Liver aging is characterized by structural remodeling and functional decline, frequently driven by mitochondrial dysfunction and senescence-associated secretory phenotype (SASP). Sestrins (SESNs) are a family of stress-inducible proteins, among which Sestrin1 and Sestrin2 are crucial for maintaining metabolic and redox homeostasis, yet their specific involvement in hepatic senescence remains unclear. In the present study, in vivo experiments were performed using WT mice at young, middle, and old ages, together with aged Sestrin1-/- and Sestrin2-/- mice. The aged mice displayed multifaceted hepatic dysfunction, accompanied by a progressive, age-dependent decline of hepatic Sestrin1 and Sestrin2 expression. Intriguingly, hepatic cellular senescence, lipid deposition, oxidative stress and inflammation were significantly exacerbated in Sestrin1-/- mice compared to Sestrin2-/- and WT mice. To further explore the underlying mechanism, senescent AML12 cells overexpressing Sestrin1 were treated with or without mitochondrial division inhibitor-1 (Mdivi-1). Mechanistically, Sestrin1 preserved mitochondrial homeostasis by promoting mitochondrial fission via dynamin-related protein 1 (Drp1), a master regulator of mitochondrial fission, and curtailing the leakage of mitochondrial DNA (mtDNA) into the cytoplasm, profoundly suppressing the cGAS-STING pathway. However, these effects were abolished upon mitochondrial fission inhibition. Given that exercise training is a potent anti-aging strategy known to upregulate SESNs protein levels, we further demonstrated that Sestrin1 is indispensable for its hepatoprotective benefits. Collectively, our results identified that the Sestrin1/Drp1/cGAS-STING axis plays a pivotal role in liver aging and positioned Sestrin1 as a vital therapeutic target, serving as a key mediator of the anti-aging benefits of exercise training.
