Biochemistry
and Aging
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IN
SEARCH OF
THE SECRETS OF AGING
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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.
Oxygen
Radicals
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.
Glucose
Crosslinking
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. 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.
DNA
Repair
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.
Heat
Shock Proteins
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.
Hormones
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.
Biochemistry
and Aging: Selected Readings
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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