Jiang Yizhou, Han Jing-Dong J
Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education, International Center for Aging and Cancer, Hainan Medical University, Haikou, China.
Hainan Academy of Medical Sciences, Hainan Medical University, Haikou, China.
Aging Cell. 2026 Feb;25(2):e70371. doi: 10.1111/acel.70371.
Aging is a multifactorial process influenced by genetic, environmental, and metabolic factors. Dysregulated nutrient sensing and metabolic dysfunction are hallmarks of aging, and reduction of insulin/IGF-1 signaling or metabolic interventions such as caloric restriction extend lifespan across species. Endogenous metabolites reflect and mediate these metabolic cues, linking nutrient status to epigenetic and transcriptional programs by serving as cofactors for chromatin-modifying enzymes or as allosteric modulators of transcription factors. Some metabolites have emerged as key regulators of longevity, integrating into networks to concurrently influence multiple aging-related pathways. In this review, we summarize evidence supporting the lifespan-extending effects of key endogenous metabolites across diverse model organisms and discuss their mechanisms of action. These insights underscore the potential of targeting metabolic networks as a multifaceted strategy to delay aging. Finally, we consider the translational promise of metabolite-based interventions to extend healthspan while minimizing adverse effects, and we note remaining challenges such as optimal dosing, context-specific effects, and demonstrating efficacy in humans.
衰老 是一个受遗传、环境和代谢因素影响的多因素过程。营养感知失调和代谢功能障碍是衰老的标志，而胰岛素/胰岛素样生长因子-1信号通路的减弱或热量限制等代谢干预措施可延长物种的寿命。内源性代谢物反映并介导这些代谢信号，通过作为染色质修饰酶的辅助因子或转录因子的变构调节剂，将营养状态与表观遗传和转录程序联系起来。一些代谢物已成为长寿的关键调节因子，整合到网络中以同时影响多个与衰老相关的途径。在本综述中，我们总结了支持关键内源性代谢物在不同模式生物中延长寿命作用的证据，并讨论了它们的作用机制。这些见解强调了将代谢网络作为延缓衰老的多方面策略的潜力。最后，我们考虑基于代谢物的干预措施在延长健康寿命同时最小化不良反应方面的转化前景，并指出仍然存在的挑战，如最佳剂量、特定背景效应以及在人类中证明疗效。
