Aging : Telomeres, Biochemistry and Oxygen Radicals

by National Institute on Aging

(Page 6 of 15)

Telomeres

Every chromosome has tails at its ends that get shorter as a cell divides. These tails, called telomeres, all have the same short sequence of DNA bases (TTAGGG in humans and other vertebrates) repeated thousands of times. These repetitive snippets do not contain any vital genetic information, but acting much like the hard, plastic covering on the ends of shoestrings, they help keep chromosomes intact.

During mitosis, the molecular machinery that replicates DNA can't completely copy the extreme ends of chromosomes. So each time a cell divides, the telomeres get shorter. Over time, scientists theorize, telomeres become so short that their function is disrupted, and this, in turn, leads the cell to stop proliferating. Average telomere length, therefore, gives some indication of how many divisions the cell has already undergone and how many remain before it can no longer replicate.

This apparent counting mechanism, almost like an abacus keeping track of the cell's age, has led to speculation that telomeres serve as molecular meters of cell division. But some scientists suspect telomere length is just one aspect of a complex mechanism. Elizabeth Blackburn, Ph.D., of the University of California, San Francisco, for instance, has accumulated evidence that some cells with extremely short, but structurally sound telomeres continue to proliferate, while others with long, but "frayed" telomeres undergo senescence. Telomere researchers also are exploring other possible ways in which these chromosome ends regulate cellular lifespan, and believe that proteins associated with telomeres play a role.

Telomere research is another territory where cancer and aging research merge. In immortal cancer cells, telomeres act abnormally - they no longer shrink with each cell division. In the search for clues to this phenomenon, researchers have discovered an enzyme called telomerase. This enzyme, which is not active in most adult cells (egg and sperm cells are among the exceptions), seems to swing into action in advanced cancers, enabling cells to replace lost telomeric sequences and divide indefinitely. This finding has led to speculation that if a drug could be developed to block telomerase activity, it might aid in cancer treatment.

Whether cell senescence is explained by abnormal gene products, telomere shortening, or other factors, the question of what senescence has to do with the aging of organisms continues to be the focus of rigorous study.

In the Lab of the Long-Lived Fruit Flies

A laboratory at the University of California, Irvine, is the home of thousands of Drosophila melanogaster, or fruit flies, that routinely live for 70 or 80 days, nearly twice the average Drosophila lifespan. Here evolutionary biologist Michael Rose, Ph.D., has bred the longlived stocks by selecting and mating flies late in life.

To begin the process of genetic selection, Rose first collected eggs laid by middle-age fruit flies and let them hatch in isolation. The progeny were then transferred to a communal plexiglass cage to eat, grow, and breed under conditions ideal for mating. Once they had reached advanced ages, the eggs laid by older females (and fertilized by older males) were again collected and removed to individual hatching vials. The cycle was repeated, but with succeeding generations, the day on which the eggs were collected was progressively postponed. After 2 years and 15 generations, the laboratory had stocks of Drosophila with longer lifespans.

The next question is what genes and what gene products are involved? Since the first experiments, Rose has bred longer life spans into fruit flies by selecting for other characteristics, such as ability to resist starvation, so the flies' long lifespans are not necessarily tied to their fertility late in life.

One possibility is that the antioxidant enzyme, superoxide dismutase (SOD), is involved. Two laboratory studies, including work by John Tower, Ph.D., at the University of Southern California, have shown that genetically altered fruit flies that produce greater amounts of SOD have extended lifespans. This finding has given a boost to the hypothesis that antioxidant enzymes like SOD are linked to aging or longevity. However, to date, similar experiments in other species have been inconclusive.

Biochemistry and Aging

As important as genes are, they do not act in a vacuum. Everyday metabolic activities - even breathing - expose cells to biochemical substances that can promote random DNAdamage and other cellular breakdowns. Of these factors, oxygen radicals and crosslinking of proteins have become focal points of scientific exploration. Gerontologists also are studying other important proteins - heat shock proteins, hormones, and growth factors - that may play a role in aging and longevity. In short, the biochemistry of aging is a rich territory with an expanding frontier.

Oxygen Radicals

Oxygen sustains us. Every cell in the body needs it to survive. Yet, paradoxically, oxygen also wreaks havoc in the body and may be a primary catalyst for much of the damage we associate with aging. This damage occurs as a direct result of how cells metabolize it.

Oxygen is processed within a cell by tiny oganelles called mitochondria. Mitochondria convert oxygen and food into adenosine triphosphate (ATP), an energy-releasing molecule that powers most cellular processes. In essence, mitochondria are furnaces, and like all furnaces, they produce potentially harmful by - products. In cells, these by - products are called oxygen free radicals, also known as reactive oxygen species.

A free radical can be produced from almost any molecule when it loses an electron from one or more of its atoms. In cells, they are commonly created when mitochondria combine oxygen with hydrogen to form water. This transformation releases energy into the cell, but it also can shred electrons from oxygen. When this happens it leaves the oxygen atom - now an unstable oxygen free radical - with one unpaired electron. Because electrons are most stable when they are paired, oxygen free radicals steal mates for their lone electrons from other molecules. These molecules, in turn, become unstable and combine readily with other molecules.

About the Author

www.nia.nih.gov
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form NIA to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people.