衰老是一个自然的过程，由于细胞和组织的功能性衰退，随着有机体的老化而决定，导致患病和死亡风险的增加。为此，人们已经做出了许多努力来控制衰老，延长寿命和健康寿命。这些努力已经导致了发现几种抗衰老药物和化合物，如雷帕霉素和二甲双胍。最近，α-酮戊二酸（AKG）被引入作为潜在的抗衰老代谢物，可以控制有机体中的多种功能，从而增加寿命并改善健康寿命。与其他合成的抗衰老药物不同，AKG是三羧酸循环（TCA循环）的代谢物之一，也称为克雷布斯循环，在体内合成。它在细胞能量代谢、氨基酸/蛋白质合成、表观遗传调节、干细胞和分化、生育和生殖健康以及癌细胞行为中发挥着关键作用。 AKG通过不同的机制发挥其作用，如抑制mTOR和ATP合成酶、调节DNA和组蛋白去甲基化和减少ROS的形成。在此，我们总结了与AKG相关的寿命和健康寿命研究的最新发现，并讨论了AKG与增加寿命、改善生殖能力以及调节干细胞和癌细胞行为所涉及的细胞和分子机制。我们还讨论了AKG延缓衰老和其他潜在应用的前景和限制。版权所有©2023 Elsevier Inc.

Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications.Copyright © 2023. Published by Elsevier Inc.