Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.

Over 50 billion cells undergo apoptosis each day in an adult human to maintain tissue homeostasis by eliminating damaged or unwanted cells. Apoptotic deficiency can lead to age-related diseases with reduced apoptotic metabolites. However, whether apoptotic metabolism regulates aging is unclear. Here, we show that aging mice and apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) mice exhibit decreased apoptotic levels along with increased aging phenotypes in the skeletal bones, which can be rescued by the treatment with apoptosis inducer staurosporine (STS) and stem cell-derived apoptotic vesicles (apoVs). Moreover, embryonic stem cells (ESC)-apoVs can significantly reduce senescent hallmarks and mtDNA leakage to rejuvenate aging bone marrow mesenchymal stem cells (MSCs) and ameliorate senile osteoporosis when compared to MSC-apoVs. Mechanistically, ESC-apoVs use TCOF1 to upregulate mitochondrial protein transcription, resulting in FLVCR1-mediated mitochondrial functional homeostasis. Taken together, this study reveals a previously unknown role of apoptotic metabolites in ameliorating bone aging phenotypes and the unique role of TCOF1/FLVCR1 in maintaining mitochondrial homeostasis.