Lactate receptor activation reduces arterial senescence in mice

In human aortic transcriptomic data, expression of the lactate receptor gene HCAR1 declined significantly with age. In cultured human endothelial and vascular smooth muscle cells, silencing this receptor induced lipid accumulation, ferroptosis, and markers of cellular senescence. In young mice, endothelial-specific deletion of GPR81 caused senescent cell accumulation, impaired lipid balance, endothelial dysfunction, and elastin disorganization. Treating cultured human vascular cells with the agonist CHBA restored fatty acid metabolism and attenuated ferroptotic stress and senescence phenotypes. In lamin A knock-in progeroid mice, CHBA treatment reduced arterial lipid accumulation and cellular senescence, shifted vascular cell composition toward a youthful state, improved endothelial integrity, and restored extracellular matrix homeostasis.