衰老细胞仍保持代谢活跃，但它们的代谢格局及其产生的影响仍未得到充分研究。在这里，我们报告了衰老时丙酮酸脱氢酶激酶 4 (PDK4) 的上调，特别是在一些基质细胞系中。衰老细胞表现出 PDK4 依赖性的有氧糖酵解增加和乳酸生成增加，但维持线粒体呼吸和氧化还原活性，从而采用特殊形式的代谢重编程。 PDK4 基质细胞的培养基在体外促进受体癌细胞的恶性，而抑制 PDK4 会导致体内肿瘤消退。我们发现乳酸通过 NOX1 促进活性氧的产生，从而驱动衰老相关的分泌表型，而 PDK4 抑制则降低 DNA 损伤的严重程度并抑制衰老相关的分泌表型。在临床前试验中，PDK4 抑制可减轻身体功能障碍并预防与年龄相关的虚弱。总之，我们的研究证实了衰老细胞的过度分解代谢性质，并揭示了细胞衰老、乳酸产生以及可能的年龄相关病理（包括但不限于癌症）之间的代谢联系。© 2023。作者。

Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.© 2023. The Author(s).