Biochemistry and Aging

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.  

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DNA is damaged throughout life; the repair process may be a major factor in aging, health, and longevity.

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DNA Damage, 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.


Research on Sunlight May Help Explain What Happens to Skin as We Age


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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.


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
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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.
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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

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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.
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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.



Hormones and Research on Aging