This project has two overall objectives: (a) to develop new stocks from wild-trapped animals that may retain genetic alleles for longer lifespan that have been lost in the laboratory adapted mouse stocks typically used for aging research; and (b) to determine whether genes that affect body size, litter size, corticosterone levels, and reproductive maturity have pleiotropic effects on age-sensitive traits such as immunity, collagen cross-linking, late-life disease, and longevity. The experimental design exploits four mouse stocks generated by this project in the preceding three years: Po and Ma, derived from tropical island populations; Id, derived from a mainland wild mouse population; and DC, a heterogeneous stock derived from four laboratory inbred mouse strains.
Aim 1 tests the hypothesis that mice of the three wild-derived stocks will be longer lived than mice of the DC control stock, and the secondary hypothesis, based on evolutionary theories, that the island-derived mice (Po and Ma) may prove longer-lived than the mainland-derived Id stock.
Aim 2 will characterize these mice using tests that provide information about early life history events (weight, reproductive maturation), stress resistance (corticosterone), or markers of aging (T cell subsets, antibody responses and collagen cross-linking). Differences among the four mouse stocks in the age-sensitive biomarkers will test the idea that differences in longevity (Aim 1) are mediated by an overall deceleration of aging-related changes. Differences among mice within each stock will test the ability of each of the traits to serve as validated biomarkers of aging, i.e. to identify mice with long lifespan and youthful levels of the other traits in the test battery.
Aim 3 will provide necropsy data for all four stocks, to see whether differences in lifespan reflect diminished risk of a range of late-life illnesses.
Aim 4 will produce and characterize F1 and F2 crosses between the wild-derived stocks and the laboratory-derived stock DC. These stocks are already known to differ in size, reproductive scheduling, immune responses, and corticosterone levels, and are hypothesized to differ in lifespan. Analysis of the segregating F2 populations will thus test the hypotheses that these life history and aging traits are controlled in part by genes with pleiotropic effects, and will also provide an estimate of the number of independently segregating loci with effects on each of the traits of interest (including lifespan) as a prelude to later QTL analyses.
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