Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives

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.

Automated summary

Aging is a natural process that causes functional decline in cells and tissues, increasing the risk of disease and death. Efforts have been made to control aging and increase lifespan and healthspan, leading to the discovery of drugs like rapamycin and metformin. Alpha-ketoglutarate (AKG) is a metabolite that shows potential as an anti-aging compound, improving longevity and reproductive health. It plays a crucial role in various cellular functions and exerts its effects through different mechanisms. This article summarizes recent studies on AKG-related lifespan and discusses its promises and limitations for delaying aging and other potential applications.