CELLS DIE ON SCHEDULE
In a famous experiment carried out in 1961, geneticist Leonard Hayflick demonstrated that fibroblast cells growing in tissue culture will divide only a certain number of times. After about 50 population doublings, cell division stops, the cell cycle blocked just before DNA replication. If a cell sample is taken after 20 doublings and frozen, when thawed it resumes growth for 30 more doublings, then stops.

An explanation of the _Hayflick limit_ was suggested in 1986 when Howard Cooke first glimpsed an extra length of DNA at the ends of chromosomes. These telomeric regions, about 5,000 nucleotides (the chemical letters of DNA), are each composed of several thousand repeats of the sequence TTAGGG. Cooke found the telomeric region to be substantially shorter in body tissue chromosomes than in those of germ line cells, the egg and sperm. He speculated that in body cells a portion of the telomere cap was lost by a chromosome during each cycle of DNA replication. Cooke was right. The cell machinery that replicates the DNA of each chromosome cannot copy the last 100 units of DNA at the chromosome_s tip. So each time the cell divides, its chromosomes get a little shorter. Eventually, after some 50 replication cycles, the protective telomeric cap is used up, and the cell line then enters senescence, no longer able to proliferate.

How do sperm and egg cells avoid this trap, dividing continuously for decades? Scientists have recently learned that all human cells contain an enzyme, telomerase, which lengthens telomeres. This enzyme is active in sperm and egg cells, maintaining their chromosomes at a constant length of 5,000 nucleotide units. In body cells, by contrast, the telomerase gene is silent.

ESCAPING CELL DEATH
Research published in January of 1998 has confirmed Cooke_s hypothesis, providing direct evidence for a causal relation between telomeric shortening and cell senescence. Using genetic engineering, teams of researchers from California and Texas transferred into human body cell cultures a DNA fragment that unleashes each cell_s telomerase gene. The result was unequivocal. New telomeric caps were added to the chromosomes of the cells, and the cells with the artificially elongated telomeres did not senesce at the Hayflick limit, continuing to divide in a healthy and vigorous manner for more than 20 additional generations.

This research shows clearly that loss of telomere DNA eventually restrains the ability of human cells to proliferate. And yet every human cell possesses a copy of the telomerase gene that, if expressed, would rebuild the telomere. Why do our cells accept aging, if they need not? The answer, it seems, is to avoid cancer. By limiting the number of divisions allotted to human cell lines, the body insures that no cell can continue to divide indefinitely. Suppression of the telomerase gene is, in a very real sense, cancer suppression. When scientists examine cancer cells, they commonly find their telomerase genes have been activated and are maintaining telomeres at full length. Thus telomere shortening is a tumor-suppressing mechanism, one of your body_s key safeguards against cancer.

AGING INVOLVES WEAR AND TEAR
Numerous theories of aging focus in one way or another on the general idea that cells wear out over time, accumulating damage until they are no longer able to function. Loosely dubbed the _wear and tear_ hypothesis, this idea implies that there is no inherent designed-in limit to aging, just a statistical one_over time, disruption, wear, and damage eventually erode a cell_s ability to function properly. There is considerable evidence that aging cells do accumulate damage. Some of the most interesting evidence concerns free radicals, fragments of molecules or atoms that contain an unpaired electron. Free radicals are very reactive chemically and can be quite destructive in a cell. Free radicals are produced as natural by-products of oxidative metabolism, but most are mopped up by special enzymes that function to sweep the cell interior free of them.

One of the most damaging free radical reactions that occurs in cells causes glucose to become linked to proteins, a nonenzymatic process called glycation. Two of the most commonly glycated proteins are collagen and elastin, key components of the connective tissues in our joints. Glycated collagen and elastin are not replaced, and individual molecules may be as old as the individual.

IS THERE A GENE CLOCK?
There is very little doubt that at least some aspects of aging are under the direct control of genes. Just as genes regulate the body_s development, so they appear to regulate its rate of aging. Mutations in these genes can produce premature aging in the young. In the very rare recessive Hutchinson-Gilford syndrome, growth, sexual maturation, and skeletal development are retarded; atherosclerosis and strokes usually lead to death by age 12 years. Only some 20 cases have ever been described.

The similar Werner_s syndrome is not as rare, affecting some 10 people per million worldwide. The syndrome is named after Otto Werner, who in Germany in 1904 reported a family affected by premature aging and said a genetic component was at work. Werner_s syndrome makes its appearance in adolescence, usually producing death before age 50 of heart attack or one of a variety of rare connective tissue cancers. The gene responsible for Werner_s syndrome was identified in 1996. Located on the short arm of chromosome 8, it seems to affect a helicase enzyme involved in the repair of DNA. The gene, which codes for a 1432 amino acid protein, has been fully sequenced, and four mutant alleles identified. Helicase enzymes are needed to unwind the DNA double helix whenever DNA has to be replicated, repaired, or transcribed. The high incidence of certain cancers among Werner_s syndrome patients leads investigators to speculate that the mutant helicase may fail to activate critical tumor suppressor genes. The potential role of helicases in aging is the subject of heated research.

Research on aging in other animals strongly supports the hypothesis that genes regulate the rate of aging. Particularly impressive results have been obtained in the nematode worm Caenorhabditis elegans, where genes discovered in 1996 seem to affect an intrinsic genetic clock. A combination of mutations can increase the worm_s life-span fivefold, the largest increase in life-span seen in any organism! Mutations in the clock gene clk-1 cause individual cells to divide more slowly, and the animal spends more time in each phase of its life cycle. Mutations in two other clock genes, clk-2 and clk-3, have similar effects. Nematodes with mutations in two of the clock genes lived three to four times longer than normal. It seems that slowing life down in nematodes extends it. Perhaps, as the _wear and tear_ theory suggests, aging results from damage to cells and their DNA by highly reactive oxidative by-products of metabolism. Living more slowly, destructive by-products may be produced less frequently, accumulate more slowly, and their damage be repaired more efficiently. Similar genes have been reported in yeasts, and attempts are now underway to isolate and clone these genes.