Project Summary Lifespan, healthspan, and the mechanisms that modulate them often vary between the sexes. This is particularly true of humans?women consistently outlive men in every modern society and historical period. The sexes also vary in their response to potentially senescence-modulating interventions and numerous studies have reported a significant life- or health-extending effect in one sex only. To date, 6 compounds evaluated by the NIA Intervention Testing Program have successfully extended lifespan in mice and all affected one sex more than the other. Surprisingly, given their near ubiquity, sex differences in response to lifespan-extending genetic or pharmacological interventions have gone largely unstudied. While such differences are of interest in their own right and are likely to be important for the development of senescence- retarding interventions in humans, sex differences can also be used as a tool to fill gaps in our understanding of specific mechanisms of aging. If manipulation of parts of a biochemical network?either by genetic or pharmacological targeting?affects health and longevity in one sex only, then by examining how that manipulation affects downstream targets in a sex-specific manner we can learn how specific components of the network impact health and longevity. Thus, sex-specific responses to senescence-retarding interventions can be used to provide a deeper understanding of the fundamental mechanisms involved in aging. This proposal exploits a unique mouse model, the Four Core Genotypes (FCG), in which sex chromosome complement is independent of gonadal sex. The overarching hypothesis of this study is that mechanisms underlying the sex-specific effects of health and longevity interventions in mice can be revealed and evaluated by investigating the health and downstream effectors of life-extending interventions in the FCG mice. We propose to evaluate this hypothesis using 17?-estradiol (17?-E2), which extends lifespan in males only, via the following Specific Aims (SAs). SA1 will test the hypothesis that metabolism, inflammatory response and specific nodes in the mTOR and associated pathways are differentially responsive to hormonal and sex chromosome manipulations using the FCG mice treated with 17?-E2 and surgical castration to uncover these sex-specific effects. SA2 will use an acute stressor, infection with Streptococcus pneumoniae, to investigate whether the sex-specific responses observed in SA1 are predictive of improved health and survival under a clinically relevant challenge involving inflammation and immune function, hallmarks of aging.