#134 : Unraveling the mTORC1 Mediated Pathway for Reproductive Longevity Rejuvenation by Targetting RPS6

Background and Aims: The mTORC1 pathway is known to play a critical role in longevity and is a central regulator for various pathways including cellular, inflammation, and metabolic pathways. Age-related functional decline in tissue was associated with dysregulation of the mTORC1 pathway. mTORC1 suppression has been shown to improve ovarian function in mice, but the underlying cause remains elusive. We aim to investigate a common denominator of mTOR1, ribosomal protein S6 (rpS6), and its role in reproductive longevity through transient inhibition of the rps6 axis using murine models. Method: Selective inhibition of the mTORC1 pathway and the rpS6 axis were achieved using rapamycin and LY2584702 Tosylate respectively. Subcutaneous injection of both drugs was administered to 48-week-old female virgin C57BL/6J mice for thrice weekly for 8 weeks. Reproductive outcomes such as mating frequencies, fecundity, and lifespan were recorded. Results: Reproductive parameters measured revealed that these 48-week-old female virgin treated mice resulted in the increase in serum Anti-Mullerian hormone levels, total number of ovarian follicles, mating frequencies and probability of live births. Untreated control mice at 62 weeks old did not yield any live births. Comparison between the two treatment groups suggested that selective inhibition of rpS6 demonstrated higher probability of live births and higher average number of live offspring per litter. Conclusion: This study provides novel insights into the roles of mTORC1 and rpS6 in both reproductive and healthy longevity. Our findings suggest temporary rpS6 inhibition successfully rejuvenated ageing ovaries, with the novel discovery in the improvement of fecundity of LY2584702 treated mice.