Kindlin-2 functional restoration through methylmalonic acid clearance by coenzyme A counteracts osteoporosis.

Old blood can induce senescence in young mice, yet the underlying mechanisms remain unclear. Here, we demonstrate that non-protein components (NPs) of aged human serum (ONPs) induce skeletal aging in young mice, with methylmalonic acid (MMA) identified as a key driver capable of independently recapitulating the skeletal aging phenotypes observed in ONP-treated mice. Photoaffinity labeling confirms Kindlin-2 as a direct intracellular MMA receptor. MMA binds directly to Kindlin-2 via a positively charged motif in its UBL domain, promoting Kindlin-2 ubiquitination and degradation, which accelerates skeletal aging. Notably, the endogenous MMA scavenger coenzyme A (CoA), a clinically approved molecule, effectively reverses MMA- and ONP-induced skeletal aging. Furthermore, CoA treatment effectively protects against skeletal aging and bone mass loss in aged or estrogen-deficient mouse models. Our study establishes MMA as a central aging factor and Kindlin-2 as its intracellular receptor, offering a potential therapeutic strategy for age-related diseases such as osteoporosis.