It is useful to think of organisms as protein-synthesizing factories. If that factory is to function at very high levels of efficiency and stability for very long periods of time, the builder should start with an excellent set of blueprints (hence the importance of understanding the constitutional genomes of individual patients), hire engineers and supervisors to oversee its construction and maturation
Ensure that the factory functions in a safe environment (hence the importance of protecting patients from teratogens, mutagens, carcinogens, and candidate "gerontogens," such as tobacco smoke), and, finally, initiate rigorous regimens of quality control throughout the life span of the factory (hence the importance of such biologic processes as DNA repair and the detection, reconstitution, and turnover of aberrant proteins).
[...] All patients are likely to have one or more such "private" modulations that can have an impact on patterns of aging. Moreover, all patients also are likely to carry a private array of suppressor mutations at other loci to postpone the age of phenotypic expression. Environmentally Triggered Diapause and Caloric Restriction Can Increase the Life Spans of Diverse Organisms Research has implicated a homologous pathway of neuroendocrine modulation of life span in diverse organisms. The most detailed understanding has come from mutational studies of C. [...]
[...] This class of gene action has received a great deal of recent attention in connection with evidence that levels of the tumor suppressor gene, p53, have been "fine-tuned" by evolution both to decrease the risk of cancer and to decrease the rate of aging. Classes of Gene Action that Escape the Force of Natural Selection In mouse models, putative excessive functioning of p53 protects against cancer but is associated with decreased life spans and conditions such as osteopenia, multiple organ atrophy, and poor wound healing. [...]
[...] The Life Course Approach to the Understanding of Aging Although future discoveries may elucidate all of the interacting variables that determine the probability of such events, chance juxtapositions of sets of such variables are likely to be responsible for much of the variance. These considerations provide great difficulties for investigators interested in performing a genetic analysis of longevity, such as the genetic contributions to achieving centenarian celebrity. The Evolutionary Biological Theory of Aging Provides a Satisfactory Explanation for Why We Age Why do animal species evolve such striking differences in their life history strategies? [...]
[...] Conclusions A genetic and evolutionary biology approach to aging emphasizes that, in age-structured populations such as humans, phenotypes whose expressions are delayed can escape the forces of natural selection because most reproducing individuals have been young. Seven classes of gene action can escape the force of natural selection, including the two "classic" types: antagonistic pleiotropy and the accumulation of constitutional mutations. Conclusions Research in diverse species points to an important role for signal transduction pathways involving insulin-like growth factors and their receptors in the modulation of the life span. [...]
[...] Putative linkages of longevity to a region on chromosome 4 and to a variety of polymorphisms await confirmation. Human Progeroid Mutations Perhaps the best-documented example is the triallellic polymorphism at the apolipoprotein E locus: an unusual polymorphic allele (APOepsilon2) is found disproportionately in centenarians, in whom the APOepsilon2 allele is unusual. The latter is also known to be a risk factor for Alzheimer-type dementia and cardiovascular disorders. Human Progeroid Mutations This deleterious allele, however, may have evolved among ancestors of some extant populations because it provided enhanced reproductive fitness in particular environments. [...]
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