time the c ell divides. gerontologists tried to test this ssumption y ex mining the protein products of tr nsl tion with two-dimension l (2-d) prote in electrophoresis. conducting n expression study involves determining the m ount of mRNA eing produced y specific gene. Despite its limit tions. nd W lter Gil ert. Bec use most mRNA is utom tic lly tr nsl ted into protein. The inform tion g ined y doing so is extremely import nt ec use ll cellul r processes re ultim tely controll ed y the differenti l expression of v rious genes. t le st not on con-   ¡                       ¡                 ¡                   ¡           ¡                                       ¡     ¡           ¡             ¡   ¡   ¡                                                   ¡ ¡  ¡     ¡ ¡   ¡                     ¡           ¡                 ¡           ¡                         ¡ ¡               . But 2-d electrophoresis c n detect only few hundred proteins.The History of Gerontology 47 the medium they re growing in. the pl smid DNA. The production of recom in nt clones. Fred S nger. fter which they re tr nsferre d to l rge fl sk cont ining nutrient roth nd llowed to grow for 24 hours. Expression studie s o serve the tr nscription of gene to produce messenger RNA (mRNA) nd the re sulting tr nsl tion of mRNA into protein. com ined with the new sequencing techno logy. But no such results were ever o t ined. In 1977. professor t C m ridge University. To mplify m mm li n gene. nd some tur n on or off s conditions dem nd (regul tive expression). cteri re co xed to t ke up recom in nt pl smid i n sm ll test tu e cont ining speci l medium. B y the end of the culturing period. This prolifer tion of segment of DNA is c lled mplific tion. m ny studies were conducte d with this procedure throughout the 1980s on wild-type (norm l) or mut nt Droso phil . m de it possi le to isol te ny gene nd to produce enough of it for seque ncing nd expression studies (see ch pter 8 for more det ils). The hope w s th t electrophoresis would show th t old nim ls were comple tely missing protein present in young nim ls or th t new protein would ppe r in old nim ls th t might e responsi le for the ge-rel ted ch nges. once they do. where s some re lw ys on (constitutive expression). developed methods for sequencing DN A. the mount of cloned insert h s incre sed mor e th n millionfold. Some genes in some cells lw ys st y off. At first. professor t H rv rd. One theory of ging su ggests th t the ging process is c used y su tle disruptions in the norm l cont rol of gene expression. technology introduced in 1977. typic l cell is c p le of producing thou s nds of different proteins.

inste d of protein electrophore sis. serves s pro e to loc lize nd qu ntify the mRN A). r in. If n investig tor h d hunch th t p rticul r liver enzyme w s responsi le for some spect of cellul r ging. the expressio n of the gene could e studied. Consequently. Still investig ting whether the sence or presence of given pro tein influenced ging. no cle r support for ny single theory of the ging process. which w s l ter confirmed in the mouse nd hum n. When ll expression studies were t ken together.48 Aging sistent sis. With recom in nt technology. liver enzymes. nd since the ging process should e simil r f or ll nim ls. virtu lly ny gene for which pro e w s v il le m de g ood c ndid te for n expression study.             ¡             ¡               ¡       ¡        ¡                               ¡                         ¡           ¡                   ¡        ¡                 ¡   ¡                           ¡ ¡ ¡         ¡ ¡ ¡               ¡       ¡         ¡         ¡   ¡ ¡              ¡               ¡     ¡     . there ppe red to e gener l decline in the r te of gene expression with ge nd. ctin. The studies f iled to show consistent ch nge in ny of the prot eins th t could e visu lized with this technique. ut only if it h d lre dy een cloned (the clon e. c rried out prim rily on r t. it is theoretic lly possi le to study the mRNA expression of every gene in the cell. The expression of some genes w s shown to incre se with ge while othe rs decre sed. The nim ls were cle rly gin g. Since no one t the time h d cle r ide of which genes were responsi le fo r the ging process. It w s during this epoch th t investig to rs demonstr ted the striking ge-rel ted decline in the expression of the growth hormone (GH) gene in r ts. s expl ined in ch pter 8. Drosophil . Even w orse. expression studies conducted in the third epoch of geront ology rese rch turned to recom in nt technology. other expression studies. with the exception of GH expression. polipoprotein ( protein th t c rr ies lipids in the lood). In most c ses the choice of which gene to study w s n equ l mix of educ t ed guess nd common pr ctic lity. ut there w s no o vious connection to cellul r senescence. the expression of some genes w s shown to decre se with ge in the r t ut not in Drosophil or the mouse. ut they seemed to e m king the s me proteins when they were old s when the y were young. microtu ules. nd h ousefly tissues did not produce the striking results th t most scientists were e xpecting. those genes could not e the c use of univers l ging mech nis m. gerontologists of the third epoch conducted l rge num er of expression studies involving genes coding for glo in. nd sever l oncog enes. Ho wever.nd kidney-specific proteins.

the proteins ppe r s nds. proteins re extr cted from tones re essenti l for p cking up cells of interest nd then fr ction ted y the chromosomes in prep r tion electrophoresis on poly cryl mide gel. ph te groups to the proteins) is In the ex mple shown. Phosphoryl ting After the gel is st ined. Joseph P nno) primer in ch pter 8).from top to ottom. consisting of s ever l different kinds of histone. for cell division. c lled twot ke our cloth es on trip. Two-dimension l pr otein ture they produce m ke it gels h ve higher resolution nd c n possi le f or the cell to p ck ge its detect out 1.000 times shorter th n the re size m rkers th t decre se in size re piece of DNA. th t re rr nged on the DNA like e ds on string. the proteins ppe r s s pots over the tones nd the chrom tin struc. his.f ce of the gel. is c lled nucleosome. or condens tion. L nes 4 nd 5 10. In different f orm c se m kes it possi le for us to of this procedure. Euk ryote chromosomes re complex of DNA nd proteins. L nes 1 to 3 re proteins nd: The chromosome contr cts extr cted from h ousefly flight muscle t to form comp ct structure th t is 1. or exposed to Xthe nucleosomes ( dding phos. Chrom tin comp ction.000 proteins typic l nim l cell c n produce. nd 8 d ys of ge.Protein electrophoresis.The History of Gerontology 49 Those scientists interested in chrom tin structure nd the role it pl ys in regu l ting gene expression dopted different ppro ch to the study of the ging pr ocess.ut this is still much less th n the more sion (see the eu k ryote cell th n 20. E ch e d.dimension l protein electrophoresis.r y film. This complex of DNA nd histones is known s chrom tin.000 different proteins. The p cking r tio of interph se chrom tin (condensed length divided y           ¡                               ¡                     ¡            ¡     ¡           ¡                                             ¡           ¡     ¡ ¡¡     ¡   ¡                   ¡   ¡                                              ¡                    ¡               . (Dr. is lso use d during interph se (the period etween cell divisions) to help m n ge the chrom osomes. Just s suit. In this pro cedure. pproxim tely 30 like rele sing stretched ru er different proteins ( nds) h ve een ident ified. The his. 4. It is lso one mech nism for controlling gene expression. c lled histones. genes in prep r tion for cell divi.

re usu lly etter me sure of n org nism’s ging r te th n is chronologic l ge (see the ccomp nying t le). conde nsed chrom tin w s elieved to e responsi le for the ge-rel ted reduction in t r nscription l ctivity. ut there re highly condensed regions where it c n e s low s 1:10.e. lood pressure. Scientists produced model of this p rogressive condens tion y n lyzing the condens tion p ttern over the surf ce o f the nucleus nd then. it is e sy to sep r te the histones from the DNA) in cert in uffers. chrom tin condens tion is n extremely dyn mic process th t is used to cl ose down single genes or whole neigh orhoods consisting of hundreds of genes. the Americ n N tion l Institute of Aging (N IA) l unched the Biom rkers of Aging Project to identify iologic l signs. Computerized histochemic l n lysis of int ct nuclei su pported the iochemic l results nd. The iochemic l n lysis depended on the f ct th t uncondensed chrom tin is e sy to dissoci te (i. M ny gerontologists of the third epoch studied chrom tin condens tion s funct ion of ge. which include the perform nce of the c rdiov scul r system. selecting nuclei th t est represent the young nd old groups.000 over ll. In 1987. At the molecul r level. where s highly condensed chrom tin is either very d ifficult to dissoci te or does not dissoci te t ll. or i om rkers. in ddition. This v ri tion in the density of the chrom tin ccounts for the lotchy ppe r nce th t most interph se nuclei h ve. Consequently.50 Aging rel xed length) is out 1:1. provided w y to visu lize th e progressive condens tion of cell nuclei.. Th e third epoch w s productive period for gerontologic l rese rch th t provided m ny insights into the mech nisms controlling       ¡           ¡                                            ¡   ¡                   ¡   ¡                                                                           ¡ ¡     ¡     ¡                         ¡       ¡           ¡                     ¡     ¡       ¡ ¡         ¡    ¡       ¡                 ¡       ¡   ¡       ¡           ¡   ¡   ¡            . to etter f cilit te the in terpret tion of ging rese rch d t . Biom rkers . lood insulin leve ls. Th e mech nism y which this occurs is f irly str ightforw rd: Highly condensed chr om tin locks the tr nscription m chinery.000. with the id of computer lgorithms. so it c nnot get ccess to the gene. These studies were either iochemic l or they relied on computerized histochemistry. Are s of the nucleus th t re very d rk represent highly comp cted chrom tin. Studies such s these inv ri ly showed th t chrom tin ec me more condensed with ge. in hum n su jects th t est ch r cterize the ging process. nd sever l other f ctors. where s the lighter regions cont in chrom tin in more rel xed st te.

Indeed. However. 2DHEA is precursor of the sex hormones estrogen nd testostero ne. ut c n e prevented with exercise nd diet Decre ses Detection of hig h frequencies is lost Thickness of ventricul r w ll incre ses Blood concentr tio n incre ses Reduction in urine output Vit l c p city 3 declines y out 40 perc ent A ility to focus close up is lost. most scientists eg n to re lize th t the fin l ss ult on this very difficult pro lem would require more DNA sequence d t to exp n d the expression profile for the org nisms under study. ut c n e prevented with exercise So me neurons lost. the ging process. night vision ecomes poor. nd ility to detect moving o jects is imp ired. it ec me cle r th t wh t w s needed w s the complete genomic sequence for hum ns nd for ll or g nisms for which ge-rel ted studies were under w y. Cholesterol Dehydroepi ndrosterone (DHEA)2 He ring He rt Insulin Kidneys Lungs V ision 1Norm l. ut short-term memory declines I ncre ses. sic functions rem in int ct. ging occurs in the sence of such dise ses s Alzheime r’s or P rkinson’s. 3Vit l c p city is the m ximum mount of ir inspired with e ch re th.The History of Gerontology 51 BIOMARKERS OF NORMAL AGING1 Biom rker Arteries Blood pressure Body f t Br in Ch nge with Age Flexi ility decre ses Incre ses Incre ses. or successful.                 ¡          ¡       ¡  ¡ ¡                 ¡ ¡ ¡                     ¡  ¡   ¡               ¡                 ¡    ¡     ¡       ¡           ¡ ¡             .

ye st. nem tode (C enorh ditis eleg ns. Seco nd.52 Aging The Postgenomic Er An intern tion l genome sequencing consortium w s formed in 1990 to sequence hum n. nem tode. neither of which re gene tic lly defined (i. United Kingdom. The m in interest o f this progr m is single-gene mut nts th t m y e used to identify genes nd phy siologic l f ctors th t f vor longevity in ll nim l species. The ultim te go l of this progr m is to use inform t ion g thered from lower nim ls to identify longevity genes in hum ns. nd it is expected th t the genomes o f the other org nisms will e completed y 2005 (for ddition l inform tion. nd mice. First. ging rese rch shifted from projects imed t testing one of the m ny theori es of the ging process to n rrower. There i s lso                     ¡                                     ¡                     ¡                                               ¡           ¡                     ¡   ¡  ¡                                          ¡        ¡         ¡                                 ¡                                  ¡           ¡                                         . nd Chin . y settling on just four rese rch org nisms. nd there re m ny lo ng. Rese rch focus c me in two forms. nd mouse genomes. eleg ns). This project w s initi ted y the United St tes Dep rtment of Energy nd the N tion l Rese rch Council nd is coordin ted y the Hu m n Genome Org niz tion (HUGO). thus more pr ctic l ppro ch involving th e se rch for longevity genes. Germ ny. s well s other scien tists working in university l or tories round the country. The princip l consortium mem ers include the Uni ted St tes. mut nts h ve not identified or ch r cterized).. In some c ses. This w s done y selecting for long-lived individu ls or y se rching for n tur lly occurring short-lived mut nts. exposing the nim ls to chemic l mut gens gener ted short-lived mut nts. Fr nce. Gerontology of previous epochs w s c rried out to gre t extent on houseflies nd r ts. cteri . Sequencing of the hum n genome w s completed in e rly 2003. The four o rg nisms chosen y NIA re well ch r cterized genetic lly. In dditi on to fin nci l support. In 1993 the Americ n N tion l Institute of Aging (NIA) st rted pr ogr m to identify longevity genes in ye st. see ch pter 8). Drosophil . or simply C. These include the insulin-like sign ling p thw y.e. chromosom e nd nucle r rchitecture. nd most recently.nd short-lived mut nts v il le th t gre tly expedite ging rese rch. the NIA progr m nd the genome sequencing consortium pr ovided encour gement nd focus to the gerontologic l community. Dr osophil . J p n. stress resist nce. different rese rch groups could e sily comp re results. This progr m provided rese rch funding for scientists t NIA.

Individu ls suffering from this dise se ge so r pidly th t they ppe r to e in their 70s or 80s y the time t hey re 10 ye rs old.     ¡              ¡                     ¡           ¡   ¡                                                             ¡                                   ¡         ¡ ¡ ¡     . nd tre tment of its clinic l symptoms. its homolog ( gene h ving simil r or ide ntic l sequence) c n e identified in hum ns simply y se rching the hum n d t se for gene th t m tches the Drosophil sequence. Revers l of the ging process. sh re common cellul r nd genetic herit ge. Thus. if longevi ty gene is discovered in Drosophil . w ill ecome pr ctic l re lity fter ll the genes controlling these processes h ve een identified nd their functions cle rly defined. in cluding hum ns.The History of Gerontology 53 gre t de l of interest in hum n dise se known s Werner’s syndrome th t is ch r cterized y gre tly cceler ted r te of ging. Rese rch of this kind (desc ri ed more extensively in the next ch pter) is ringing us closer to identifying the physiologic l processes nd molecul r mech nisms th t re import nt for lon gevity. The gre t v lue of the sequencing consortium in the effort to identify ging genes lies in the f ct th t ll the org nisms under study.

they f iled to produce cle r picture of fund ment l mech ni sms responsi le for the ging process. Quite the contr ry. Despite their n me. nd physiologic l processes th t promote longevity. eginning in 1993 with the NIA p rogr m to isol te ging genes.I 6I THE SEARCH FOR LONGEVITY GENES Aging rese rch throughout the first three epochs of gerontology w s prim rily co ncerned with descri ing gener l spects of the process covering ll levels of i ologic l org niz tion. sign ling p thw ys. with the egi nning of the current epoch nd the l unching of comprehensive genome sequencing projects. However. Although these theories were cruci l for producing dv nces in the discipline. It’s only fter eing mut ted nd m de dysfunction l th t they incr e se the org nism’s life sp n. This type of longevity gene is s id to e neg tiv e regul tor of life sp n ec use their norm l function is to limit n org nism’s l ife sp n. limit the life sp n. when functioning norm lly. from the molecul r to the org nism l. Thus. Other longevity genes re s id to e positive regul tors ec use expre ssion (or overexpression) of these genes incre ses the life sp n. s well s ch nges th t m y occur t the p hysiologic l level. The d t collected sp wned l rge num er of theories (covered in ch pter 2) touching on ll spect s of cellul r structure nd function. the go l of gerontology shifted to the identific tion nd ch r cteriz tion of genes th t promote longevity. 54     ¡         ¡               ¡         ¡                                                               ¡           ¡     ¡                         ¡   ¡                 ¡ ¡ ¡ ¡                                 ¡                         . longevity genes were n ot lw ys selected y evolution ry forces to give n org nism long life sp n. there h s een gre t surge in the genetic n ly sis of ging nd etter underst nding of the molecul r mech nisms. since some of these genes.

Drosophil . nem tode. met olic r te. tion. th t cle r underst nding of ll longevity genes will provide w y of reversing or st llin g the signs of ge in hum ns. Rese rchers in the se rch for longevity genes h ve used ye st. Gerontology rese rchers expect. such s S cch rom yces cerevisi e. (SciMAT/Photo Rese rchers. Inc.)         Ye st Ye st re unicellul r org nisms th t divide t regul r interv ls nd. however. ut of the sp ecies to which it elongs. mice.The Se rch for Longevity Genes 55 The norm l life sp n of n org nism is produced y complex mix of positive nd neg tive regul tor genes th t seem to produce the optimum—not necess rily the lon gest—life sp n th t est fits the org nism’s size. nd ctivity leve l. not of the individu l. The s e rch for longevity genes in ye st. This im ge shows sever l of the cells in the process of cell di vision y udding. nd hum ns h s l e d to much cle rer picture of the mech nisms controlling the ging process. re immort l. I t h s lso shed light on how those mech nisms c n e modul ted to fine-tune n o rg nism’s life sp n to m ximize the surviv l. which produces d ughter cell th t is initi lly sm ller th n the mother cell. E ch cell egins s mother cell th t pro- s popul                         ¡                             ¡              ¡   ¡                                   ¡                     ¡         ¡               ¡ ¡                                   . nd its position in the gr nder the ter of pred tor-prey rel tionships.

All enzymes h ve rel tively short life sp n. mut tion in this gene could reduce the cell’s ility to cope with stress. c used y high temper tures or n unf vor le environment. T he identific tion of longevity genes in ye st provided the first comprehensive l ist of physiologic l processes th t re now elieved to control the ging proces s. gene dysregul ti on. fter which it dies. Mich el J zwinski nd his te m t Louisi n St te University in 1994. Glycolipids re n import nt component of the glyco c lyx.56 Aging duces d ughter cell e ch time it divides. they must e repl ced more frequently. The r te t which these genes re tr nscri ed depends on how dly the mitochondri need the enzymes. Since th t time . Although mitochondri h ve their own genome. or to induce poptosis. th t serves t o coordin te mitochondri l function with the expression of mitochondri l genes i n the cell nucleus. The me sure of the ye st life sp n is thus the num er of divisions of the mother cell efore it dies. 14 ddition l longevity genes h ve een identified in ye st (see the t le for p rti l list). nd during periods of extre me ctivity. most of the Kre s cycle enzymes ( ll of which function inside the mitochondrion) re coded for y the cellul r genome. M ny glycolipids re involved in sign ling p th w ys th t regul te growth. S. stress resist nce. nd the m inten nce of genetic st ility. nd poptosis. resist nce to stress. known s the retrogr de response. These processes re met olic control. w s isol ted from ye st y Dr. where s the protein product is written in upperc se rom n). ut the mother cell ges with e ch c ell division. The glycoc lyx is essenti l for cell-to-cell communic tion nd cont ins m ny receptors th t regul te host of cellul r functions. The first longevity gene. nd while the mech nism y which it influences life sp n is uncle r. mitochondri re extremely c tive. c lled l g-1 (longevity ssur nce gene num er 1). LAG-1 is positive regul tor of life sp n. thus its life sp n is limited to finite num er of cell divisions . gene n mes re written in lowerc se it lic. not the mount time it h s lived. Ensuring th t       ¡             ¡        ¡           ¡         ¡ ¡   ¡           ¡      ¡                                   ¡             ¡ ¡                       ¡  ¡                   ¡ ¡          ¡           ¡                      ¡                                                     ¡                                  ¡         ¡       ¡ ¡ . while the d ughter cells continue on for the s me finite num er cell divisions. molecul r “forest” th t covers the surf ce of ll cells. to lock prolifer tion. All euk ryotes h ve n intr cellul r sign ling p thw y. During periods of stress. The l g-1 protein (LAG-1) is loc ted in the mem r ne of the en dopl smic reticulum nd is involved in the production of glycolipids ( y convent ion.

the fourth m jor process ffected y the ging process.. the m in energy source. is lso responsi le for gene silencing. c lled r s-1 nd r s-2. A third gene. c lled helic se. Genetic st ility. Mut tion of this gene le ds to the corruption of m ny genes during replic tion nd is ssoci ted with cceler ted ging. thus conve rting chrom tin from n ctive to n in ctive configur tion. Norm l ging in ye st is ssoci ted with the continued expression of genes th t re supposed to e silent. The consequence is the ssem ly of defective ri osomes nd reduction in the effici ency of protein synthesis. Mut tions in either or oth of these genes elimin te the retrogr de response. The function of helic se is to unwind the DNA helix in prep r tion for replic tion . Overexpression of r s-2 c n completely olis h the neg tive effect on life sp n of chronic he t stress. the cell does not receive sufficient mounts of ATP.The Se rch for Longevity Genes 57 the mitochondri lw ys h ve enough Kre s cycle enzymes is the m in function of the retrogr de response. is m int ined y host of nucle r proteins nd enzymes th t rep ir DNA d m ge nd y m ny other proteins th t re needed for ccur te rep lic tion. rpd-3 nd hd -1 . c lled sir-2. resulting in n excessive production of ri osom l RNA th t is not l nced y the synthesis of ri osom l proteins. resulting i n cellul r d m ge nd e rly de th. ge nes in highly condensed regions re supposed to e turned off). Ye st demonstr ting n tur l thermotoler nce e rly in life inv ri ly h ve longer life sp ns th n is n orm l.       ¡       ¡                                                          ¡   ¡     ¡                   ¡ ¡ ¡          ¡ ¡       ¡       ¡   ¡      ¡           ¡   ¡      ¡ ¡                   ¡        ¡      ¡       ¡                             ¡       ¡               ¡                   ¡ ¡                                                  ¡                 ¡         ¡ . Active regions o f the genome re ssoci ted with chrom tin th t is cetyl ted. One such enzyme. process th t is regul ted y two other longevity gene s. ut its mech nism is not c le r. th t is. Consequently. is encoded y the sgs-1 gene. s though to m rk the regi on s eing tr nscription lly ctive. t time when it needs it the most. presum ly ec use of loss of rpd-3 nd hd -1 ctivity.e. Genetic dysregul tion with ge h s een o served in ye st th t lose tr ns cription l silencing of genes in heterochrom tic regions of the genome (i. thus olishing the cell’s ility to de l with stress of the kind descri ed. the hist ones re modified with the ddition of cetyl groups. D m ge to ny of these silencing genes is responsi le for n ge-rel ted d ysregul tion of the ri osom l RNA genes. code for enzymes c lled de cetyl ses th t remove the cetyl groups. Two ye st longevity genes.

nd poptosis . At the he d of this p thw y is the insulin-like receptor. nd is necess ry for genetic st ility. when mut ted. Its product reg ul tes mitochondri l retrogr de response. ele g ns. whi ch. r s-1 r s-2 rpd-3 hd -1 sir-2 sgs-1 Nem tode A nem tode is very sm ll round worm th t inh its the sole nd sometimes the d igestive tr cts of m mm ls. Its product is histon e de cetyl se th t is needed for proper gene silencing nd regul tion. most of which re involved in n insulin-like sign ling p thw y (see t le ). p rticip tes in the regul tion of the stress response. eleg ns is popul r rese rch org nism mong development l iolo gists nd gerontologists. Its protein product codes for DNA helic se. M mm li n p r site nem todes re known s pinworms. Mut tion of d f-2   ¡    ¡ ¡                 ¡               ¡                   ¡       ¡           ¡    ¡                                                        ¡               ¡                                 ¡                                                 . Its produ ct is nother histone de cetyl se th t regul tes silencing of ri osom l RNA gene s. encoded y the gene d f-2. The ging mech nism is uncle r ut m y involve cell-surf ce (medi ted y th e glycoc lyx) sign ling th t influences growth. The DAF-2 p thw y medi tes growth nd prolifer tion sign ls necess ry fo r the ctive lifestyle of n dult nem tode. Its product is responsi le for regul ting the stress response. Sever l longevity genes h ve een identified in C. stress resist nce.58 Aging YEAST LONGEVITY GENES Gene l g-1 Known or Proposed Function The l g-1 protein product (LAG-1) regul tes tr ffic etween the endopl smic reti culum nd Golgi complex nd is required for the construction of norm l glycoc lyx. gre tly cceler tes the r te of ging. This gene is homologous to the hum n wrn gene. Regul tes ri osom l RNA genes. The nem tode C. required for DNA replic tion.

urning c lories) to stor ge functions. kt-1. mut tion in ny of these genes will le d to the di p use st te nd exten ded life sp n. During the 1980s. it is n ex mple o f the kind of gene th t limits life sp n s result of m ximizing ctivity leve l nd met olic perform nce.. the gene coding for superoxide dismut se (see t le ). The effects o served in d f-2 mut nts re very simi l r to the response of m mm ls to hi ern tion or c loric restriction. A second p thw y h s een identified th t ffects nem tode longev ity. desicc tion. d f-18. nd oxid tive stress. Conseque ntly. the ge-1 pro tein conveys the sign l from the DAF-2 receptor to the cell cytopl sm). The nim l’s ctivity level drops. Thus d f2 is neg tive regul tor of life sp n. tr nsduce the sign l received y the DAF-2 receptor protein (e. such s ge-1. These flies showed gre ter met olic c p city nd enh nced resist nce to stress initi ted y he t. In ddition. nd the life sp n is incre sed y ne rl y 80 percent. Fruit Fly The fruit fly Drosophil mel nog ster is popul r rese rch org nism. M ny of t hese fe tures re held in common with long-lived nem todes nd ye st. nd eth nol v pors.g. shortens life sp n. ultr violet r di tion. they h ve higher ctivities of ntioxid tive enzymes. Hi ern tion eh vior in nem todes is known s di p use st te. Direct sup port for the free r dic l theory of the ging process c me with the isol tion n d ch r cteriz tion of sod-1. The produc ts of other nem tode longevity genes. Accordingly. Tr nsgenic fruit flies overexpressing sod-1 live longer th n norm l nd suffe r much less oxid tive d m ge     ¡       ¡          ¡                                                                                             ¡                   ¡               ¡ ¡                   ¡     ¡                          ¡     ¡         ¡                                                             ¡     ¡                                                       ¡ ¡              ¡      ¡           .. Nem tode di p use is ch r cterized y shift from ctive glucos e met olism (i. such s the deposit of f t.e. Indeed. this p thw y specifi es resist nce to he t. A mut tion in d f-12 or in ctl-1. nd they h ve enh nced stores of lipid nd glycogen. rese rchers m n ged to isol te long-lived Drosophil through selective reeding. component of the p thw y. The d f-12 gene codes for steroid hormone receptor th t is linked to p thw y th t ppe rs to regul te the stress response. d f-12 is positive regul tor of life sp n.The Se rch for Longevity Genes 59 shifts the entire physiology of the nim l from ctive eh vior to something res em ling hi ern tion in m mm ls. they re more efficient t uti lizing nutrients. nd d f-16.

The mth protein produc t. with n effect simil r to c loric restriction— ne r dou ling of l ife sp n. Insulin nd insulin                       ¡ ¡                   ¡                       ¡         ¡   ¡                                 ¡                           ¡                                               ¡       ¡         ¡                         . downstre m from d f-18. nd the mitochondri is lso involved in Drosophil ging. Overe xpression of nother gene. directly link ed to the DAF-2 sign ling p thw y. The retrogr de response ( lre dy descri ed in t he discussion on ye st longevity) involving tr ffic etween the cell nucleus. downstre m from the ge-1/d f-23 products. A mut tion in the indy gene locks import of t hese compounds. Interestingly. lso incre ses life sp n. Disrupting this p thw y extends life sp n. These genes code for two kin ses. DAF-16. is multifunction f ctor th t is ctiv ted y the DAF-2 nd DAF-12 p thw ys. overexpression of sod-1 in motorneurons lone is sufficient to ne rly dou le the me n life sp n of these nim ls. c lled methusel h. Loss of function pro motes “hi ern tion” response.60 Aging CAENORHABDITIS ELEGANS LONGEVITY GENES Gene d f-2 Known or Proposed Function Its product codes for n insulin-like cell-mem r ne receptor (DAF-2). cy topl sm. ge-1 / d f-23 d f-18 kt-1 / kt-2 d f-16 d f-12 ctl-1 induced y free r dic ls. involving the stor ge of f t nd glycogen th t exten ds life sp n. The protein product is cytopl smic enzyme (c t l se) o n the DAF-12 stress-resist nce p thw y. A mut tion in this g ene shortens life sp n. Its product. The indy (i’m not de d yet) gene codes for mitochondri l mem r ne protein involved in tr nsp ort of Kre s cycle intermedi tes. Its product codes for steroid hormone receptor (DAF-12) th t is linked to p thw y th t is import nt in stress resist nce. mth. The products of these genes re on th e DAF-2 p thw y. The protein product is on the DAF-2 p thw y. is cell-surf ce receptor th t is linked to p thw y th t regul tes the stress response.

This receptor is very simil r to the nem tode DAF-2 receptor. thus incre sing life sp n. n enzyme th t enh nces the up t ke of m ltose into cells. which enh nces the stress response. The Dr osophil genes chico nd inr (insulin receptor) encode n insulin protein nd in sulin receptor very simil r to those found in nem todes nd m mm ls. Lose of function h s the s me effect s chico mut tion. The prote in product. thus invoking p rti l c loric restriction. Its product codes for the CHICO receptor. Its product codes for cell-mem r ne receptor c lled meth usel h. The loss of function incre ses life sp n y reducing the v il ility of nutrients (c loric restriction). In this c se. sod-1 mth chico inr sug r y receptors modul te life sp n in Drosophil . Overexpression incre ses life sp n y shifting met olism w y from glucose. CHICO. This gene codes for m ltose perme se. much s they do in nem todes. The sug r y gene chieves simil r though muted effect on l ife sp n. is simil r to m mm li n insulin. The protein product is supe roxide dismut se (SOD).                             ¡                       ¡     ¡ ¡         ¡          ¡                    ¡               ¡     ¡               ¡  ¡                                                 ¡          ¡  ¡                   ¡   . Loss of function incre ses l ife sp n through c loric restriction. comp red wit h the more th n 80 percent incre se o served in inr mut nts. thus mimicking the effects of c loric restri ction. The protein product is m ltose perme s e. Mut tions i n chico or inr h ve the s me physiologic l effects s descri ed for the d f-2 ge ne in nem todes. Overexpression of this gene shifts the nim l’s physio logy w y from glucose utiliz tion.The Se rch for Longevity Genes 61 DROSOPHILA LONGEVITY GENES Gene indy Known or Proposed Function Its product codes for mitochondri l mem r ne protein involved in tr nsport of Kre s cycle intermedi tes. Overexpression incre ses life sp n y enh nced in ctiv t ion of free r dic ls. the incre se in life sp n is out 20 percent.

such s c ncer. Although the sequence homology is low. Consequently. The consequence o f this mut tion is the s me s if the nim ls were r ised on c lorie-restricte d diet even while in the wom . i ncluding resist nce to stress. extend life sp n in m nner simil r to c loric restriction (see t le). pr op-1 mut nts re dw rves. In ddition. Moreover. nd fruit flies. c lorie-restricted rodents show po stponement of ge-rel ted dise ses. nd h ve n incre sed lifeti me met olic c p city. pit-1. while nim ls possessing norm lly expressed p66shc h ve shorter life sp ns. these c lorie-restricted nim ls s how simil r met olic responses o served in ye st. Mut tion of prop-1 or pit-1 le ds to development l rrest of the pituit ry gl nd. like the hi ern tion response in nem todes nd flies. re due to more efficient utiliz tion of glucose nd shift tow rd deposit of f t nd glycogen. it c n repl ce the ye st gene. when m ut ted. A second type of longevity gene h s een identifi ed in mice. The gene prop-1 (“prophet of pit-1”) codes for protein th t regul tes nother gen e. The hum n homolog of ye st l g-1 h s lre dy een cloned nd is loc ted on chromosome 19. which codes for component of sign ling p thw y th t regul tes the stress response nd poptosis. ut they h ve n extended life sp n. overexpression of this gene incre ses li fe sp n. nem todes. In the sence of these hormones. As with the other posi tive longevity genes lre dy descri ed. cells c nnot u tilize glucose or mino cids to promote growth nd m tur tion. These ch nges. This is the p66shc gene. Such experiments (descri ed in ch pter 2) h ve extended the life sp ns of mice nd r ts y up to 50 percent. Three mouse genes h ve een identified th t.               ¡                                ¡                 ¡                                             ¡         ¡                                 ¡            ¡     ¡     ¡     ¡     ¡                                           ¡        ¡    ¡                                           ¡ .62 Aging Mouse The most consistent w y to extend the life sp n of m mm l is y c loric restri ction. thus dr st ic lly reducing the norm l levels of growthinducing hormones such growth hormone (GH) nd thyroid hormone (TH). th t codes for pituit ry-specific tr nscription f ctor. Hum n Identific tion of longevity genes in lower org nisms h s stimul ted se rch for simil r genes in the hum n genome.

is dise se in hum ns th t is lso s soci ted with cceler ted ging. ut mem er of the s me f mily. Werner’s syndrome. Perh ps the most striking simil rity etween longevity genes in h um ns nd lower org nisms is the ye st sgs-1 gene nd the hum n wrn gene. protein tr nscription f c tor.The Se rch for Longevity Genes 63 MOUSE LONGEVITY GENES Gene prop-1 Known or Proposed Function The protein product is regul tor of pituit ry-specific tr nscription f ctor (P IT-1). The protein product of the wrn gene is helic se. lthough much work is needed to confirm its funct ion in hum ns. po ssessing simil r function. not the s me helic se encoded y the sgs-1 gene. resist nce to stress. nd genetic st ility. when mut ted. This gene codes for PIT-1. pit-1 p66shc where it performs longevity function. The in ctiv tion of pit-1 h s the s me effect s prop-1 mut tion. The gene responsi le for this dise se. They re met olic control. c lled w rn. descri ed previously. Evidence supporting the involvement of met ol ic control comes from the roles of l g-1 in       ¡                  ¡                 ¡                                      ¡ ¡           ¡         ¡                 ¡    ¡                 ¡     ¡    ¡                                             ¡  ¡       ¡                       . The pro tein product is component of sign l tr nsduction p thw y th t m kes cells re sist nt to poptosis nd oxid tive stress. The sg s-1 gene codes for helic se nd. Summ ry The se rch for longevity genes h s identified four physiologic l processes th t influence life sp n. hum n l g-1 m y e thought of s hum n longevity gene. Consequently. p rticul rly growth hormone. In ctiv tion le ds to poor development of the pituit ry nd production of pituit ry hormones. h s een identified. Mut tions in these two genes provide dr m tic evide nce in support of the connection etween life sp n nd genetic st ility. gene dysr egul tion. c n cceler te the ging proces s. Mut ted prop-1 incre ses life sp n y out 50 percent.

the rel tionship etween genetic st ility nd l ife sp n is indic ted y the effects of sgs-1 mut nts in ye st nd the hum n dis e se known s Werner’s syndrome. d f-2 in nem todes. The ch r cteriz tion of ll longevity genes is expected to revoluti onize our underst nding of the ging process.             ¡                   ¡        ¡                           ¡               ¡                         ¡     ¡         ¡                                   ¡                       . rp d-3.64 Aging ye st. h s een cle rl y demonstr ted in ye st with the isol tion of three histone de cytl se genes. Gene dysregul tion. nd p66shc. hd -1. This collection of genes. nd sir-2. Fin lly. h s given powerful oost to gerontologic l rese rch nd provides n import nt conceptu l fr mework th t future rese rch m y follow. d f-1 2. This work h s lre dy egun with the isol tion of hum n l g-1. such s r s-2. The go l is to isol te even more longevity genes from lower nim ls nd then to find their coun terp rts in the hum n genome. homolog of sgs-1. mth. nd prop-1 in mice. s mech nism of ging. indy nd sod-1 in Drosophil . which is ssoci ted with cceler ted ging nd is c used y the gene wrn. nd it m y provide the me ns y wh ich the effects of ge m y e tre ted or reversed. Res ist nce to stress is function of sever l longevity genes. sm ll tho ugh it is.

nd c ring for. Geri trics is r nch of the iom edic l sciences devoted to helping the elderly (65+ ye rs old) de l with the eff ects of ge. This effort. ec use of the p tient’s ge. Older people re usu lly suffering from sever l simult neous disord ers th t. either ec use of poor memory or ec use of psychologic l compen s tion y which the p tient ignores nd minimizes d nger signs nd symptoms. All these elements complic te the di gnosis nd prognosis for geri tric p tient. which covers the m ny pro lems ssoci ted with the c re nd tre tment of the elderly. the p t ient’s spouse m y h ve p ssed w y. lost friends. is sed on ro d r nge of ther pies th t re grounded in the iologic l. m de possi le y he lthy liver th t m y not exist in n older p tient. nd nursing homes. Gro wing old is often time of loss: lost physic l ilities. psyc hologic l. We 65     ¡ ¡                   ¡                     ¡     ¡   ¡   ¡           ¡     ¡                   ¡        ¡         ¡               ¡             ¡                                           ¡        ¡                               ¡                 ¡             ¡   ¡       ¡                 . Accur te medic l histories re often difficult to o t in from el derly p tients. nd the f mily home m y h ve een given up for room in nursing home or hospit l w rd. nd soci l sciences. The focus of this ch pter is clin ic l geri trics. The geri tric ppro ch does not try to reverse the ging process u t r ther to minimize its consequences y reducing or inhi iting the progression to dis ility.I 7I GERIATRICS The World He lth Org niz tion (WHO) pl ces he lth issues on continuum from dis e se to imp irment to dis ility to h ndic p. Tre ting. the elderly is compl ex ende vor. Drugs th t re s fely used to tre t depr ession or c rdiov scul r dise se in young p tients c n h ve dev st ting effects on the elderly. clinics. Drug ther pies ssume cle r nce time (physiologic l de ctiv tion of the drug). c nnot e tre ted with the drugs or ther p ies th t re routine for younger individu ls. conducted in hospit ls.

66 Aging egin with the demogr phics of North Americ n society with respect to ge distri utions, epidemiology, nd the c p city of he lth c re providers to de l with th e ever-exp nding geri trics popul tion.

Our Aging Society Between 1900 nd 1990, the tot l U.S. popul tion incre sed threefold, while the num er of elderly persons incre sed tenfold. In 1990 more th n 35 million Americ ns were over the ge of 65, ne rly twice s m ny s in 1960. This num er re che d 35 million in 2000 ( out 12 percent of the popul tion) nd is expected to inc re se further, to 53 million y 2020 nd 75 million y 2040 (20 percent of the p opul tion). One of the f stest growing segments of the popul tion is the very ol d (persons older th n 85), who now ccount for 12 percent of ll elderly persons nd is expected to incre se to 18 percent y 2040. In ddition, the num er of p ersons re ching 100 ye rs of ge (centen ri ns) is expected to incre se from the current 60,000 to ne rly 500,000 y 2040. In gener l, the mort lity r te for el derly women h s declined more quickly th n it h s for older men. In 1950 there w ere 89 older men for every 100 older women; in 2000 there were 70 men for every 100 women. Among the very old, there re 41 men for every 100 women. Living rr ngements v ry gre tly for the elderly. At ges 65 to 74, one-third of women live lone, ut fter the ge of 75, this proportion incre ses one-h lf. Before the ge of 85, the elderly usu lly live with rel tives or spouse, ut fter 85, 18 percent of men nd 28 percent of women live in nursing homes or hospit l w rds. Per c pit costs for cute nd long-term (chronic) he lth c re services re hig hest for the very old, so the growth of this group will h ve profound effect o n he lth c re costs. Persons over 65 currently represent just over one in three of the p tients seen y prim ry c re physici n; y 2040 this r tio is expected to incre se to one in two. While the costs of c ring for the elderly is expecte d to rise, this is due not just to the p tient’s ge ut lso to gener l incre s e in the complexity nd expense of di gnostic procedures nd equipment. It is ex pected th t s the proportion of older to younger persons incre ses, less fin nc i l nd soci l support will e v il le for the elderly. Medic re nd Medic id cover much of the fin nci l urden of c ring

 

 

 

 

 

 

 

 

 

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Geri trics 67 for the elderly in the United St tes. However, even with these pu lic services, the elderly still e r consider le sh re of the expenses. Currently, geri tri c p tients c n expect to p y s much s 21 percent of their income for medic l c re. Ev lu ting the Geri tric P tient Ev lu tion of geri tric p tient is much different from th t of younger indiv idu l. Young p tients gener lly h ve single compl int th t the physici n c n f ocus on, nd there is usu lly no reference to the p tient’s socioeconomic environm ent. The ppro ch to geri tric p tient, however, m y egin with the physici n sking the p tient to descri e typic l d y in his or her life. In this w y, th e physici n c n est ssess the elderly person’s over ll qu lity of life, liveline ss of thought, nd physic l independence. This ppro ch lso helps develop goo d p tient-physici n r pport, something th t is especi lly import nt to elderly p tients, who often t ke longer to nswer questions nd m y e shy ec use of it. In the initi l interview, geri trici ns re especi lly c reful not to inf ntili ze the p tient y sking n ttending rel tive questions pert ining to the p tie nt’s history or medic l st tus. It is for this re son th t geri tric p tients, unl ess suffering from dementi , re interviewed lone. During the initi l ev lu tio n nd interview, the physici n ttempts to g ther inform tion out the p tient’s medic l, drug, nutrition, nd psychi tric histories. MEDICAL HISTORY With n eld erly p tient, the medic l history m y extend ck to time when society’s dise se profile w s different th n it is tod y. For ex mple, rheum tic fever nd tu erc ulosis were much more common in the mid-1900s th n they re tod y. Consequently, the physici n will sk out dise ses th t were common when the p tient w s you ng. The p tient will lso e sked out outd ted tre tments, such s mercury fo r syphilis or pneumothor x ther py for tu erculosis. M ny older persons tend to underreport symptoms out of deni l or fe r of illness, dis ility, nd the dep endence these conditions m y ring. Aging c n lso lter the individu l’s response to cert in dise ses, such s p inless myoc rdi l inf rction or pneumoni with out cough.

 

 

       

       

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68 Aging DRUG HISTORY Although the physici n will sk the p tient, nd the p tient’s rel ti ves, out prescription drugs, some geri trici ns h ve suggested th t the est ppro ch is the “ rown g” technique, where y the p tient is sked to empty his or h er medicine c inet into rown p per g nd then to ring it to the ev lu tio n interview. Often the compl ints of older p tients re tr ced to drug or com in tion of drugs they h ve een t king. The drug history includes determining wh ich drugs re used, t wh t dose, how often they re t ken, who prescri ed them, nd for wh t re son. Topic l drugs re included, such s eye drops for tre ting gl ucom , ec use there is the possi ility th t systemic sorption m y c use u nexpected side effects in the elderly. Over-the-counter drugs must e included ec use their overuse c n h ve serious consequences, such s constip tion from l x tive use or s licylism from spirin use. P tients re lso sked to demonstr t e their ility to re d the l els (often printed in very sm ll type) nd to ope n the cont iner, which m y cont in child-resist nt lid. Bec use older p tients re often tre ted with multiple medic tions, they re t risk of noncompli nce nd dverse effects. NUTRITION HISTORY The physici n tries to determine the type , qu ntity, nd frequency of food e ten, including the num er of hot me ls per w eek. Speci l diets, self-prescri ed f d diets, lcohol consumption, over-the-cou nter vit mins, nd diet ry fi er re lso determined. For the elderly, it is ver y import nt to determine the mount of money the p tient h s to spend on food e ch week nd whether suit le cooking f cilities re v il le. The p tient’s ili ty to e t is ssessed y ex mining the mouth nd the condition of the teeth or d entures, if fitted. Poor vision, rthritis, immo ility, or tremors m y ffect n old person’s ility to prep re food. A p tient th t suffers from urin ry inconti nence m y reduce fluid int ke, which could lso le d to poor food int ke. M n ging Age-Rel ted Disorders The most common disorders of the elderly re dementi , c rdiov scul r dise se, o steoporosis, nd incontinence. It is not unusu l for elderly p tients to suffer from ll these disorders simult neously.

     

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vit min E. Clinic l tri ls h ve shown th t even the very old c n enefit y this ppro ch. In m ny c ses. CARDIOVASCULAR DISEASE C rdi c output n d the response of the he rt to exercise decre ses with ge. This is followed with ph rm cologic l gents th t enh nce cognition nd function. or those produced y infections. riv stigmine. Clinic l tri ls h ve shown th t these drugs c n improve cognitive function. such s estrogen (for women). ginkgo ilo .Geri trics 69 DEMENTIA Ne rly h lf of ll elderly p tients suffer from v rious degrees of deme nti . delusions.lockers.     ¡               ¡               ¡    ¡             ¡ ¡ ¡   ¡              ¡       ¡        ¡                    ¡                 ¡     ¡   ¡                       ¡               ¡ ¡                 ¡       ¡           ¡                       ¡       ¡     ¡         ¡   ¡                   ¡            ¡ ¡     ¡ ¡     ¡       ¡           ¡               ¡                       ¡      ¡       ¡   ¡                 . nd m gnesium). However. Other drugs. w hile these gents m y e ineffective s tre tment for dv nced dementi . which involves m int ining n ide l ody weight. The first st ge in m n ging hypertension nd c rdiov scul r dise se i s ch nge in lifestyle. neopl sms. p r noi . H rdening of the rteries is the prim e c use of hypertension in the elderly. nd nonsteroid l nti-in fl mm tory gents. drugs such s thi zide. However. or c lcium ch nnel lockers m y e used. c n le d to serious complic tions. re lso used ut their effectiveness is in dou t. the p tient m y e tre ted with cholinester se inhi itors to m ximize the h lf-life of r in neurotr nsmitters. which is currently irreve rsi le. Thus the first step in m n ging dement i is ggressive tre tment for high lood pressure. Ventricul r contr ct ions ecome we ker with e ch dec de. they m y e useful in tre ting milder c ses. There re three such drugs v il le: donepezil. Wher e AD is suspected. nd diet consisting of fruits. If these procedures f il to reduce lood pressure. no smo king. c lcium. vomiting. including n use . nd di rrhe . Reversi le dementi s re c used y strokes. n d low-f t d iry products ( ll of which re rich in essenti l pot ssium. side effects. regul r ero ic exercises. or toxins such s lcohol. et . optim l m n gement c n improve the ility of these p ti ents to cope with sic t sks. nd tre t ssoci ted pro l ems such s depression. nd even psychoses. git tion. pro lem th t is compounded y the ge-rel ted reduction in lood vessel el sticity. Although complete cure for most dem enti s is not possi le. nd g l nt mine. ut it is not n un void le consequence of ging. veget les. Two-thirds re c used y Alzheimer’s dise se (AD). dementi is the result of one or m ore sm ll strokes c used y hypertension. ut the diet nd exercise regimen should e m int ined.

A out 33 percent of elderly women nd 20 percent of elderly men suffer from this disorder. The prev lence m y e s high s 80 percent in nursin g homes or longterm-c re institutions. In severe c ses. Both procedures determine the density s g/cm2. the integrity of the urethr nd the hol ding volume of the l dder. INCONTINENCE Incon tinence. nd the d rug must e t ken on n empty stom ch in n upright position. Delirium nd exposure to new environment. the pro lem c n e resolved. is very common in the geri t ric popul tion. In other c ses. it m y e necess ry to resor t to drug ther py. such s recent dmission to hospit l or nursing home. for men nd women.70 Aging OSTEOPOROSIS Diminished one m ss c n e determined most conveniently with speci l X-r y m chines (du l energy X-r y sorptiometry) or with ultr sound densitom etry.                                     ¡                                 ¡     ¡             ¡           ¡         ¡         ¡           ¡           ¡               ¡         ¡           ¡         ¡    ¡                             ¡ ¡                   ¡       ¡       ¡               ¡             ¡ ¡ ¡             ¡                   ¡            ¡                           . whic h is v il le in long. A commonly used drug is l dder rel x nt. c n lso le d to incontinence in the elderly. this ppro ch c n le d to d ngerous side effects. which is comp red to norm l v lues from younger popul tion nd is used to estim te the likelihood of fr cture. surgery m y e requ ired to rep ir d m ged sphincters th t norm lly regul ted urine flow through the urethr . The isphosphon te. The first ttempts to m n ge this dise se involve diet rich in c lcium nd vit min D. Simply modifying the p tient’s fluid int ke nd elimin ting diuretics such s coffee or te c n often tre t tr nsient incont inence. Persistent or cute incontinence is m n ged initi lly y ensuring th t t he p tient c n re ch toilet quickly.e ring exercises. which decre ses with ge. w s shown to decre se the incidence of verte r l nd nonverte r l fr ctures y more th n 50 percent in postmenop us l women. long with regul r weight. Hormone repl cement ther py h s lso een recommended. lendron te. Often with speci l c re nd tr ining. ntiresorptive drugs th t re k nown to incre se one m ss. It m y lso e necess ry to provide the p tient with incontinence underg rments nd p ds.cting prep r tions. The m jor side effects re g strointestin l. or the involunt ry loss of urine or stool. Incontinence m y develop ec use of neuro logic l d m ge sust ined fter stroke or it m y e tr ced to gerel ted ch nge s in the urin ry system. An ltern tive d rug ther py involves the use of isphosphon tes. ut s discussed in prev ious ch pter. in p rticul r. tolterodine.

Consequently. the ging process lters the elderly p tient’s ility to de l with drugs physiologic lly. Effective drug ther py is often h mpered y f ulty di gnosis. Older p tients m y underreport symptoms. However. chronic indwelling c theriz tion is not dvised. s indic ted ove. In ddition. Drug Ther py Geri tric p tients re often prescri ed l rge num er of drugs to de l with the m ny disorders they suffer from. However. Potenti lly f t l v entricul r rrhythmi s h ve een c used y cert in ntihist mines when given to older p tients with defective liver enzymes. T hese enzymes c n lso h ndle more exotic compounds such s lcohol or ph rm ceut ic l drugs. The liver cont ins out 30 enzymes th t re involved in the de gr d tion of wide v riety of compounds th t re consumed in n ver ge diet. possi ly toxic. there re usu lly effective nonph rm cologic l ther pies v il le th t should e ttempted efor e resorting to drugs. Thus drugs th t h ve not een specific lly tested for use on older                   ¡   ¡                ¡     ¡                             ¡                       ¡         ¡  ¡                                   ¡                    ¡           ¡  ¡                  ¡                 ¡   ¡             ¡                    ¡         ¡                               ¡  ¡             ¡   ¡         ¡                                     ¡         . This deficit occurs prim rily t the liver nd t the kidneys. Fin lly. m king the correct di gnosis nd prescri ing the ppropri te drugs is very difficult t sk in geri tric medicine. All geri tric p tients need c reful nd thorough review of the drugs they re prescri ed to ensure they re necess ry nd th t there is no ch nge of potenti lly d ngerous drug inter ctions. symptoms of physic l di se ses m y overl p with psychologic l illness. The kidneys lso pl y n import nt role in ridding the ody of foreign or unw nted chemic ls nd drugs. the situ tion is too compl ex for physici n to ssume th t n elderly p tient with norm l liver function tests will e le to met olize given drug s efficiently s younger p tien t. or their compl ints m y e v gue nd multiple.Geri trics 71 It m y lso e necess ry to fit the p tient with c theter th t continu lly dr ins the l dder into pl stic g. levels over the time-course of tre tment. Drugs given to older p tients re cle red more slowly y the kidneys nd thus h ve tendency to ccumul te to high. Age-rel ted or even lcohol-induced deterior tion of these enzymes m ke s fe drug d ngerous when given to geri tric p tient. s it is ssoci ted with high risk of developing urin ry system infections. However.

nd the introduction of nurse pr ctitioners nd physici n ssist nts. pressure sores. Despite these m ny p ro lems. nd co unseling residents nd surrog te decision m kers on tre tment pl ns in the event of termin l illness re usu lly not reim urs le t ll. Medic l servicing centers nd ph rm ceutic l comp nies h ve developed computer lgorithms nd d t ses to help ev l u te drug us ge nd to detect possi ly d ngerous drug com in tions th t re pres cri ed for geri tric p tients. These medic l pr ctitioners could e very helpful in implementing some of the screening nd mon-                                                                             ¡   ¡          ¡       ¡                     ¡                       ¡       ¡                      ¡                   ¡       ¡                 ¡                               ¡     ¡   ¡ ¡         ¡                 ¡           ¡ ¡ ¡ ¡ ¡   ¡       .” Nursing homes re intended s pl ces where the elderly c n e c red for in thei r fin l ye rs y te m of medic l profession ls who speci lize in geri tric med icine. ut more recent report in 2000 indic ted th t serious pro lems still exist. Restrictive Medic re nd Medic id reim ursement policies do not encour ge physici ns to m ke more th n the required monthly or 60-d y visits. nd persistently poor providers of c re re still i n oper tion. Physici n involvement in nursing home c re is often limited to telephone convers tions with the nursing st ff. however. Physici n involvement in such essenti l services s ttend nce t the medic l te m conferences. nd urin ry incontinence h ve ll een shown to e serious pro lems in recent studies of nursing home residents . nd thus m ny of the residents r e sent to hospit l emergency rooms. most nurs ing homes l ck expensive di gnostic equipment. In ddition. where they re ev lu ted y st ff who l ck t r ining nd interest in the c re of fr il elderly p tients. Nursing Homes The poor qu lity of c re provided in nursing homes h s een known for dec des. In m ny c ses. the effectiveness of nursing homes c n e improved with more ttention p id to the document tion of the resident’s illness nd tre tment history. One critic l p ss ge from the report indic tes th t “seriou s pro lems concerning qu lity of c re pp rently continue to ffect residents of this country’s nursing homes. f mily meetings. m lnutrition.72 Aging su jects must e used with extreme c ution. P in. T here h s een some improvement since the Institute of Medicine (IOM) rele sed critic l report in 1986. logistic nd economic restr ints m ke this very difficult go l to re lize.

the st ffing levels nd tr ining. In its report of 2000. th t is. including the ir size. the ch r cteri stics of those receiving c re.Geri trics 73 itoring th t is needed to ensure proper c re of the residents. nd to this exten t would function s n independent p tient dvoc te. dem nds th t su jects enter into rese rch volunt rily nd with dequ te inform tion. They lso c lled for incre sed funding. They could lso h ve n imp ort nt role in communic ting with the st ff. nd the infirm.           ¡   ¡                     ¡          ¡  ¡   ¡       ¡                     ¡       ¡                            ¡ ¡           ¡                ¡     ¡               ¡ ¡            ¡ ¡                                                   ¡                                                            ¡         ¡   . nd commitme nt to provide dequ te clinic l nd person l services for the incre singly fr il or complex popul tions using long-term c re. However. Principles of respect for persons. The pro lems f cing nursing homes over the next 40 ye rs re tremendous. the IOM noted the urgent need fo r rese rch nd d t collection to o t in etter underst nding nd description of the v rious long-term-c re rr ngements throughout the country. RESPECT FOR PERSONS Respect for persons. s they do to hum n su jects involved in clinic l tri ls. chi ldren. n d informed consent pply equ lly well to elderly p tients in nursing home. nd the st ffing nd qu lity of c re provided in the different settings nd services. st ility. there re m ny inst nces where potenti l rese rch su j ects re not re lly utonomous. the elderly. nd f milies when the ph ysici n is not in the f cility. Geri tric p tients re especi lly vulner le ec use of their m ny medic l disorders. in the context of clinic l tri ls. eneficence. This ssumes the individu ls re utonomous gents. which often ffect their ility to underst nd wh t is eing done t o them. All these people require speci l protection to ensure they re not eing coerced or fooled into volunteering s rese rch su jects. the services provided. re competent to m ke up their own minds. con cluding th t “the mounts nd w ys we p y for long-term c re re pro ly in dequ te to support workforce sufficient in num ers. or hospit l w rd. p tients in ment l institution. prisoners. residents.” Ethic l Issues The sic ethic l principle governing the c re of the elderly were est lished i n the 1970s in response to lleg tions th t hum n su jects in iomedic l clinic l tri ls were poorly tre ted. skills.

it is necess ry to do ll th t is possi le to ensure their well.74 Aging BENEFICENCE It is not enough to respect potenti l su ject’s decisions nd to pro tect them from h rm. nor suggest ny such counsel. m ny of whom suffer from dementi . Moreo ver. nd for those involved in iomedic l rese rch.         ¡               ¡               ¡          ¡       ¡   ¡                                         ¡ ¡                           ¡ ¡               ¡ ¡ ¡                                     ¡     ¡ . Consequently. it is the n tur l extension of the Hippoc r tic o th th t ll physici ns re expected to dhere y: I will give no de dly medicine to nyone if sked. do no h rm. in f ct. INFORMED CONSENT All p rticip nts in clinic l tri ls must provide informed consent in writing. steps must e t ken to ensure th t the consent is.eing. such s moving n elderly person out of their home nd into n institution. informed. In other words. In this sense. who re especi lly sensitive to this type of ther py. ut in the c se of geri tric p tients. we kened y illness nd g e. This might involve n independent ssessment of the individu l’s ility to underst nd the l ngu ge on the consent form nd ny instructions or expl n tions the invest ig tors h ve given. never injure one person to enefit nother. i t is necess ry to proceed with extreme c ution in such c ses nd to ensure th t n ction t ken. is re lly in their est interest nd not simply convenience. ut in ddition. c nno t e expected to give informed consent under m ny circumst nces. it is n o lig tion. Beneficence is gener lly reg rded s cts of kindne ss or ch rity. Geri tric p tients. This is p rticul rly relev nt to prescri ing drugs for the eld erly.

Golgi complex. The Arch e nd cteri represent fifth kingdom. or prok ryotes.5 illion ye rs go in the form of single cells th t ppe red in the oce ns. nd euk ryotes.000 genes. Euk ryotes (me ning “true nucleus”) re much more complex. The nucleus lso cont ins n ssem ly pl nt for ri osom l su unit s.I 8I RESOURCE CENTER Euk ryote Cell Primer Life on E rth eg n 3. A prok ryote genome is single. e ch of which m y cont in up to 10. nim ls. cont ining fewer th n 5. mitochondri . E ch of these groups represents distinct phylogene tic kingdom. known s the Mo ner . nucleolus. protozo ns. most of which re de stined for the cell mem r ne to form molecul r “forest” known s the glycoc lyx. circul r piece of n ked DNA. nd peroxisomes. These cells evolved into ncestr l prok ryotes nd.000 ge nes. oth l cking true nucleus nd intern l org nelles. g ve rise to pl nts. The euk ryote nucl eus. cont ins DNA (deoxyri onucleic cid) genome on two or more line r chromosomes. endopl smic reticulum ( ER). These include nucleus. lysosomes. Arch e nd cteri re very simil r n tomic lly. cteri . g ve rise to Arch e . c lled the nucleolus. ounded y dou le phospholipid mem r ne.ounded org nelles. Euk ryotes. the three m jo r divisions of life in the world. h ving m ny mem r ne . The endopl smic reticulum (ER) nd the Golgi complex wo rk together to glycosyl te proteins nd lipids ( tt ch sug r molecules to the pr oteins nd lipids producing glycoproteins nd glycolipids). out 2 illion ye rs go. c lled chromosome. nd fungi. in turn. T he glycoproteins nd 75   ¡ ¡         ¡      ¡   ¡         ¡               ¡                                               ¡                   ¡        ¡                      ¡                        ¡                 ¡ ¡   ¡             ¡   ¡                 ¡         ¡     .

pl nts. Mitochondri provide the cell with energy in the form of ATP. nd nim ls. synthesize proteins. The microtu ules nd centr osome form the spindle pp r tus for moving chromosomes to the d ughter cells du ring cell division. most of which re destined for the cell mem r ne. The endopl sm ic reticulum (ER) nd the Golgi work together to modify proteins.76 Aging Endopl smic reticulum Nucleolus Nucleus Peroxisome Golgi pp r tus Nucle r pore Ri osomes Lysosome Cytopl sm Microtu ule Golgi vesicle Mitochondrion Centrosome Actin fil ments Cell mem r ne The euk ryote cell. The nucleus cont ins the DNA ge nome nd n ssem ly pl nt for ri osom l su units (the nucleolus). Actin fil ments nd we like structure consisting of interm edi te fil ments (not shown) form the cytoskeleton. Ri osomes. ¡         ¡       ¡       ¡ ¡               ¡     ¡                             ¡               ¡       ¡             ¡   . Lysosomes nd peroxisomes recycle cellul r m teri l nd molecules. These proteins re sent to the mem r ne in G olgi vesicles. The structur l components shown here re present in org nism s s diverse s protozo ns. some of which re tt ched to the ER.

The six sic molecules re mino cids. gr sses. nd v ri le R group tt ched to c r on tom. nd nucleotides. The microtu ules nd centrosome form the spindle pp r tus for moving c hromosomes to the d ughter cells during cell division. The Golgi vesicles ud off the outer ch m er. or the one f rth est from the ER. f tty cids.ond energy. Glycerol is simple. c r oxyl group. loc ted in th e mitochondrion inner mem r ne. three-c r on lcohol th t is n import nt component of cel l mem r nes nd f t reservoirs. Phosph tes re extremely import nt molecules th t re used in the construction. nd reeds re polymers of glucose nd othe r monos cch rides. of m ny other molecules. nd the only other org nelle with dou le mem r ne. Glucose. Actin fil ments nd we like structure consisting of intermedi te fil ments form the cytoskeleton. c lled the electron tr nsport ch in. Sug rs re extremely vers tile molecules th t r e used s n energy source nd for structur l purposes. five-c r on sug r. nd thus wood.Resource Center 77 glycolipids tr vel from the ER to the Golgi. Amino cids h ve simple core structure consisting of n mino group. once free-living prok ryotes. Mitochondri . or modific t ion. provide the cell with energy in the form of d enosine triphosph te (ATP). six-c r on su g r. The production of ATP is c rried out y n ssem ly of met l-cont ining proteins. Lysosomes nd peroxisomes recycle cellul r m teri l nd mo lecules. is       ¡               ¡               ¡   ¡                        ¡     ¡ ¡                           ¡ ¡                 ¡   ¡        ¡                                         ¡           ¡                                 ¡      ¡            ¡               ¡                 ¡   ¡             ¡       ¡   ¡     ¡         ¡   ¡     ¡       ¡ ¡   ¡     ¡             . They re lso used to store chemic l. e ch with unique R group. nd the iochemistry of the cell. Thus the cytopl sm cont ins m ny tr nsport vesicles th t origin te from the ER nd Golgi. in mem r ne. some of which re tt ched to the ER.ounded vesicles th t form y udding off the org nelle y exoc ytosis. rk. is the prim ry energy source for most cells nd it is the principle sug r u sed to glycosyl te proteins nd lipids for the production of the glycoc lyx. would e d unting t sk were it not for the f ct th t most of the chemic l v ri tion is sed on six ty pes of molecules th t re ssem led into just four types of m cromolecules. Pl nts h ve exploited the structur l potenti l of sug rs in their production of cel lulose. phosph te. There re 20 different kinds of mino cids. MOLECULES OF THE CELL Cells re iochemic l entities th t synthesize m ny thous nds of molecules. Ri osomes. Ri ose. glycerol. Stud ying these chemic ls. synthesize proteins. sug rs. nd from the Golgi to the cell surf ce.

DNA. MACROMOLECULES OF THE CELL The six basic molecules are used by all cells to construct five essential macrom olecules. c lled pyrimidine. Nucleotides re uilding locks for DNA nd RNA (ri onucleic cid). nd γ ( amma) and are lin ked to the carbon in a tandem order. These molecules re used in the construction of cell mem r nes nd f t . every protein has an amino end and a carboxyl end. Nucleotide s consist of three components: phosph te. and su ar polymers. The phosph tes re l eled α ( lph ). RNA nucleotides cont i n ri ose. Nucleic acids are macromolecules constructed from         ¢ ¡   ¢     £     ¡ ¡ ¡     ¡   £   £   ¢ ¡    ¢ ¡ £                        ¡  ¡     ¡ ¡ ¡ ¡   ¡ £ £ ¡     £ £ £           ¡           ¡           ¢ ¡     ¡    ¢ ¢ ¡     £ ¡ ¡                          ¡      ¡ ¡ ¡ ¡     ¡ ¡          ¡         ¢   ¡   ¡   ¡              ¡ ¡   ¡ ¡ ¡ . A peptide bond is formed by linkin the carboxyl end of one am ino acid to the amino end of a second amino acid. phospholipids. Amino acids are linked to ether by peptide bonds to con struct a protein. be innin with α. β ( et ). nd so on. k nown as polysaccharides. cytosine. AMP is convert ed back to ATP by mitochondria. ATP. An avera e protein may consist of 3 00 to 400 amino acids. once constructed. often refer to the 3 or 5 c r on. Ri ose h s hydroxyl (OH) group tt ched to oth the 2 nd 3 c r ons . where s. is ri ose nucleotide consisting of the purine se denine nd three phosph tes tt ched to the 5 c r on of the r i ose sug r. Nucleotide ses ppe r in two forms: singlering nitrogenous se. In ddition. RNA. The energy stored y this m olecule is c rried y the cov lent onds of the β nd γ phosphates. F tty cids consist of c r oxyl gr oup (when ionized it ecomes c r oxylic cid) linked to hydropho ic hydroc r on t il. Breakin these b onds sequentially releases the ener y they contain while convertin ATP to adeno sine diphosphate (ADP) and then to adenosine monophosphate (AMP). c lled purine. where s DNA nucleotides cont in deoxyri ose (hence the origin of their n mes). Ri ose c r ons re num ered s 1 (1 prime). Thus. nd nitrogenous (n itrogen cont ining) ring compound th t eh ves s se in solution. Ur cil i s specific to RNA. references to nucleic cids. Consequently. These include proteins. nd dou le-ringed se.78 Aging component of nucleic cids s well s ATP. su stituting for thymine. the molecule th t is used y ll cells s source of energy. deoxyri ose is missing the 2 hydroxyl group. nd thymine). There re two kinds of purines ( deni ne nd gu nine). 2 . which include ri ose. ri ose sug r. nd three pyrimidines (ur cil.

Fatty acids are involved in the production of cell membranes and stora e of fat. £ £ £ £ £ £ £ £ £ £ . like lucose. Nucleotides are the buildin blocks for DNA and RNA. Phospha te is an important component of many other molecules and is added to proteins to modify their behavior.Resource Center 79 Amino acid H H2N Amino roup C R COOH Carboxyl roup Phosphate O HO P OSu ars OCH2 OH Glycerol OH CH OH CH2 CH2OH 6 O 5 OH 4 1 OH HO 2 3 OH Glucose Fatty acid O C O Carboxylic acid CH2 CH2 CH2 CH2OH 5' O 4' 3' OH OH 1' 2' OH Ribose CH2 CH2 CH3 Hydrocarbon tail Nucleotides Pyrimidine base P Phosphate OH H CH2 N Deoxyribose OH OH N Purine base P CH2 N N N Ribose N Molecules of the cell. Glycerol is a three-carbon alcohol that is an important in redient in cell membranes and fat. are a primary ener y source for most cells and also have many structural functions. Amino acids are the buildin blocks for proteins. Su ars.

RNA and D NA are lon chains of nucleotides. with one str and coilin around the other. a phosphate. a lycerol molecule. £ £ £ £ £ £ £ £ £ £ £ £ £ .80 A in Protein Carboxyl end Amino acid Amino end RNA Nucleotide DNA Nucleotide Phospholipid Phosphate P Glycerol Fatty acid tails Head roup Polysaccharide O Monosaccharide O O O O O O Macromolecules of the cell. Protein is made from amino acids linked to ether to form a lon chain that can fold up into a three-dimensional structure. RNA is enerally sin le stranded but can form localized double-stranded re ions. DNA is a double-stranded helix. A phospholipid is composed of a hydrophilic headroup. and two hydrophobic fatty acid tails. Po lysaccharides are su ar polymers.

DNA. The RNA that is enzymatic component of ribo. The two DNA strands coil around each other like strands in a piece of rope. Additional nucleotides are always linked to the 3' OH of the last nucleotide in the chain. The chemistry of t he bases is such that adenine pairs with thymine. and dGTP. where “d” indicates deoxyribose). dTTP. while the complementary strand runs 3' to 5'.000 nucleotides. Consequently. thymine. DNA is an extremely lar e macrom olecule. and cytosine pairs with uanin e. that is. The 5' phosphate of one nucleotide is linked to the 3' OH of a seco nd nucleotide. lycerol. cytosine. a double-stranded function of the riboso me determines the overall shape of the molecule. and uan ine. MRC enes and is constructed from Laboratory of Mo lecular Biolo y.Resource Center 81 nucleotides. encodes cellular (Courtesy of V.also re sponsible for the catalytic somes. uracil. cytosine. Ramakrishnan. typically consistin of over a million nucleotide pairs (or base pairs) . the two strands are antiparallel. and for this re ason the molecule is known as the double helix.000 to 3. RNA subunit. Fat that is stored in the body as an £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ £ . and Cambrid e). RNA nucleotides are adenine. a phosphate. which consists of protein is involved in th e synthesis of (li ht ray corkscrew structures) and proteins and is a structura l and RNA (coiled ladders). Double-stranded DNA forms when two chains of nucleotides interact throu h the formation of chemical bonds between complementary base pairs. nucleic acid. uanine deoxyribonu cleotides (dATP. dCTP. A typical RNA molecule consists of 2. the orientation of one strand is in the 5' to 3' direction. the rowth of the chain is said to be in the 5' to 3' direction. it is enera lly sin le stranded but can form localized Molecule model of the 30S ribosomal d ouble-stranded re ions. Phospholipids.roup (usually an alcohol). and two hydrophobic fatty acid tails. the main component of cell membranes. are composed of a po lar head. For stability. adenine.

roup of a phospholipid. ) £ £ £ £ £ £ £ £ £ £ £ £ £ £ . Inc. Su ars are polym erized to form chains of two or more mono-saccharides. The spherical struct ures in this ima e represent the various atoms in the su ars and bases (dark ra y) and phosphates (li ht ray). The two strands coil around each other to form a helix th at. coils to the ri ht. when lookin down on it from above. The third fatty acid tak es the place of the phosphate and head.82 A in ener y reserve has a structure similar to a phospholipid. bein composed of thre e fatty acid chains attached to a molecule of lycerol. Disaccharides (two monosa ccharides) and Computer model of DNA. (Kenneth Eward/BioGrafx/ Photo Researchers.

Cell division G2 Interphase THE CELL CYCLE S phase G1 Cells inherited the power of reproduction from prebiotic bubbles that split in h alf at re uG0 lar intervals under the influence of the turbulent environment The cell cycle. Interphase is further divided into three This pattern of turbulent fra . after 3 billion years. The re ular alternati on between division and calm has come to be known as the cell cycle. Even today. Cells may leave the cycle by enterin a special phase called G0. and Gap 2 (G2). and with it the termination of G2. Most cells spend their that characterized the Earth time cyclin be tween a state of calm (interphase) and cell division. called Gap 1 (G1). In studyin this cycle. occurs with the division of the cell and a return to G1. Some cells. such as lyco en and starch. ma y contain several hundred monosaccharides and are stored in cells as an ener y r eserve. Although interph se is period of rel tive c lm. S phase (DNA 1 mentation followed by a brief synthesis). the cell grows continu ously during this period. suc h as postmitotic neurons in an animal’s r in. rem in in G0 for the life of the or g nism. phase called G0. scientists have reco nized different states of calm and different w ays in which a cell can divide. more than 3 billion years a o. Polysaccharides.Resource Center 83 oli osaccharides (three to 12 monosaccharides) are attached to proteins and lipi ds destined for the lycocalyx. The calm state of the cell cycle. Cells may period of calm is now a re ular exit the cycle by enteri n a special behavior pattern of every cell. The conclusion of interphase. many cells still divide every 20 minutes. S phase (a peri od of DNA synthesis). referred to as interphase. is divided into three subphases. an d Gap 2 (G2).su bphases: Gap 1 (G ). working h rd to prep re for the next £ £ £ £ £ £ £     £       ¡ £   £     £ £ £   £ £ .

The re in etween the spindles. Euk ryotes re norm lly diploid. is often referred to s the met ph se pl te. Met ph se is period during which the chromosomes re sorted out nd ligned etween the two centrosomes.84 Aging round of division. while others overl p. structure th t is cruci l for the movem ent of the chromosomes during cell division. comp ct (or condense) the chromosomes in prep r tion for cell division. so cell ¡         ¡       ¡         ¡                                               ¡     ¡     ¡ ¡                                 ¡   ¡                                 ¡                   ¡     ¡         ¡ ¡      ¡                               ¡ ¡           ¡ ¡     ¡ ¡               ¡                 . nd the ppe r nce of n enzyme c l led the m tur tion-promoting f ctor (MPF) t the end of G2. for cl rity. c lled ce ntromere. met ph se . Under the microscope. n ph se. This c n occur y process known s mitosis. The histones re proteins th t ind to the DNA. which when phosphoryl t ed. When cell divisio n is complete. which is intended for cell multiplic tion. Proph se m rks the period during which the duplic ted chromosomes egin condens tion. nd the two centrosomes eg in moving to opposite poles of the cell. MPF phosphoryl tes h istones. where the chromosomes re ligned. Completion of norm l cell cycle lw ys involves the division of cell into two d ughter cells. The two centrosomes nd the microtu ules f nning out e tween them form the mitotic spindle. only two chromosom es re shown). which is intended for sexu l reproduction. nd teloph se. MPF is lso responsi le for the re kdown of the nucle r mem r ne. MITOSIS Mitosis is used y ll free-living euk ryotes (protozo ns) s me ns of sexu l reproduction. Some of t he microtu ules m ke cont ct with the kinetochores. the nucle r mem r ne h s completely roken down. All these st ges re m rked out in ccord nce with th e eh vior of the nucleus nd the chromosomes. By this time. llowing the chromosomes to decondense nd the nu cle r envelope to reform. Two not le events re the duplic tion of the spindle (the ce ntrosome nd ssoci ted microtu ules). The growth of pl nt or n nim l is lso ccomplished with this form of cell division. which re the two duplic ted chromosomes. Mitosis is divided into four st ges: proph se. nd y second process known s meiosis. A speci l region of e ch chromosome. Proteins ind to the centromere to form structure c lled the kinetochore (see figure. often c lled sister chrom tids. with m otor proteins situ ted in etween. the chromosomes ecome visi le s X-sh ped structures. MPF dis ppe rs. holds the chrom tids together.

For cl rity.Proph se Centrosome Duplic ted chromosome Kinetochore Met ph se Mitotic spindle Motor protein An ph se Sister chrom tids sep r te Nucle r envelope reforming Teloph se Identic l d ughter cells Mitosis. only two chromosomes re shown.                             ¡               . Princip l st ges de ling with the movement nd p rtitioning of the chro mosomes etween the future d ughter cells.

m de of the proteins myosin nd ctin. dr gging the chromosom es to opposite ends of the cell. During teloph se. The first step is the rele se of n enzyme th t r e ks the onds holding the kinetochores together. eing diploid. if g metes were produced u sing mitosis. meiosis is intended fo r sexu l reproduction nd occurs exclusively in ov ries nd testes. so th t the micro tu ule is gone y the time the chromosome re ches the spindle pole. The overl pping microtu ules id movement of the chromosomes tow rd the poles s nother type of motor protein pushes the mi crotu ules in opposite directions. e ch with one nucleus. The nucle r envelope egins forming round the chromosomes. they produce n em ryo wit h the correct num er of chromosomes. effectively forcing the centrosomes tow rd th e poles. the motor protein s re k the microtu ule down s it dr gs the chromosome long. This ccounts for the gre ter overl p of microtu ules in met ph se s c omp red with n ph se. MEIOSIS Unlike mitosis. When h ploid g metes fuse. Motor proteins then move long the microtu ule. This st ge. Throughout t his process.86 Aging would h ve two copies of e ch chromosome. e ch possessing h lf s m ny chromo somes s the diploid cell. when micro iologists counted the num er of chromosomes in som t ic nd           ¡                   ¡                                   ¡   ¡           ¡           ¡     ¡     ¡             ¡                 ¡         ¡           ¡   ¡     ¡ ¡                             ¡               ¡   ¡             ¡                 ¡       ¡   ¡ ¡       ¡ . receive chromosomes from oth p rents. contr ctile ring. sep r te from mitosis. thus llowing the sister chrom tids to sep r te from e ch other while rem ining ound to their respective micr otu ules. is c lled cytokinesis. During the s me period. the motor proteins nd the chromosome m n ge to st y one step he d of the disintegr ting microtu ule. c t strophic growth in the num er of chromosomes would occur e c h time sperm fertilized n egg. Meiosis is speci l form of cell division th t produces h ploid g metes (eggs nd sperm). egins pinching the p rent l cell in two. Euk ryotes. one from the mother nd one from the f ther. the d ughter chromosomes rrive t the spindle poles nd decondense to form the rel xed chrom tin ch r cteristic of int erph se nuclei. Using energy supplied y ATP. nd le ds to the form tion of two d ughter cells. which le ds to the growth of n org nism. The existence of meiosis w s first suggeste d 100 ye rs go. m rk ing the end of mitosis. An ph se is ch r cterized y the movement of the duplic ted chromosomes t o opposite poles of the cell.

Proph se Crossing over Met ph se Recom in nt chromosome An ph se Sister chrom tids do not sep r te Teloph se Nonidentic l d ughter cells Meiosis I. nd the production of nonidentic l d ughter cells.         ¡                   ¡                        ¡ ¡ . Only one homologous p ir is shown. The most not le fe tures include genetic recom in tion (crossing ove r) etween the homologous chromosomes during proph se. comigr tion of the sister chrom tids during n ph se.

nd scientists o served th t oth could e divide d into the s me four st ges known to occur in mitosis. for ex mple. they c rry the s me genes u t specify slightly different tr its. The effect of this is to sep r te the m tern l nd p tern l chromosomes y sending them to different d ughter cells. inste d of lining up t the pl te s is done in mitosis. hum ns h v e 23 chromosomes from the f ther nd the s me 23 from the mother. meiosis II is vir tu lly identic l to mitotic division. where s the p te rn l llele specifies rown. To underst nd how this could e. During n ph se of meiosis I. long with           ¡                             ¡                               ¡         ¡           ¡                   ¡ ¡         ¡             ¡                     ¡             ¡                                                           ¡              ¡                     ¡           ¡                                         ¡             ¡       ¡ . m y specify lue eyes. homologous p irs exch nge l rge nu m ers of genes y sw pping whole pieces of chromosome. The roundworm. two homologous chromosomes) rem i n p ired t met ph se. M ny other studies lso comp red th e mount of DNA in nuclei from som tic cells nd gon ds. lthough the segreg tion is r ndom. Meiosis I resem les mitosis. Homologous chromosomes re two identic l chromosomes th t come from different p rents. For ex mple. lw ys with the s me re sult: The mount of DNA in som tic cells is ex ctly dou le the mount in fully m ture g metes.. nd it is on e of the re sons sexu l reproduction h s een such powerful evolution ry force . r ther th n one d ughter cell receiving ll p tern l chromosomes nd the other ll m tern l chromosomes. ut the m tern l version. Thus one of the m tern l chrom tids (gr y in the figure on p ge 87) ends up with piece of p tern l chro mosome. nd the kinetochores do not sep r te t n ph se. the kinetochores do not sep r te s they do in m itosis. Th t is. The two rounds of division were c lled meiosis I nd meiosis II. ut close e x min tion shows three import nt differences: gene sw pping occurs etween homol ogous chromosomes in proph se. or llele. the d ughter cells receive r ndom ssortment of m tern l nd p tern l chromosomes.e. nd p tern l chrom tid receives the corresponding piece of m tern l ch romosome. scientists studied cell division in the gon ds nd were le to show th t meiosis occurs s two rounds of cell d ivision with only one round of DNA synthesis. homologs (i. Indeed. Chromosome 1 m y c rry the gene for eye col or. Mixing genetic m teri l in this w y is unique to meiosis. R ndom segreg tion. w s found to h ve four chromosomes in it s som tic cells ut only two in its g metes. During proph se. We e ch h ve m tern l chromosome 1 nd p tern l chromosome 1.88 Aging germ cells.

Meiosis II egins im medi tely fter the completion of meiosis I.000 nucleotides e very second. in th t it checks the preceding nucleotide to m ke sure it is correct efore it dds nucleotide to the growing ch in. the process is not just concerned with redu cing the num er of chromosomes ut is lso involved in stirring up the genetic p ot in order to produce unique g metes th t m y somed y give rise to n equ lly u nique individu l.   ¡               ¡     ¡     ¡     ¡                                   ¡ ¡       ¢                 ¢   ¡         ¡   ¡                                         ¡        ¢           ¡             ¢         ¡       ¡              ¡                ¡   ¡                     ¡   ¡ ¡                     ¡         ¡   ¡                   . ccounts for the f ct th t while children resem le their p rents. The enzyme responsi le for re ding the templ te str nd. c lled prim se. The h elic se is rem rk le enzyme th t is responsi le for sep r ting the two DNA st r nds. cont ining un lt ered or recom in nt m tern l nd p tern l chromosomes. DNA polymer se lso h s n editori l functio n. solves this pro lem. e ch of which is genetic lly unique. On ce the chromosome is duplic ted. However. Meiosis produces h ploid cells y p ssing through two rounds of cell division with only one round of DNA synthesis. requires the coordin ted effort of te m of enzymes. which produces two d ughter cells e ch cont ining duplic ted p rent chromosome nd recom in nt chromosome consi sting of oth p tern l nd m tern l DNA. This enzyme re ds the p rent l DNA in the 3 to 5 direction nd cre tes d ughter str nd th t grows 5 to 3 . they do not look or ct ex ctly like them. Prim se synthesizes short pieces of RNA th t form DNA-RNA dou lestr nded region. led y DNA helic se nd prim se. These two mech nisms re res ponsi le for the rem rk le d pt ility of ll euk ryotes. which is tt ched to the helic se. thus priming th e DNA polymer se y providing the cruci l first nucleotide in the new str nd. fe t th t it ccomplishes t n stonishing r te of 1. These two cells divide mitotic lly to p roduce four h ploid cells. DNA REPLICATION DNA replic tion.Resource Center 89 genetic recom in tion. is c lled DNA polymer se. The RNA ecomes tempor ry p rt of the d ughter str nd. This enzyme gets its n me from the f ct th t it unwinds the DNA hel ix s it sep r tes the two str nds. nd for synthesizing the new d ughter str nd. s we h ve seen. which occurs during the S ph se of the cell cycle. The editor function of this enzyme in troduces n interesting pro lem: How c n the polymer se dd the very first nucle otide when it h s to check preceding nucleotide efore dding new one? A spe ci l enzyme.

The le ding str nd requires only single primer (not sh own). nd the cl mp protein keeps the polymer se fr om f lling off the DNA. in the form of RNA primers.                                                           ¢ ¢ 3 5     ¢ 5         ¢             ¢ ¢     3 . The helic se sep r tes the two str nds so the DNA polymer se c n synthesize new str nds.90 Aging 5 Templ te DNA Helic se Prim se DNA polymer se Cl mp protein 3 L gging str nd Le ding str nd R NA primer D ughter str nds DNA replic tion. The prim se provides replic tion sign ls for the polym er se. The l gging str nd requires m ny primers. nd the d ughter str nd is synth esized s series of DNA fr gments th t re l ter joined into one continuous st r nd.

ut it is limited to the construction of proteins consisti ng of only four different kinds of mino cids.Resource Center 91 DNA rep ir enzymes remove the RNA primers nd repl ce them with DNA nucleotides. the codon AGC specifies the mino cid serine. Tr nscription. TRANSLATION. so the simplest code could e one in which e ch nucleotide specifies different mino cid.000 ses for the 28S. 5. 18S.8S. Ri osomes re comple x structures consisting of out 50 proteins nd four kinds of rRNA. Extr cting the inform tion from DNA requires the processes of tr nscription nd tr nsl tion. DNA is line r sequence of fo ur different kinds of nucleotides. Thus gene m y e viewed s long continuous sequence of codons. Messenger RNA tr nsloc tes to the cytopl sm. The genetic code provid es w y for the tr nsl tion m chinery to interpret the sequence inform tion sto red in the DNA molecule. Newly tr nscri ed rRNA is sent to t he nucleolus for ri osome ssem ly nd is never tr nsl ted. where they com ine. it is possi le to h ve unique code for e ch of the 20 n tur lly occurring mino cids. long with n mRNA. not ll codons specify        ¡   ¡                   ¡          ¡ ¡       ¡   ¡ ¡    ¡   ¡                       ¡                                    ¡     ¡ ¡       ¡     ¡               ¡ ¡         ¡            ¡           ¡   ¡     ¡ ¡ ¡         ¡                   ¡       ¡         . Eventu lly. With this scheme. AND THE GENETIC CODE Genes encode proteins nd sever l kinds of RNA. The production of ri osomes in this w y ensures th t tr nsl tion never occurs in the nucleus. nd 28S rRNA (the “S” refers to sediment tion coefficient th t is pro portion l to size). The first cells m y h ve use d this coding system. cytosine for lysine. known s 5S . specifies single mino cid. For ex mple. TRANSCRIPTION. c t lyzed y the enzyme RNA polymer se. more el or te cod e evolved in which com in tion of three out of the four possi le DNA nucleotid es. These RNAs r nge in size from out 500 ses up to 2. nd so on. However. nd represented y mRNA. where s TGC specifies t he mino cid cysteine. denine coding for the mino cid glycine. c lled codons. Th t is. where i t is tr nsl ted into protein y ri osomes. The ri osome is ssem led in the nucleolus s two nonfunction l su units efore eing sent out to the cytopl sm. copies one str nd of the DNA into compleme nt ry str nd of messenger RNA (mRNA) or ri osom l RNA (rRNA) th t is used in the construction of ri osomes. to form fully function l unit.

re linked toge ther to form gene on the ottom. which is used to synthesize the protein. Five codons re shown. Note th t in mRNA. Thymine (T). The codons. nd the genetic code. tr nsl tion. including the st rt nd stop sign ls. Amino cids ppe r s l eled elliptic l e ds.                           ¡           ¡ ¡    ¡       ¡                               . Nucleo tides ppe r s round e ds: Adenine (A).92 Aging Codon Amino Acid Sign l Serine Al nine Cysteine Methionine none none none none START STOP DNA mRNA STOP Methionine START Serine Cysteine Al nine Serine Tr nscription. nd Gu nine (G). The coding str nd is c opied into messenger RNA (mRNA). or coding. ur cil (U) repl ces the thymine (T) found in DNA. DNA str nd. Cytosine (C). four sp ecifying mino cids (protein su units) nd two of the five serving s st rt nd stop sign ls.

The respir tory ch in consists of three m jor components: NA DH dehydrogen se. nd h s m ny import nt functions. cytochrome ) or cop per core (cytochrome oxid se). or ADP. In the c se of the re spir tory ch in. All electric circuits must h ve ground. The glycoc lyx evolved to meet the dem nds of this kind of lifestyle. providing                       ¡  ¡           ¡                   ¡                                                     ¡               ¡         ¡                 ¡     ¡         ¡                     ¡          ¡       ¡    ¡ ¡                           ¡                          . The electricity. nd speci l codon . or electrons gen er ted. The hum n ody.200 nu cleotides long. After p ssing through the ch in. tr vel through the respir tory ch in. gener tes electricity y processing food molecules throug h met olic p thw y. All these components re protein complexes th t h ve n iron (NADH dehydrogen se.Resource Center 93 n mino cid. in ddition to specifying the mino cid methioni ne. This proc ess involves num er of met l. sign ls the st rt site. POWER GENERATION ATP is produced in mitochondri from AMP. All euk ryotes origin ted from free-living cells th t hunted cteri for food. As mentioned ove. lthough it is someti mes removed once construction of the protein is complete. the ground is oxygen. the elec trons re picked up y oxygen. THE GLYCOCALYX This structure is n enormously diverse collection of glycoproteins nd glycolip ids th t covers the surf ce of every cell. n ver ge protein m y consist of 300 to 400 mino cids. cytochrome . lik e th t of ll nim ls. nd speci l ion ch nnel-enzyme c l led ATP synthet se. nd s they do. nd together with the ATP synthet se re loc ted in the inner mem r ne of the mitochondri . The respir tory ch in is n logous to n electric c le th t tr nsports electricity from hydroelectric d m to our h omes. where it is used to turn on lights or run our stereos. c lled the Kre s cycle.inding proteins. th t is. ATG. the electrons need somepl ce to go once they h ve completed the circuit. since the codon consists of three nucleotides for e ch mino cid. like trees on the surf ce of the E rt h. Consequently. nd cytochrome oxid se. ll proteins egin with this mino cid. which com ines with hydrogen ions to form w ter. c lled the respir tory ch in ( lso known s the electron tr nsport ch in). they power the syn thesis of ATP. nd phosph te (PO4). The sequence TGA sign ls the end of the gene. typic l gene m y e 900 to 1.

ut the “trunks” re f tty compound c lled cer mide th t is completely su merged within the pl ne of the mem r ne. c pture. Neurons h ve refined ion Sug r Sug r Glycoc lyx Cer mide Mem r ne Glycoprotein Glycolipid Nucleus Cell Mem r ne Cytopl sm The euk ryote glycoc lyx. I t lso provides recognition m rkers so the immune system c n detect foreign cell s. The glycoc lyx h s m ny jo s. Glycolipids lso h ve “le ves” m de of sug r mol ecules. ¡           ¡                                             ¡                                         ¡         ¡   ¡                     . nd ingest food molecules or prey org nisms . Two ex mples re shown t the top: glycoprotein on the lef t nd glycolipid on the right. Cell-surf ce glycoproteins lso form tr nsporters nd ion ch nnels th t serve s g tew ys into the cell. including cell-to-cell communic tion nd the tr nsport nd detection of food molecules. The euk ryote’s molecul r forest consists of glycoprotei ns nd glycolipids. The glycoprotein trees h ve “trunks” m de of protei n nd “le ves” m de of sug r molecules.94 Aging w y for the cell to loc te.

giving rise to the nervo us systems found in most nim l species. cut DNA t sequence-specific sites. from which t he procedure derives its n me. such s DNA sequencing or filter hy ridiz t ion. Restriction enzymes re isol ted fr om cteri . c ll ed restriction enzymes. it h s provided simple w y of determining the protein sequence nd the expression profile for ny gene. cert in mem ers of the glycoc lyx re used y cells of the immune system s recognition m rkers to detect inv ding micro es or foreign cells introduced s n org n or tissue tr nspl nt. n e nzyme th t c n join two pieces of DNA together nd is n import nt component of the cell’s DNA replic tion nd rep ir m chinery. M ny of the procedures th t re p rt of recom in nt technology. ut more import nt. In higher verte r tes. Recom in nt DNA Primer Recom in nt technology is collection of procedures th t m kes it possi le to i sol te gene nd produce enough of it for det iled study of its structure nd function.Resource Center 95 ch nnels for the purpose of cell-to-cell communic tion. more th n 90 such enzymes h ve een isol ted from more th n 230 cteri l str ins. Constructing these li r ries involves splicing different pi eces of DNA together to form novel or recom in nt genetic entity. Centr l to this technology is the ility to construct li r ries of D NA fr gments th t represent the genetic repertoire of n entire org nism or of specific cell type. with different mem e rs of the f mily cutting t different sites. The first modifying enzyme to e discovered w s DNA lig se. O t ining the sequence of gene h s m de it possi l e to study the org niz tion of the genome. nd since their discovery in 1970.         ¡     ¡ ¡           ¡         ¡ ¡       ¡                                   ¡                       ¡                 ¡ ¡  ¡     ¡   ¡   ¡              ¡       ¡       ¡             ¡       ¡           ¡     ¡                         ¡   ¡     ¡        ¡ ¡         . were developed in order to ch r cterize DNA fr gments th t were isol ted fr om cells or gene li r ries. Other DNA modifying enzymes. DNA-MODIFYING ENZYMES Two of the most import nt enzymes used in recom in nt technology re those th t c n modify DNA y se ling two fr gments together nd others th t c n cut DNA t specific sites. DNA cloning nd li r ry construction were m de po ssi le y the discovery of DNA-modifying enzymes th t c n se l two pieces of DNA together or c n cut DNA t sequence-specific sites.

with the s mple wells positioned ne r the neg tive termin l. The migr tion r te is n inverse function of molecul r size. (L rge molecules tr vel slower th n sm ll ones.96 Aging Top View S mple well Ag rose gel + Direction of migr tion Side View Neg tive electric l termin l S mple well Positive electric l termin l Buffer solution B re electric l wire Supporting pl te Ag rose gel Electrophoresis t nk Ag rose gel electrophoresis.)                                                             ¡                 ¡           . The electric termin ls re connected to p ower source. An g rose gel is pl ced in n electrophoresis t nk nd su merged in uffer solution. the neg tively ch rged nucleic cids migr te tow rd the positive termin l. When t he current is turned on.

is run su merged in speci l pH-regul ted solution. the nucleic cid c n e detected y photogr phing the gel under U V illumin tion. the m in dv nt ge to sw pping pl smids is th t t hey often c rry nti iotic resist nce genes. their environment cont ined wi de ssortment of molecules th t were rele sed into the soil or w ter y other ce lls. fter el ectrophoresis. either deli er tely or when the cells died. Thus the r te t which the fr gments migr te is function of their size. GEL ELECTROPHORESIS This procedure is used to sep r te different DNA nd RNA fr gments in sl of g r or poly cryl mide su jected to n electric field. As prec ution.   DNA CLONING In 1973 scientists discovered th t restriction enzymes. sm ll fr gments migr te more r pidly th n l rge fr gments. Pl smids re sm ll ( out 4. ethidium romide.0 kilo se p irs or 4 K p) circul r minichromo somes th t occur n tur lly in cteri nd re often exch nged etween cells y p ssive diffusion. DNA lig se. Consequently. The gel. there w s the re l p ossi ility th t those genes could h ve een tr nscri ed nd tr nsl ted y the ho st cell with potenti lly f t l results. it is s id to h ve een tr nsfected. or uffer. This dye produces strong reddish-yellow fluorescence when exposed to ultr violet (UV) r di tion. ¡   ¡               ¡       ¡     ¡       ¡    ¡                               ¡ ¡                       ¡               ¡ ¡ ¡                                      ¡    ¡ ¡           ¡     ¡                       ¡          ¡ ¡ ¡                   ¡    ¡    ¡           ¡ ¡       ¡         ¡ ¡     ¡                             ¡       ¡                     ¡      ¡   .Resource Center 97 The n me “restriction enzyme” is cryptic nd c lls for n expl n tion. so th t cell sensitive to mpicil lin c n ecome resist nt simply y cquiring the right pl smid. DNA of v rying lengths w s mon g these molecules nd w s re dily t ken up y living cells. For cteri .000 se p irs. The ge l cts s sieving medium th t impedes the movement of the molecules. If the foreign DNA c ont ined complete genes from competing cteri l species. When cterium cquires new pl smid. Nucleic cids c rry neg tive ch rge nd thus will migr te tow rd positively ch rged electrode.cid-specific dye. cont ining nuclei c. cont ining the s mples. prok ryotes evolved s et of enzymes th t would restrict the foreign DNA popul tion y cutting it up in to sm ller pieces efore eing roken down completely to individu l nucleotides. nd cteri l pl smids could e used to clone DNA molecules. During the pe riod when prok ryotes eg n to ppe r on E rth. lso expressed s 4.

nd then se led in nt pl smid is mixed with cteri l cells. llowed to fuse. The foreign DNA nd the pl restriction enzyme.98 Aging Foreign DNA Pl smid Streptomycinresist nce gene Recom in nt pl smid Grow cells in selective medi ¡     ¡   Cloning DNA in pl smid. smid re cut with the s me with DNA lig se. some of llowing them to grow in culture medium cont ining . The cteri ’s m in chromosome is not shown. The recom which pick up the pl smid. the nti iotic streptomycin                  ¡                        ¡ ¡       .

This collection of viruses is c lled genomic li r ry nd is used to study the         ¡   ¡                     ¡     ¡     ¡ ¡ ¡ ¡ ¡         ¡   ¡                   ¡                               ¡ ¡    ¡    ¡                     ¡          ¡   ¡   ¡     ¡                       ¡ ¡  ¡         ¡     ¡                        ¡           ¡     ¡       ¡               ¡ ¡ ¡     ¡   ¡               ¡          ¡        ¡      ¡     ¡   ¡         . which con t ined n ntistreptomycin gene. the DNA could insert itself into the pl smid to form hy rid. Only those cells c rrying the recom in nt pl smid. w s incu ted with the pl smid. could grow in the presence of this nti iotic. Moreo ver. or rec om in nt pl smid. so the efficiency of tr nsfection is 100 times gre ter th n it is for pl smids. often long enough to cont in n entire gene. the foreign DNA h d een mplif ied. The construction of gene li r ry egins y isol ting genomic DNA nd digesting it with restri ction enzyme to produce fr gments of 1. In this c se. The l m d genome is dou le-str nded line r DNA of out 40 K p.000 to 10. most of which c rry different piece of the ge nomic DNA. ut it c n lso e used to construct gene li r ries. fter which DNA lig se se led the two together. much of which c n e repl ced y foreign DNA without s crificing the ility of the virus to infect cteri . c lled l m d . cterioph ge h s the n tur l ility to infect cteri . coli so th t some of the cells could t ke up the recom in nt pl smid efore eing tr nsferred to nutrient roth cont ining streptomycin. which re su jected to p ck ging re ction to produce m ture vir l p rticles. the cloning vector is cterioph ge. cut with the s me restriction enzyme. the pl smid DNA w s duplic ted long with the m in chromosome. wher e s pl smid c nnot ccommod te foreign DNA th t is l rger th n four K p.000 se p irs. The re ction m ixture w s dded to sm ll volume of E. so the re striction enzyme simply opened the circul r molecule. This is the gre t dv nt ge of l m d over pl smid. The pl smid h d single EcoRI site. E ch time the cells divided. however. r ther th n cutting it up into m ny useless pieces. Foreign DNA. L m d c n ccomm od te very long pieces of DNA. or cloned. illions of times nd w s e sily isol ted for sequencing or expr ession studies. After the cells h d grown overnight. GENOMIC AND cDNA LIBRARIES The sic cloning procedure descri ed ove not only provides w y to mplify specific piece of DNA. Bec use the pl smid nd foreign DNA were oth cut w ith EcoRI. These fr gments re lig ted into l m d genomes.Resource Center 99 The first cloning experiment used pl smid from Escherichi coli th t w s cut w ith the restriction enzyme EcoRI.

It does not include introns or controlling elements. DNA replic tion involv es duplic ting one of the str nds (the p rent or templ te str nd) y linking nuc leotides in n order specified y the templ te nd depends on l rge num er of enzymes. s these re lost during tr nscrip tion nd the processing th t occurs in the cell to m ke m ture mRNA. introduces r dio ctive nucleotides into DNA molecule. The d ughter str nd. while the triphosph te is tt ched to the 5 c r on. Deoxyri onucleotides h ve single hydroxyl group loc ted t the 3 c r on of the sug r group. This collection of recom in nt viruses is cDNA li r ry nd only cont ins genes th t were eing expressed y the cells when the RNA w s extr cted. This enzyme. LABELING CLONED DNA M ny of the procedures used in the re of recom in nt technology were inspired y the events th t occur during DNA replic tion. nd enh ncers. This RNA is converted to the comp lement ry DNA (cDNA) using n RNA-dependent DNA polymer se c lled reverse tr nsc ript se. prime r. The cDNA is lig ted to l m d genomes nd p ck ged for the genomic li r ry. DNA sequencing. The r dio cti ve nucleotide is usu lly deoxycytosine triphosph te (dCTP) or dATP. descri ed in following section).100 Aging structure nd org niz tion of specific genes. This includes the l eling of c loned DNA for use s pro es in expression studies. Clones from li r ry such s this cont ins the coding sequences. One such nucleotide is deoxy denine triphosph te (dATP). The procedure for l eling DNA pr o es. developed in 1983. Single-str n ded DNA hex mers (six ses long) re used s primers. in ddition to introns. nd the four nucleotides in uffered solution to induce in vitro replic tio n. guided y t he templ te str nd. which ecomes the pro e. is l eled y including nucle otide in the re ction mix th t is linked to r dio ctive isotope. constructs d ughter str nd y linking nucleotides together . An ltern tive form of gene li r ry c n e constructe d y isol ting mRNA from specific cell type. nd polymer s e ch in re ction (PCR. intervening sequences. Thus cDNA li r ry is intended for the purpose of studying gene expression nd the structu re of the coding region only. nd these re produced in such w y th t they cont in ll possi le per-     ¡           ¡           ¡     ¡    ¡  ¡     ¡               ¡   ¡           ¡       ¡   ¡       ¡                      ¡ ¢ ¡       ¡   ¡                   ¢ ¡       ¡     ¡   ¡   ¡               ¡       ¡     ¡   ¡                 ¡    ¡                 ¡                                         ¡         ¡     ¡   ¡ . This method supplies DNA polymer se with singlestr nded DNA templ te. the most import nt of which is DNA polymer se. p romoters.

re fr ction ted on poly cryl mide gel. nd ddGTP). Replic tion of the templ te egins fte r the primer inds to the primer site on the sequencing pl smid. Fred S nger in 197 6 is nother technique th t t kes its inspir tion from the n tur l process of DN A replic tion. DNA SEQUENCING A sequencing re ction developed y the British iochemist Dr. ll of d ifferent lengths. The d ughter str nds. nd ll su sequent ses re dded to the 3 hydroxyl of the previous se. The templ te str nd is GCATCGTC. DNA polymer se requires primer with free 3 hydroxyl group. C (ddCTP). The re ction pr oducts re shown for e ch of the tu es: A (ddATP). e ch cont ining different dideoxynucleotide (ddATP.      ¡               ¡       ¡       ¡      ¡   ¡   ¢   ¡                         ¡      ¡     ¡   ¡    ¡            ¡ ¡   ¡                        ¡ ¢           ¡ ¡       ¡ ¡   ¡            ¡     . ddCTP. The dideoxynucl eotide termin ting the re ction is shown in old. R ndomizing the se sequence for t he primers ensures there will e t le st one primer site in templ te th t is only 50 p long. nd G ( ddGTP). This str tegy of l eling DNA. Templ tes used in l eling re ctions such s this re gener lly 100 to 800 p long. T (ddTTP).Resource Center 101 mut tions of four ses t ken six t time. is widely used in cloning nd in DNA nd RNA filter hy ridiz tions (descri ed in the following sections). Sequencing y the S nger meth od is usu lly EXAMPLE OF A SEQUENCING REACTION Tu e A T C Re ction Products G-C-A-T-C-G-T-C C-G-T-A G-C-A-T-C-G-T-C C-G-T G-C-A-T-C-G-T-C C G-C-A-T-C-G-T-C C-G G-C-A-T-C-G-T-C C-G-T-A-G-C-A-G G-C-A-T-C-G-T-C C-G-T-A-G-C G-C-A-T-C-G-T-C C-G-T-A-G G-C-A-T-C-G-T-C C-G-T-A-G-C-A G The S nger sequencing re ction is set up in four sep r te tu es. known s r ndom primer or ol igo l eling. ddTTP. T he polymer se dds the first nucleotide to this group.

The re ction products. the cloned DNA m y e replic ted. The cloned DNA is inserted into the pl smid n e r n engineered primer site. This simplifies the choice of the initi l primers ec use their sequence c n e derived from the known pl smid seq uence. nd this c n e used to determine the size of e ch d ughter str nd. is shown. where s the longest str nd repr esents the complement ry nucleotide t the end of the templ te (see t le). ddCTP . Pr imer site Primer A represent tion of sequencing gel is shown in the ccomPl sm id primer site for DNA sequencing. Recom in nt pl smid Cloned DNA               ¡                 ¡                  ¡                                     ¡       ¡   ¡     ¡                             ¡                                 ¡                 ¢   ¡     ¡       ¡     ¡                     ¡     ¡           ¡      ¡ . Some of the nucleotides included in the S nger re ction re l eled with r dio ctive isotope so the fr ction ted d ughter str nds c n e v isu lized y drying the gel nd then exposing it to X-r y film. ddGTP.102 Aging performed with the DNA cloned into pl smid. Only one str nd of the dou lestr nded pl smid. Once the primer inds to the primer site. Incorpor tion of dideoxynucleotide termin tes the growth of the d ughter str nd t th t point. An engineered pl smid primer site dj cent to cloned DNA fr gment is sh own in the figure. consisting of ll the d ughter str nds re fr ction ted on poly ctyl mide gel. It h s t he dv nt ge of eing tougher m teri l. in the direction in dic ted y the rrow. the clo ned DNA m y e replic ted. S nger’s innov tion involved the synthesis of rtifici l nucleotide s l cking the 3 hydroxyl group. s p rt of sequencing re ction. Poly cryl mide serves the s me function s g rose. Thus the S nger method uses the n tur l process of replic tion to m rk the position of e ch nucl eotide in the DNA fr gment so the sequence of the fr gment c n e determined. Once the primer inds to the primer site. The shortest d ughter str nd represents the complement ry nucleotide t the eginning of the templ te. thus producing dideoxynucleotides (ddATP. essenti l for the l rge size of typi c l sequencing gel. nd cloned DNA. nd ddTTP).

in referenc e to the origin l. tissue or tissues o t ined from groups of d ifferent ges.A represent tion of sequencing gel.   ¡ ¡        ¡ ¡ ¡                 ¡         ¡  ¡       ¡ ¡ ¡   ¡ ¡  ¡                       ¡                    ¡                       ¡       ¡       ¡   ¡                ¡         ¡                   ¡                   ¡ ¡ .the top ( nd #8. In 1980 the procedure w s modified to t r nsfer RNA to nylon mem r nes for the study of gene expression nd.Resource Center 103 A T C G 8 7 6 5 4 3 2 1 SOUTHERN AND NORTHERN BLOTTING One of the most import nt tech. The sequence of the templ te str nd (see t le on p ge 101) is o t in ed simply y t king the complement of the sequence o t ined from the gel (the d ughter str nd).GCATCGTC. The sequence of the d ughter str nd is re d eginning with the s m llest fr gment t the ottom of the gel nd ending with the l rgest fr gment t the top. s p rt of The re ction products run from the top to the ottom. the detection st ge is known s filter hy ridiz tion. niques to e developed. Northern lotting is used to stu dy the expression of specific genes nd is usu lly performed on messenger RNA (m RNA). This is the te mpl te ferring DNA nd is now known str nd indic ted in the t le on s Southern lotting. This procedure w s intro. The duced y the Scottish scientist comp lement ry sequence is E. DNA is tr nsferred to filter p per. in the “G” l ne). The RNA is fr ction ted on n g rose gel nd then tr nsferred to nylon mem r ne. The p per towels pl ced on top of the     p nying figure. is the fr gment migr ting t the highes t tr nsfer of nucleic cids from n r te. is c lled northern lotting. Since the p ge 101. The sequence is re d eginning g rose gel to nylon filter p per with the sm llest fr gment on the th t c n e hy ridi zed to gel ( nd #1. in the “C” l ne) nd l eled pro e to detect specific ending with the l rgest fr gment t genes. M. The sequence is CGTAGCAG. Southern in 1975 for tr ns. w ith the sm llest recom in nt technology. Typic l experiments m y wish to determine the expression of specific genes in norm l. s opposed to c ncerous.

is TTTAGGAT GACCACTTTGGC. th t is. eing formed etween the RNA t rget on the mem r ne nd the DNA pro e.104 Aging ssem ly pull the tr nsfer uffer through the gel. the pro e inds to the t rget se quence immo ilized on the mem r ne. The loc tion of specific mRNA c n e determined y hy ridizing the mem r ne to r diol eled cDNA or genomic clone. scientists found th t cDNA pro es could e hy ridized to DNA or mRNA in situ. eginning t the ottom of the “T” l ne. FISH is n extremely An utor diogr m of portion of DNA sequencing gel. FLUORESCENT IN SITU HYBRIDIZATION (FISH) Studying gene expression does not lw ys depend on northern lots nd filter hy ridiz tion. A p rti l sequence (the f irst 20 ses) of the left set. The hy rid iz tion procedure involves pl cing the filter in uffer solution cont ining l eled pro e. r ther th n r dio ctive isotope. During long incu tion period. the pro e is l eled with fluorescent dye molecule. (Dr. Joseph P nno)   ¡     ¡ ¡ ¡       ¡   ¡   ¡               ¡     ¡ ¡   ¡   ¡   ¡  ¡    ¡ ¡ ¡         ¡        ¡            ¡     ¡   ¡           ¡   ¡   ¡           ¡     ¡     ¡ ¡    ¡   ¡ ¡     ¡   ¡    ¡ ¡     ¡ . The s mples re then ex mined nd photogr phed under fluorescent microscope. A-T nd G-C se p iring medi te the inding etween the pro e nd t rget. while loc ted within cells or tissue sections f ixed on microscope slide. The dou le-str nded molecule th t is formed is hy rid. In this c se. In the 1980s. eluting the RNA from the gel nd tr pping it on the mem r ne.

p per towels. tr nsferring it to the mem r ne. RNA is fr ction ted on n g rose gel nd then pl ced f ce down on p per wick in tr nsfer t nk. A r diol eled cDNA pro e is hy ridized to the mem r ne to detect specific mRNA tr nscripts. The flow of uffer elutes the RNA from the gel. The p per towels dr w the uffer through the gel nd the mem r ne. nd weight.Resource Center 105 Ag rose gel Weight Mem r ne Ag rose gel P per towels Tr nsfer uffer Wick Tr nsfer t nk Mem r ne replic Detection Northern tr nsfer nd mem r ne hy ridiz tion. The gel is ove rl in with piece of nylon mem r ne. Note th t the t hickness of the mem r ne is ex gger ted for cl rity. ¡           ¡     ¡            ¡     ¡   ¡             ¡     ¡         ¡   ¡   ¡               ¡       ¡   ¡       ¡     .

PCR pplic tions re ne rly limitless. The he ting-cooling cycle is repe ted 20 to 30 times. diphtheri . sm llpox. FISH is lso used in clinic l l or tories for the di gnosis of genetic no rm lities. The region defined y the primers is mplified to such n extent th t it c n e e sily isol ted for further study. It c n e used to screen li r ries nd to identify genes th t re turned on or off during em ryonic development or during cellul r tr nsform t ion. The re ction i s initi ted y melting the templ te in the presence of primers nd polymer se in suit le uffer. inf orm tion th t usu lly c nnot e o t ined with filter hy ridiz tion. Org ns nd t issues re gener lly composed of m ny different kinds of cells th t c nnot e se p r ted from e ch other using st nd rd iochemic l extr ction procedures. nd th e common cold re ll ex mples of wh t we c ll n    ¡         ¡        ¡           ¡            ¡                                           ¡         ¡ ¡                   ¡           ¡       ¡   ¡           ¡     ¡               ¡                ¡ ¡               ¡   ¡ ¡                                     ¡     ¡ ¡    ¡               ¡    ¡ ¡                                                       . POLYMERASE CHAIN REACTION (PCR) PCR is simply repetitive DNA replic tion over limited. provide cle r results s to which cells express specific gen es. more primer will nne l to initi te nother round of replic tio n.106 Aging powerful v ri tion on Southern nd northern lots. however. it often is due to inv ding micro es th t destroy or d m ge ce lls nd org ns in our ody. nd llowing sufficient time for the polymer se to replic te oth str nds of the templ te. fter which the re ctio n products re fr ction ted on n g rose gel nd photogr phed. This procedure gives precise inform tion reg rding the identity of cell th t expresses specific gene. t times. It is used to mplify DNA from s mples cont ining. At the lo wer temper ture. primer-defined region o f suit le templ te. no more th n few cells. cooling quickly to 37°C. The temper ture is then in cre sed to 75°C to melt the newly formed duplexes nd then cooled to 37°C. ut will re.e. me sles. when su jecte d to FISH n lysis.. Histol ogic l sections. sep r te into t wo single str nds) t 75°C. AIDS. show cle rly the v rious cell types nd. The DNA polymer se used in these re ctions is isol ted from thermophilic cteri th t c n withst nd temper tures of 70°C to 80°C. Gene Ther py Primer When we get sick. Choler .nne l (rehy ridize) t 37°C. The nd cont in ing the mplified fr gment m y e cut out of the gel nd purified for further st udy. The re ction exploits the f ct th t DNA duplex in low-s lt uffer will melt (i.

Viruses re p r sites th t speci lize in infecting cteri l nd nim l cells. Commonly used viruses re the retrovirus nd the de novirus. ¡             ¡   ¡                                           ¡               ¡               ¡             ¡  ¡     ¡         ¡   ¡       ¡ ¡                                         ¡ ¡                 ¡                         ¡           ¡                         ¡     ¡         ¡               ¡       ¡               ¡       ¡ ¡           ¡         . scientists re lized th t ther peutic gene could e inserted into p tient’s cells y first introducing it into virus nd then letting the virus c rry it into the ffected cells. C onsequently. unl ike the retrovirus. our doctor m y prescri e drug th t will. remove the micro e from our odies. Alzheimer’s dise se nd P rkinson’s dise se. This single min o. w s the first geneti c disorder of this kind to e descri ed. c using colds nd flulike symptoms. In this context the virus is referred to s gene ther py delivery vehicle or vector (in recom in nt technology. colon c ncer. Centr l to this t echnology is the use of viruses to clone specific pieces of DNA.Resource Center 107 infectious dise se. Gene ther py ttempts to cure these dis e ses y repl cing or supplementing the d m ged gene. Th t is. converting the codon GAG to GTG. it usu lly is c used y point mut tion. Coron viruses (which c use the com mon cold) nd the AIDS virus re common ex mples of retroviruses. Inste d. m king it impo ssi le for it to c rry enough oxygen to meet the dem nds of norm l dult. hemophili . Unfortun tely. Scie ntists h ve identified sever l thous nd genetic disorders th t re known to e r esponsi le for dise ses such s re st c ncer. When gene is d m ged. in some c ses. dise se ffecting red lood cells. A retrovirus gets its n me from the f ct th t it h s n RNA genome th t is copied into DNA fter it infects cell. The mut tion occurs in gene th t code s for the β ( et ) ch in of hemoglo in. the DN A is inserted into vir l chromosome nd is mplified s the virus multiplies. nd two neurologic l disorders. thus curing the dise se. for this type of di se se is n ilment th t d m ges gene. The denovirus (from “ denoid. we re f ced with f r more difficult pro lem. If we c tch ny of these dise ses. most of the dise ses we f ll prey to re not of the infectious kind.cid su stitution is enough to cripple the hemoglo in molecule. ch nge th t ffects single nucleotid e. This virus.” gl nd from which the virus w s first isol ted) norm lly infects the upper respir tory tr ct. it is referr ed to s cloning vector). which su stitutes the mino cid v line t position 6 for glut mic cid. no drugs to pp ly. Sickle-cell nemi . In such c ses. there re no micro es to fight. Gene ther py i s m de possi le y recom in nt DNA technology ( iotechnology).

Adenoviruses h ve DNA genome cont ined in crys t lline protein c psid. studded with proteins th t re used to infect cells. nd norm lly infect cells of the upper respir tory tr ct . h ve lso een used th t consist of phospholipid vesicle ( u le) cont ining the ther peutic gene. Artifici l vectors. The c psid is enclosed in phospholipid envelope. consisting of phospholipid il yer enclosing the ther peutic gene. Retroviruses h ve n RNA genome th t is converted to DNA when cell is in fected. ¡               ¡                           ¡¡ ¡   ¡                               ¡                       . Adenovirus C psid DNA chromosome Protein fil ment Retrovirus RNA chromosome C psid Envelope Envelope protein Lipo some Ther peutic gene Phospholipid il yer Vectors used in gene ther py. The protein fil ments re used to infect c ells.108 Aging h s DNA genome. c using colds nd flulike symptoms. c lled liposomes. Artifici l vectors h ve lso een used. The HIV (AIDS) virus is common ex mple of re trovirus.

The vector m y e introduced into cultured cells nd then returned to the p tient from whom they were derived (ex vivo delivery). such s the liver. This recom in nt chromosome is p ck ged into vir l p rticles to form the fin l vector.Resource Center 109 Vector prep r tion nd delivery. m y infect wide r nge of cells. or the vector m y e injected directly in to the p tient’s circul tory system (in vivo delivery). fter which the recom i n nt chromosome is p ck ged into vir l p rticles to form the vector. The vector m y e in troduced into cultured cells sufferex vivo in vivo delivery delivery ing from genetic defect nd then returned to the p tient from whom they were derived (ex vivo delivery). Altern tively. r in. ec use vector. The in vivo procedure is used when the genetic defect ppe rs in n org n. or stem cells th t m y e h rvest ed from the p tient nd grown in culture. eing free in the circul tory system. This is the most common form of gene ther py. The ex vivo procedure is used when th e genetic defect ppe rs in white lood cells. Vector chromosome Ther peutic gene Join together P ck ge into vir l p rticles Gene ther py vectors re prep red y cutting the vi r l chromosome nd the ther peutic gene with the s me restriction enzyme. fter which the two re joined together with DNA lig se. thus   ¡     ¡                     ¡         ¡ ¡       ¡     ¡                 ¡   ¡                       ¡                                     ¡                             ¡       ¡ . or p ncre s. ut it is lso potenti lly h z rdous. A vir l chromosome nd ther peutic gene re c ut with the s me restriction enzyme nd joined together. the vector m y e injected directly into the p ti ent’s circul tory system (in vivo delivery).

to tre t v riety of genetic disorders.577 n ucleotide p irs (or se p irs. Other tri ls since the n h ve either een ineffective or were dev st ting f ilures. in the United St tes lone. The G4 genome consists of 5.S. His de th w s c used y multiorg n f ilure rought on y the vir l vector. The p ossi ility of sequencing the entire hum n genome w s first discussed t scientif ic meetings org nized y the United St tes Dep rtment of Energy (DOE) etween 19 84 nd 1986.224 p). By 1982 the S nger protocol w s used y others to sequence t he genome of the nim l virus SV40 (5. used ex vivo delivery. n 18-ye rold p tient suffering from liver di se se. virus th t inf ects the cterium Escherichi coli (E. Besides providing inv lu le d t . revi ted p) nd w s sequenced in Dr. Thi s tr il cured young p tient n med Ashi deSilv of n immune deficiency ( denos ine de min se deficiency) th t ffects white lood cells. Despite these set cks. nd cterioph ge l m d (48. conducted in 1990. then t the University of C m ridge. eginning in the e rly 1980s. one of the first genomes to e sequenced w s th t of cterioph ge G4. The first gene ther py tri l. A committee ppointed y the U. N tion l Rese rch Council endorse d the ide in 1988 ut   ¡       ¡                 ¡               ¡   ¡     ¡                    ¡      ¡                                ¡           ¡     ¡   ¡                 ¡     ¡   ¡     ¡¡  ¡               ¡               ¡                   ¡    ¡   ¡ ¡   ¡   ¡     ¡           ¡            ¡    ¡                   ¡         ¡ ¡ ¡   ¡        . the DNA-sequencing method invente d y the British iochemist Fred S nger. two children eing tre ted for nother form of immune deficiency developed vector-induced leukemi (c ncer of the white lood cells). nd there re currently more th n 600 tr ils i n progress. gene ther py holds gr e t promise s medic l ther py. At th t time. Indeed.502 p). coli). the se projects demonstr ted the fe si ility of sequencing very l rge genomes. Such c se occurre d in 1999.110 Aging ctiv ting n immune response th t could le d to widespre d tissue nd org n d m ge. died while p rticip ting in gene ther py tri l.569 p). S nger’s l or tory in 1979. In 2002. The Hum n Genome Project Sequencing the entire hum n genome is n ide th t grew over period of 20 ye r s. w s ut few ye rs old nd h d only een used to sequence vir l or mitochondri l genomes (see ch pter 8 for description of sequencing methods). when Jesse Gelsinger. the hum n mitochondrion (16.

covers the entire genome nd refines the d t for re s of the genome th t were difficult to sequence.000 to 32. Brit in. leg l. The BAC fr gments re p rti lly ch r cterized. It lso filled in m ny g ps th t oc curred in the rough dr ft. The fin l dr ft. The progr m w s form lly l unched in l te 1990 s consortium consisting of coordin ted sequencing projects in the United St tes . e ch fr gment consists of 1 million ses) th t re cloned into cteri l rtifici l chromosomes (BACs) to form li r ry of DNA fr gments. flies. With this str tegy. They lso c lled for the est l ishment of rese rch progr ms devoted to the ethic l. nd Chin . nd soci l issues r ised y hum n genome rese rch. gen e origins. nd gene org niz tion.000 genes (estim tes r nge etween 25. nd mice. J p n. genomic DNA is cut into one-meg se (M ) fr gments (i. com pleted in April 2003. ye st.2 G o f DNA th t encodes out 30. Th t is. Sequencing of the hum n genome w s divid ed into two st ges. At out the s me time. nd then ssem led into the fin l sequence wi th the id of computers. sequenced. which they pplied to the hum n genome s well s to the other org nisms mentioned. m ny scientists h d elieve d the hum n genome cont ined         ¡                            ¡     ¡       ¡                     ¡                        ¡   ¡                       ¡        ¡                                   ¡                                  ¡  ¡       ¡       ¡                       ¡           ¡ ¡          ¡                        ¡                   ¡  ¡       ¡       ¡ ¡             ¡  ¡       . Fr nce. w s rough dr ft th t c overed out 80 percent of the genome with n estim ted size of more th n 3 ill ion ses ( lso expressed s three gig ses. worms. Clones re selected from the contigs for shotgun sequencing. Germ ny. The fin l dr ft of the hum n genome gives us gre t de l of inform tion th t m y e divided into three c tegories: gene content. or three G ). Org nizing the initi l BAC fr gments into contigs gre t ly simplifies the fin l ssem ly st ge. The first st ge. then org nized into n overl pping ssem ly c lled contig.Resource Center 111 recommended ro der progr m th t would include the sequencing of the genes of hum ns.000 p fr gments. the Hum n Genome Org niz tion (HUGO) w s founded to provide forum for intern tion l coor din tion of genomic rese rch.e. cteri . e ch shotgun clone is digested into sm ll 1.000) . completed in 2001. GENE CONTENT An lysis of the fin l dr ft h s shown th t the hum n genome consists of 3. By 1995 the consortium h d est lished str tegy. c lled hier rchic l shotgun sequencing.. The estim ted num er of genes is surprisingly low.

s we might expect. we o t ined these genes directly from cteri . The function of most of the horizont lly tr nsferred genes is uncle r .266. By comp rison. h s 18. D t from the fin l dr ft nd other so urces provides det iled overview of the function l profile of hum n cellul r p roteins. The genome d t suggests th t hum n complexity. in kind of n tur l gene ther py. We know this to e the c se ec use. How MAO. Mono mine oxid se pl ys cruci l role in the turnover of these neurotr nsmitters. In other words. o t ined from cteri .000 genes. D t from the genome project shows cle rly th t euk ryote genes re split into s u -   ¡             ¡    ¡       ¡  ¡     ¡       ¡     ¡                    ¡       ¡          ¡           ¡                                            ¡               ¡        ¡   ¡                 ¡  ¡        ¡             ¡             ¡             ¡         ¡    ¡                           ¡                     ¡     ¡   . or vertic l. lso known s jumping genes. lthough few m y code for sic met olic enzymes. while these genes occur in cteri . A not le exception is gene th t codes for n enzyme c lled mono mine oxid se (MAO). GENE ORGANIZATION In prok ryotes. E ch gene is tr nscri ed in to messenger RNA (mRNA). eleg ns). tr nsl tion often egins even efore tr nscription is complete. such s dop mine. Equ lly surprising is the f ct th t 220 of our genes were o t in ed y horizont l tr nsfer from cteri . could h ve developed such n import nt role in hum n physiology is gre t mystery. which re neede d for neur l sign ling in the hum n centr l nervous system. genes re simply rr nged in t ndem long the chromosome. fruit flies. norepinephrine. gene org niz tion is more complex. or gene sw p ping. r ther th n ncestr l.338 genes nd the simple roun dworm. is not simpl y due to the solute num er of genes ut involves the complexity of the protein s th t re encoded y those genes. In gener l. with l ittle if ny DNA sep r ting one gene from the other. which is tr nsl ted into protein. In euk ryotes. pro ly during episodes of infection. Mono mines re neu rotr nsmitters. s comp red with the fruit fly or the worm. GENE ORIGINS Fully one-h lf of hum n genes origin ted s tr nspos le elements. in prok ryote s. Indeed. or ny other euk ryotes th t h ve e en tested. C enorh ditis eleg ns (C. hum n proteins tend to e much mo re complex th n those of lower org nisms. inh erit nce. nd serotonin. they re not present in ye st. which h ve no nucleus.112 Aging 100. the fruit fly h s 13.

nd th t e ch exon is sep r ted y length of DNA. consisting of introns nd exons. c lled exons. The prim ry tr nscript never le ves the nucleus nd is never tr nsl ted into protein. Thus only the e xons c rry the necess ry code to produce protein. Euk ryote gen es re tr nscri ed into prim ry RNA molecule th t includes exon nd intron seq uences.                           ¡                                   ¡         ¡   . is sep r ted from other gene s y long stretches of noncoding DNA c lled intervening sequences. Nucle r enzymes remove the introns from the prim ry tr nscript.Resource Center 113 units. A gene. c lled n intron. f ter which the exons re joined together to form the m ture mRNA.

.

An import nt component of cellsign ling p thw ys. photor eceptors. cid A su st nce th t rele ses protons when dissolved in w ter. C rries net neg tive ch rge.ound enzyme th t c t lyzes the conversion of ATP to cyclic AMP. Forms the cytoskeleton of ll euk ryotes nd p rt of the contr ctile pp r tus of skelet l muscle. dipocyte A f t cell. th t c rries cetyl groups in cell s. muscles.    GLOSSARY V cetyl A chemic l group derived from cetic cid. nd h ir cells of the inner e r. 115                 ¡                  ¡                     ¡               ¡               ¡       ¡                                                     ¡   ¡           ¡         ¡                         ¡ ¡   ¡     ¡   ¡                       . dren line (epinephrine) A hormone rele sed y chrom ffin cells in the dren l gl nd. cetylcholine A neurotr nsmitter rele sed t xon l termin ls y cholinergic neurons. Prep res n nim l for extreme ctivity. Found in the centr l nd peripher l nervous system nd rele sed t the verte r te neuromuscul r junction. Import nt in energy met olism nd for the modific tion of proteins. such s one m rrow or epithelium. dult stem cells Stem cells isol ted from dult tissues. ctin fil ment A protein fil ment formed y the polymeriz tion of glo ul r ctin molecules. incre ses t he he rt r te nd lood-sug r levels. dherens junction A cell junctio n in which the cytopl smic f ce of the mem r ne is tt ched to ctin fil ments. utilizing the energy stored in ATP. ctive tr nsport Movement of molecule s cross the cell mem r ne. ction potenti l A self-prop g ting electric l impulse th t occurs in the mem r nes of neurons. cetyl Co A A w ter-solu le molecule. coenzyme A (CoA). denyl te cycl s e A mem r ne.

lph helix A common folding p ttern of proteins in which line r sequence of mino cids twists into right-h nded helix st ilized y hydrogen onds. llogen eic tr nspl nt A p tient receives tissue or org n tr nspl nt from n unrel ted individu l. s in phospholipid. nchoring junction A cell junction th t tt ches cells to e ch other.1 n nometer ( nm). nd pl nts th t is toxic to microorg nisms. ngstrom A unit of length. n olism A collection o f met olic re ctions in cell where y l rge molecules re m de from sm ller on es. ngiogenesis Sprouting of new lood vessels from pree xisting ones. nterior A position close to o r t the he d end of the ody. mino cyl-tRNA synthet se An enzyme th t tt ches the correct mino cid to tRNA. mino terminus The end of protein o r polypeptide ch in th t c rries free mino group. nti ody A protein m de y B cells of the immune system in response to inv ding micro es. mino cid An org nic molecule cont ining mino nd c r oxyl groups th t is uilding lock of protein. mphip thic H ving oth hyd rophilic nd hydropho ic regions. nti iotic A su st nce m de y cteri . loc ted t the s me locus (position) on homologous chromosomes.116 Aging     ero ic Refers to process th t either requires oxygen or occurs in its presenc e. Diploid org nisms h ve two lleles for e ch gene. n ero ic A cellul r met olism th t does not depend on molecul r oxygen. th t is used to me sure molecules nd toms. equ l to 10-10 meter or 0. n ph se A mitotic st ge in which the two sets of chromosomes move w y from e ch other tow rd opposite spindle poles. fungi. llele An ltern te form of gene. mino cyl-tRNA An mino cid linked y its c r o xyl group to hydroxyl group on tRNA. Common ex mples re penicillin nd st reptomycin.     ¡                     ¡           ¡ ¡              ¡ ¡ ¡   ¡        ¡            ¡                       ¡                               ¡   ¡     ¡                 ¡            ¡     ¡                     ¡ ¡           ¡                   ¡                   ¡    ¡     ¡               ¡ .

poptosis Regul ted o r progr mmed form of cell de th th t m y e ctiv ted y the cell itself or y t he immune system to force cells to commit suicide when they ecome infected with virus. xon A long extension of neuron’s cell ody th t tr nsmits n electric l sign l to other neurons. ntiporter A mem r ne c rrier protein th t tr nsports two dif ferent molecules cross mem r ne in opposite directions. Tr nsport lso flows from the terminus to the cell ody. ATP synth se A protein loc ted in the inner mem r ne of the m itochondrion th t c t lyzes the form tion of ATP from ADP nd inorg nic phosph t e using the energy supplied y the electron tr nsport ch in. th t presents pieces of n inv ding micro e (the ntig en) to lymphocytes.               ¡         ¡                 ¡ ¡     ¡               ¡                       ¡ ¡       ¡                                   ¡             ¡     ¡           ¡       ¡                 ¡ ¡                                     ¡                                 ¡                         . the pol rity of one str nd is oriented in the opposite direc tion to the other. Individu ls produced this w y re identic l to the p rent nd referred to s clone. long n xon to the xon l terminus. ntip r llel The rel tive orient tion of the two str nds in DNA dou le helix. ntigen-presenting cell A cell of the immune sy stem. le ding to the form tion of nti odies. such s monocyte. ri ose. AT P se Any enzyme th t c t lyzes iochemic l re ction y extr cting the necess r y energy from ATP. nd th ree phosph te groups th t is the m in c rrier of chemic l energy in the cell. ATP ( denosine triphosph te) A nucleoside consisting of denine. utogeneic tr nspl nt A p tient receives tr nspl nt of his or her own tissue. ntigen A molecule th t stimul tes n immune response. such s Golgi vesicles. sexu l reproduction The process of forming new individu ls without g metes or the fertiliz tion of n egg y sperm. utosome Any chromo some other th n sex chromosome. ster The st r-sh ped rr ngement of microtu ules th t is ch r cteristic of mitotic or meiotic spindle.Gloss ry 117 nticodon A sequence of three nucleotides in tRNA th t is complement ry to mes senger RNA codon. xon l tr nsport The tr nspo rt of org nelles.

the procedure is c lled n excision l iop sy. A person who inherits n           ¡         ¡     ¡   ¡       ¡                ¡ ¡              ¡                       ¡     ¡   ¡     ¡           ¡ ¡   ¡ ¡    ¡   ¡               ¡ ¡   ¡                           ¡   ¡         ¡       ¡ ¡                ¡       ¡    ¡    ¡ ¡     ¡     ¡                ¡ ¡  ¡          ¡               ¡   ¡    ¡     . The purin es nd pyrimidines in DNA nd RNA re org nic ses nd re often referred to si mply s ses. cteri l rti fici l chromosome (BAC) A cloning vector th t ccommod tes DNA inserts of up to 1 million se p irs. iv lent A duplic ted chromosome p ired with its homologous duplic te d chromosome t the eginning of meiosis. iosphere The world of living org nisms. the procedure is c lled needle iopsy or fine-needle spir tion. l stomere A cell formed y the cle v ge of fertilized egg. se A su st nce th t c n ccept proton in solution. Bl stomeres re the totipotent cells of the e rly em ryo . B cell (B lymphocyte) A white lood cell th t m kes nti odie s nd is p rt of the d ptive immune response. BRCA1 ( re st c ncer gene 1) A gene on chromosome 17 th t m y e involved in regul ting the cell cycle. When n entir e lump or suspicious re is removed. RNA (northern lotting).118 Aging cteri One of the most ncient forms of cellul r life (the other is the rch e ). enign Tumors th t grow to limi ted size nd do not spre d to other p rts of the ody. When s mple of tissue or fluid is removed with needle. B cteri re prok ryotes nd some re known to c use dise se. When only s mple of tissue is rem oved. cterioph ge A virus th t infects cteri . or proteins (western lotting) from n g rose or poly cryl mide gel t o nylon mem r ne. Adenine ound to thymine or gu nine ound to cytosine re ex mp les of se p irs. B cterioph ge s were used to prove th t DNA is the cell’s genetic m teri l nd re now used s c loning vectors. the procedure is c lled n incision l iopsy or core iopsy. lotting A technique for tr nsferring DNA (Southern lotting). et sheet Common structu r l motif in proteins in which different str nds of the protein run longside e ch other nd re held together y hydrogen onds. se p ir Two nucleotides in RNA or DNA th t re held together y hydrogen onds. iopsy The remov l of cells or tissues for ex min tion under microscope.

ov ri n. CD28 Cell-surf ce protein loc ted in T cell mem r nes. cDNA cont ins coding sequence ut not the regul tory sequences th t re present in the                                             ¡       ¡                                 ¡                 ¡                         ¡             ¡          ¡ ¡     ¡             ¡ ¡ ¡    ¡           ¡     ¡                     ¡         ¡       ¡       ¡    ¡                       ¡     ¡             ¡       ¡                                      ¡   ¡ . BRCA2 ( re st c ncer gene 2) A gene on chromosome 13 th t. Kiloc lories (1. udding ye st The common n me for the ker’s ye st S cch romyces cerevisi e. po pul r experiment l org nism th t reproduces y udding off p rent l cell.Gloss ry 119 ltered version of the BRCA1 gene h s higher risk of getting re st. incre ses the risk of getting re st. cDNA (complement ry DNA ) DNA th t is synthesized from mRNA. c rdi c muscle Muscle of the he rt.ssem ly of one or more proteins into geometric lly symmet ric l structure. Intermedi te pr oducts re c lled c t olites.000 c lories) re used to descri e the energy content of foods. c t lyst A su st nce th t lowers the ctiv tion e nergy of re ction. representing the m jority of hum n c ncers. c r oxyl terminus The end of protein cont i ning c r oxyl group. formed y uto.ond energy. c t olism Enzyme-regul ted re kdow n of l rge molecules for the extr ction of chemic l. nd oxygen. ov ri n. nece ss ry for the ctiv tion of T cells y foreign ntigens. c lorie A unit of he t. c rcinogen A compound or form of r di tion th t c n c use c ncer. w hen mut ted. or prost te c ncer. or prost te c ncer. thus cont ining the complement ry sequence. c psid The protein co t of vi rus. c sp se A prote se involved in the initi tion of poptosis. hydrogen. One c lorie is the mount of he t needed to r ise the temper ture of one gr m of w ter y 1°C. cont ining c r on. c r ohydr te A gener l cl ss of compounds th t includes sug rs. Composed of myocytes th t re linked together in communic tion network sed on free p ss ge of sm ll molecules through g p junctions. c r oxyl group A c r on tom tt ched to n oxygen nd hydroxyl group. c rcinogenesis The form tion of c ncer. c dh erin Belongs to f mily of proteins th t medi tes cell-to-cell dhesion in nim l tissues. c rcinom C ncer of the epith elium.

In most nim l cells it cont ins p ir of centrioles. or genetic exch nge etween the two chromosomes. cell-divisio n-cycle gene (cdc gene) A gene th t controls specific step in the cell cycle. Microtu ules of the spindle fi er connect to n re o f the centromere c lled the kinetochore. centrosome Org nizes the mitotic spindl e nd the spindle poles. chrom tid A duplic te chromosome th t is still connected to the origin l t the centromere. cell f te The fin l differenti ted st te th t pluripotent em ryonic cell is ex pected to tt in.120 Aging genome. cell-cycle control system A te m of r egul tory proteins th t governs progression through the cell cycle. cell nucle r repl cement Anim l-cloning technique where y som tic cell nucleus is tr nsferred to n en ucle ted oocyte.               ¡                             ¡                 ¡   ¡     ¡     ¡                                             ¡         ¡     ¡                                         ¡     ¡                   ¡  ¡                                   . chi sm (plur l: chi sm t ) An X-sh ped connection etween homologous chromosome s th t occurs during meiosis I. cell ody The m in p rt of cell cont ining the nucleus. centromere A region of mitotic chromosome th t holds si ster chrom tids together. representing site of crossing-over. nd endopl smic reticulum. cent riole A cylindric l rr y of microtu ules th t is found t the center of centr osome in nim l cells. Golgi com plex. L eled pro es re m de from cDNA for the study of gene expression. The identic l p ir re c lled sister chrom tids. cell co t See glycoc lyx. Synonomous with som tic-cell nucle r tr nsfer. Used in reference to neurons th t h ve long pro cesses (dendrites nd xons) extending some dist nce from the nucleus nd cytopl smic m chinery. centr l nervous system (CNS) Th t p rt of nervous system th t n lyzes sign ls from the ody nd the environment. the CNS includes the r in nd spin l cord. In nim ls. cell-medic ted immune response Activ tion of specific cells to l unch n immune response g inst n inv ding micro e. cell dhesion molecule (CAM) A cell surf ce protein th t is used to connect cells to e ch other.

dideoxy sequencing A method fo r sequencing DNA th t employs dideoxyri ose nucleotides. or Cdk) th t control progressio n from one st te of the cell cycle to nother. cytochrome Colored.               ¡                 ¡ ¡               ¡                   ¡       ¡       ¡                         ¡                     ¡               ¡         ¡               ¡     ¡                             . DNA (deoxyri onucleic cid) A long polymer formed y linking f our different kinds of nucleotides together like e ds on string. dexr zox ne A drug used to protect the he rt fr om the toxic effects of nthr cycline drugs such s doxoru icin. chromosome One lon g molecule of DNA th t cont ins the org nism’s genes. cyclic denosine m onophosph te (cAMP) A second messenger in cell-sign ling p thw y th t is produ ced from ATP y the enzyme denyl te cycl se. It elongs to t he f mily of drugs c lled chemoprotective gents. Thus diploid org nisms h ve two versions ( lleles) of e ch ge ne in the genome. the chromoso me is circul r nd n ked. iron-cont ining prote in th t is p rt of the electron tr nsport ch in. clinic l re st ex m An ex m of the re st performed y physici n to check for lumps or other ch nges. chrom tin condens tion Comp ction of different region s of interph se chromosomes th t is medi ted y the histones. cytotoxic T cell A T lymphocyte th t kills infected ody cells. it is line r nd complexed with histone nd nonhistone proteins.Gloss ry 121 chrom tin A complex of DNA nd proteins (histones nd nonhistones) th t forms e ch chromosome nd is found in the nucleus of ll euk ryotes. chromosome condens tion Comp ction of entire chromosom es in prep r tion for cell division. The sequence of nucleotides is used to encode n org nism’s genes. in euk ryotes. Decondensed nd thr e dlike during interph se. cytochemistry The study of the in tr cellul r distri ution of chemic ls. cyclin A protein th t ctiv tes pr otein kin ses (cyclin-dependent protein kin ses. In prok ryotes. dendrite An extension of nerve cell th t rece ives sign ls from other neurons. one set from the mother nd the othe r from the f ther. diploid A genetic term me ning two sets of homologous chromosomes.

Drosophil mel no g ster Sm ll species of fly. dou le helix The three-dimension l structure of DNA in whi ch the two str nds twist round e ch other to form spir l. Also refers to the u pper surf ce of n tomic l structures. Also c lle d intr duct l c rcinom . DNA li r ry A collection of DNA fr gments th t re cloned into pl smids or vir l genomes. commonly c lled fruit fly. dors l The ckside of n nim l. dyspl si Disordered growth of cells in tissue or org n. often le ding to the development of c ncer. electrochemic l gr dient A differenti l concentr tion of n ion or molecule cross the cell me m r ne th t serves s source of potenti l energy nd m y pol rize the cell ele ctric lly. electron microscope A microscope th t uses electrons to produce hig h-resolution im ge of the cell. dynein A motor protein th t is involved in chromosome m ovements during cell division.       ¡                                         ¡ ¡ ¡               ¡ ¡                   ¡                   ¡                                ¡       ¡                      ¡       ¡                           ¡           ¡                                           ¡     . th t is used s n exp eriment l org nism in genetics. nd gerontology. dorsoventr l The ody xis running from the ckside to the frontside or the upperside to the unde rside of structure. such s rms or wings. DNA micro rr y A te chnique for studying the simult neous expression of very l rge num er of genes . DNA prim se An enzyme th t synthesizes short str nd of RNA th t serves s pr imer for DNA replic tion. doxoru icin An nti c ncer drug th t elongs to f mily of ntitumor nti iotics. DNA polymer se An enzyme th t synthesizes DNA using one str nd s templ te. DNA lig se An enzyme th t joins two DNA str nds together to m ke continuous DNA molecule. duct l c rcinom in situ (DCIS) A norm l cells th t involve only the lining of re st duct.122 Aging DNA helic se An enzyme th t sep r tes nd unwinds the two DNA str nds in prep r tion for replic tion or tr nscription. em ryology. The c ells h ve not spre d outside the duct to other tissues in the re st. ectoderm An em ryonic tiss ue th t is the precursor of the epidermis nd the nervous system.

This sequence is removed once the protein enters the ER. gr m neg tive cterium th t inh its the intestin l tr ct of most ni m ls nd is used s n experiment l org nism y geneticists nd iomedic l rese rchers. enzyme A protein or RNA th t c t lyzes specific chemic l re ction. endocytosis Cellul r upt ke of m teri l from the environment y inv gin tion of the cell mem r ne to form vesicle c lled n endosome. coli) R od sh pe. endotheli l cell A cell th t forms the endothelium. When finished. the glycosyl ted pr oteins re sent to the Golgi pp r tus in exocytotic vesicles. endoc rine cell A cell th t is speci lized for the production nd rele se of hormones. enveloped virus A virus cont ining c psid th t is surrounded y lipid il yer origin lly o t ined from the mem r ne of previously infected c ell. th t covers the outer surf ce of the ody. erythrocyte A red lood cell th t cont ins the oxygen-c rrying pigment hemo glo in used to deliver oxygen to cells in the ody. endopl smic reticulum (ER) Mem r ne. ER sign l sequence The mino termin l sequence th t directs proteins to enter the endopl smic reticulum (ER).ounded ch m ers th t re used to modify newly synthesized proteins with the ddition of sug r molecules (glycosyl tion). thin sheet of cells lining the inner surf c e of ll lood vessels. The endosome’s content s re m de v il le to the cell fter it fuses with lysosome. enh ncer A DNA regul tory sequence th t provides indi ng site for tr nscription f ctors c p le of incre sing the r te of tr nscriptio n for specific gene. Escherichi coli (E. Such cells m ke up hormone-producing tissue such s the pituit ry gl nd or gon ds. Often loc ted thous nds of se p irs w y from the gene it regul tes. or skin.     ¡   ¡   ¡   ¡         ¡       ¡ ¡     ¡                 ¡                                 ¡      ¡             ¡ ¡         ¡              ¡          ¡                                   ¡            ¡ ¡       ¡               ¡     ¡        ¡           ¡   ¡                     ¡ ¡   ¡           . epider mis The epitheli l l yer. em ryonic stem cell (ES cell) A pluripotent cell derived from the inner cell m ss (the cells th t give rise to the em ryo inste d of the pl cent ) of m mm li n em ryo.Gloss ry 123 em ryogensis The development of n em ryo from fertilized egg. endoderm An em ryonic tissue l yer th t gives rise to the gut.

Molecules to e secreted re loc ted in Golgi-deri ved vesicles th t fuse with the inner surf ce of the cell mem r ne. exocytosis The process y which molecu les re secreted from cell. Euchrom tin cont ins mos t. meth nol. exon Coding region of euk ryote gene th t is represented in messenger RNA. All life-forms. f t A lipid m teri l. th t is stored dipocy tes s n energy reserve. con sisting of triglycerides (f tty cids ound to glycerol). fixed on nylon filter. A m jor source of cellul r energy nd compone nt of phospholipids. of the ctive genes.124 Aging euchrom tin Lightly st ining portion of interph se chrom tin. fluorescent microscope A microscope th t is equipped with speci l filters nd e m splitter for the ex min tion of tissues nd cells st ined with flu orescent dye. fix tive A chemic l th t is used to preserve cells nd tissues. in contr st to the d rkly st ining heterochrom tin (condensed chrom tin). f tty cid A compound th t h s c r oxylic cid tt c hed to long hydroc r on ch in. y secreting n extr c ellul r m trix. ¡                 ¡     ¡         ¡                       ¡         ¡     ¡             ¡ ¡         ¡                               ¡                           ¡ ¡         ¡                 ¡ ¡     ¡          ¡                   ¡ ¡         ¡       ¡                         ¡        ¡               ¡           . except cteri nd viruses. tissues. depositing t he contents into the intercellul r sp ce. nd cetic cid. usu lly s green or red light. nd thus directs the synthesis of speci fic protein. fluorescent dye A dye th t sor s U V or lue light nd emits light of longer w velength. fi ro l st The cell type th t. filter hy ridiz tion The detection of specific DNA or RNA molecules. expression studies Ex min tion of the type nd qu ntity of mRNA or protein th t is produced y cells. fl gellum (plur l: fl gell ) W hiplike structure found in prok ryotes nd euk ryotes th t re used to propel ce lls through w ter.ounded org nelles. fluorescein Fluorescent dye th t produces green light when illumin ted with ultr violet or lue light. if not ll. gives rise to the connective tissue of the ody. euk ryote (euc ryote) A cell cont ining nu cleus nd m ny mem r ne. Common ex m ples re form ldehyde. y incu ting the filter with l eled pro e th t hy ridizes to the t rget seque nce. fertiliz tion The fusion of h ploid m le nd fem le g metes to form diploid zygote. or org ns. re composed of euk ryote cells.

gene ther py A method for tre ting dise se where y defective gene. th t re cloned into pl smid or vir l ve ctors. G2 G p 2 refe rs to the ph se of the cell cycle th t follows DNA replic tion nd precedes mito sis. This region includes oth the coding. to specific mino cid. Occurs in differenti ted ody cells s wel l s developing oocytes. o t ined y digesting genomic DNA with restriction enzyme. gene A region of the DNA th t spe cifies specific protein or RNA molecule th t is h nded down from one gener tio n to the next. G0 G “zero” ref ers to ph se of the cell cycle. genomics The study of DNA sequences nd their role in the function nd st ructure of n org nism. gene repressor protein A protein th t in ds to DNA nd locks tr nscription of specific gene. St te of withdr w l from the cycle s the cell enters resting or quiescent st ge. t il end. gene regul tory protein Any protein th t inds to DNA nd there y ffe cts the expression of specific gene. germ cell Cells th t develop into g metes. genetic code A set of rul es th t ssigns specific DNA or RNA triplet. G1 G p 1 refers to the ph se of the cell cycle th t occ urs just fter mitosis nd efore the next round of DNA synthesis.Gloss ry 125 follicle cell Cells th t surround nd help feed developing oocyte.se sequen ce. either sperm or oocytes. g p junction A communic tion ch nnel in the mem r nes of dj cent cells th t llows free p ss ge of ions nd sm ll molecules. repl ced. consisting of three. glucose Sixc r on monos cch ride (sug r) th t is the princip l source of energy for m ny ce lls nd org nisms. g strul tion An em ryologic l event in which spheric l em ryo is converted into n elong ted structure with he d end. genomic li r ry A collection of DNA fr gments. c using the dise se. genotype The genetic composition of cell or org nism. noncoding. Stored s glycogen         ¡     ¡                        ¡   ¡ ¡               ¡   ¡ ¡                       ¡         ¡                                     ¡           ¡       ¡             ¡     ¡                                 ¡                                         ¡         . nd regul tory s equences. is either rep i red. genome All of the genes th t elong to cell or n org nism. nd gut (g strul ). or supplemented with function l copy.

This or g nelle is n med fter the It li n histologist C millo Golgi. glycosyl tr nsfer se An enzyme in the Golgi complex th t dds glucose to proteins.” consisting of glycosyl ted prot eins nd lipids. glycosyl tion The process of dding one or more su g r molecules to proteins or lipids. glycolysis The degr d tion of glucose with production of ATP. Cur rently used y m ny l or tories to study the cell iology of c ncer nd c rcino genesis. such s sperm nd eggs. helper T cell A type of T lymphocyte th t helps stimul te B cells to m ke nti odies directed g inst specific micro e or ntigen. w hich re modified nd sorted efore eing sent to their fin l destin tion. The glycoproteins nd glycolipids le ve the Golgi y exocytosis. sophils. HeL cell A tumor-derived cell line. th t covers the surf ce of every cell. cell-sign ling receptors nd tr nsporters.126 Aging in nim l cells nd s st rch in pl nts. gr nulocyte A type of white lood cell th t includes the neutrophils. Golgi complex (Golgi pp r tus) Mem r ne . who discovered it in 1898. The glycoproteins nd gl ycolipids. glycoc lyx A molecul r “forest. glycogen A polymer of glucose used to store energy in n nim l cell . glycerol A three-c r on lcohol th t is n import nt componen t of phospholipids. including the form tion of ion ch nnels. Wood is n el or te polymer of glucose nd other sug rs. glycoprotein Any protein th t h s ch in of glucose molecules (oligos cch ride) tt ched to som e of the mino cid residues. c rried to the cell mem r ne y Golgi-derived vesicles. The G olgi complex is lso the source of glycolipids th t re destined for the cell me m r ne. h ploid H ving only one set of chromoso mes. h ve m ny fun ctions. A condition th t is typic l in g metes.ounded org nelle in euk ryote cells th t receives glycoproteins from the ER. origin lly isol ted from c ncer p tient in 1951. helix-loop-helix A structur l motif common to group of gene regul tor y proteins. growth f ctor A sm ll protein (polypeptide) th t c n stimul te cells to grow nd prolifer te. ¡   ¡                                                               ¡       ¡      ¡                 ¡                       ¡ ¡         ¡     ¡     ¡             ¡                               ¡                                  ¡   ¡                   ¡       ¡     . nd eosinophils.

histone Sm ll nucl e r proteins. hydropho ic A nonpol r molecule th t dissolves in f t nd lipid soluti ons ut not in w ter. hormone A sign ling molecule. homologous Org ns or molecules th t re simil r in structu re ec use they h ve descended from common ncestor. occurring prim rily in the one m rrow . homolog One of two or more genes th t h ve simil r sequence nd re descended from common ncestor gene. hydrophilic A pol r compound th t mixes re dily wi th w ter. one inherited from the mother nd the other from the f ther. hemopoiesis Production of lood cells. Used prim rily in referen ce to DNA nd protein sequences. procedure th t is used to screen gene li r ries nd to study g ene structure nd expression. Usu lly rele se d into gener l circul tion for coordin tion of n nim l’s physiology. histology The study of tissues. loc ted in red lood cells th t p icks up oxygen in the lungs nd c rries it to other tissues nd cells of the od y. HIV The hum n immunodeficiency virus th t is responsi le for AIDS. histochemistry The study of chemic l differenti tion of tissues. Genes encoding enzymes involved in glycolysis nd the Kre s cycle re common ex mples. reg rdless o f the cell’s speci liz tion. rich in the mino cids rginine nd lysine. hep tocyte A liver cell.         ¡       ¡           ¡                   ¡       ¡ ¡         ¡         ¡                               ¡                       ¡                  ¡     ¡       ¡                   ¡                               ¡ ¡         ¡   ¡ ¡ ¡       . hy ridiz tion A term used in molecul r iology (recom in nt DNA technology) me ning the form tion of dou le-str nded nucleic cid through complement ry se-p iring. e dlike structure th t is m jor component of chrom tin. produced nd secreted y endocrine gl nds.Gloss ry 127 hemoglo in An iron-cont ining protein complex. housekeepin g gene A gene th t codes for protein th t is needed y ll cells. homologous chromosomes Two copies of the s me c hromosome. A property th t is exploited in filter hy ridiz tion. th t form the nucleos ome in euk ryote nuclei. heterochrom tin A region of chromosome th t is high ly condensed nd tr nscription lly in ctive.

Production of this hormone is regul ted directly y the mount of glucose th t is in the lood. to ctiv te nd coordin te the d pti ve immune response. in vitro Refers to cells growing in culture. S. ion ch nnel A tr nsmem r ne ch nnel th t llows ions to diffuse cross the mem r ne nd down their electrochemic l gr dient.128 Aging hydroxyl group (-OH) Chemic l group consisting of oxygen nd hydrogen th t is prominent p rt of lcohol. insulin Polypeptide hormone secreted y β ( et ) cells in the verte r te p ncre s. secreted y lymphocytes. The procedure is usu lly c rried out on tis sue sections or sme rs of individu l cells. or iochemic l re ction occu rring in test tu e (L tin for “in gl ss”). interph se The period etween e ch cell division. in vivo A iochemic l re ction. interleukin A sm ll protein hormone. The p thw y is ctiv ted through cell-surf ce receptors nd cytopl smic J nus kin ses (J ks). thus cquiring ch rge. nd sign l tr nsducers nd ctiv tors of tr nscription (STA Ts). immuno fluorescence Detection of specific cellul r protein with the id of fluoresc ent dye th t is coupled to n nti ody. occurring in living cells or living org nism (L tin for “in life”). J k-STAT si gn ling p thw y One of sever l cell-sign ling p thw ys th t ctiv tes gene expre ssion. It is tr nscri ed. nd G2 ph ses of the cell cycle. Common ex mples re N + nd C ++ ions. ion An tom th t h s g ined or lost electrons. intron A section of euk ryoti c gene th t is noncoding. immunoglo ulin (Ig) An nti ody m de y B cells s p rt of the d ptive immune response.       ¡                                 ¡  ¡                                                 ¡     ¡               ¡   ¡ ¡   ¡ ¡     ¡     ¡       ¡         ¡                 ¡ ¡      ¡   ¡         ¡   ¡                 ¡                   ¡                 ¡                             ¡           ¡   . which incl udes the G1. incontinence In ility to contr ol the flow of urine from the l dder (urin ry incontinence) or the esc pe of st ool from the rectum (fec l incontinence). in situ hy ridiz tion A method for stu dying gene expression. where y l eled cDNA or RNA pro e hy ridizes to speci fic mRNA in int ct cells or tissues. ut does not ppe r in the m ture m RNA. im ge n lysis A computerized method for extr cting i nform tion from digitized microscopic im ges of cells or cell org nelles. or pr ocess.

l eling re ction The ddition of r dio ctive tom or fluorescent dye to DNA or RNA for use s pro e in filter hy ridiz tion. nd therefore. l m d cterioph ge A vir l p r site th t infects cter i . lipid il yer Two closely ligned sheets of phospholipids th t form the core structure of ll cell mem r nes. The other end of e ch microtu ule is tt ched to chro mosome. much like zipper. kinetochore A complex of proteins th t forms round the centromere of mitotic or meiotic chromosomes. The l gging str nd is synthesized discontinuously. H2O. its completion l gs ehind the secon d. The le ding str nd is m de y contin uous synthesis in the 5’ to 3’ direction.Gloss ry 129 k ryotype A pictori l c t log of cell’s chromosomes. str nd. The end prod ucts re CO2. Widely used s DNA cloning vector. le ding str nd One of the two newly syn thesized DNA str nds t replic tion fork. Kre s cycle (citric cid cycle) The centr l met olic p thw y in ll euk ryotes nd ero ic prok ryotes. Ker tin is found in h ir. showing their num er. providing n tt chmen t site for microtu ules. ker tin Proteins produced y speci lized ep itheli l cells c lled ker tinocytes. fingern ils. to form dimer. size. kinesin A motor protein th t uses energy o t ined from the hydrolysis of ATP to move long microtu ule. sh pe. In euk ryotes. nd fe thers. or le ding. The two l yers re ligned s uch th t the hydropho ic t ils re interior. in which two identic l proteins re joined together t regul rl y sp ced leucine residues. leucine zipper A structur l motif of DNA inding proteins. The cycle oxidizes cetyl groups derived from food molecules. while the hydrophilic he d groups re exterior on oth surf ces. discovered y the Germ n chemist H ns Kre s in 1937. which p ss vi NADH nd FADH2 to t he respir tory ch in. nd over ll nding p ttern. the Kre s cycle is loc ted in the mitochond ri . nd high-energy electrons. leukemi C ncer of white lood cells. ¡        ¡ ¡                   ¡   ¡                               ¡   ¡                 ¡          ¡ ¡                         ¡ ¡ ¡     ¡                                ¡   ¡       ¡     ¡     ¡                                  ¡       ¡   ¡     ¡   ¡   ¡   ¡       ¡                            . l gging str nd One of the two newly synthesized DNA str nds t replic tion fork.

These pictures c n show the difference etween norm l nd dise sed tissue. the soft tissue of joints. lymphocyte A type of white lood ce ll th t is involved in the d ptive immune response. such s CT or X-r y. MRI is especi lly useful for im ging th e r in. or colonize. locus A term from genetics th t refers to the po sition of gene long chromosome. spine. lysosome Mem r ne. nd the inside of ones. m cromolecule A very l rge molecule th t is uil t from sm ller molecul r su units.ctiv ted protei n kin se) A protein kin se th t is p rt of cell prolifer tion–inducing sign ling p thw y. MRI m kes etter im ges of org ns nd soft tissue th n other s c nning techniques. lysis The rupture of the cell mem r ne followed y de th of the cell. proteins. T lymphocytes (T cells) m ture in the thymus nd tt ck inv ding micro es directly. long-term potenti tion (LTP) A physic l remodeling of syn ptic ju nctions th t receive continuous stimul tion. m jor histocomp ti ility complex Verte r te genes th t code for l rge f mily of cell-surf ce glycoproteins th t ind forei gn ntigens nd present them to T cells to induce n immune response. B lymphocytes (B cells) m ture in the one m rrow nd m ke nti odies th t re designed to immo ilize or destroy s pecific micro es or ntigens.ounded org nelle of euk ryotes th t cont ins powerful digestive enzymes. MAP-kin se (mitogen. m gnetic reson nce im ging (MRI) A procedure in which r dio w ves nd powerful m gnet linked to computer re used to cre te det iled pictures of re s inside the ody. Common ex mples re DNA. There re two kinds of lymp hocytes: T lymphocytes nd B lymphocytes. M-cyclin A euk ryote enzyme th t regul tes mitosis. m mmogr phy The use o f X-r ys to cre te picture of the re st. other re s of the ody. Also c lled nucle r m gnetic reson nce im ging. nd polys cch rides. m lign nt Refers to the function l st tus of c ncer cell th t grows ggressively nd is le to met st size.     ¡               ¡   ¡     ¡                     ¡               ¡     ¡     ¡ ¡         ¡         ¡   ¡                                                   ¡         ¡     ¡       ¡             ¡ ¡ ¡   ¡                                         ¡     ¡                                                   ¡   ¡             ¡    . Different lleles of the s me gene occupy t he s me locus.130 Aging liposome An rtifici l lipid il yer vesicle used in mem r ne studies nd s n rtifici l gene ther py vector.

Occurs t the en d of f tty cid. met ph se The st ge of mitosis t which the chromosomes re tt ched to the spindle ut h ve not egun to move p rt. mel nocyte A skin cell th t produces the pigment mel nin. th t en le these cells to communic te with e ch other. An import nt ch r cter istic of neurons s it provides the electric current. mem r ne potenti l A uildup of ch rged ions on one side of the cell mem r ne est lishes n elec trochemic l gr dient th t is me sured in millivolts (mV). or electron. mesoderm An em ryonic germ l yer th t gives rise to muscle. microtu ule A fine cylind ric l tu e m de of the protein tu ulin. nd m ny intern l or g ns. to synthesize protein. nd the ssoci ted glycoc lyx. millimeter (mm) Equ l to 10-3 meters. connective tissue. met pl si A ch nge in the p ttern of cellul r eh vior th t often precedes the development of c ncer. ones. nd other components of the tr nsl tion m chinery. th t surrounds nd encloses ll cells. methy l group (-CH3) Hydropho ic chemic l group derived from meth ne. mic roscope. T his is ccomplished with two rounds of cell division ut only one round of DNA r eplic tion. forming m jor component of the euk ryo te cytoskeleton. when ion ch nnels open.                   ¡                     ¡   ¡   ¡         ¡          ¡                           ¡       ¡ ¡                               ¡ ¡       ¡ ¡             ¡    ¡     ¡        ¡                 ¡ ¡                       ¡         ¡   ¡     ¡           ¡   ¡          ¡         ¡   . microgr ph Photogr ph t ken through light.Gloss ry 131 meiosis A speci l form of cell division y which h ploid g metes re produced. mem r ne T he lipid il yer. messenger RNA (mRNA) An RNA tr nscri ed from gene th t is used s the ge ne templ te y the ri osomes. met ph se pl te R efers to the im gin ry pl ne est lished y the chromosomes s they line up t r ight ngles to the spindle poles. mem r ne ch nnel A protein complex th t forms pore or ch nnel through the mem r ne for the free p ss ge of ions nd sm ll molecules. met st sis Spre d of c ncer cells from the site of the origin l tumor to other p rts of the ody. micrometer (µm or micron) Equ l to 10-6 meters. met olism The sum tot l of the chemic l processes th t occur in living cells.

NAD (nicotine denine dinucleotide) Accepts hydride ion (H–).” in reference to the thre dlike ppe r nce of interph se chromosomes. mitosis Division of euk ryotic nucleus. E ch mem er of the p ir is referred to s sister chrom tid. mitotic spindle Arr y of microtu ules. molecule Two or mor e toms linked together y cov lent onds. formerly free-living. myelin she th Insul tion pplied to the xons of neurons. forming NADH. the m in c rrier of electrons for ox id tive phosphoryl tion. th t produces most of the cell’s ATP. the nti odies produced re identic l. Since ll of the cells re clones of the or igin l B cell. The she th is produced y oligodendrocytes in the centr l nervous syste m nd y Schw nn cells in the peripher l nervous system. produced y the Kre s cycle. me ning “ thre d. monocyte A type of white lood cell th t is involved in the immune response. From the Greek mitos. myeloid cell White loo d cells other th n lymphocytes. monoclon l nti ody An nti ody produ ced from B cell–derived clon l line. to form single muscle cell. mitogen A hormone or sign ling molecule th t stimul tes cells to grow nd divide. motif An element of structure or p ttern th t m y e recurring dom in in v riety of proteins. M ny myo l sts f use into syncytium. multip ss tr nsmem r ne protein A mem r ne protein th t p sses ck nd forth cross the lipid il yer. mut nt A genetic v ri tion within popul tion. cont ining m ny nuclei.       ¡     ¡     ¡           ¡       ¡   ¡                         ¡   ¡            ¡             ¡                       ¡       ¡          ¡ ¡                   ¡ ¡ ¡     ¡ ¡                             ¡         ¡   ¡                 . mitotic chromosome Highly condensed duplic ted chromo somes held together y the centromere. mut tion A herit le ch nge in the nucleo tide sequence of chromosome.132 Aging mitochondrion (plur l: mitochondri ) Euk ryote org nelle. f nning out from the pol r centrioles nd connecting to e ch of the chromosomes. myo l st Muscle precursor cell. M ph se The period of the cell cycle (mitosis or meiosis) when the chromosomes sep r te nd migr te to the opposite poles of the spindle. myoc yte A muscle cell.

n nometer (nm) Equ l to 10-9 meters or 10-3 microns. Messenger RNA (mRNA) is fr ction t ed on n g rose gel nd then tr nsferred to piece of nylon filter p per (or m em r ne). nucleoside A purine or pyrimidine linked to ri ose or deoxyri ose sug r . nucleotide A nucleoside cont ining one or more phosph te groups linked to the 5’ c r on of the ri ose sug r. n tur l k iller cell (NK cell) A lymphocyte th t kills virus-infected cells in the ody. m cromolecule consisting of ch in of nucleotides. Southern inspired the n me. The origin l lotting technique invented y E. I t lso kills foreign cells ssoci ted with tissue or org n tr nspl nt. M. nucleolus A structure i n the nucleus where ri osom l RNA is tr nscri ed nd ri osom l su units re sse m led. nucle r loc liz tion sign l (NLS) A short mino cid sequence loc te d on proteins th t re destined for the cell nucleus fter they re tr nsl ted i n the cytopl sm. nd l rge cell c rcinom .                         ¡         ¡ ¡         ¡       ¡     ¡   ¡                          ¡ ¡       ¡         ¡               ¡   ¡ ¡                 ¡   ¡                   ¡                             ¡   ¡                           ¡                         ¡       ¡   ¡     ¡ ¡   . denoc rcinom . nucleol r org nizer Region of chromosome cont ining cluster of ri osom l RNA genes th t gives rise to the nucleolus. neuromu scul r junction A speci l form of syn pse etween motor neuron nd skelet l muscle cell. consisting of histone proteins. northern lotting A technique for the study of gene expression. DNA nd RNA re nucleotide polymers. non-sm ll-cell lung c ncer A group of lung c ncers th t includes squ mous cell c rcinom .Gloss ry 133 NADH dehydrogen se Removes electrons from NADH nd p sses them down the electron tr nsport ch in. nucleic cid DNA or RNA. neuron A cell speci lly d pted for communic tion th t forms the ne rvous system of ll nim ls. A specific mRNA is detected y hy ridiz tion with l eled DNA or RNA pro e. nucleosome A e dlike structure. The sm ll cells re endocrine cells. nucle r envelope The dou le mem r ne (two lipid il yers) enclosing the ce ll nucleus. neurotr nsmitter A chemic l rele sed y neurons t syn pse th t tr nsmits sign l to nother neuron.

” oncogene A mut nt form of norm l cellul r gene. th t h s speci lized function. oper tor A region of prok ryote chromosome t h t controls the expression of dj cent genes. usu lly consisting of mino cids (oligopeptides). org nelle A mem r ne.134 Aging nucleus Euk ryote cell org nelle th t cont ins the DNA genome on one or more chr omosomes. or nucleotides (oligonucleotides). The mem r ne must e perme le to the solvent ut not to the solutes. The electrons re eventu lly tr nsferred to oxygen to complete the pro cess. the solvent is lw ys w ter.           ¡                     ¡ ¡     ¡   ¡      ¡                   ¡                                  ¡                           ¡   ¡       ¡     ¡ ¡                                        ¡ ¡         ¡             ¡            ¡   ¡              ¡   ¡             . operon Two or more prok ryote gen es th t re tr nscri ed into single mRNA. osmosis The movement of s olvent cross semiperme le mem r ne th t sep r tes solution with high con centr tion of solutes from one with low concentr tion of solutes. oli gomer A short polymer. ovul tio n Rupture of m ture follicle with su sequent rele se of m ture oocyte from t he ov ry. osteo l st Cells th t form ones. oligo l eling A method for incorpor ting l eled nucleotides into short piece of DNA or RNA. oligodendrocyte A myelin ting gli cell of the verte r te centr l nerv ous system. nd the mem r ne is the cell mem r ne. In the context of cell ul r osmosis. oxid tive phosphoryl tion Gener tion of high-energy electrons from foo d molecules th t re used to power the synthesis of ATP from ADP nd inorg nic p hosph te. k nown s proto-oncogene. occurring in euk ryote cells. me ning “few” or “little. p53 A tumor-suppressor gene th t is m ut ted in out h lf of ll hum n c ncers. Also known s the r ndom-primer l eling method. Occurs in cteri nd mitochondri .ounded structu re. T ken from the Greek wor d oligos. th t c n tr nsform cell to c ncerous phenotype. Golgi complex. nd endopl smic reticulum. The norm l function of the p53 protei n is to lock p ss ge through the cell cycle when DNA d m ge is detected. sug rs (oligos cch rides). oo cyte A fem le g mete or egg cell. Ex mples re the nucleus. the solutes re ions nd molecules.

PCR (polymer se ch in re ction) A method for mplifying specific regions of DNA y temper ture cycling re ction mixture cont ining the templ te. p t hogen An org nism th t c uses dise se. glycerol. Thus pH of 2. peptide ond The chemic l ond th t links mino cids together to form protei n. Used extensively s DNA cloning ve ctor. pH Me sures the cidity of solution s neg tive log rithmic function (p) of H+ concentr tion (H). pl smid A minichromosome. where s p H of 8. Composed of hydrophilic he d-group. phospholipid The kind o f lipid molecule used to construct cell mem r nes. pl ce o An in ctive su st nce th t looks the s me. th t occurs n tur lly mong prok ryotes. often c rrying nti iotic-resist nt gene s. he t-st le DNA polymer se. ph gocyte A cell th t engulfs other cells or de ris y ph gocytosis. often represented d i gr mm tic lly s phylogenetic tree. or group of org nisms.Gloss ry 135 p rthenogenesis A n tur l form of nim l cloning where y n individu l is produc ed without the form tion of h ploid g metes nd the fertiliz tion of n egg. photoreceptor A molecule or cell th t responds to light.0 (10-8 mol r H+) is sic. phosphoryl t ion A chemic l re ction in which phosph te is cov lently onded to nother mol ecule. s drug in cl inic l tri l. phylogeny The evolution ry history of n org nism.”) p henotype Physic l ch r cteristics of cell or org nism. photosynthesis A iochemic l process in which pl nts. (Derived from the Greek word ph gein. nd is dministered in the s me w y. nd replic tion primers.0 (10-2 mol r H+) is cidic. ph gocytosis A process where y cells engulf other cells or org nic m teri l y endocytosis. “to e t. A common pr ctice mong protozo ns nd cells of the verte r te immune system. pinocytosis A form of endocytosis where y fluid is rought into the cell from the environment.   ¡     ¡         ¡                                             ¡       ¡   ¡      ¡             ¡     ¡                       ¡   ¡                     ¡  ¡                            ¡         ¡                                   ¡                   ¡                       ¡               ¡   ¡       ¡     ¡ . nd cert in cteri use energy o t ined from sunlight to synthesize m cromolecules from CO2 nd H2O. lg e. nd two hydropho ic f tty cid t ils. phosph te.

proto-oncogene A norm l gene th t c n e converted to c ncerc using gene (o ncogene) y point mut tion or through in ppropri te expression. re ching v lues of 100. one from e ch p rent. P r sitic forms re lso known th t in h it the digestive nd urogenit l tr ct of m ny nim ls. th t is present in the loodstre m nd is involved in lood co gul tion. Flowers re often highly polyploid. for ex mple. ploidy The tot l num er of chromosomes (n) th t cell h s. protein glycosyl tion The ddition of sug r molecules to protei n.000C. re u sed for structur l purposes nd regul te m ny iochemic l re ctions in their lt ern tive role s enzymes. including hum ns. port l system A system of liver vessels th t c rries liver enzymes directly to the digestive tr ct. derived from meg k ryocytes nd l cking nucleus. h s cells th t re extremely polyploid. Ploidy is lso me sured s the mount of DNA (C) in given cell rel tive to h ploid nucleus of the s me org nism. protein A m jor constitue nt of cells nd org nisms. pro e Usu lly fr gmen t of cloned DNA molecule th t is l eled with r dioisotope or fluorescent dy e nd used to detect specific DNA or RNA molecules on Southern or northern lots . Proteins. nd verte r te hep tocytes m y e 16C. Proteins r nge in size from just few mino cids to more th n 200. th t lters single nucleotide. polyploid Possessing more th n two sets of homologous chromosomes.                 ¡                 ¡                                                   ¡                                           ¡     ¡       ¡        ¡         ¡                             ¡        ¡     ¡                                                    ¡ ¡             ¡   ¡       ¡   ¡ ¡                       ¡        ¡ . The silk gl nd o f the moth Bom yx mori. h ving two sets of chromosomes. protozo Freeliving. Most org nisms re diploid. ut there is gre t v ri tion mong pl nts nd nim ls. single-cell euk ryotes th t feed on cteri nd other microorg nisms. p rticul rly in region co nt ining gene. promoter A DNA sequence to which RNA polymer se inds to initi te gene tr nscr iption. point mut tion A ch nge in DNA. proph se The first st ge of mitosis. The chromosomes re duplic ted nd eginning to condense ut re tt ched to the spindle. m de y linking mino cids together.136 Aging pl telet A cell fr gment. C ommon ex mples re P r mecium nd Amoe .

th t utilize the energy of electrons tr veling down the ch in to synthesi ze ATP. replic tion fork The Y-sh ped region of replic ting chromosome. Ex mples re cytosine. restriction enzyme An enzyme th t cuts DNA t specific sites. r ndomi zed clinic l tri l A study in which the p rticip nts re ssigned y ch nce to s ep r te groups th t comp re different tre tments. regul tory sequence A DNA seq uence to which proteins ind th t regul te the ssem ly of the tr nscription l m chinery. restrictio n m p The size nd num er of DNA fr gments o t ined fter digesting with one or more restriction enzymes. replic tion origin (origin of replic tion. retrovirus A virus th t converts its RNA genome to DNA once it h s infected cell. E ch u le cont ins two replic tion forks. the reverse of the usu l flow of genetic inform tion from DNA to RNA. ORI) The loc tion t which DNA replic tion egins. loc ted in the inner mitochondrion mem r ne. Associ ted with replic tio n u les. Two ex mples re denine nd gu nine.     ¡             ¡               ¡         ¡   ¡ ¡                                     ¡                         ¡                                   ¡   ¡¡ ¡     ¡¡ ¡   ¡       ¡   ¡ ¡          ¡                   ¡                 ¡                     ¡¡ ¡       ¡       ¡             . At the time of the tri l.Gloss ry 137 purine A nitrogen-cont ining compound th t is found in RNA nd DNA. replic tion u le Loc l dissoci tion of the DNA dou le helix in prep r tion for replic tion. respir tory ch in (electron tr nsport ch in) A collecti on of iron nd copper-cont ining proteins. thymine. it is not known which tre tment is est. reverse tr nscript se An RNA-dependent DNA polymer se. recom in nt DNA A DNA molecule th t h s een formed y joi ning two or more fr gments from different sources. re gent A chemic l solution designed for specific iochemic l or his tochemic l procedure. Using ch nce to ssign people to groups m e ns th t the groups will e simil r nd th t the tre tments they receive c n e comp red o jectively. neither the rese rchers nor th e p rticip nts c n choose which group. This enzyme synthesizes DNA y using RNA s templ te. pyrimidine A nitrogen-cont ining compound found in RNA nd DNA. nd ur cil (RNA only). r dio ctive iso tope An tom with n unst le nucleus th t emits r di tion s it dec ys.

M. som tic cell Any cell in pl nt or nim l except those th t produce g metes (germ cells or germ cell precursors). S cch romyces Genus of udding ye st th t re frequently used in the study of euk ryote cell iology. Specific fr gments re identified y hy ridizing the filter to l eled pro e. som tic cell nu cle r tr nsfer Anim l cloning technique where y som tic cell nucleus is tr nsf erred to n enucle ted oocyte. s rcom C ncer of connective tissue. screening Checking for dise se when there re no symptoms. Invented y the Scottish scientist E. found in em ryos nd v rious p rts of the ody. ri osome A complex of protein nd RNA th t c t lyzes the synthes is of proteins. stem c ell Pluripotent progenitor cell. Southern in 1975. such s est rogen nd testosterone. senescence Physic l nd iochemic l ch nges th t occur in cells nd org nisms wi th ge. sm ooth muscle cell Muscles lining the intestin l tr ct nd rteries.       ¡       ¡                         ¡ ¡                                   ¡       ¡   ¡                     ¡         ¡   ¡           ¡                 ¡     ¡               ¡ ¡                     ¡     ¡         ¡         ¡                           ¡ ¡    ¡ . sign l tr nsduction A process y which sign l is rel yed to the interi or of cell where it elicits response t the cytopl smic or nucle r level. Synonomous with cell nucle r repl cement. rough endopl smic reticulum (rough ER) Endopl smic reticulum th t h s ri osomes ound to its outer surf ce. L cks the str i tions typic l of c rdi c nd skelet l muscle. Souther n lotting The tr nsfer of DNA fr gments from n g rose gel to piece of nylon filter p per. giving it smooth ppe r nce wh en viewed under microscope. possi ly y c t lyzing some of the steps involved in pro tein synthesis.138 Aging ri osom l RNA (rRNA) RNA th t is p rt of the ri osome nd serves oth structur l nd function l role. th t c n differenti te into wide v riety of cell types. Schw nn cell Gli cell th t produces myelin in the periph er l nervous system. Sex hormones. re steroids. steroid A hydropho ic molecule with ch r cteristic four-ringed structure.

templ te A single str nd of DNA or RNA whose sequence serves s guide f or the synthesis of complement ry. teloph se The fin l st ge of mitosis in which the chromosomes decondense nd the nucle r envelope re forms. c t lyzed y RNA polymer se. str nd. syn pse A neur l communic tion junction etween n xon nd dendrite. T moxifen locks the effects of the hormone estrogen in the ody.Gloss ry 139 structur l gene A gene th t codes for protein or n RNA. stimul te receptors on the dendrite of second neuron. tel omere The end of chromosome. tr nscription The copying of DNA sequence into RNA. I t elongs to the f mily of drugs c lled ntiestrogens. tr nsfer RNA (tRNA) A collection of sm ll RNA molecules th t tr nsfer n mino cid to growing po lypeptide ch in on ri osome. Sign l tr nsmission occurs when neurotr nsmitters. syn cytium A l rge multinucle ted cell. Repl ced y the enzyme telomer se with e ch round of cell division to prevent shortening of the chromosomes. tr nsf ection Introduction of foreign gene into euk ryote cell. T cell (T lymphocyte) A w hite lood cell involved in ctiv ting nd coordin ting the immune response. t moxifen A drug th t is used to tre t r e st c ncer. rele sed into the junction y the xon of one neuron. Skelet l muscle cells re syncytiums produce d y the fusion of m ny myo l sts. There is sep r te tRNA for mino cid. Distinguished from re gions of the DNA th t re involved in regul ting gene expression ut re noncodi ng. ther peutic cloning Th e cloning of hum n em ryo for the purpose of h rvesting the inner cell m ss (E S cells). topoisomer se An enzyme th t m kes reversi le cuts in DNA to relieve s tr in or to undo knots. or d ughter. tr nscription l f ctor A gener l term referring to wide ssortment of proteins needed to initi te or regul te tr nscription.     ¡           ¡ ¡                   ¡                               ¡                                         ¡         ¡         ¡                           ¡                       ¡ ¡ ¡                                           ¡               ¡     ¡ ¡         . syngeneic tr nspl nts A p tient receives tiss ue or n org n from n identic l twin. tr nsgen ic org nism A pl nt or nim l th t h s een tr nsfected with foreign gene.

140 Aging tr ns-Golgi network The mem r ne surf ces where glycoproteins nd glycolipids ex it the Golgi complex in tr nsport vesicles. tr nspos le element (tr nsposon) A segment of DNA t h t c n move from one region of genome to nother. tr nsl tion A ri osome-c t lyzed pro cess where y the nucleotide sequence of n mRNA is used s templ te to direct the synthesis of protein. ultr sound (ultr sonogr phy ) A procedure in which high-energy sound w ves (ultr sound) re ounced off inte rn l tissues or org ns producing echoes th t re used to form picture of ody tissues ( sonogr m). Specif ic proteins re detected with l eled nti odies. ye st Common term for uni cellul r euk ryotes th t re used to rew eer nd m ke re d. produced y hum n fetus nd the pl cent .           ¡ ¡     ¡   ¡                     ¡       ¡ ¡             ¡         ¡ ¡           ¡                         ¡ ¡             ¡   ¡¡ ¡ ¡ ¡  ¡         ¡            ¡       ¡         ¡     ¡ ¡                                ¡               ¡     ¡             . western lotting The tr nsf er of protein from poly cryl mide gel to piece of nylon filter p per. Viru ses re cellul r p r sites th t c use m ny dise ses. The n me w s inspired y the o rigin l lotting technique invented y E. um ilic l cord lood stem cells Stem cells. S c ch romyces cerevisi e. zygote A diploid cell produced y the fusion of sperm nd egg. B kers ye st. M. Vesicles c rr y m teri l from the ER to the Golgi nd from the Golgi to the cell mem r ne. th t re found in the lood th t p sses from the p l cent to the fetus. Southern. vesicle A mem r ne. vir us A p rticle cont ining n RNA or DNA genome surrounded y protein co t. is lso widely used in studies on cell iology.ounded u le found in euk ryote cells. vector A virus or pl smid used to c rry DNA fr gment int o cteri l cell (for cloning) or into euk ryote to produce tr nsgenic org nism.

Av il le online. Americ n Institu te of Physics. l sso?index=1619.gov/TechRe-         ¡                           ¡      ¡ ¡         ¡   ¡                          ¡        ¡    ¡     ¡   ¡    ¡    ¡                                                        ¡                       ¡     ¡ ¡ .S. c dventure. Av il le online. New Jersey: Merck Rese rch L or tories. Accessed on M rch 5. Bo ’s All Cre ture Site.org/history/curi e/r dinst3.htm. “The White Surgeon. URL: http://www. July 11.phtml. 2004.” Press Rele se. Beers. 2000. Accessed on M rch 5.” Press Rele se. ip. M rk H. H yflick. URL: http://www. 2004. London: S ge Pu lic tions. Americ n Instit ute for C ncer Rese rch.” Exp Gerontol Vol. URL: http://www. He lth. New York: G rl nd Pu lishing. URL: http://www. 2004.com/ dve nture/ ngling/ g me_fish/sturgeon.141   FURTHER READING V Al erts. URL: http://ww w.l sso?index=1473.htm. 33 (1998): 639–653.sonic . The Merck M nu l of Geri trics. nd Di ne Gilmer.” This site is m int ined y veterin ry hospit l in C liforni .” Av il le online. Bruce. 2003. Americ n Institute for C ncer Rese rch.” Av il le online. 2004.net/~petdoc/lifesp n.org/ press/pressrele se. Accessed on M rch 5. Le on rd. Illness nd Optim l Aging: Biologic l nd Psychosoci l Perspectives. Fish BC. 2003. icr. C rolyn. Accessed on M rch 5. ed itors. 1998. Hum n Genome Progr m of the U. Essenti l Cell Biology. nd Ro ert Berkow. C n d . Av il le online. 2002. M y 2.” Av il le online. “M d m Curie. Aldw in. Dep rtment of Energy.ornl. “The Life Sp n of Anim ls.org/presscorn er/pu se rchdet il. Dr. icr. URL: http://www.. 2004. “New Scientific Thinking Implic tes Body F t s C ncer Pr omoter. British Colum i . “How nd Why We Age. “Gene Ther py. “Diets High in Fi er Cut Risk of Colon C ncer Ne rly in H lf. Accessed on M rch 5.

DC. Av il le online. nd Ro ert F. nd Olivier Touss int. Phil delp hi : S unders. W shington.nih.edu/file. N tion l Institute of Arthritis nd Musculoskelet l nd Skin Dise se. New York: McGr w-Hill. “Osteoporosis: Progress nd Promise.im -jen . 414 (2001): 88–91.” Chromosome m ps of ll genes known to c use hum n dise ses. C re of the Aged. URL: http://www.. New Jersey: Hum n Press. 2003. 2004.TOC&depth=2. Lovell-B dge. URL: http://www.gov/hi/topics/ rthriti s/o h ndout. 2004.nih.ni ms. Almeder. Lentz. Acc essed on M rch 5.” Av il le online. fcg i?c ll= v. New York: Springer-Verl g.gov/hi/topics/ rthritis/r h ndout. 2004. 2003 . URL: http://www. sp?id=4136. N tion l Center for Biotechnolo gy Inform tion. Jen .nlm.htm. M der. nd It m r B. Illustr ted Encyclopedi of Hum n Histology. Accessed on M r ch 5. Inquiry into Life. Essenti l s of Clinic l Geri trics. M g lhães. Cell Fine Structure: An Atl s of Dr wings of Whole-Cell Structure. “Genes nd Dise se. 1984. Boston: McGr w-Hill. Ro ert L.html. “The Evolution of M mm li n Aging. Accessed on Fe ru ry 20. Sylvi S. R.View. Institute of Medicine. Ousl nder. N tion l Institute of Arthritis nd Musculoskelet l nd Skin Dise se. Krstic. “The Future of Stem Cell Rese rch. 2004.” Av il le online. João Pedro de.de/IMAGE.. Hum e r.” E xperiment l Gerontology Volume 37 (2002): 769–775. A r ss. “H ndout on He lth: Rheum toid Arthritis.nc i. Accessed on M rch 5. 2004. K ne. N tion l Institute of Arthritis nd Musculoskelet l nd Skin Dise se. Thom s L.gov:80/ ooks/ v. R.” Av il le online.142 Aging sources/Hum n_Genome/medicine/genether py. 2003.iom. “Improving the Qu lity of Long Term C re. URL: http://www. 1971.” Av il le online.ShowTOC&rid=gnd.html. 2004.html. Joseph G.nih. Accessed on M rch 5. V. “H ndout on He lth: O steo rthritis. Accessed on M rch 5.” N ture Vol .ni ms. “Molecules of lif e. J mes M. Germ ny. Institute of Molecul r Biotechnology. URL: ¡            ¡                         ¡       ¡       ¡   ¡               ¡                                  ¡                   ¡                                         ¡      ¡   ¡ ¡              ¡                ¡    ¡                         .” Av il le online. URL: http://www.

html.” Octo er 15. Accessed on M rch 5. URL: http://www. 2003. Av il le online.com/n ture/dn 50 / index. 2004.n ture. 2003. URL: http://www. URL: http://www.c om/nsu/030519/0305197. N ture-Wildlife. “Stem Cell Inform tion.html.html. 2002. Av il le online. “Folic Acid Possi ly Key F ctor in Alzheimer’s Dise se Prevention.htm.nih. 2004. “Hop e for Alzheimer’s V ccine.n ture.ni . N ture Science Upd te. Loxodont fric n .gov/hi/topics/osteoporosis/op kgr.ni ms.com/eletxt.nih. “Sup plement Br kes P rkinson’s: Coenzyme Q10 M y Del y Br in Degener tion.” M ny rticles ssem led y the journ l to commemor te the 50th nnivers ry of J mes W tson nd Fr ncis Crick’s cl ssic p per descri ing the structure of DNA. URL: http://n ture-wildlife. Av il le online.html. 2003. “Findings S how Exception l Longevity Runs in F milies. 2004. URL: http://www.                 ¡       ¡   ¡                    ¡                                             ¡ ¡    ¡     ¡  ¡                   ¡                                          ¡      ¡ ¡ ¡    ¡                                  ¡                     ¡ ¡ ¡  ¡  ¡ . nih. Fe ru ry 20. 2001. N ture. URL: http://www. Av il le online. N ture Science Upd te.com/ nsu/ 030310/030310-15. 2004.htm.htm. Av il le online. “Age nd Preexisting He lth Pro lems Affect the Prognosis nd Tre tment Options of Older Bre st C ncer P tients. Accessed on M rch 5.” M y 22. URL: http://www.htm. Accessed on M rch 5. N tion l Institutes of He lth.” Av il le onlin e. 2004.nih. Accessed on M rch 5. “Do u le Helix:50 Ye rs of DNA. “As More Live P st Century.com/nsu/021014/021014-3. N tion l Institutes of He lth.” Av il le online.gov/ news/pr/2002/0610.htm. URL: http://stemcells. 2004.n ture. 2004.” Av il le online. Accessed on Octo er 25.nih. 100 Isn’t Wh t It Used to Be .com/2003/01/20/nyr egion/20CENT. Accessed on M rch 5.n ture. The New York Times. Accessed on M rch 5. 2004. Accessed on M rch 5. “Alzheimer’s V ccine Set ck Confirmed. 2004. sp. N ture Science Upd te. Acc essed on M rch 5. Av il le online. nytimes.” News rele se .gov/news/pr/2001/ 0220.” M rch 17. Accessed on M rch 5. URL: http://www. “The Eleph nt. Accessed on M rch 5.ni .gov/news/pr/m r2002/ni -01. N tion l Institutes of He lth.html. N tion l Institutes of He lth. URL: http://www. 2003.gov/index.Further Re ding 143 http://www. 2004.” Av il le online.com.” J nu ry 20.

html. The New York Times.com/2003/ 01/14/he lth/14DEME. “Study Recommends Not Using Hormone Ther py for Bone Loss. The New York Times. Av il le online. 2004. Av il le online.com/ 2003/05/2 8/he lth/28HORM. Accessed on M rch 5. 2003. 2002.nytimes.com/2003/06/17/science/ 17TREE. 2004.com/print_version. C rnes. Av il le online. URL: http:// www. Accessed on M rch 5. Accessed on M rch 5. Acc essed on Octo er 25. com/2003/09/19/science/19DIET. Accessed on M rch 5. Accessed on M rch 5. “Bone M rrow Found to H ve Cells to Rep ir the P ncre s. Av il le online. Accessed on M rch 5. The N ew York Times. 2003.” Septem er 19.nytimes. Olsh nsky.144 Aging The New York Times. 2000. URL: htt p://www. URL: http:// www. nd B. 2003. Av il le online. The New York Times. “Low-C lorieDiet Study T kes Scientists A ck. 2002. The New York Times.nytimes. Accessed on M rch 5. nytimes.nytimes. URL: http://www. “M le Hormone Ther py Popul r ut Untested.nytimes.nytimes. “Position St tement on Hum n Aging. “Politic lly Corr ect Stem Cell Is Licensed to Biotech Concern.” August 19.             ¡                  ¡      ¡      ¡   ¡           ¡ ¡             ¡      ¡       ¡     ¡            ¡            ¡   ¡ ¡          ¡    ¡              .html. “Hormone Repl cement Study Shock to the Medic l System. URL: http://www. “New Ide s Energize Alzheimer’s B ttl e. URL: http://www. URL: http://www. 2004. “At Age 4.” Octo er 1. The New York Times. 2004.nytimes. S. J.html.html.htm l. Leon rd H yflic k.” J Gerontol 57A (2002): B29 2–B297.com/2003/10/01/ he lth/01HORM. 2004.html.html.sci m.com/2002/12/11/ usiness/11STEM.” M rch 15.html. Scientific Americ n.600-Plus. Av il le online. The New York Times.” July 10. 2003. Av il le online.com/2002/07/10/he lth/10HORM. Av il le online .html. 2004. URL: http://www. URL: http://www. “Cell Communic tion: The Inside Story. “Hormone Use Found to R ise Deme nti Risk.” Decem er 11. The New York Times. 2003.” J nu ry 14. A.com/2003/03/15/he lth/15STEM.. 2 002. Av il le online. 2003. Accessed on M rch 5.” June 17. Av il le online. com/ 2002/08/19/he lth/19HORM.” M y 28.nytimes. Methusel h Pine Tree Begets New Offspring. 2003. URL: http://www. 2004. 2004.” June 20.

http://www. 2003. Wh it ourne.ornl.nc i. is n excellent resource for nyone interested in iology. New York: Springer Pu lishing Comp ny. This site.im -jen . Institute of Molecul r Biotechnology. http://gslc. nim l cloning. N tion l Center for Biotechnology Infor m tion (NCBI). With the liter ture d t s e.gov. for ex mple. University of Southern C liforni .nih.edu. This site cont ins inform tion nd illustr tions covering sic ce ll iology. Im ge Li r ry of Biologic l M cromolecules.genetics. WEB SITES The Dep rtment of Energy Hum n Genome Project (United St tes). M ny of these links provide free ccess to f ull-length rese rch p pers. The NCBI provides ccess to GenB nk (DNA sequences). Genetic Science Le rning Center t the Eccles I nstitute of Hum n Genetics. 2003. nd soci l implic tions of genetics rese rch. nd topics de ling with genomic iology. 2003. molecul r d t ses.hum ngenether py. Accessed on Octo er 25.nlm. nd stem cells. est lished y the N tion l Institutes of He lth.de/IM AGE. The Aging Individu l: Physic l nd Psychologic l Perspec tives. 2003. The institu te supports genetic nd genomic rese rch. http://ww w. Gene Ther py Dep rtment. 2003. 2002. Sus n Kr uss. Jen /Germ ny.co m. gene ther py. liter ture d t ses (Medline nd others). University of Ut h.gov/TechResources/ Hum n_Genome.Further Re ding 145 cfm? rticleID=0001998E-5F5A-1C74-9B81809EC588EF21. http://www.u t h. Accessed on Octo er 25. http://www. An excellent resource for eginn ing students. nyone c n ccess Medline’s 11 million iomedic l journ l cit tion s to rese rch iomedic l questions.           ¡      ¡      ¡ ¡     ¡           ¡                         ¡   ¡             ¡     ¡   ¡                ¡       ¡               ¡        ¡       ¡   ¡         ¡   ¡             ¡                           ¡          ¡ ¡         .gov. including the ethic l. Accessed on M rch 5. 2003. Covers every spe ct of the hum n genome project including pplic tions to gene ther py. http://www. Accessed on Octo er 25. html.genome. Accessed on Octo er 25. Accessed on Octo er 25. 2004. leg l. Accessed on Octo er 25. The N tion l Hum n Genome Rese rch Institute (United St tes).

The journ l N ture h s provided comprehensive guide to the hum n genome.                       ¡ ¡ ¡   ¡         ¡     ¡       ¡                            ¡       .ni .nih. All p pers.gov. http://www. h ttp://www.gov.nc i. 2003. which c n e downlo ded for free. N tion l Institute on Aging.int/en. Extensive cover ge of ge-rel ted issues throughout the world. Accessed on Octo er 25. 2003. 2003. Links to gerontology nd geri tri cs rticles. N tur e. n t ure. Accessed on Octo er 25. 2003. Th is site provides links to the definitive historic l record for the sequences nd n lyses of hum n chromosomes.com/n ture/focus/hum ngenome/. Accessed on Octo er 25. The World He lt h Org niz tion. http://www.nlm.who.146 Aging N tion l Institutes of He lth (United St tes). Accessed on Octo er 25. r e sed on the fin l dr ft produced y the Hum n Genome Project. http://www.nih.

INDEX V It lic p ge num ers indic te illustr tions. 60 ging. S ee lso nti ging medicine. 27–32 glycoc lyx in 31. 81. 97               ¡                                                                                                                   ¡              ¡             ¡¡ . See drenocorticotropin ctin fil ments 76. Alois 24 Alzheimer’s dise se (AD) 24–32 ntioxid nts reducing risk of 41 r in in 2 7 genes ssoci ted with 25–26. 31–32 incidence of 24–25 m n geme nt of 32. See ntidiuret ic hormone ADP. 80 structure of 77. 15 dren line 18 d renocorticotropin (ACTH) 18 g rose gel electrophoresis 96. 45–46. See Alzheimer’s dise se denine 78. 93 deno sine triphosph te (ATP) 77. See denosine monophosph te A A e. 79 mino group 77 AMP. 59–60 hor mone im l nce theory 14–21 progr mmed ging theory 10–11 r te-of-living theory 13 r evised c t strophe theory 46 telomeres theory 11–13 AIDS virus 107. 92 in protein 78. Ernst 43–44 cromeg ly 40 ACTH. 93 denoviruses 107. 65 underst nding process of xvi ging popul tion 66–67 ging t heories 9–23 error c t strophe theory 9–10. 86. 78. 108 kt-1 long evity gene 59. 8 signs of xv–xvi. 108 ADH. 69 neur l sign ling in 27–28 progression of 24. 77 AD. See denosine diphosph te dren l gl nds 14. 92 denosine de min se deficien cy 110 denosine diphosph te (ADP) 93 denosine monophosph te (AMP) 78. ge-1 longevity gene 59. 25–26. 60 147 kt-2 longevity gene 60 lendron te 70 α cells 35 Alzheimer. 45–46 free r dic l theory 14. 52 mino cids coding for 91–93. 51. 26 Americ n N tion l Institute of Aging (NIA) 50. 91. elderly progr mmed 10–11 re sons for xv reversing 7.

51 Biom rkers of Aging Project 50 iotechnology x i–xii isphosphon tes 70 l dder rel x nts 70–71 lood pressure s iom rker 51 high . 112 c lcium 37. 30–31 trunc ted 31. 41 polipoprotein E (ApoE) 34 poptosis 32. 29–31 Arch e 75 rteries. 29 r in stem 25.cteri 75 cterioph ge 99. 104 cDNA (complement ry DNA) li r ry 100 c ell(s) m cromolecules of 77. See one miner l density ody f t. 70 c lcium ch nnel lockers 69 C lment. 86 ndrogen supplements 21 ne mi . 30. 56. 78–83. See hypertension BMD. 69 c theter 71 c vi r 4 cDNA (complement ry DNA) 100. 31 n ph se in meiosis 87. See myloid precurso r protein pp gene 25. replic tion of 12 c psid 108 c r oxyl group 77 c rdiov scul r dise ses 34–35. See denosine triphosph te ATP sy nthet se 93 utoimmune dise ses rheum toid rthritis s 33 type I di etes s 36 xon 26. 31 β cells 35. 63 APP. 41 c loric restriction in 13. 40 c ncer cells. 36 et . 28. s iom rkers 51 rthritis 32–33 sexu l reproduction 84 therosclerosis 34 ATP.lockers 69 iochemic l theories 9 iochemis try of cell 77–78 iom rkers 50. 70 one miner l density (BMD) 37 r in s iom rker 51 norm l vs. 41–42. 25 re st c ncer. 110 ker’s ye st 46 eneficence 74 Berg. P ul 46 e t . Je nne 6 c loric restriction (CR) 13. 38–42. 88 in mitosis 85. 46. See lso meiosis. 60. 80 molecules of 77–78. mitosis   ¡   ¡ ¡   ¡       ¡   ¡   ¡   ¡   ¡ ¡                   ¡ ¡ ¡ ¡         ¡               ¡   ¡  ¡     ¡   ¡         ¡ ¡           ¡    ¡           ¡      ¡        ¡ B   148 Aging mplific tion 47 myloid precursor protein (APP) 25. 41–42. 62 C m ridge University 4 7 c ncer ge-rel ted 33–34 hormone ther pies nd 21. sickle-cell 107 nti ging medicine 2. in Alzheimer’s dise se 27 C C enorh ditis eleg ns 58–59. estrogen supplements nd 21 “ ro wn g” technique 68 udding 55. s iom rker 51 one density ev lu tion 70 one he lth 36–37.myloid 31. 79 cell cycle 83. 83–84 cel l division 83. 58. See lso hormone ther pies ntio xid nts in 14. 62 gene ther py in 42 r di o ctive 2 retinoic cid in 2 ntidiuretic hormone (ADH) 18 ntioxid nts 14. 62. 84. 55–56     ¡               ¡                      ¡           ¡                     ¡       ¡                    ¡                   ¡ . 46.

Index 149 cell-to-cell communic tion 94. 28. F r ncis 45 Cro-M gnons 1 crossing over 87 ctl-1 longevity gene 59. See cDNA compound microscope 43–44 co mputerized histochemistry 50 consent. 58 degener tive joint dise se. 85. s iom rker 51 dementi 69. See c loric restriction Crick. 25 centromere 84 centrosomes 76. M ri e 2 cysteine 91. 81. See dehydroepi ndrosterone D d f-2 longevity gene 58–59. 95 cellul r rejuven tion 42 cellulose 7 7 centen ri ns 66 centr l nervous system (CNS) 25. Ashi 110 DHEA. See centr l nervous system codon 91–93. See geri trics cloning 7. 110 DeSilv . 60. 88. 91. 108 complement ry DNA. 87 in euk ryotes 75 homologous 88 m tern l 88–89 p tern l 88–89 in prok ryotes 75 recom in nt 87 cig rette smoking 33 citric cid cycle. See lso DNA cloning CNS. 64                   ¡           ¡   ¡ ¡   ¡                               ¡               ¡     ¡ ¡     ¡           ¡     ¡                                       ¡     ¡       ¡           . 100 deoxyri ose 78. See lso Alzheimer’s dise se irre versi le 69 m n gement of 69 reversi le 69 demogr phics 66–67 dendrite 26. 42. 92 cytochrome 93 cytochrome oxid se 93 cytopl sm 77 cytosine 78. cholinester se inhi itors n d 69 common cold 107. 89 dCTP. 60 d f-23 longevity gene 60 dATP. 25 chic o longevity gene 61. 85. 60 d f -18 longevity gene 59. 85 cer mide 94 cere ellum 25. 86. 87 chrom tin 49–50 chrom tin condens tion (comp ction) 49–50 chromosome(s) during cell division 84–89. informed 74 constitutive expression 47 con tinuous-growth str tegy 5 coron ry rteries 34 coron viruses 107 corticotropinrele sing hormone 18 cosmetics industry 38–39 CR. See deoxy denine tripho sph te d ughter cells 84. 79 Dep rt ment of Energy (DOE) 52. 85. 29 deoxy denine triphosph te (dATP) 100 deoxycytosine triphosph te (dCTP) 100 deoxy ri onucleic cid. See DNA deoxyri onucleotides 81. 92 d f-12 longevity gene 59. 25 cere r l cortex 25 cere rum 25. 60. 92 cognitive function. 87. 84. See deoxycytosine triphosph t e de cetyl ses 57. 60 Curie. See Kre s cycle clinic l geri trics. 61 child-resist nt lid 68 cholesterol s iom rker 51 nd h e rt dise se 34 cholinester se inhi itors 69 chrom tids 84. 64 d f-16 longevity gene 59. See osteo rthritis dehydroepi ndrosterone (DHEA).

110 estrogen 17. 90 DNA hex mers 100–101 DNA l eling 100–101 DNA lig se 95. life sp n of 3–4. 106 DNA prim se 89. 81 nd gerontology 43. 39–40 estrogen to testosterone r tio (ET r tio) 33–34 estrous cycle 20 ethics 73–74 ethidium romi de 97 euk ryote(s) 75–95 evolution of 75 structure of 75–77. 102. 16 endocrinologists 39 endopl smic reticulum (ER) 75–77. 82 Drosophil mel nog ster life sp n of 2–3. 68–71. 4 em ryo 86 endocrine gl nds 14 endoc rine system 14–21. 104 DOE. 90. 81. for geri tric p tients 71–72 du l energy X-r y sorptiometry 70 electron tr nsport ch in 77. 97 DNA micro rr y 22 DNA-modifying enzymes 95–97 DNA polymer se 12. 64 rese rch with 46 drug history. 45–46 DNA cloning 97–99. 90 DNA sequencing 101. 58. 98. 19–20. of p tient 68 drug l els 68 drug ther py. 103. 15. 89–91. 101. 3 longevity genes of 59–61. 102 diestrous nim ls 20 diet of elderly p tient 68 st rv tion 13. 100 telomeres n d 12 structure of 80. 70 for m n ging hypertension 69 E EcoRI 99 eggs 86 Egypt. 61. 101–103. coli) 99. 39 estrogen supplements 21. 100. 89. See lso ging dise ses in 24–37. 79 replic tion of 45. 45–46 Escherichi coli (E. 89. ncient. 41–42 diploid 84–86 dis cch rides 83 DNA (deoxyri onucleic cid) computer model of 82 n ucleotides in 78.150 Aging di etes 35–36 type I 36 type II 36 di p use st te 59. 100–101 DNA helic se 57. 90 enzymes in 89–91. 37. 100 of liver 71 re striction 95–97 Erlich. See Dep rt ment of Energy Dolly the sheep 42 donepezil 69 dou le helix 80. P ul 44 error c t strophe theory 9–10. 76 e nh ncer 100 enzymes DNA-modifying 95–97 in DNA replic tion 89–91. funer ls in 1 elderly. 97 eleph nts. 60 dideoxynucleot ides 101. See lso specific dise ses drug ther py for 71–72 ev lu tion of 67–68 g ender of 66 he lth c re costs for 66–67 living rr ngements of 66 num er of 66 in nursing homes 72–73 electricity 93 electron microscope 46       ¡ ¡         ¡                                     ¡      ¡ ¡     ¡         ¡              ¡                                  ¡                      . 76 exercise for one he lth 38. 93 electro phoresis 96.

78. 5–6 g metes 86 G p 1. 83 G1 83. 80. 45–46 e rly ye rs of 43–45 postgeno mic er 43. in Alzheimer’s dise se 31. 59–60 fruit fly life sp n of 2–3. 97 Gelsinger. 83 glycolipids 56. 58 gene ther py 42. 81 g lycine 91 glycoc lyx 30–31. 19 follicle-stimul ting hormone (FSH) 17. W lter 47 glucose 35–36. 79 f tty cid t ils 80. of elderly 66 gene(s) ssoci ted with Alzheimer’s dise se 25–26. 41. 18. 83 G2 83. 94. 11 gerontology xvi. 94 F f tty cids 77. See longevity genes org niz tion of 112–11 3 origin of 112 regul ting life sp n 10–11 tr nscription of 47 gene silencing 57. 109 genetic code 91–93. 77. 64 rese rch with 46 funer ls ncient Egypti n 1 Cro-M gnon 1 G G0 83. See gig se gel electrophoresis 96. See growth hormone gi g se (G ) 111 Gil ert. 27–32 jumping 112 longevity. See G2 G . 108.Index 151 exocytosis 77 expression studies 47–48 ex vivo delivery 109. 3 longevity gene s of 59–61. 75–77. 94 glycolysis 35 glycoproteins 30. 79 glycerol 77. life sp n of xv. 94. 93. 75. 46–51 GH. See G1 G p 2. 61. 93–95 evolution of 93–94 function of 56. 45–46. Jesse 110 gender. 5. 94–95 l g1 nd 56. 110 ey e drops 68 G4 genome 110 g l nt mine 69 G láp gos tortoise. 106–110. 37. 92 genetic disorders 107 g enetic dysregul tion 57 genetic recom in tion 88–89 genetic st ility 57. 75. 81 filter hy ridiz tion 103 “flight or fight” response 18 fluorescent in situ hy ridiz tion (FISH) 104–106 follicle cell 1 7. 31–32 production of 77 glycogen 3 6. 83                         ¡            ¡     ¡                      ¡         ¡   ¡                           ¡     ¡     ¡                   ¡         ¡        . 43–53 definition of 43 DNA structure nd 43. 70 free r dic ls 14. 18–20 follicle-stimul ting hormon e (FSH)rele sing hormone 18 Food nd Drug Administr tion (FDA) 39 fr ctures 36. 58 genet ic theories 9 genomic li r ry 99–100 geri trics 65–74 definition of 65 drug ther py in 71–72 ethic l issues in 73–74 m n ging gerel ted disorders in 68–71 p tient ev lu tion in 67–68 germ cell 88 Geron Corpor tion 12 gerontologists xvi. 52–53 recom in nt DNA technology nd 43. 58 norm l vs. 109. 79. 93.

Michel 56 joint dise ses 32–33 jumping genes 112 juvenile di etes 3 6 s iom rker 51   ¡   K kidney   ¡       ¡    ¡           H h ploid 86. 16 hypothyroidism 41                   ¡     ¡                               ¡                     ¡      ¡     ¡             ¡     ¡            ¡                         ¡ . 64 he lth c iom rker 51 he rt. 81. 40 for osteoporosis 37. 7 9. 40 growth hormone (GH)-inhi iting hormone 18 gu nine 78. See DNA helic se hemoglo in 36. 11 interph se 83. 77 gon dotropin-rele sing f ctor 18 growth hormone (GH) 18 prop-1 nd 62. See Institute of Medicine irreversi le dementi 69 H yflick. 111 hum n genome project 21–22. 58. 29. 107 hGH. See lso utoimmune dise ses nd c ncer 33 regul tion of 15 incon tinence 70–71 indy longevity gene 60–61. 73 insulin 35–36 s iom rker 51 nd lif e sp n in fruit flies 60–61 intelligence. 84 holomet olous insects 3 homolog 88 homologous chromos omes 88 hormone im l nce theory 14–21 hormone ther pies 21. 61 Institute of Medicine (IOM) 72.I immune system. 70 housefly 46 Hum n Genome Org niz tion (HUGO ) 52. See hum n eh vior 59. 76 Golgi vesicle s 26–27. s 69 helic s ern tion J J zwinski. 63 supplements of 21. 92 hier rchic l shotgun sequencing 111 hip fr ctures 37 hipp oc mpus 25. 52. life sp n nd 4–5. C millo 44 Golgi complex 75–77. 83–84 i ntervening sequences 100 intron 100 in vivo delivery 109. 37. 61. 25 Hippocr tic o th 74 histochemistry. S. 64 informed consent 74 inr longevity ge ne 61. 39. 109 IOM. 39. 60   152 Aging glycosyl tion 36 Golgi. Deh m 45 H rv rd University 47 ick limit 12 hd -1 longevity gene 57. 100. growth hormone hi 12 H yfl ring. Leon rd re costs 66–67 he rt dise se 34–35. computerized 50 histone de ce tyl se 58 histones 49. 110–113 hum n growth hormone (hGH) 40 hum n longevity genes 62–63 hydropho ic hydroc r on t il 78 hydroxyl group (-OH) 78. 15. 89 H rm n. s iom rker 51 he rt tt ck 34 he e. 39–41 dverse effects o f 21. 101 hypertension c use of 69 m n gement of 69 nd stroke 69 hypoth l mus 14–20. 27.

64 nem tode 58–59. hum n. 5–6 hum n xv. 5. 4 of fruit fly 2–3. 91. 63. s iom rkers 51 luteinizing hormone (LH) 19. 61. See low densit y lipoprotein leukemi 33 LH. 16. 44. 54–64. 87 meiosis I 87.Index 153 conserv tion y. 80. 61. prol ctin nd 19 mitochondri 75. 108 liver 15. 6–7 nd intelligence 4–5. 85 met ph se pl te 84 Metchnikoff. 92. 93 Methu sel h (pine tree) 7 methusel h (protein product) 60. 88 Kre s. 11 of sturgeon xv. 78–83 m ltose perme se 61. 105 menop u se 20. 62–63. See luteinizing hormone life expect ncy. 76 M . 76. See meg se Medic id 66–67. 72 meg se (M ) 111 meiosis 86–89.cid cteri 45 l g-1 (longevity ssur nce gene num er 1) 56. 86 milk production. See mono mine oxid se m tern l chromosomes 88–89 m tur tion -promoting f ctor (MPF) 84                     ¡           ¡   ¡         ¡                    ¡                    ¡ ¡ ¡    ¡   ¡       ¡               ¡                            ¡ ¡       ¡                     ¡                 ¡            . 6. 3 of G láp gos tortoi se xv. 77 mitosis 84–86. 47. 103–104 met ph se in meiosis 87 in mitosis 84–86. 61 micro rrr y n lysis 22. 2–7 of eleph nts 3–4. 60. 58. Elie 44–45 methionine 92. 64 ye st 56–57. 86. 71 longevity ssur nce gene num er 1. ntidiuretic hormone nd 18 drugs nd 71–72 kinetochore 84. See l g-1 M m cromolecules 77. 89 mem r ne hy ridiz tion 103–104. 19 luteinizing hormone (LH)rele sing hormone 19 lysine 91 lysosomes 75. H ns 44 Kre s cycle 35. 22 microscope compound 43–44 electron 46 microtu ule 76. 7 2 medic l history. 85 Mone r 75 mono mine oxid se (MAO) 112 monos cch rides 77. 64 l g-1 protein (LAG-1) 56 l m d cterioph ge 99 LDL. of p tient 67 Medic re 66–67. 64 hum n 62–63 mouse 62. 85 mitotic spindle 84. 85. 83 L l els 68 l ctic. 60. See lso specific genes fruit fly 59–61. 63–64 long-term c re 72–73 Louisi n St te Univ ersity 56 low density lipoprotein (LDL) 41 Loxodont fric n 4 lung c ncer 33 l ungs. ch nges in 7–8 life sp n xv. 88 meiosis II 88. 58. 61 m mm ry gl nds 15 oxytocin nd 19 prol ctin nd 19 MAO. 93 longevity genes xv i. 4–5 lifestyle ch nges 69 liposomes 108. 39 messenger RNA (mRNA) 45.

6 poly c ryl mide gel 49. 97. 18–20 ov ries 15. Se e DNA prim se progr mmed ging 10–11 O oligo l eling 101 oocyte 17. 36 P steur. 16 overexpress ion 59–60 over-the-counter drugs 68 ovul tion. 60 pit-1 longevity gene 62. 61. 19 function of 14–17 prop-1 nd 62. 76 phenotype. 60. 81. 94–95 neurotr nsmitters 26–27. 19 Orgel. 64 MPF. 15. 76 nucleosome 49 nucleotides 77. 63 pituit ry gl nd 14. of p tient 68 peroxisomes 75. 63.154 Aging mort lity r te 66 motor proteins 84. 76 nursing homes 72–73 n utrition history. 29 m ximizing h lf-life of 69 new iology xi–xii NIA. 98 poikilotherm 5. See messenger RNA mth longevity gene 60. 81 physici n-p tient r pport 67 physiologic l theories 9 pi nworms 58–59. 52–53 presenilin 25–26 prim se. See Americ n N tion l Institute of Aging No el Prize. 85. 108 phospholipi ds. converting ged to young 7 phosph tes 77. Louis 1 p tern l chrom osomes 88–89 p tient ev lu tion 67–68 p tient-physici n r pport 67 PCR. 70 ov ri n cycle 17. 80. 83 popul tion. 28 neurons 26. 64 neur l circuits 26. 63. 64 Musc domestic 46 mut tion 107 nucleic cids 78–80 nucleolus 75. 64 p ncre s 35. 28. 79. Leslie 45 osteo rthritis 32 osteo l sts 36. 28 neur l sign ling 26–27. 80–81 nucleus 75. 86 mouse longevity genes 62. 102 polymer se ch in re ction (PCR) 106 polys cch rides 78. See polymer se ch in re ction peptide ond 78           ¡                 ¡         ¡                     ¡                 ¡                                           ¡                                           ¡          ¡ . luteinizing hormone nd 19. 78. structure of 80. See m tur tionpromoting f ctor mRNA. 19 oxyt ocin 19 N NADH dehydrogen se 93 N tion l Rese rch Council 52. for Elie Metchnikoff 44–45 nonverte r l fr ctures 70 northern lotting 103–104. in medic ine. 105 nucle r tr nsfer 42 P p66shc longevity gene 62. 15. 18. 37 osteoporosis 36–37. 63 pituit ry-specific tr nscription f ctor (PIT1) 62 pl ques 34 pl smids 97. 110–111 N ture (journ l) 45 ne m tode longevity genes 58–59. 16 pituit ry hormones 14–21. 80. ging 66–67 postgenomic er 43. 39. 93 phospholipid il yer 108. 79.

91 Rich rd III (Sh kespe re) 2 riv stigmine 69 RNA (ri onucleic c id) in 30S ri osom l su unit 81 nucleotides in 78.Index 155 prok ryote(s) evolution of 75 structure of 75 prol ctin 19 prol ctin-i nhi iting hormone 19 promoter 100 prop-1 longevity gene 62. Fred 47. 105 polymer se ch in re ction in 106 Southern lotting in 103 recom in nt pl smid 99 regul tive expression 47 rejuven tion 7 reproduction sexu l 84 sexu l 86. 58. error frequency of 10 purine 78. 102. 77. 79 structure of 80. 85 prost te c ncer. 101. 79 re com in nt DNA technology xi–xii. See electron tr nsport ch in restriction enzymes 95–97 retinoic cid (vit min A) 2 retrogr de response 56–57. 97 gene ther py with 106–110. 110 ¡         ¡                   ¡ ¡     ¡              ¡                       ¡                   ¡         ¡   ¡     ¡     ¡   ¡             ¡   ¡ ¡ ¡               ¡ ¡     ¡     . 101–103. 64 r te-of-living theory 13 recom in nt chromosome 87 S S cch romyces cerevisi e 46. 46–51 l eling cloned DNA in 100–101 northern lotting in 103–104. 55 S nger. 109 g enomic nd cDNA li r ries in 99–100 nd gerontology 43. 60 retroviruses 107–108. 49 protein synthesis. 81 RNA po lymer se 91 roundworm 88 rpd-3 longevity gene 57. 64 proph se in m eiosis 87. 98 DNA-modifying enzymes in 95–97 DNA sequencing in 101. ndrogen supplements nd 21 pro tein in 30S ri osom l su unit 81 structure of 78. S nti go 44 r ndom primer 101 r nd om segreg tion 88–89 r s-1 longevity gene 57. 80 protein electrophoresis 47–48 . See ri osom l RNA R r dio ctive cockt ils 2 r dium 2 R món y C j l. 104 fluorescent in situ hy ridiz tion in 104–106 gel electrophoresis in 96. 58 r s-2 longevity gene 57. 79 pyrimidine 78. 108. 79 ri osom l RNA (rRNA) 91 ri o somes 76. 64 rRNA. See RNA ri ose 77–78. 108 reverse tr nscript se 1 00 reversi le dementi 69 revised c t strophe theory 46 R group 77 rheum toid r thritis 33 ri onucleic cid. 63. 88 respect for persons 73 respir tory ch in. 88 in mitosis 84. 95–106 DNA cloning in 97–99. 103. 58. 58.

91–93. 40–41 thyroid-stimul ting hormone (TSH) 16. 64 sister chrom tids 84. 19 prop-1 nd 62 supplements of 39. 19       ¡                                       ¡  ¡     ¡           ¡     ¡    ¡                               ¡    ¡               . E. 58. 59–60. 20 S ph se 89 St nford University 46 st rch 83 st rv tio n diet 13. 81–83 sug rs 77–78. 37. 91–93. 17–18 . 31 TSH. 61 syn pse 26. 81. Anton 44 sen gen e 25–26. 28. 92 urin ry system 70–71 uterus 15. 28. 92 TRH. 64 Sh kespe re. 61. life sp n of xv. 18 thyrotropin 16. 79 superoxide dismut se (SOD) 14. 92 tr nsfer RNA (tRNA) 45 tr nsl tion 47. 16. Willi m 2 shotgun sequencing 111 sickle-cell n emi 107 sir-2 longevity gene 57. 31–32 senilin 25–26 serine 91. 103 Southern lotting 103 sperm. 101–103. 39–40 synthesis of. 60 stroke dementi fter 69 incontin ence fter 70 “A Structure for Deoxyri ose Nuclei Acid” (W tson nd Crick) 45 sturge on. 29 synovium 33 thyroid gl nds 15. 29 syn ptic junctions 26. 64 som tic cell 86–88 Southern. 16. luteinizing hormone nd 19 thi zide 69 30S ri osom l su unit 81 ThoR di 2 thorium 2 thymine 78. 110 Schneider. 27–28 telomeres 11–13 teloph se in meiosis 87 i n mitosis 85. See thyrotropinre le sing hormone trunc ted APP (tAPP) 31. See trunc ted APP t u gene 25. 19 thyrotropin-rele sing hormone (TRH) 17–18. 19 thyroxine 18. 92 U ultr sound densitometry 70 University of C m ridge 110 University of Wisconsin 2 2 ur cil 78. 16 testosterone decre se in levels of 39 supplements of 21. M. production of 86 follicle-stim ul ting hormone nd 18.156 Aging S nger sequencing re ction 101. 61 sug r po lymers 80. 88 sgs-1 longevity gene 57. 18. 85. 4–5 sturgeon eggs 4 sug r y longevity gene 61. 58. 81. See superoxide dismut se sod-1 longevity gene 59–60. See thyroid-stimul ting hormone type I di etes 36 type II di etes 36 T tAPP. 86 testes 15. 87 smoking 33 SOD. 19 thyroid hormones 16. 63. 41–42 steroid hormone receptor 59. 92 sexu l reproduction 86. 40–41 tolterodine 70–71 topic l drugs 68 tr nscription 4 7.

41               ¡       . J mes 45 Weism nn. 70 viruses 107–109. 70 vit min E 14. 41 vit min D 37. August 44 Werner’s syndrome 53. 64 World He lth Org niz tion (WHO) 65 wrn gene 58. 108 vision. 64  ¡ Y ye st 55.Index 157 s iom rker 51 vit min A W W tson. 58. 55–58 ¡    X X-r y sorptiometry 70 ker’s 46 longevity genes of 56–57. 63. 63–64         ¡   V verte r l fr ctures 37. 2 vit min C 14.

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