2.5: Genes and Aging

Importance

Genes play several significant roles in aging. Many genes seem to influence the very different lifespans among different species (e.g., flies, mice, humans). Of the estimated 30,000 genes in humans, scientists estimate that 70 to 7,000 of them may influence aging itself.

Genes related to aging help determine an organism's ML and XL. Evidence for this includes differences (e.g., weeks to decades) in ML and XL among different species; effects from selective breeding; effects from placing new genes into animals (i.e., transgenic animals); and effects from specific gene mutations. In humans, genetic impact on ML and XL is also shown by the similarity in lifespans within families and the even greater similarity in lifespans among twins. Genes also influence the onset and nature of age-related diseases plus the effects of lifestyle and environmental factors in aging processes. In addition, genes undergo significant accumulated alteration and damage during life, and portions of genes move from place to place within cells (i.e., transposable elements). These two alterations also seem to influence aging and diseases.

Though genes have a major role in aging and age-related diseases, scientists estimate that only 35 percent of the variance among human lifespans can be accounted for by variation among genes. For identical twins, the figure is 40-70 percent. The same seems true for many other animals. The remaining variation between ML and age-related diseases is due to lifestyle, environmental factors, and occasional incidents (e.g., accidents). For example, lifespans and age-related diseases are not identical for identical twins, who have identical genes. For identical twins, the more differences between their lifestyles, the greater the differences in aging and genetically caused age-related diseases (e.g., Alzheimer's disease). Finally, the impact of genes on ML and age-related diseases decreases with advancing age, especially at very advanced ages.

Nature and nurture

Genes influence how the environment affects aging, and the environment influences how genes affect aging. Environmental factors may have different effects on genes at different times because age changes make genes more or less sensitive as time passes. Environmental factors include external influences and internal ones (e.g., hormones). Genes influencing age-related diseases may also be affected by environmental factors, and these effects may be different at different ages (e.g., pre- or postmenopause). Human ML, health in later years, and perhaps even XL may be increased by avoiding harmful lifestyle and environment factors while increasing beneficial ones.

Some disease-promoting genes become active or important only at older ages (e.g., Alzheimer's disease, certain cancers). These genes may be time-dependent or may be triggered by lifestyle or environmental factors. When human ML was low, few people got these diseases. Since human ML is increasing, these genes will have a growing impact. Some unknown or unnoticed genetically-induced diseases may become significant. The effect may be to put additional limitations on the increase in ML. Alternatively, since mortality rates decrease after age 100, genes that promote high ML may start to overpower such late-acting detrimental genes.

Methods of study

One way to identify genes affecting human aging involves finding similar genes in animals. Popular animals for such studies include a small worm found in soil (C. elegans), fruit flies (D. melanogaster), and laboratory mice. Diverse techniques are used to study the genetics of aging in these and other animals. Examples include selective breeding; placing genes from one animal into another (i.e., transgenic research); and mutating genes.

The genes that control normal aging and human XL are still unknown, though genes affecting the immune system (e.g., MHC genes), blood pressure regulators (e.g., ACE), and brain neurons (e.g., APOE) are good candidates. Genes that influence aging, ML and XL in some nonhuman species (e.g., C. elegans, D. melanogaster) have been identified.

Age-related abnormalities

Genes that influence or cause age-related human disease have been studied in detail (e.g., cancer, Alzheimer's disease). Controversy exists about whether such genes should be viewed as normal variations of age-related genes or as abnormal disease conditions. Among these are genetic conditions that promote progeroid syndromes. People with these syndromes show changes that resemble aging but that occur at much earlier ages than normal. Examples include Down's syndrome and Werner's syndrome.

Down's syndrome occurs in people having an extra chromosome 21. The extra chromosome is present because of abnormal formation of an egg cell in the ovary. Progeroid symptoms include more rapid shortening of telomeres; shorter Hayflick limits in skin cells; increased risk of brain changes resembling Alzheimer's disease; and a shorter ML.

Werner's syndrome (WS) is caused by loss of a region of chromosome 8. The condition develops only if a person has the mutation on both copies of chromosome 8 (i.e., autosomal recessive mutation). People with only one mutation will not show the disease, but they can transmit the disease to their children.

Indications of WS appear during adolescence. Manifestations include slow DNA synthesis; rapid telomere shortening; abnormal chromosome structure; increased DNA damage from *FRs; lower Hayflick limits in skin cells; premature graying (age 20); hair thinning (age 25); thinning skin; premature skin aging; atrophy of the subcutaneous tissues of the limbs; loss of fat from arms and legs; calcification of soft tissues and blood vessels; heart disease; muscle thinning; osteoporosis; cataracts (age 30); diabetes (age 34); skin ulcers (age 33); increased cancers; aging voice (age 27); death (age 30-50).