Genes that Modulate Longevity and Senescence

Abstract

Modern gerontology is faced with a major paradox. On the one hand, we have the evolutionary biologists who have concluded that the modulation of longevity and senescence is under highly polygenic controls, that multiple mechanisms are likely to be involved, and that much of the pathology that unfolds is stochastic in origin. Let us refer to members of this camp as the “complificationists.” On the other hand, some biologists point to three lines of evidence that seem to challenge this view. They believe that aging may be produced by a small number of major mechanisms, perhaps even a single major mechanism, such as oxidative damage to macromolecules. Let us refer to members of this camp as the “simplificationists.” They emphasize the exceedingly well documented observations that calorically restricted rodents have substantially greater life spans than their well fed brethren do. They also point to experiments with nematodes (Caenorhabditis elegans) and fruit flies (Drosophila melanogaster). In both organisms, simple genetic manipulation, including single gene mutations, may lead to substantial increments of life span. For the case of aging in man, they emphasize research on the Werner syndrome, a recessive progeroid syndrome caused by a mutation in a helicase gene. Homozygotes exhibit an acceleration of multiple aspects of the senescent phenotype, including four of the major geriatric disorders associated with human aging (arteriosclerosis, cancer, diabetes mellitus and osteoporosis).