The senescence of vascular smooth muscle cells (VSMCs) is an important cause of cardiovascular disease such as atherosclerosis and hypertension. These senescence may be triggered by many factors, such as oxidative stress, inflammation, DNA damage, and senescence-associated secretory phenotypes (SASPs). Mitochondrial oxidative stress induces cellular senescence, but the mechanisms by which mitochondrial reactive oxygen species (mtROS) regulates cellular senescence are still largely unknown. Here, we investigated the mechanism responsible for the anti-aging effect of metformin by examining links between VSMC senescence and mtROS in in vitro and in vivo. Metformin was found to increase p-AMPK (Ser485), but to decrease senescence-associated phenotypes and protein levels of senescence markers during ADR-induced VSMC senescence. Importantly, metformin decreased mtROS by inducing the deacetylation of superoxide dismutase 2 (SOD2) by increasing SIRT3 expression. Moreover, AMPK depletion reduced the expression of SIRT3 and increased the expression of acetylated SOD2 despite metformin treatment, suggesting AMPK activation by metformin is required to protect against mitochondrial oxidative stress by SIRT3. This study provides mechanistic evidence that metformin acts as an anti-aging agent and alleviates VSMC senescence by upregulating mitochondrial antioxidant induced p-AMPK (Ser485)-dependent SIRT3 expression, which suggests metformin has therapeutic potential for the treatment of age-associated vascular disease.

血管平滑肌细胞（VSMCs）的衰老是导致动脉粥样硬化、高血压等心血管疾病的重要原因。这些衰老可能由许多因素触发，例如氧化应激、炎症、DNA 损伤和衰老相关的分泌表型 (SASP)。线粒体氧化应激诱导细胞衰老，但线粒体活性氧（mtROS）调节细胞衰老的机制仍然很大程度上未知。在这里，我们通过在体外和体内检查 VSMC 衰老与 mtROS 之间的联系，研究了二甲双胍抗衰老作用的机制。发现二甲双胍增加 p-AMPK (Ser485)，但在 ADR 诱导的 VSMC 衰老过程中降低衰老相关表型和衰老标志物的蛋白质水平。重要的，二甲双胍通过增加 SIRT3 表达诱导超氧化物歧化酶 2 (SOD2) 的去乙酰化，从而降低 mtROS。此外，尽管二甲双胍治疗，AMPK 消耗降低了 SIRT3 的表达并增加了乙酰化 SOD2 的表达，这表明二甲双胍激活 AMPK 是防止 SIRT3 引起的线粒体氧化应激所必需的。该研究提供了机制证据，表明二甲双胍可作为抗衰老剂并通过上调线粒体抗氧化剂诱导的 p-AMPK (Ser485) 依赖性 SIRT3 表达来缓解 VSMC 衰老，这表明二甲双胍在治疗与年龄相关的血管疾病方面具有治疗潜力。尽管二甲双胍治疗，AMPK 耗竭降低了 SIRT3 的表达并增加了乙酰化 SOD2 的表达，这表明二甲双胍激活 AMPK 是防止 SIRT3 引起的线粒体氧化应激所必需的。该研究提供了机制证据，表明二甲双胍可作为抗衰老剂并通过上调线粒体抗氧化剂诱导的 p-AMPK (Ser485) 依赖性 SIRT3 表达来缓解 VSMC 衰老，这表明二甲双胍在治疗与年龄相关的血管疾病方面具有治疗潜力。尽管二甲双胍治疗，AMPK 耗竭降低了 SIRT3 的表达并增加了乙酰化 SOD2 的表达，这表明二甲双胍激活 AMPK 是防止 SIRT3 引起的线粒体氧化应激所必需的。该研究提供了机制证据，表明二甲双胍可作为抗衰老剂并通过上调线粒体抗氧化剂诱导的 p-AMPK (Ser485) 依赖性 SIRT3 表达来缓解 VSMC 衰老，这表明二甲双胍在治疗与年龄相关的血管疾病方面具有治疗潜力。