Short‐Term Rapamycin Mitigates the Senescence of Ovaries and Somatic Stem Cells in Multiple Organs in Reproductively Aged Mice

Reproductive aging in females is marked by ovarian senescence and a concomitant decline in somatic organ function. Mechanistic target of rapamycin (mTOR) signaling is a central regulator of aging. Rapamycin has been shown to confer anti-aging benefits in young and middle-aged females; however, whether mTOR inhibition remains effective once reproductive aging is established remains unclear. Here we analyzed transcriptomics of oocytes and granulosa cells from reproductively aged (10-month-old) mice and identified upregulation of ribosome biogenesis and cytoplasmic translation, consistent with hyperactive mTOR signaling. We then evaluated the effects of short-term rapamycin treatment during the perimenopausal period. One month of rapamycin treatment effectively suppressed mTOR signaling and reduced cellular senescence, inflammation, fibrosis, and oxidative damage in the ovary, lung, small intestine, and skeletal muscle. Rapamycin also alleviated somatic stem exhaustion across multiple tissues by reducing DNA damage and senescence markers, restoring stem cell abundance, and improving differentiation capacity. Despite these improvements in the somatic microenvironment, rapamycin failed to restore fertility or serum estradiol levels in reproductively aged females. Importantly, the beneficial effects on mTOR activity, stem cell function, and tissue homeostasis were largely reversed following treatment withdrawal. Together, our findings demonstrate that short-term mTOR inhibition initiated after reproductive aging can transiently ameliorate systemic and ovarian aging phenotypes while highlighting a key limitation: reproductive function is not recoverable once advanced reproductive aging has occurred. And these results indicated the importance of intervention timing and suggest the therapeutic scope of rapamycin during female reproductive aging.