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Proteins, in their myriad forms and functions, are the substances
most responsible for the day-to-day functioning of living organisms.
Some of these proteins seem to affect the way we age and how long
we live. |
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Treacherous
oxygen molecules, protective enzymes, hormones that seem to turn back
the clock, and proteins that may speed it up: The biochemistry of
aging is a rich territory with an expanding frontier. Major areas
of exploration include oxygen radicals and glucose crosslinking of
proteins, both of which damage cells; the substances that help prevent
and repair damage; and the role of specific proteins, particularly
heat shock proteins, hormones, and growth factors.
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Oxygen
Radicals
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Demolishing
proteins and damaging nucleic acids, oxygen radicals are thought to
be the villains in the day-to-day life of cells. The free radical
theory of aging, first proposed by Denham Harman at the University
of Nebraska, holds that damage caused by oxygen radicals is responsible
for many of the bodily changes that come with aging. Free radicals
have been implicated not only in aging but also in degenerative disorders,
including cancer, atherosclerosis, cataracts, and neurodegeneration.
They
damage cells and may cause tissues and organs to age.
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A free radical
is a molecule with an unpaired, highly reactive electron. An oxygen-free
radical is a byproduct of normal metabolism, produced as cells turn
food and oxygen into energy.
In need of
a mate for its lone electron, the free radical takes an electron
from another molecule, which in turn becomes unstable and combines
readily with other molecules. A chain reaction can ensue, resulting
in a series of compounds, some of which are harmful. They damage
proteins, membranes, and nucleic acids, particularly DNA, including
the DNA in mitochondria, the organelles within the cell that produce
energy.
But free radicals
do not go unchecked. Mounted against them is a multilayer defense
system manned by anti-oxidants that react with and disarm these
damaging molecules. Anti-oxidants include nutrients -- the familiar
vitamins C and E and beta carotene -- as well as enzymes, such as
superoxide dismutase (SOD), catalase, and glutathione peroxidase.
They prevent most, but not all, oxidative damage. Little by little
the damage mounts and contributes, so the theory goes, to deteriorating
tissues and organs.
Support for
the free radical theory comes from studies of anti-oxidants, particularly
SOD. SOD converts oxygen radicals into the also harmful hydrogen
peroxide, which is then degraded by another enzyme, catalase, to
oxygen and water.
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| Anti-Oxidants
and Aging Gerbils
A
boost for the hypothesis that high levels of anti-oxidants
can slow the aging process comes from a study of N-tert-butyl-alpha-phenylnitrone
or PBN in gerbils. Although it does not occur naturally
in the body, PBN works in much the same way as beta-carotene
and other anti-oxidants by binding and neutralizing free
radicals.
Older
gerbils had been shown to have increased levels of oxidized
protein in their brains by two researchers, Robert A. Floyd
at the Oklahoma Medical Research Foundation and John M.
Carney at the University of Kentucky. Curious about the
effects of anti-oxidants in older animals, Floyd and Carney
designed an experiment to learn whether PBN could lower
oxidized protein levels in gerbils' brains. Over a period
of 14 days they gave PBN to two groups of gerbils, one made
up of young adults, the other of older adults.
As
the older gerbils were treated with PBN, their levels of
oxidized protein decreased until they were nearly comparable
to levels found in the younger animals. After treatment
ended, oxidized protein gradually returned to pretreatment
levels. PBN had no effect on the young gerbils.
While
it is only one study and more are needed, this investigation
supports the idea that maintaining anti-oxidant defense
levels may be critical during aging. It also suggests that
an intervention such as PBN may someday provide the means.
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At the National
Institute on Aging (NIA), Richard Cutler has found that SOD levels
are directly related to life span in 20 different species; longer-lived
animals have higher levels of SOD, suggesting that the ability to
fight free radicals has something to do with longer life spans.
Levels of other anti-oxidants -- vitamin E and beta-carotene, for
example -- have also been correlated with life span.
Other studies
have shown that inserting extra copies of the SOD gene into fruit
flies extends their average life span. In three different laboratories,
researchers have reported that transgenic fruit flies, carrying
extra copies of the gene for SOD, live 5 to 10 percent longer than
average.
Other experimental
evidence lends support to the free radical hypothesis. For example,
higher levels of SOD and catalase have been found in long-lived
nematodes. And in another important study, giving gerbils a synthetic
anti-oxidant has reduced high levels of oxidized protein, a sign
of aging, in their brains. 
The discovery
of anti-oxidants raised hopes that people could retard aging simply
by adding them to the diet. Unfortunately taking SOD tablets has
no effect on cellular aging; the enzyme is simply broken down in
the body during digestion. And when anti-oxidant vitamins are added
to cells, they compensate by halting production of their own anti-oxidants,
leaving free radical levels unchanged.
Researchers
have not abandoned all hope for dietary anti-oxidants, however.
Current studies, for example, are exploring the possibility that
vitamin C can reduce heart disease by blocking oxidation of low-density
lipoproteins. Oxidation of these cholesterol-carrying proteins is
thought to be a key element in hardening of the arteries. In addition,
there is evidence that vitamin E in the diet may be linked to heart
attacks, with low vitamin E intake appearing to increase the risk.
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Glucose
Crosslinking
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Another suspect
in cellular deterioration is blood sugar or glucose. In a process
called non-enzymatic glycosylation or glycation, glucose molecules
attach themselves to proteins, setting in motion a chain of chemical
reactions that ends in the proteins binding together or crosslinking,
thus altering their biological and structural roles. The process is
slow but increases with time.
Crosslinks,
which have been termed advanced glycosylation end products (AGEs),
seem to toughen tissues and may cause some of the deterioration
associated with aging. AGEs have been linked to stiffening connective
tissue (collagen), hardened arteries, clouded eyes, loss of nerve
function, and less efficient kidneys.
These are
deficiencies that often accompany aging. They also appear at younger
ages in people with diabetes, who have high glucose levels. Diabetes,
in fact, is sometimes considered an accelerated model of aging.
Not only do its complications mimic the physiologic changes that
can accompany old age, but its victims have shorter-than-average
life expectancies. As a result, much research on crosslinking has
focused on its relationship to diabetes as well as aging.
One happy
finding is that the body has its own defense system against crosslinking.
Just as it has anti-oxidants to fight free-radical damage, it has
other guardians, immune system cells called macrophages, that combat
glycation. Macrophages with special receptors for AGEs seek them
out, engulf them, break them down, and eject them into the blood
stream where they are filtered out by the kidneys and eliminated
in urine.
Glucose,
the fundamental source of energy, reacts with and crosslinks
essential molecules.
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The only apparent
drawback to this defense system is that it is not complete and levels
of AGEs increase steadily with age. One reason is that kidney function
tends to decline with advancing age. Another is that macrophages,
like certain other components of the immune system, become less active.
Why is not known, but immunologists are beginning to learn more about
how the immune system affects and is affected by aging (see The
Immune System). And in the meantime, diabetes researchers are
investigating drugs that could supplement the body's natural defenses
by blocking AGE formation.
Crosslinking
interests gerontologists for several reasons. It is associated with
disorders that are common among older people, such as diabetes;
it progresses with age; and AGEs are potential targets for anti-aging
drugs. In addition, crosslinking may play a role in damage to DNA,
which has become another important focus for research on aging.
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DNA Repair
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In the normal
wear and tear of cellular life, DNA undergoes continual damage. Attacked
by oxygen radicals, ultraviolet light, and other toxic agents, it
suffers damage in the form of deletions, or destroyed sections,
and mutations, or changes in the sequence of DNA bases that
make up the genetic code.
Biologists
theorize that this DNA damage,
DNA
is damaged throughout life; the repair process may be a major
factor in aging, health, and longevity.
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which gradually
accumulates, leads to malfunctioning genes, proteins, cells, and,
as the years go by, deteriorating tissues and organs.
Not surprisingly,
numerous enzyme systems in the cell have evolved to detect and repair
damaged DNA. The repair process interests gerontologists. It is
known that an animal's ability to repair certain types of DNA damage
is directly related to the life span of its species. Humans repair
DNA, for example, more quickly and efficiently than mice or other
animals with shorter life spans. This suggests that DNA damage and
repair are in some way part of the aging puzzle.
In addition,
researchers have found defects in DNA repair in people with a genetic
or familial susceptibility to cancer. If DNA repair processes decline
with age while damage accumulates, as scientists hypothesize, it
could help explain why cancer is so much more common among older
people.
Gerontologists
who study DNA damage and repair have begun to uncover numerous complexities.
Even within a single organism, repair rates can vary among cells,
with the most efficient repair going on in terms (sperm and egg)
cell. Moreover, certain genes are repaired more quickly than others,
including those that regulate cell proliferation.
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Research
on Sunlight May Help Explain
What Happens to Skin as We Age
As
anyone who reads beauty magazines knows, sunlight damages
skin in ways that seem similar to aging. It causes wrinkles,
to begin with. And in both normal aging and photoaging
-- the process initiated by sunlight -- the skin becomes
drier and loses elasticity. Although gerontologists think
that the normal or intrinsic aging process is probably not
the same as photoaging, there are enough similarities to
make this a tantalizing field of study.
The
process of photoaging may hold clues to normal aging because
many of the same cells are affected. Photoaging, for example,
damages collagen and elastin, the two proteins that give
skin its elasticity. These proteins decline as we age, along
with the fibroblast cells that manufacture them. In addition,
the enzymes that break down collagen and elastin increase.
Other
changes occur in keratinocytes, upper-layer skin cells that
are shed and renewed regularly. In the normal aging process
the turnover of keratinocytes slows down and in photoaging,
they are damaged. Still other skin cells, called melanocytes,
are also affected by both processes: they decline with normal
aging, are killed in photoaging. (Stopped in their tracks
by sunlight, these normally migratory cells show up as freckles
in light skin.)
What
we don't know yet is exactly how photoaging damages cells.
Ultraviolet light can damage DNA and could be the culprit.
Free radicals could be involved in some way. Researchers
continue to explore these and other factors in the effort
to understand photoaging.
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Especially intriguing is repair to a kind of DNA that resides not
in the cell's nucleus but in its mitochondria. These small
organelles are the principal sites of metabolism and energy production,
and cells can have hundreds of them. Mitochondrial DNA is thought
to be injured at a much greater rate than nuclear DNA, possibly
because the mitochondria produce a stream of damaging oxygen radicals
during metabolism. Adding to its vulnerability, mitochondrial DNA
is unprotected by the protein coat that helps shield DNA in the
nucleus from damage.
Research has
shown that mitochondrial DNA damage increases exponentially with
age, and several diseases that appear late in life, including late-onset
diabetes, have been traced to defects in mitochondria. While such
disorders seem to be linked to metabolism, it is not yet known whether
age-associated damage also impairs metabolism.
Researchers
are searching for answers to this and other questions. They would
like to know, for example, how much mitochondrial DNA damage occurs
in specific parts of the body, such as the brain, what causes the
damage, and how it could be prevented.
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Heat Shock
Proteins
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Despite their
name, heat shock proteins (HSPs) are produced when cells are exposed
to various stresses, not only heat. Their expression can be triggered
by exposure to toxic substances such as heavy metals and chemicals
and even by behavioral and psychological stress.
Produced
in response to stress, HSPs decline with age.
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What attracts
aging researchers to HSPs is the finding that the levels at which
they are produced depend on age. Old animals placed under stress --
physical restraint, for example -- have lower levels of a heat shock
protein designated HSP-70 than young animals under similar stress.
Moreover, in laboratory cultures of cells, researchers have found
a striking decline in HSP-70 production as cells approach senescence.
Exactly what
role HSPs play in the aging process is not yet clear. They are known
to help the cell disassemble and dispose of damaged proteins and
to facilitate the making and transport of new proteins. But what
proteins are involved and how they relate to aging is still the
subject of speculation and study.
Researchers
like Nikki Holbrook at the NIA's Gerontology Research Center in
Baltimore, Maryland, are investigating the action of HSP-70 in specific
sites, such as the adrenal cortex (the outer layer of the adrenal
gland). Here, and in blood vessels and possibly other sites, the
expression of HSP-70 appears to be closely related to hormones released
in response to stress, such as the glucocorticoids and catecholamines.
Eventually, answers to the puzzle of heat shock proteins may throw
light on some parts of the neuroendocrine system, whose hormones
and growth factors also appear to be major factors in the aging
process.
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Hormones
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In 1989, at
Veterans Administration hospitals in Milwaukee and Chicago, a small
group of men aged 60 and over began receiving injections three times
a week that dramatically reversed some signs of aging. The injections
increased their lean body (and presumably muscle) mass, reduced excess
fat, and thickened skin. When the injections stopped, the men's new
strength ebbed and signs of aging returned.
Declining
levels of these chemical messengers may trigger some aging
processes.
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What the men
were taking was recombinant human growth hormone (GH), a synthetic
version of the hormone that is produced in the pituitary gland and
plays a critical part in normal childhood growth and development.
Now researchers are learning that GH, or the decline of GH, seems
also to play a role in the aging process in at least some individuals.
The idea that
hormones are linked to aging is not new. We have long known that
some hormones decline with age. Human growth hormone levels decrease
in about half of all adults with the passage of time. Production
of the sex hormones estrogen and testosterone tends to fall off.
Hormones with less familiar names, like melatonin and thymosin,
are also not as abundant in older as in younger adults.
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| Hormones
and Research on Aging
Produced
by glands, organs, and tissues, hormones are the body's
chemical messengers, flowing through the blood stream and
searching out cells fitted with special receptors. Each
receptor, like a lock, can be opened by the specific hormone
that fits it and also, to a lesser extent, by closely related
hormones. Here are some of the hormones and other growth
factors of special interest to gerontologists.
Estrogen.
The female hormone, estrogen is used in hormone replacement
therapy to relieve discomforts of menopause. Produced mainly
by the ovaries, it slows the bone thinning that accompanies
aging and may help prevent frailty and disability. After
menopause, fat tissue is the major source of a weaker form
of estrogen than that produced by the ovaries.
Growth
Hormone. This product of the pituitary gland appears
to play a role in body composition and muscle and bone strength.
It is released through the action of another trophic factor
called growth hormone releasing hormone, which is produced
in the brain. It works by stimulating the production of
insulin-like growth factor, which comes mainly from the
liver. All three are being studied for their potential to
strengthen muscle and bones and prevent frailty among older
people.
Melatonin.
This hormone from the pineal gland responds to light and
seems to regulate various seasonal changes in the body.
As it declines during aging, it may trigger changes throughout
the endocrine system.
Testosterone.
The male hormone, testosterone is produced in the testes
and may decline with age, though less frequently or significantly
than estrogen in women. Researchers are investigating its
ability to strengthen muscles and prevent frailty and disability
in older men when administered as testosterone therapy.
They are also looking at its side effects, which may include
an increased risk of certain cancers, particularly prostate
cancer.
DHEA.
Short for dehydroepiandrosterone, DHEA is produced in the
adrenal glands. It is a weak male hormone and a precursor
to some other hormones, including testosterone and estrogen.
DHEA is being studied for its possible effects on selected
aspects of aging, including immune system decline, and its
potential to prevent certain chronic diseases, like cancer
and multiple sclerosis.
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Hormone Replacement
We also know
that when some declining hormones are replaced, various signs of
aging diminish. Most, like growth hormone, are still in the experimental
stage, but one, estrogen, is used in medical practice to alleviate
the discomforts of menopause. Estrogen replacement therapy also
lessens the accelerated bone loss that comes with menopause and
may help prevent cardiovascular disease. Preliminary studies suggest
that testosterone replacement may likewise have benefits for aging
men, by increasing bone and muscle mass and strength. However, questions
about cancer and other risks surround both estrogen and testosterone
replacement therapy and have not yet been resolved.
A hormone
that has attracted the interest of many researchers is DHEA (short
for dehydroepiandrosterone), which is abundant in youth but begins
to decline in humans at about age 30. Very low levels of DHEA have
been linked to cardiovascular disease in men, some cancers, trauma,
and stress; low levels are also associated with old age, particularly
in the unwell, institutionalized elderly. In animal studies, replacing
DHEA has had startling anti-aging effects. Large doses of the hormone
have restored older animals' strength and vigor.
How DHEA works
is still not clear. Circulating through the blood stream in an inactive
form, called DHEA sulfate, this hormone becomes active when it comes
in contact with a specific cell or tissue that "needs" it. When
this happens, the sulfate is removed.
DHEA seems
to be needed, for example, to assist in the function and proliferation
of immune cells. In experiments with mice, DHEA sulfate boosted
the older animals' levels of a substance called interleukin-2, important
in the immune response.
Growth Factors
Hormones
are aided and abetted by an arsenal of other substances that also
stimulate or modulate cell activities. Known collectively as growth
or trophic factors, these include substances such as insulin-like
growth factor (IGF-1), which mediates many of the actions of GH.
Another trophic factor of interest to gerontologists is growth hormone
releasing hormone, which stimulates the release of GH.
The mechanisms
-- how hormones and growth factors produce their effects -- are
still a matter of intense speculation and study. Scientists know
that these chemical messengers selectively stimulate cell activities
which in turn affect critical events, such as the size and functioning
of skeletal muscle. However, the pathway from hormone to muscle
is complex and still unclear.
Consider growth
hormone. It begins to stimulating production of insulin-like growth
factor. Produced primarily in the liver, IGF-1 enters and flows
through the blood stream, seeking out special IGF-1 receptors on
the surface of various cells, including muscle cells. Through these
receptors it signals the muscle cells to increase in size and number,
perhaps by stimulating their genes to produce more of special, muscle-specific
proteins. Also involved at some point in this process are one or
more of the six known proteins that bind with IGF-1; their regulatory
roles are still a mystery.
As if the
cellular complexities weren't enough, the action of growth hormone
also may be intertwined with a cluster of other factors -- exercise,
for example, which stimulates a certain amount of GH secretion on
its own, and obesity, which depresses production of GH. Even the
way fat is distributed in the body may make a difference; lower
levels of GH have been linked to excess abdominal fat but not to
lower body fat.
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Biochemistry
and Aging: Selected Readings
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Ames, B.N.,
"Endogenous DNA Damage as Related to Nutritionand Aging," in Ingram,
D.K., Baker, G.T., Shock, N.W., eds., The Potential for Nutritional
Modulation of Aging Processes, Trumbull, CT: Food and Nutrition
Press, 1991.
Blake, M.J.,
Udelsman, R., Feulner, G.J., Norton, D.D.,Holbrook, N.J., "Stress-Induced
HSP70 Expression in Adrenal Cortex: A Glucocorticoid Sensitive,
Age-Dependent Response," Proceedings of the National Academy
of Sciences 87:846-850, 1991.
Cerami, A.,
"Hypothesis: Glucose as a Mediator of Aging,"Journal of the American
Geriatric Society 33:626-634, 1985.
Daynes, R.A.,
and Araneo, B.A., "Prevention and Reversal ofSome Age-Associated
Changes in Immunologic Responses by Supplemental Dehydroepiandrosterone
Sulfate Therapy," Aging: Immunology and Infectious Disease
3:135-157, 1992.
Harman, D.,
"The Free Radical Theory of Aging," in Warner,H.R., et al., eds.,
Modern Biological Theories of Aging, New York: Raven, 1987.
Rudman, D.,
Feller, A.G., Nagraj, H.S., et al., "Effects ofHuman Growth Hormone
in Men Over 60 Years Old," The New England Journal of Medicine
323:1-6, 1990.
Stadtman,
E.R., "Protein Oxidation and Aging," Science 257:1220-1224,
1992.
Wallace, D.C.,
"Mitochondrial Genetics: A Paradigm for Agingand Degenerative Diseases?"
Science 256:628-632, 1992.
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