Short‐term rapamycin treatment increases ovarian lifespan in young and middle‐aged female mice

Abstract

SummaryAlthough age‐related ovarian failure in female mammals cannot be reversed, recent strategies have focused on improving reproductive capacity with age, and rapamycin is one such intervention that has shown a potential for preserving the ovarian follicle pool and preventing premature ovarian failure. However, the application is limited because of its detrimental effects on follicular development and ovulation during long‐term treatment. Herein, we shortened the rapamycin administration to 2 weeks and applied the protocol to both young (8 weeks) and middle‐aged (8 months) mouse models. Results showed disturbances in ovarian function during and shortly after treatment; however, all the treated animals returned to normal fertility 2 months later. Following natural mating, we observed prolongation of ovarian lifespan in both mouse models, with the most prominent effect occurring in mice older than 12 months. The effects of transient rapamycin treatment on ovarian lifespan were reflected in the preservation of primordial follicles, increases in oocyte quality, and improvement in the ovarian microenvironment. These data indicate that short‐term rapamycin treatment exhibits persistent effects on prolonging ovarian lifespan no matter the age at initiation of treatment. In order not to disturb fertility in young adults, investigators should in the future consider applying the protocol later in life so as to delay menopause in women, and at the same time increase ovarian lifespan.

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…Then, we performed rescue experiments with rapamycin, an mTOR inhibitor. Rapamycin treatment has been reported to prolong ovarian lifespan (Dou et al., 2017), and inhibition of mTORC1 or mTORC1/2 within ovaries during chemotherapy co‐treatment resulted in preservation of primordial follicle counts (Goldman et al., 2017). In the current study, oocyte competence was significantly improved both in vivo and in vitro by rapamycin treatment (Figure 7).…”

Inhibition of the NLRP3 inflammasome prevents ovarian aging

“…This mechanism may be key to the improvement of ovarian lifespan induced by the inhibition of NLRP3. Further, the support of many of the strategies to improve the reproductive aging and ovarian lifespan through the improvement of autophagy (26,28,29).…”

Rapamycin, proliferation and geroconversion to senescence

“…Rapamycin similarly preserved RPP during cell cycle arrest caused by pharmacologic inhibitors of CDK4/6, DNA damaging drugs, HDACi and phorbol ester [29,58,[65][66][67]. Suppression of senescence by rapamycin was further confirmed in vitro and in vivo [26,40,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. In addition to rapamycin, everolimus and ridaforolimus (two rapalogs), pan-mTOR inhibitors, nutlin-3a (a p53-inducer), hypoxia and contact inhibition all inhibit mTOR and thus maintain RPP in arrested cells [2,[32][33][34]58,[82][83][84][85][86].…”