mTORC1-Induced Bone Marrow-Derived Mesenchymal Stem Cell Exhaustion Contributes to the Bone Abnormalities in Klotho -Deficient Mice of Premature Aging.

Stem cell exhaustion is a hallmark of aging. -deficient mice ( mice) is a murine model that mimics human aging with significant bone abnormalities. The aim of this study is using mice to investigate the functional change of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the underlying mechanism. We found that deficiency leads to bone abnormalities. In addition, BMSCs manifested hyperactive proliferation but functionally declined both in vivo and in vitro. Mammalian target of rapamycin complex 1 (mTORC1) activity was higher in freshly isolated BMSCs, and autophagy in BMSCs was significantly decreased, possibly through mTORC1 activation. Conditional medium containing soluble Klotho protein (sKL) rescued hyperproliferation of BMSCs by inhibiting mTORC1 activity and restoring autophagy. Finally, intraperitoneal injection of mTORC1 inhibitor rapamycin restored BMSC quiescence, ameliorated bone phenotype, and increased life span of mice in vivo. This research highlights a therapeutic strategy to maintain the homeostasis of adult stem cell pool for healthy bone aging.