Aging is accompanied by striking changes across cell types, tissues and organs, with accumulating evidence supporting divergent trajectories of aging between females and males. Our lab studies drivers of such differences across several compartments, leveraging  mouse models. First, a key compartment whose activity can be actively modulated by sex-dimorphic mechanisms throughout life is the immune system, whose function declines sharply with aging. Indeed, aspects of the immune responses differ between sexes, with a more robust immune response in females and an increased susceptibility to infection in males. One of our main cell models are macrophages, a core component of the innate immune system. Excitingly, we observed strong sex-differences in macrophage transcriptional and functional phenotypes, and as well as sex-dimorphic “omic” changes with aging, which show partial dependence on ovarian hormone exposures. Second, we have been taking advantage of a mouse model of adult somatic sex reprogramming to investigate the long-term impact of adult sex hormone exposure on shaping sex-differences with aging, with a focus on brain and cognition. Together, our data suggests that mechanisms involving both gonadal hormones and sex chromosomes fine-tune different aspects of mammalian aging and, thus, overall health and lifespan of males vs. females.