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Biology of Aging PDF
OF
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AGING
2
AGING UNDER THE
MICROSCOPE
CELL
NUCLEUS
DNA
ILLUSTRATION AND INFORMATION ADAPTED FROM WWW.GENOME.GOV
To answer questions about why and how we age, some scientists look for mechanisms or
pathways in the body that lead to aging. Our cells constantly receive cues from both inside and
outside the body, prompted by such things as injury, infection, stress, or even food. To react and
adjust to these cues, cells send and receive signals through biological pathways. Some of the
most common are involved in metabolism, the regulation of genes, and the transmission
of signals. These pathways may also be important to aging.
healthier longer.
One approach to aging biology research The naked mole rat, a mouse-size rodent
is called “comparative biology.” It involves that lives underground, has been widely used
comparing two or more similar species that have in comparative research. It lives approximately
very different lifespans—one lives much longer 17 years in the wild and more than 28 years
than the other—to understand how the longer- in captivity. Its relative, the mouse, lives a
lived species has, as one NIA-funded researcher maximum of 4 years. What accounts for this
puts it, “exceptional resistance to basic aging startling difference? Naked mole rats have lower
processes.” Comparative biology studies metabolic rates and body temperature, meaning
generally focus on species that live at least twice
that they require less energy to survive. They
as long as their close relatives.
have low concentrations of blood glucose (blood
A few possible theories explain what may be sugar), insulin, and thyroid hormone, so they are
taking place among these longer-lived animals: less susceptible to certain diseases. Naked mole
►►They experience a slower rate of rats are better able to withstand some types
age-related decline. of biological stress and, at this point, there has
►► They can survive even when their organs and/or never been a case of cancer reported in these
systems break down and have minimal function. animals. All these factors and likely others yet to
►►They are better able to tolerate cellular be determined contribute to their healthier and
damage or diseases. longer life.
14 GENETICS
HUMAN GENETIC BLUEPRINT
CELL
23 PAIRS OF CHROMOSOMES
GENES NUCLEUS
ILLUSTRATION ADAPTED FROM ALZHEIMER'S DISEASE: UNRAVELING THE MYSTERY
C G
A
T C
T
G
A DNA STRAND
BASES
16 GENETICS
THE FUTURE OF AGING RESEARCH
EPIGENETICS
An emerging area of research called “epigenetics” opens the door to a scientific
blending of two worlds that for decades were thought of as totally separate—
that is nature and nurture, or more specifically genetics and the environment.
Epigenetics research looks at how your environment, over time, can affect how
your genes work and influence your development, health, and aging.
At the center of this research is the Epigenetics might also explain variations
epigenome—chemical modifications, or in lifespan among laboratory mice that are
marks, on our DNA, or in proteins that genetically identical and seemingly raised
interact with DNA, that tell it what to do, in the exact same environment. Scientists
where to do it, and when to do it. The marks theorize that the difference in their
that make up the epigenome are affected lifespans may result from a disparity in the
by your lifestyle and environment and may amount of nurturing they received when
change, for example, based on what you eat very young. The mice with the shorter
and drink, if you smoke, what medicines lifespan might have been less adept at feed-
you take, and what pollutants you encounter. ing and, therefore, got less of their mother’s
Changes in the epigenome can cause milk, or their mother may have licked them
changes in gene activity. Most epigenetic less, or they may have slept farther away from
changes are likely harmless, but some could the center of the litter. Receiving less nurtur-
trigger or exacerbate a disease or condition, ing may have influenced their epigenetics,
such as your risk for age-related diseases. marking the genes that control aging.
In some cases, scientists find that these
As epigenetic research moves forward,
epigenetic changes driven by the environ-
scientists hope to answer three key questions:
ment can be inherited by the offspring.
Identical, maternal twins are ideal for
• How do changes in the epigenome trans-
late into long-term differences in health
epigenetic research. At birth, twins have
and aging?
nearly the same genetic blueprint; however,
over time, they may have fewer identical • Do single events influence the epigenome?
traits. Careful study of these changes may • If single events can change the epigenome,
help scientists better understand environ- does the organism’s age (or stage of devel-
mental and lifestyle’s influence on genes. opment) at the time of the change matter?
18 GENETICS
TELOMERASE
20 GENETICS
THE FUTURE OF AGING RESEARCH
Stem cells can come from a variety of sources. people with severe burns on the outmost
Adult stem cells are candidates for regen- layer of their eyes (the cornea) by using
erative medicine approaches for several stem cells grown in the laboratory.
reasons—doctors can use the patient’s own Researchers are also looking for alterna-
stem cells; stem cells can develop into nearly tives to stem cells that have similar healing
any type of cell based on where they are abilities and can be used in regenerative
inserted and other factors; and stem cells medicine. It appears that certain cells,
continue to function normally during an like skin cells, can be reprogrammed to
almost infinite number of cell divisions, act as artificial stem cells, called induced
making them essentially immortal. There-
pluripotent cells.
fore, in theory, if stem cells were inserted in a
damaged part of the body, they could develop Many questions about stem cell (and
into area-specific cells that could potentially induced pluripotent cell) therapy need to be
restore function. But does that work? That’s answered: Do older adults have enough stem
what researchers are trying to find out. cells for this type of therapy or do they need
to be donated from someone else? Would
Findings from early research on regen-
creating stem cells from an older person’s
erative medicine, primarily in animal
skin cells work? Would stem cell therapy restore
models, show potential for stem cell treat-
health and vigor to an older person or only
ment. For example, inserting mouse ovarian
work in a younger person? How would stem
cells created from a female donor’s stem
cell therapy work on the cellular level—would
cells into infertile mice restored the mice’s
stem cells replace the non-functioning cells
ability to reproduce. Another study in
mice found that function could be restored or would they reactivate and repair the dam-
to injured muscle tissue by reactivating aged cells? Would stem cell therapy work in
existing stem cells rather than transplanting all areas of the body, or only in some areas?
new ones. The ability to reactivate dormant While many questions remain, the prospect
adult stem cells continues to be investigated. of regenerative medicine could have impor-
In a 2010 Italian study with human partici- tant implications for the treatment of many
pants, researchers restored vision to some degenerative diseases.
24 METABOLISM
HEAT SHOCK PROTEINS
STRESS
The first C. elegans worm genetically manipulated to have a longer lifespan
was resistant to stress caused by heat. Subsequently, researchers learned
that a common thread among all long-lived animals is that their cells (and in
some cases the animals as a whole) are more resistant to a variety of stresses,
compared to animals with an average or shorter lifespan.
Scientists also found that age-related dam- and if these longer-lived animals are resis-
age to DNA and proteins is often reversible tant to all or only certain sources of stress.
and does not cause problems until the dam- In addition, researchers are studying
age evokes a stress response. This suggests the relationship between psychological
that the stress response, rather than the stress and aging. In one study, mothers of
damage itself, is partially responsible for severely and chronically sick children had
age-related deterioration. shorter telomeres, relative to other women.
Some biologists have started looking In other research, caregivers of people with
at stress resistance when choosing animal Alzheimer’s disease were found to have
models to study as examples of successful shortened telomeres. These findings could
aging. Researchers can test stress resistance suggest that emotional or psychological
in young animals and then continue study- stress might affect the aging process. More
ing only those animals demonstrating high research on the mechanisms involved is
resistance. Ongoing studies will determine needed before scientists can make any
if there is a direct cause-effect relationship conclusions about clinical implications.
between stress resistance and longevity,
26 METABOLISM
calorie consumption from the normal diet
with a balanced amount of protein, fat, vita-
mins, and minerals. In the 1930s, investigators
found that laboratory rats and mice lived
up to 40 percent longer when fed a calorie-
restricted diet, compared to mice fed a normal
diet. Since that time, scientists observed that
calorie restriction increased the lifespan of
many other animal models, including yeast,
worms, flies, some (but not all) strains of
mice, and maybe even nonhuman primates.
In addition, when started at an early age or as
a young adult, calorie restriction was found
to increase the health span of many animal
models by delaying onset of age-related dis-
ease and delaying normal age-related decline.
Two studies of calorie restriction in non-
human primates (the animals most closely
Does how much you eat related to humans) have had intriguing
results. In a study conducted at NIA, monkeys
affect how long you live? fed a calorie-restricted diet had a notably
decreased and/or delayed onset of age-related
Your body needs food to survive. However, the diseases, compared to the control group of
very process of extracting energy from food— “normal” eaters. In a University of Wisconsin
metabolizing food—creates stress on your body. study supported by NIA, calorie-restricted
Overeating creates even more stress on the rhesus monkeys had three times fewer age-
body. That’s part of the reason why it can lead to related diseases compared to the control
a shorter lifespan and serious health problems group. The Wisconsin study also found that
common among older people, including cardio- rhesus monkeys on a restricted diet had fewer
vascular disease and type 2 diabetes. age-related deaths compared to their normal
Calorie restriction, an approach primarily fed controls. In 2007, when the findings from
(but not exclusively) used in a research set- the study conducted at NIA were published,
ting, is more tightly controlled than normal it was too early to determine whether calo-
healthy eating or dieting. It is commonly rie restriction had any effects on lifespan.
defined by at least a 30 percent decrease in Research in primates continues.
28 METABOLISM
those that scientists think may be pertinent or maximum lifespan. These findings suggest
to calorie restriction. The most relevant are that resveratrol does not affect all aspects of
the sirtuins and mTOR (mammalian target the basic aging process and that there may
of rapamycin) pathways as discussed on be different mechanisms for health versus
page 16. In several, but not all cases, disrupting lifespan. Research on resveratrol continues
these pathways means the organism no lon- in mice, along with studies in nonhuman
ger responds positively to calorie restriction. primates and people.
These two pathways have been important Rapamycin, another possible calorie
for identifying at least two compounds that restriction mimetic, acts on the mTOR path-
may mimic the effects of calorie restriction: way. This compound’s main clinical use is to
resveratrol and rapamycin. help suppress the immune system of people
Resveratrol, found naturally in grapes, who have had an organ transplant so that
wine, and nuts, activates the sirtuin pathway. the transplant can succeed. A study by NIA’s
It has been shown to increase the lifespan Interventions Testing Program, as discussed
of yeast, flies, worms, and fish. In 2006, NIA on page 7, reported in 2009 that rapamycin
researchers, in collaboration with university extended the median and maximum lifespan
scientists funded by NIA, reported on a study of mice, likely by inhibiting the mTOR path-
comparing mice fed a standard diet, a high way. Rapamycin had these positive effects
fat-and-calorie diet, or a high fat-and-calorie even when fed to the mice beginning at
diet supplemented with resveratrol beginning early-old age (20 months), suggesting that
at middle age. Resveratrol appeared to lessen an intervention started later in life may still
the negative effects of the high fat-and-calorie be able to increase longevity. Researchers are
diet, both in terms of lifespan and disease. In now looking at rapamycin’s effects on health
a 2008 follow-up study, investigators found span and if there are other compounds that
that resveratrol improved the health of aging may have similar effects as rapamycin on
mice fed a standard diet. It prevented age- and the mTOR pathway.
obesity-related decline in heart function.
Scientists do not yet know how resveratrol,
Mice on resveratrol had better bone health,
rapamycin, and other compounds that dem-
reduced cataract formation, and enhanced
onstrate effects similar to calorie restriction
balance and motor coordination compared to
will influence human aging. Learning more
non-treated mice. In addition, resveratrol was
about these calorie restriction mimetics, and
found to partially mimic the effects of calorie
the mechanisms and pathways underlying
restriction on gene expression profiles of
calorie restriction, may point the way to future
liver, skeletal muscle, and adipose (fatty) tissue
healthy aging therapies.
in the mice. However, the compound did not
have an impact on the mice’s overall survival
32 IMMUNE SYSTEM
ORGANS OF THE IMMUNE SYSTEM
BARRIERS — TONSILS
NOSE, MUCOUS
LYMPH NODES
LYMPHATIC VESSELS
THYMUS
LYMPH NODES
SPLEEN
ADAPTED FROM WWW.NIAID.NIH.GOV
BONE MARROW
LYMPH NODES
LYMPHATIC VESSELS
ALTERING OLDER
ADULTS' IMMUNITY
Our ability to survive the germs in older people, or is immunosenescence
around us is based on a tightly somehow beneficial within the context of
controlled immune system. Too the aging body?
little of an immune response Given the delicate balance of the
makes us susceptible to infection, immune system, gerontologists suspect that,
including life-threatening pneumonia. along with its more obvious negative con-
Conversely, an overactive immune response sequences, immunosenescence might have
is at the root of autoimmune diseases a protective role in seniors. More research
common among older people and may is needed before scientists fully understand
contribute to age-related chronic diseases the aging immune system and determine
like Alzheimer’s disease, osteoarthritis, whether changing an immune response
diabetes, and heart disease. So, should sci- would lead to an increase or a decrease in
entists try to change the immune response health span and lifespan in humans.
34 IMMUNE SYSTEM
THE PROMISE
OF RESEARCH
be a sign of what to expect during her mythical elixir promised to restore people
own golden years. And, the man in to their younger selves. But research may
middle age can know that he looks and very well offer us the means to a healthier,
feels better when making healthy food longer life. And, with that, we may have
choices and staying physically active the opportunity to spend more time with
without understanding the intricacies our loved ones, the opportunity to meet
of metabolism and biological stress. our great-great-grandchildren, and the
Aging is part of us, it’s part of life. opportunity to enjoy more life experiences.
Antioxidants – Compounds that may protect Enzyme – A protein that increases the rate of a
cells from oxygen free radicals by preventing or specific chemical reaction.
slowing the process of oxidation. Some anti-
oxidants are enzyme proteins like superoxide Fibroblast – One of the major cell types found
dismutase (SOD) and catalase, while others are in skin and other tissues. Fibroblasts secrete
nutrients, such as vitamin C. molecules that have important structural
properties for tissues and organs, and they
Calorie restriction – A diet that is lower by a change with age.
specific percent of calories than the normal diet,
but includes all essential nutrients. At this time Free radicals – Unstable molecules that react
calorie restriction is an experimental interven- readily with other molecules to try to become
tion being studied to determine its impact on stable. Oxygen free radicals are produced nor-
health and longevity. mally when food is metabolized and may cause
damage to cells. Over a lifetime, this damage
Cell senescence – A process in which a cell may contribute to aging.
turns off its capacity to produce new cells, stops
dividing, and has limited function. Cell senes- Gene – A region of DNA containing code that
cence may contribute to aging, but it may also can be read to make proteins in the cell. Genes
be a protective mechanism against cancer (a are responsible for many heritable traits.
disease state in which cells continue to divide
without control).
Immunosenescence – The age-related decline
in functions of the immune system.
Centenarian – A person who has lived at least
100 years.
Life expectancy – The average number of
years that members of a population (or species)
Chromosome – A structure inside cells contain- live; also known as average lifespan.
ing DNA, which carries our genetic information
and is responsible for heritable traits.
Lymphocytes – White blood cells that are
important to the immune system. A decline in
DNA – Abbreviation for deoxyribonucleic acid; lymphocyte function with advancing age is be-
DNA contains the genetic code for all animals ing studied for insights into aging and disease.
and plants, from single-cell organisms to humans.
Maximum lifespan – The greatest age reached
by any member of a given population (or species).
36
BIBLIOGRAPHY
Mitochondria – Cell organelles that Austad, S.N., “Comparative Biology of Aging,” Journal of
Gerontology: Biological Sciences, 64A(2): 199-201, 2009.
produce energy necessary for life from the
foods we eat. Mitochondria contain DNA, Bartke, A., “Insulin and Aging,” Cell Cycle, 7(21):
which may be damaged by oxygen free radi- 3338-3343, 2008.
cals produced during this process. Damage
Bartke, A., “The Somatotropic Axis and Aging: Mechanisms
of mitochondrial DNA may contribute to and Persistent Questions about Practical Implications,”
aging. Mitochondria also are involved in Experimental Gerontology, 44(6-7): 372-374, 2009.
controlling cell death.
Barzilai, N. and Bartke, A., “Biological Approaches to
Proteins – Molecules arranged in a specific Mechanistically Understand the Healthy Life Span Exten-
sion Achieved by Calorie Restriction and Modulation of
order determined by DNA. Proteins are Hormones,” Journal of Gerontology: Biological Sciences,
essential for all life processes. Certain proteins, 64A(2): 187-191, 2009.
such as those protecting against free radicals
Bauer, M.E., “Chronic Stress and Immunosenescence: A
and those produced by the immune system,
Review,” NeuroImmunoModulation, 15: 241-250, 2008.
are studied extensively by gerontologists.
Baur, J.A., Pearson, K.J., Price, N.L., et al., “Resveratrol
Stem cells – Cells with the potential Improves Health and Survival of Mice on a High-Calorie
to become many different types of cells Diet,” Nature, 444: 337-342, 2006.
found in the body. Stem cells are also able
Blagozklonny, M.V. and Campisi, J., “Cancer and Aging,”
to replicate almost indefinitely without Cell Cycle, 7(17): 2615-2618, 2008.
becoming abnormal.
Buffenstein, R., “The Naked Mole-Rat: A New Long-Living
Telomerase – An enzyme that restores Model for Human Aging Research,” Journal of Gerontology:
Biological Sciences, 60A(11): 1369-1377, 2005.
telomeres to the ends of chromosomes in
certain cells, such as egg and sperm cells. This Calvanese, V., Lara, E., Kahn, A., and Fraga, M.F., “The Role
telomere lengthening insures that the cells of Epigenetics in Aging and Age-Related Diseases,” Ageing
can continue to divide and multiply. Research Reviews, 8: 268-276, 2009.
Chen, W.H., Kozlovsky, B.F., Effros, R.B., et al., “Vaccination Garinis, G.A., van der Horst, G.T.J., Vijg, J., and Hoeijmakers,
in the Elderly: An Immunological Perspective,” Trends in J.H.J., “DNA Damage and Ageing: New-Age Ideas for an Age-
Immunology, 30(7): 351-359, 2009. Old Problem,” Nature Cell Biology, 10(11): 1241-1247, 2008.
Christensen, K., Doblhammer, G., Rau, R., and Vaupel, J.W., Geiger, H. and Rudolph, K.L., “Aging in the Lympho-hema-
“Ageing Populations: The Challenges Ahead,” Lancet, 374: topoietic Stem Cell Compartment,” Trends in Immunology,
1196-1208, 2009. 30(7): 360-365, 2009.
Christensen, K., McGue, M., Petersen, I., et al., “Exceptional Globerson, A. and Barzilai, N., “The Voyage to Healthy
Longevity Does Not Result in Excessive Levels of Disability,” Longevity: From Experimental Models to the Ultimate
Proceedings of the National Academy of Sciences, 105(36): Goal,” Mechanisms of Ageing and Development, 126:
13274-13279, 2008. 225-229, 2005.
Colman, R.J., Anderson, R.M., Johnson, S.C., et al., “Calorie Guarente, L., “Sirtuins in Aging and Disease,” Cold Spring
Restriction Delays Disease Onset and Mortality in Rhesus Harbor Symposia on Quantitative Biology, 72: 483-488, 2007.
Monkeys,” Science, 325: 201-204, 2009.
Guevara-Aguirre, J., Balasubramanian, P., Guevara-Aguirre,
Cox, L.S. and Mattison, J.A., “Increasing Longevity through M., et al., “Growth Hormone Receptor Deficiency Is Associ-
ated with a Major Reduction in Pro-Aging Signaling, Cancer,
Caloric Restriction or Rapamycin Feeding in Mammals:
and Diabetes in Humans,” Science Translational Medicine,
Common Mechanisms for Common Outcomes?”
3(70): 70ra13, 2011.
Aging Cell, 8: 607-613, 2009.
Hadley, E.C., Lakatta, E.G., Morrison-Bogorad, M., et al.,
Cuervo, A.M., “Autophagy and Aging: Keeping that Old
“The Future of Aging Therapies,” Cell, 120: 557-567, 2005.
Broom Working,” Trends in Genetics, 24(12): 604-612, 2008.
Harrison, D.E., Strong, R., Sharp, Z.D., et al., “Rapamycin
Cuervo, A.M., “Calorie Restriction and Aging: The Ultimate
Fed Late in Life Extends Lifespan in Genetically Heteroge-
‘Cleansing Diet,’” Journal of Gerontology: Biological
neous Mice,” Nature, 460: 392-395, 2009.
Sciences, 63A(6): 547-549, 2008.
Herbig, U., Ferriera, M., Condel, L., et al., “Cellular
DiCarlo, A.L., Fuldner, R., Kaminski, J., and Hodes, R., “Aging
Senescence in Aging Primates,” Science, 311: 1257, 2006.
in the Context of Immunological Architecture, Function
and Disease Outcomes,” Trends in Immunology, 30(7): 293- Hildt, E., “Living Longer: Age Retardation and Autonomy,”
294, 2009. Medicine, Health Care, and Philosophy, 12(2): 179-185, 2009.
Finch, C.E., “Update on Slow Aging and Negligible Senes- Kennedy, B.K., “The Genetics of Ageing: Insight from
cence—A Mini-Review,” Gerontology, 55: 307-313, 2009. Genome-Wide Approaches in Invertebrate Model Organ-
isms,” Journal of Internal Medicine, 263: 142-152, 2008.
Fraga, M.F., Ballestar, E., Paz, M.F., et al., “Epigenetic Differ-
ences Arise During the Lifetime of Monozygotic Twins,” Khrapko, K. and Vijg, J., “Mitochondrial DNA Mutations
Proceedings of the National Academy of Sciences, 102(30): and Aging: Devils in the Details?” Trends in Genetics, 25(2):
10604-10609, 2005. 91-98, 2009.
38
Kirkwood, T.B.L., “Understanding the Odd Science of Aging,” Ostan, R., Bucci, L., Capri, M., et al., “Immunosenescence and
Cell, 120: 437-447, 2005. Immunogenetics of Human Longevity,” NeuroImmuno-
Modulation, 15: 224-240, 2008.
Leslie, M., “Searching for the Secrets of the Super Old,”
Science, 321: 1764-1765, 2008. Panda, A., Arjona, A., Sapey, E., et al., “Human Innate Immu-
nosenscence: Causes and Consequences for Immunity in
Martin, G.M., Bergman, A., and Barzilai, N., “Genetic Deter- Old Age,” Trends in Immunology, 30(7): 325-333, 2009.
minants of Human Health Span and Life Span: Progress and
New Opportunities,” PLoS Genetics, 3(7): 1121-1130, 2007. Pawlikowska, L., Hu, D., Huntsman, S., et al., “Association
of Common Genetic Variation in the Insulin/IGF-1
Mattison, J.A., Roth, G.S., Lane, M.A., and Ingram, D.K., Signaling Pathway with Human Longevity,” Aging Cell,
“Dietary Restriction in Aging Nonhuman Primates” in 8: 260-472, 2009.
Mobbs, C.V., Yen, K., Hof, P.R. (eds): Mechanisms of Dietary
Restriction in Aging and Disease. Interdisciplinary Topics Pearson, K.J., Baur, J.A., Lewis, K.N., et al., “Resveratrol Delays
in Gerontology. Basel, Karger, 35: 137-158, 2007. Age-Related Deterioration and Mimics Transcriptional
Aspects of Dietary Restriction without Extending Life Span,”
Mattson, M., “Dietary Factors, Hormesis and Health,” Cell Metabolism, 8: 157-168, 2008.
Ageing Research Reviews, 7: 43-48, 2008.
Pedersen, P.L., “Mitochondrial Matters of the Heart:
Mattson, M., “Energy Intake, Meal Frequency, and
A Plethora of Regulatory Modes to Maintain Function
Health: A Neurobiological Perspective,” Annual Review
for a Long Lifetime,” Journal of Bioenergetics and
of Nutrition, 25: 237-260, 2005.
Biomembranes, 41: 95-98, 2009.
Sierra, F., Hadley, E., Suzman, R., and Hodes, R., “Prospects
for Life Span Extension,” Annual Review of Medicine, 60:
457-469, 2009.
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