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