SELECTION FOR MAXIMUM LONGEVITY IN MICE

In both mice and men, during the adult life span, aging causes an expo nential increase in vulnerability to almost all pathologies, Thus, agi ng is a serious public health problem. Altering the basic mechanisms t hat control normal aging would be a powerful approach to reduce damage from aging processes, so research identifying these mechanisms is of vital importance. Because life spans are determined by the first biolo gical system to malfunction, it is likely that basic mechanisms are in volved in life span extension of animals already having maximum normal life spans for the species. When life spans of a species are extended , all biological systems must function for unusually long times. If th ere are a limited number of genes for basic mechanisms that control ag ing rates in multiple biological systems, then life spans can be exten ded relatively easily. If not, extending maximum life spans would requ ire changes in impractically large numbers of genes, all genes involve d in functional life spans of every biological system. In fact, life s pans appear to increase rapidly during evolution, suggesting that chan ges in only a few genes are required. These genes are likely to contro l underlying mechanisms timing aging in multiple biological systems. T he purpose of selection for increased life span is to identify these g enes. An important potential problem is that all species have many def ective genetic alleles that can cause early disease and death. Selecti on studies must be designed to distinguish between altering basic mech anisms of aging, and simply avoiding early pathologies due to defectiv e alleles. Animal models that are short lived for their species should be avoided, because their deaths almost always result from genetic de fects unrelated to mechanisms of normal aging. During selection, allel es not causing early pathologies-may appear to increase life spans by replacing defective alleles in genetic regions linked to early patholo gies; however, these affect early disease, not basic mechanisms of agi ng. A more subtle potential problem is that caloric restriction increa ses life spans in mice. Selection for long lived mice should focus on more basic mechanisms than breeding mice that voluntarily consume fewe r calories, The fact that aging rates in different biological systems are not necessarily coordinated in different individuals suggests that normal aging is timed by more than one mechanism. Thus, the objective in selection for maximum longevity is to capture the entire set of al leles that increase longevity in a species, Wild populations are not p ractical to use, despite some theoretical advantages, as genes retardi ng aging would be confounded with those reducing the stress of captivi ty. Currently we use four-way crosses of inbred strains that represent maximal genetic diversity. Genetic regions important in increasing lo ngevity will be identified using microsatellite markers distinguishing each of the four starting strains over the entire genome. Other genet ic techniques proven useful for studying characteristics that are quan titatively controlled by multiple genes may also be useful in studying mechanisms timing aging; these techniques include diallele crosses, r ecombinant inbred lines, bilineal congenic lines and correlated geneti c markers. Copyright (C) 1997 Elsevier Science Inc.