Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations

Age-related osteoporosis is characterized by the deterioration in bone volume and strength, partly due to the dysfunction of bone marrow mesenchymal stromal/stem cells (MSCs) during aging. Alpha-ketoglutarate (alpha KG) is an essential intermediate in the tricarboxylic acid (TCA) cycle. Studies have revealed that alpha KG extends the lifespan of worms and maintains the pluripotency of embryonic stem cells (ESCs). Here, we show that the administration of alpha KG increases the bone mass of aged mice, attenuates age-related bone loss, and accelerates bone regeneration of aged rodents. alpha KG ameliorates the senescence-associated (SA) phenotypes of bone marrow MSCs derived from aged mice, as well as promoting their proliferation, colony formation, migration, and osteogenic potential. Mechanistically, alpha KG decreases the accumulations of H3K9me3 and H3K27me3, and subsequently upregulates BMP signaling and Nanog expression. Collectively, our findings illuminate the role of alpha KG in rejuvenating MSCs and ameliorating age-related osteoporosis, with a promising therapeutic potential in age-related diseases.