Mammalian aging may be too complex to show major changes as the result of a single gene. Therefore this project will capture sets of genes that increase longevity. Identifying these will lead to mechanisms causing aging, and suggest means of retarding it. The mouse models used are mammals similar to human beings, and should have similar mechanisms of aging. Treatments retarding deleterious effects of aging would be of great benefit to human health. Selective breeding for increased longevity and increased reproductive life span. Four sets of 4 way cross initial populations will be constructed from 16 inbred strains showing maximum genetic diversity. This diversity will maximize the availability of genes controlling aging. Selection for long life will be conducted independently in each 4-way cross. Each generation will be preserved as frozen embryos. Specific control lines will be produced from specific crosses of Fl hybrids. After the rate of increase in longevity with selection slows, the 4 different selected populations can be intercrossed, and further selected for longevity to test whether each population has unique genes with additive beneficial effects that further increase life span. For mice to live longer, all biological systems must function longer, since the life span is limited by the first system to fail. Therefore genes slowing age-related physiological and pathological changes in many different biological systems should be captured. Genes retarding aging in multiple systems are likely to lead to underlying mechanisms of aging. Mapping longevity genes. DNA will be collected from all mice whose longevity is measured, and a full battery of micro-satellite markers used to locate chromosome regions that may be important in longevity. Candidate genes will be suggested by information about these regions from the mouse genome project Some candidates from old individuals will be identified in 3 years. However the likelihood of identifying important genes is greatly enhanced by multigenerational comparisons, and by looking for regions in which lines selectively bred for increased life spans consistently differ from controls in all 4 selection experiments. This will be done when DNA samples from selected and control populations are compared. Testing mechanisms of aging. Genes related to longevity and to rates of aging in different biological systems will suggest mechanisms. We will compare rates of aging in different biological systems, testing correlations with particular genes.
