This work overturns the assumption that stem cell dysfunction is locally contained, showing a rare Tet2-deficient muscle stem cell pool propagates systemic inflammaging through succinate transfer and H4K31 succinylation, exposing new rejuvenation targets.
Age-related Tet2 downregulation in muscle stem cells triggers systemic inflammaging and multi-organ aging through a metabolic-epigenetic cascade in which disruption of the Tet2-Hdac11-Acod1-SDH axis causes succinate accumulation that drives H4K31 succinylation-mediated inflammatory gene activation, and sporadic fusion of these metabolically dysregulated stem cells during muscle homeostasis delivers excess succinate to myofibers, transforming skeletal muscle into a persistent source of pro-inflammatory signals that sustains whole-body chronic inflammation and accelerates aging across multiple organs.
Inflammaging, the sustained chronic inflammation, is a hallmark of aging, yet its sustained activation mechanism remains elusive. Here, we identified muscle stem cells (MuSCs) as a driver of systemic inflammaging, evidenced by the multi-organ inflammation and aging phenotypes in MuSC specific Tet2 knockout mice. Tet2-Hdac11-Acod1-SDH axis maintained normal succinate level in MuSCs. Tet2 knockout disrupted this enzymatic cascade and led to succinate accumulation, fueling H4K31succ elevation to directly activate inflammatory gene transcription in MuSCs. The excess succinate was delivered to muscle fibers by sporadic fusion of Tet2 knockout MuSCs during muscle homeostasis, activated pro-inflammatory program, and transformed muscle to a persistent pro-inflammatory factor secretory organ, sustaining systemic inflammaging. Moreover, Tet2 was downregulated in aged MuSCs suggesting that this coupled metabolic-epigenetic mechanism was active in physiological aging. These findings reveal that a small subset of dysregulated MuSCs activate sustained whole-body inflammaging and multi-organ aging, providing new targets for rejuvenation strategy development.