Exercise attenuates atherosclerosis by inhibiting eWAT aging via targeting SIRT1/pyruvate carboxylase pathway

Aging is the primary risk factor for atherosclerosis (AS). Epididymal white adipose tissue (eWAT) is a key driver of organismal aging and age-related diseases. Exercise is known to protect against AS, but the role of aging eWAT in this process remains unclear. To this end, we investigated whether exercise inhibits AS by regulating aging eWAT and elucidated the involved mechanisms. ApoE^-/- and C57BL/6 mice were fed a high-fat diet (HFD) to mimic poor lifestyle habits and explore eWAT senescence evolution. We found eWAT is a senescence-susceptible organ, exhibiting time-dependent deterioration under unhealthy lifestyle conditions. Furthermore, eWAT transplantation experiments confirmed that aging eWAT accelerates AS progression in both local and distal vascular regions. Exercise significantly ameliorated HFD-induced eWAT remodelling and inflammation, thereby inhibiting AS progression. Bioinformatics and lipidomic analyses identified that SIRT1 is essential for the anti-senescent eWAT effects of exercise by suppressing pyruvate carboxylase (PC). Contrarily, SIRT1 downregulation in eWAT with adeno-associated virus (AAV) reversed the exercise protective effects. Similarly, senolytic treatment (dasatinib plus quercetin) or PC downregulation with AAV also attenuated eWAT aging and AS progression. Our results demonstrate that exercise attenuates unhealthy lifestyle-induced premature aging of eWAT delays the progression of associated AS by modulating the SIRT1/PC axis. Thus, targeting this signaling axis may represent a novel therapeutic strategy for preventing AS and could serve as a potential alternative to exercise intervention.