Theories of aging

Aging is the process of growing older and includes changes in both biology and psychology.
Biology refers to the way the body functions. Psychology describes how the mind functions.
How people age has to do with genetics, environment, and lifestyle over a lifetime. The process
of aging is complex, and may derive from a variety of different mechanisms and exist for a
variety of different reasons. Aging is a universal biological phenomea, at least amongst
eukaryotic organisms. Yet the average lifespan within and between species can vary greatly.
This suggests that both genetic and environmental factors contribute to aging. Theories that
explain aging can generally be divided between the programmed and error theories of aging.
Programmed theories imply that aging is regulated by biological clocks operating throughout
the life span. 

This regulation would depend on changes in gene expression that affect the systems
responsible for maintenance, repair and defense responses. Error theories blame environmental
insults to living organisms that induce cumulative damage at various levels as the cause of
aging (e.g., DNA damage, oxygen radicals, cross-linking). One potential cause of senescence is
the accumulation of mutations in DNA, eventually leading to the progressive loss of key genes.
Another is the shortening of telomeres in the process of DNA replication during cell division.

Evolutionary theories

One view is that it is due to a particular DNA programming that has the sole purpose to "clean"
Earth from old genes and assure offspring better living conditions through benign mutations.
One possible mechanism may be "senescence genes". Genes which have a deleterious effect on
individual's fitness are selected against by natural selection. Mutations in these genes which
postpone the deleterious effect of the gene to a later time in individual's life history reduce the
effect of natural selection to the gene, because the selection has less time to act on it. If the
gene doesn't have a negative effect until after the individual has reproduced, the gene may
escape natural selection altogether, because when selection starts to affect the gene, it has
already propagated to the next generation.
An alternative view of looking at this question is: why do humans live so long? No other primate
has such an extended post-reproductive phase of life. The "grandmothering theory" of evolution
holds that because humans can teach their young, there was an evolutionary advantage for
groups of humans who had a few older survivors to teach and care for the young. There is no
particular evidence for this theory.

Gene regulation

The first genetic component of aging was first identified in the budding yeast Saccharomyces
cerevisiae. Replicative yeast cell aging is defined as the number of cell division (daughter cells)
that can be produced by any given mother cell. Calorie restriction in yeast results in lifespan
extension (each mother cell can produce more daughter cells). The gene Sir2 was identified as
a gene required for lifespan extension by calorie restriction, and yeast cells without sir2 have a
decreased lifespan. Sir2 is a NAD+-dependent histone deacetylase, and is required for genomic
silencing at three loci: the yeast mating loci, the telomeres and the ribosomal DNA (rDNA).
Yeast replicative aging is caused by homolgous recombination between rDNA repeats; excision
of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs
replicate and preferentially segregate to the mother cell during cell division, and are believed to
result in cellular senescence by titrating away essential nuclear factors. Lately research on a
worm called Caenorhabditis elegans has demonstrated that aging is in part regulated by genes.
The worm's short life span can be increased by more than 200 percent through genetic
engineering. For example, mutations that affect insulin-like signaling in worms, flies and mice
are associated with extended lifespan. This planned-obsolescence theory focuses on the genetic
programming encoded within our DNA. We are born with a unique genetic code, a
predetermined tendency to certain types of physical and mental functioning, and that genetic
inheritance has a great deal to say about how quickly we age and how long we live. To use a
macabre analogy it's as though each of us comes into the world as a machine that is
preprogrammed to self-destruct. Each of us has a biological clock ticking away set to go off at a
particular time, give or take a few years. When that clock goes off it signals our bodies first to
age and then to die.
However, as with all aspects of our genetic inheritance the timing on this genetic clock is
subject to enormous variation, depending on what happens to us as we grow up and on how
we actually live (the old "nature versus nurture" debate). Anti-aging medicine addresses this
issue by augmenting the basic building blocks of DNA within each of our cells, preventing
damage to and increasing repair of DNA. In this way we believe anti-aging treatment can help
us escape our genetic destinies, at least to some extent.

The free radical theory

This exciting development in anti-aging research was first introduced by R. Gerschman in 1954,
but was developed by Dr. Denham Harman of the University of Nebraska, College of Medicine.
"Free radical" is a term used to describe any molecule that differs from conventional molecules
in that it possesses a free electron, a property that makes it react with other molecules in highly
volatile and destructive ways. In a conventional molecule the electrical charge is balanced.
Electrons come in pairs so that their electrical energies cancel each other out. Atoms that are
missing electrons combine with atoms that have extra electrons, creating a stable molecule with
evenly paired electrons and a neutral electrical charge. The free radical on the other hand has
an extra negative charge. This unbalanced electrical energy tends to make the free radical
attach itself to other molecules as it tries to steal a matching electron to attain electrical
equilibrium. Some scientist speak of these free radicals as "promiscuous," breaking up the
happy marriages of paired electrons in neighboring molecules in order to steal an electron
"partner" for themselves. In doing so they create free radicals and extensive bodily damage.
Free-radical activity within the body is not only or even primarily negative. Without free-radical
activity, that is without biochemical electricity, we would not be able to produce energy,
maintain immunity, transmit nerve impulses, synthesize hormones or even contract our
muscles. The body's electricity enables us to perform these functions and that electricity comes
from the unbalanced electron activity of free radicals.
But free radicals also attack the structure of our cell membranes, creating metabolic waste
products, including substances known as lipofuscins. An excess of lipofuscins in the body is
shown as a darkening of the skin in certain areas, so-called "aging spots." Lipofuscins in turn
interfere with the cells ability to repair and reproduce themselves. They disturb DNA and RNA
synthesis, interfere with synthesis of protein, lower our energy levels, prevent the body from
building muscle mass and destroy cellular enzymes, which are needed for vital chemical
processes. This type of free-radical damage begins at birth and continue until we die. In our
youth its effects are relatively minor since the body has extensive repair and replacement
mechanisms that in healthy young people function to keep cells and organs in working order.
With age however the accumulated effects of free-radical damage begin to take their toll. Free-
radical disruption of cell metabolism is part of what ages our cells; it may also create mutant
cells leading ultimately to cancer and death.

Free radicals attack collagen and elastin, the substances that keep our skin moist, smooth,
flexible and elastic. These vital tissues fray and break under the assaults of free radicals, a
process particularly noticeable in the face, where folds of skin and deep-cut wrinkles are
testaments to the long-term effect of free-radical damage.

Another way of looking at free-radical changes is to think of its as oxidation, the process of
adding oxygen to a substance. Another word for oxidation is rust and in a sense our aging
process is analogous to the rusting away of a once-intact piece of metal. Because forms of
oxygen itself are free radicals, our very breathing and our otherwise healthy aerobic exercise
generate free radicals that help along the aging process. Substances that prevent the harmful
effects of oxidation are known as antioxidants. Natural antioxidants include vitamin C, vitamin E
and beta carotene, the substance that our body uses to produce vitamin A. Specialists in anti-
aging medicine prescribe a host of natural and manufactured antioxidants to help combat the
effects of aging.

Another substance that combats free-radical damage is known as a free-radical scavenger.

Free-radical scavengers actually seek out free radicals and harmlessly bind them before they
can attach themselves to other molecules and/or cause cross-linking. As we'll see in subsequent
chapters many vitamins and minerals and other substances fight aging by acting as free-radical
scavengers. The wear and tear theory of aging

The wear and tear theory of aging suggests that years of damage to cells, tissues and organs
eventually wears them out, killing them and then the body. The damage begins at the level of
molecules within our cells. The DNA that makes up our genes sustains repeated damage from
toxins, radiation and ultraviolet light. Our bodies have the capacity to repair DNA damage, but
not all of those repairs are accurate or complete. Thus the damage progressively accumulates.
Our mitochondria, the tiny "powerhouses" inside our cells that transform energy into useful
form, are also susceptible to accumulated errors, and they have only a small capacity for repair.
At the ends of our chromosomes are "caps" of DNA called telomeres, which shorten with each
cell division. When they have reached a critically short length, the cells can no longer divide,
but rather become senescent. Studies published in the August 2001 issue of the Journal of the
American Geriatric Society have noted that loss of telomeres leads to DNA damage. Addition of
the enzyme telomerase, which repairs shortened telomeres, to cell cultures, appears to
maintain cells in a youthful state, perhaps by preventing some of the DNA damage that
telomere shortening can cause. While the relationship between this inability to divide at the
cellular level and broader aging at the organism level is not well characterized, these studies
give indirect support to the wear and tear theories of aging.
Evidence to support the wear and tear theory of aging comes from insect observations. For
example, few cells in the wing muscles of adult fruit flies reproduce, and while week-old fruit
flies can fly 110 minutes without landing, month-old fruit flies must land after 19 minutes.
Additional evidence comes from the accumulation of mitochondrial damage with aging in some
insects. However, scientists point out that this wear and tear could easily be viewed as a result
of aging and not a cause of it. Another argument against wear and tear as a major cause of
aging is the fact that while some investigators report an age-related decline in the ability of
certain animals (beagles, mice and rats) to repair their damaged or worn DNA, other scientists
studying beagles, mice and hamsters did not observe such a decline.

Scientists at the University of Chicago looked at the effect of a lifetime of exposure to stress
hormones such as cortisol, a naturally occurring steroid whose levels rise in our circulation
under physically and emotionally stressful conditions. They note that circulating cortisol levels
rise as we age. They also noted that while cortisol levels fall at night in younger adults, in older
adults, the levels do not fall as far, increasing our exposure to high levels of cortisol. They
speculate that the drop-off in variability of cortisol levels is due to the wear and tear of lifelong
exposures to stress.

The cross-linking theory of aging

The cross-linking theory of aging is based on the observation that with age, our proteins, DNA
and other structural molecules develop inappropriate attachments or cross-links to one another.
These unnecessary links or bonds decrease the mobility or elasticity of proteins and other
molecules. Proteins that are damaged or no longer needed are normally broken down by
enzymes called proteases, and the presence of cross-linkages inhibits the activity of proteases.
These damaged and unneeded proteins, therefore, stick around and can cause problems. Some
research supports this theory. Cross-linking of the skin protein collagen has been shown to be
at least partly responsible for wrinkling and other age-related changes in skin. Cross-linking of
proteins in the lens of the eye is also believed to play a role in age-related cataract formation.
Researchers speculate that cross-linking of proteins in the walls of arteries or the filtering
systems of the kidney account for at least some of the atherosclerosis (once called hardening of
the arteries) and age-related decline in kidney function observed in older adults. Another study
conducted at the Bjorksten Institute in Wisconsin treated brain tissue from young animals with
known cross-link-inducing compounds. That brain tissue soon looked quite similar to older brain
tissue with its naturally cross-linked brain proteins, adding evidence in support of this theory of
aging.
Somewhat indirect experimental evidence in support of the cross-linking theory of aging can be
found in studies that look at drugs that prevent cross-linking, and the impact of taking those
drugs on the various components of the aging process. Studies done in China and in the United
Kingdom on the molecule carnosine are provocative. Carnosine occurs in very low
concentrations in the brain and other tissues. In the laboratory, carnosine has been shown to
delay the senescence or aging of human cells called fibroblasts. Carnosine works by preventing
cross-linking of proteins.(4) The more recent Chinese studies suggest carnosine might be of
benefit in delaying the formation of cataracts, in which cross-linking is thought to play a part.

Although many scientists agree that cross-linking of proteins, and perhaps the cross-linking of
DNA molecules as well, is a component of aging, the lack of other direct experimental evidence
at this time leaves many unconvinced that it is a primary cause of aging.

Cellular senescence

Lately the role of telomeres has aroused general interest, especially with a view to the possible
genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres
with each cell cycle is also believed to influence the vitality of the cell, thus contributing to
aging. There have, on the other hand, also been reports that cloning could alter the shortening
of telomeres.
Chemical damage
It is also suggested that damage to long-lived biopolymers, e.g., structural proteins and DNA,
caused by ubiquitous chemical agents in the body, such as oxygen and sugars, are in part
responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of
biopolymers, or chemical attachment of unnatural subtituents (haptens) to biopolymers. Oxygen
spontaneously generates low levels of reactive oxygen species such as singlet oxygen,
peroxides and superoxide ion, which can in turn generate free radicals which can damage
structural proteins and DNA. Certain metal ions found in the body, such as copper and iron,
may participate in the process. (In Wilson's disease, a hereditary defect which causes the body
to retain copper, some of the symptoms resemble accelerated senescence.) These processes
are termed oxidant damage and are the target of the currently popular nutritional antioxidants.
Sugars such as glucose and fructose can react with certain amino acids such as lysine and
arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called
glycation. These adducts can further rearrange to form reactive species which can then cross-
link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-
structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-
associated disorders much earlier than the general population, but can delay such disorders by
rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to
oxidant damage in a process termed glycoxidation.

Chemical damage to DNA can lead to mutations (see above). Chemical damage to structural
proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can
lead to vessel-wall stiffness and thus hypertension, and vessel wall thickening and reactive
tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure.