ATPIF1-driven metabolic remodeling in osteoclasts promotes age-related cortical bone loss

Abstract Age-related cortical bone loss is driven in part by increased osteoclast activity, but the mechanisms that sustain osteoclast function during skeletal aging remain poorly defined. Here, we show that aging remodels osteoclast metabolism, increasing glycolytic ATP production and reshaping metabolites linked to early tricarboxylic acid (TCA) cycle metabolism. Metabolomic profiling identified a glycolysis-coupled TCA node marked by increased isocitrate and -ketoglutarate in aged osteoclasts. These cells also exhibited prolonged survival and reduced activation of regulated cell-death pathways; in mice, this was accompanied by increased bone resorption, while human osteoclasts from aged donors similarly showed prolonged persistence. Mechanistically, ATPase inhibitory factor 1 (ATPIF1) was required for this aging-associated metabolic state. Osteoclast-lineage deletion of Atpif1 reduced IDH3A expression, -ketoglutarate accumulation, glycolytic ATP production, and resorptive function ex vivo, while attenuating age-related cortical bone loss and porosity in vivo. Pharmacologic perturbation of IDH3-linked metabolism similarly suppressed glycolytic ATP production and osteoclast activity and increased cortical bone mass in aged mice. Together, these findings identify glycolysis-centered metabolic rewiring as a mechanism that sustains osteoclast survival and resorption during skeletal aging and implicate an ATPIF1–IDH3A metabolic axis as a potential therapeutic target for age-associated osteoporosis.