The Genetic Connection

Each year on her birthday, Jeanne Calment sent her lawyer a note, which read, "Excuse me if I'm still alive, but my parents didn't raise shoddy goods." Her brother, who died at age 97, apparently wasn't too "shoddy" himself. When another super centenarian, Sarah Knauss of Allentown, Pennsylvania, died in 1999 at age 119, her daughter was 96.

Some families seem blessed with long lives. In fact, siblings of centenarians have a four times greater chance of living into their early nineties than most people, according to researchers at the New England Centenarian Study in Boston. A coincidence? Hardly. What likely helps set these hardy individuals apart are extraordinary sets of genes, the coded segments of DNA (deoxyribonucleic acid), which are strung like beads along the chromosomes of nearly every living cell. In humans, the nucleus of each cell holds 23 pairs of chromosomes, and together these chromosomes contain about 30,000 genes.

There is little doubt that genes have a tremendous impact on aging and longevity. Based on studies of identical twins, who share the exact same set of genes, scientists now suspect that lifespan is determined by both environmental and genetic factors, with genetics accounting for up to 35 percent of this complex interaction. Although different animal species vary up to 100 times in lifespan - humans live five times longer than cats, for instance - scientists are discovering some surprising similarities between our genes and those of other species. Even single-celled yeast, one of nature's simplest organisms, may provide scientists with important genetic clues about human aging and longevity.

Tracking Down a Longevity Gene

Investigators are finding clues to aging and longevity in yeast, one-celled organisms that have some intriguing genetic similarities to human cells. In a laboratory at Louisiana State University Medical Center in New Orleans, Michal Jazwinski, Ph.D., has found genes that seem to promote longevity in these rapidly dividing, easy-to-study organisms.

Yeast normally have about 21 cell divisions or generations. Jazwinski observed that over the course of that lifespan, certain genes in the yeast are more active or less active as the cells age; in the language of molecular biology, they are differentially expressed. So far, Jazwinski has found 14 such genes in yeast.

Selecting one of these genes, Jazwinski tried two different experiments. First, he introduced the gene into yeast cells in a form that allowed him to control its activity. When the gene was activated to a greater degree than normal, or overexpressed, some of the yeast cells went on dividing for 27 or 28 generations; their period of activity was extended by 30 percent.

In his second experiment, Jazwinski mutated the gene. When he introduced this non-working version into a group of yeast cells, they had only about 12 divisions.

The two experiments made it clear that the gene, now called LAG-1, influences the number of divisions in yeast or, according to some researchers' ways of thinking, its longevity. (LAG-1 is short for longevity assurance gene.) But how it works is still a mystery. One small clue lies in its sequence of DNA bases - its genetic code - which suggests that it produces a protein found in cell membranes. One next step is to study the function of that protein. Similar sequences have been found in human DNA, so a second investigative path is to clone the human gene and study its function. If there turns out to be a human LAG-1 counterpart, new insights into aging may be uncovered.

In another laboratory, Leonard Guarente, Ph.D., of the Massachusetts Institute of Technology found that mutation of a silencing gene - a gene that "turns off" other genes - delayed aging 30 percent in yeast. The gene, which is also found in C. elegans and other animals, produces an enzyme that alters the structure of DNA, which, in turn, alters patterns of gene expression.

Longevity Genes

Researchers have found evidence of several genes that seem to be related to longevity determination. Longevity-related genes have been found in tiny roundworms called nematodes, in fruit flies, and even in mice. Like yeast, nematodes and fruit flies have attracted a lot of attention from gerontologists because their short lifespans and their well-characterized genetic composition make them relatively easy to study. Investigators, for instance, can perform nearly 2,000 roundworm studies in the time it would take them to do one human study.

Under normal conditions, some genes are thought to manufacture proteins that limit lifespan. But when these same genes are mutated, they either produce defective proteins or no proteins at all. The net effect is these mutations promote longevity.

For instance, a mutation of a gene whimsically named "I'm Not Dead Yet" or INDY, can double the lifespan of fruit flies. In studies supported by the NIA, these fruit flies not only lived longer, they thrived. By the time that 80 to 90 percent of normal flies were dead, many of the INDY flies were still vigorous and capable of reproduction. At least two other life-extending genetic mutations have been detected in the fruit fly genome.

Tags: Aging

About the Author

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.