Identification of the mechanisms responsible for the ovary-dependent extension of longevity and health span

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PROJECT SUMMARY/ABSTRACT Two hallmarks of the aging process are dyslipidemia and chronic inflammation. Replacement of senescent ovaries in old mice with young ovaries ameliorates age-associated dyslipidemia and chronic inflammation and extends longevity. Depletion of the germ cells prior to transplantation unexpectedly enhanced the longevity- extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of chronic inflammation and dyslipidemia. In primitive species, depletion of gonadal germ cells can significantly extend longevity and health. However, these effects are dependent on the retention of the somatic gonad and the up-regulation of Foxo signaling. In mammals, Foxo suppresses the de novo methylase Dnmt3b, which reduces the age-associated erosion of methylation patterns and abates age-related epigenetic reprogramming. Ovarian Foxo signaling is significantly reduced at menopause due to the loss of Foxo- producing ovarian tissue. Our long-term goal is to identify ovarian factors that promote health and reduce age- related disease risks. Our objective in this application is to 1) determine how transplanted new ovaries, which extend life and health span, affect age-related changes in methylation, transcription, metabolism and immune function and 2) to identify germ cell-independent factors that play a role in ovarian tissue-dependent extension of health. Our central hypothesis is that 1) genomic regions that normally become differentially methylated during aging will undergo fewer methylation changes under the influence of transplanted young ovaries, resulting in decreased dyslipidemia and chronic inflammation, 2) that many of these survival-enhancing ovarian influences are germ cell-independent and 3) that somatic cells isolated from young ovaries will provide a similar benefit as intact or germ-cell depleted young ovaries when transplanted in post-reproductive female mice. To test our hypotheses, we propose three specific aims to determine how young germ cell-containing young ovaries (Aim 1), germ cell-depleted young ovaries (Aim 2) and somatic cells isolated from young ovaries (Aim 3) affect age-related changes in health, DNA methylation, transcription, dyslipidemia and chronic inflammation in post-reproductive mice. We hypothesize that transplantation of young ovaries will improve health and slow/avert DNA methylation changes and block the epigenetic reprogramming of metabolism- and immune-regulating genes in post-reproductive female mice and that depletion of germ cells from young ovaries and somatic cells isolated from a young ovary will provide similar health and molecular changes as in recipients of intact young ovaries. We expect to identify mechanisms of an evolutionarily conserved, gonad- dependent survival-enhancing strategy designed to preserve the organism's germline transmission potential. We also expect to reveal a germ cell-independent survival mechanism and may provide the basis for a clinical therapeutic model, where young-ovary mimicking, patient-derived iPS cells will be transplanted to aged women to elude age-associated disease risks and significantly improve quality of life.