Modulation of Lifespan and Healthspan by Meiosis Genes

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ABSTRACT: Modulation of Lifespan and Healthspan by Meiosis Genes The impact of advanced maternal age on fertility decline is well established, but how germline fitness influ- ences organismal health and aging remains unclear. It is known that reproductive defects augur detrimental long-term consequences in both sexes. For instance, early age-at-natural-menopause (ANM) has been linked to greater risk of mortality. Women with late ANM exhibit younger ‘epigenetic aging’ profiles and brothers of women with prolonged reproductive longevity show extended lifespan. Menopause itself triggers susceptibility to a host of comorbidities unrelated to reproduction such as cardiovascular disease and dementia, as does tes- tosterone decline in men. Thus, a compelling body of clinical and epidemiological evidence indicates that germline status influences overall organismal health and aging. However, human studies do not address cau- sality nor reveal the mechanisms by which the immortal germline may influence aging of the mortal somatic tissues. We have utilized the unique strengths of Caenorhabditis elegans to assess how perturbing meiosis, a pro- cess that occurs exclusively in germ cells, impacts the length of life and rate of aging of the animal. This pro- posal is based on our discovery that disruption of meiosis accelerates somatic aging. We found that mutations in C. elegans genes operating at different steps of meiosis shortened lifespan, impaired healthspan and desta- bilized protein homeostasis. Importantly, meiotic mutants exhibited prematurely aged transcriptional profiles reminiscent of old C. elegans and aging human tissues, suggesting that germline dysfunction triggers a con- served molecular-aging signature. Thus, we hypothesize that genes that govern meiotic fidelity in germ cells influence organismal lifespan and healthspan. Our study has revealed a hitherto unknown link between the nuclear events of meiosis in germ cells and the aging of both the gonadal tissue and the organism. This exploratory study aims to find the missing links in this pathway: what are the signals between the germ line and soma that lead to organismal aging (Aim 1), does the meiotic nuclear dysfunction lead to aging of the gonad as well and how is this connected to somatic aging (Aim 2). Notably, many of the genes we studied have human homologs with roles in mammalian meiosis and have been implicated in reproductive senescence. The transcriptional similarities we identified between meiosis mutants and aging human tissues suggest avenues to unravel potential evolutionarily conserved mechanisms underpinning the meiotic control of health and longevity. This study will establish the foundation for future mechanistic- and conservational- studies.