title: Genetic instability as the primary cause of human aging.
abstract: The origins of aging of higher forms of life, particularly humans, is presented as the consequence of an evolved balance between 4 specific kinds of dysfunction-producing events and 4 kinds of evolved counteracting effects in long-lived forms. Among the deleterious events, particular importance is assigned to damage to DNA, but damage of a different kind than classical mutations. The evolution in man's ancestors of means to counteract the kinds of events that limit the life-spans of short lived mammals is postulated to be the indirect consequence of the prior evolution of superior mental capacities. Further, it is shown that the human species rapidly evolved its life-extending mutations because of the special circumstances afforded by the subdivision of the species into small semi-isolated (genetically) tribes of 10-100 individuals in which polygamy was the key factor in rapid incorporation of life- and well-being-extending new features. These conditions permit at least one or two orders of magnitude more of such beneficial genes to have been incorporated into our genomes during the 100,000 years or so of extremely rapid human evolution that evidently occurred about 100,000 to 200,000 years age than has been posited by other workers. The sources of damage to DNA are then considered, with special emphasis on free-radical derivatives of molecular oxygen and evidence is presented that longer lived forms of mammals have peroxide lysing enzymes that produce a lower steady state of damaging radicals derived from this compound. Evidence that so-called "classical" mutations cannot be the source of aging is then reviewed. A different kind of mutation, one that is not increased in proportion to point mutations by mutagens, namely deletion of tandemly duplicated copies of genes, is discussed and the evidence that such damage (gene loss) occurs in an amount sufficient to account for the major losses in function during aging is presented. The most likely mechanisms of such loss plus the prospects for evolving and bio-engineering means to counteract these losses together with some implications regarding the documented loss of NORs with age (as regards rDNA loss) together with key areas for intensive present and future research on aging are presented.
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D005075:Biological Evolution; D004275:DNA, Ribosomal / Q000378:metabolism; D004285:Dogs; D006801:Humans; D008393:Marriage; D051379:Mice; D009154:Mutation; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D010545:Peroxides / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D004275:DNA, Ribosomal; D010545:Peroxides