Selection for maximum longevity in mice.

Abstract

In both mice and men, during the adult life span, aging causes an exponential increase in vulnerability to almost all pathologies. Thus, aging is a serious public health problem. Altering the basic mechanisms that 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 biological system to malfunction, it is likely that basic mechanisms are involved 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 there are a limited number of genes for basic mechanisms that control aging rates in multiple biological systems, then life spans can be extended relatively easily. If not, extending maximum life spans would require changes in impractically large numbers of genes, all genes involved in functional life spans of every biological system. In fact, life spans appear to increase rapidly during evolution, suggesting that changes in only a few genes are required. These genes are likely to control underlying mechanisms timing aging in multiple biological systems. The purpose of selection for increased life span is to identify these genes. An important potential problem is that all species have many defective genetic alleles that can cause early disease and death. Selection studies must be designed to distinguish between altering basic mechanisms of aging, and simply avoiding early pathologies due to defective alleles. Animal models that are short lived for their species should be avoided, because their deaths almost always result from genetic defects unrelated to mechanisms of normal aging. During selection, alleles not causing early pathologies may appear to increase life spans by replacing defective alleles in genetic regions linked to early pathologies; however, these affect early disease, not basic mechanisms of aging. A more subtle potential problem is that caloric restriction increases life spans in mice. Selection for long lived mice should focus on more basic mechanisms than breeding mice that voluntarily consume fewer 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 alleles that increase longevity in a species. Wild populations are not practical to use, despite some theoretical advantages, as genes retarding aging would be confounded with those reducing the stress of captivity. Currently we use four-way crosses of inbred strains that represent maximal genetic diversity. Genetic regions important in increasing longevity will be identified using microsatellite markers distinguishing each of the four starting strains over the entire genome. Other genetic techniques proven useful for studying characteristics that are quantitatively controlled by multiple genes may also be useful in studying mechanisms timing aging; these techniques include diallele crosses, recombinant inbred lines, bilineal congenic lines and correlated genetic markers.