The long-term goal of our research is to identify the role of young ovaries in production of therapeutic juvenile protective factors in form of exosomes carrying putative pro-longevity microRNAs (miRNAs). With the growing population of elderly people, there is a growing incidence of age-related diseases including metabolic syndrome, insulin resistance and diabetes mellitus. There is a well-established link between health and the function of reproductive organs and longevity. Importantly, it was shown that transplanting young ovaries into old mice delays aging and increases lifespan by over 40%. Unfortunately, the detailed mechanism by which young ovaries provide these longevity benefits is still undetermined. One of the possible benefits could be linked to an enhanced production of sex hormones, yet it was also shown that eliminating sex hormone producing cells in ovaries before transplantation, still produced pro-longevity benefits. Importantly, for the purpose of this proposal our novel findings suggest that ovaries express and secrete a variety of different exosomes containing miRNAs that might play an important role in the stability of transcriptome in gonads and diversity of different distant organs. Based on our findings we propose the general hypothesis is that young ovaries increase healthspan and longevity by secreting exosomes enriched with miR-181b-5p and miR-1249-3p, which target genes involved in insulin signaling. In the proposed studies we will investigate the effects of ovaries from young or long-living animals on the production and secretion of putative pro-longevity miRNA and the mechanism by which these miRNAs modulate high insulin sensitivity during aging. To test our hypothesis we propose three specific aims: Specific Aim 1: Determine if ovaries serve as a source of circulating factors that improve healthspan. Specific Aim 2: Assess the influence of ovarian-derived miRNAs on insulin sensitivity Specific Aim 3: Determine the ovarian secretory pattern of circulating exosomal miRNAs in mice and human ovaries.