GENETICS AND THE PATHOBIOLOGY OF AGING

Genetics offers a powerful approach to the elucidation of mechanisms u nderlying specific components of the senescent phenotype of our specie s. Perhaps thousands of gene variations have escaped the force of natu ral selection and thus play roles in the genesis of different patterns of ageing in man. It is possible that a subset of these genes may be of particular importance in how most people age. While variations at t he Werner helicase locus could be one such example, several lines of e vidence suggest that mutation at that locus leads to a 'private' mecha nism of ageing. It will be important, however, to investigate polymorp hisms underlying the regulation of expression of this gene in the gene ral population. Polymorphisms (normally occurring variants of a gene, or sequence of DNA), rather than mutations, may also prove to be more relevant to our understanding of the differing susceptibilities of peo ple to common disorders such as late onset Alzheimer's disease. Polymo rphic forms of the Apolipoprotein E gene is a good example. It remains to be seen if the pathogenetic framework (beta amyloidosis) derived f rom studies of the several rare mutations responsible for early onset familial forms of the disease proves relevant to the pathogenesis of t he vastly more prevalent sporadic forms of the disorder. In contrast t o the satisfying progress on the genetics of the diseases of ageing, r esearch on the genetic basis for unusually robust retention of structu re and function in old age has been neglected and requires a higher pr iority for the future. Such research should include studies of environ mental agents and should address mechanisms of 'sageing', a stage in t he life course characterized by an extensive utilization of behavioura l and physiological adaptations to compensate for functional declines. For the genetics of longevity, we have to turn to genetically tractab le organisms such as nematodes and fruit flies. Such studies have prov ided significant support for the oxidative stress theory of ageing. It will be important to learn more about the age-related pathologies and pathophysiologies of these organisms.