An ANGPTL8‐AKT2‐mTOR Axis Drives Adipose Senescence and Aging‐Related Functional Decline

ABSTRACT

Adipose tissue senescence is increasingly recognized as a key driver of systemic aging and age‐related functional decline, yet the endocrine regulators that actively promote this process remain poorly defined. Angiopoietin‐like protein 8 (ANGPTL8) is a metabolic factor implicated in lipid metabolism and inflammation and has been associated with multiple aging‐related disorders. However, its direct role in adipose tissue senescence and organismal aging remains unclear. Here, we identify ANGPTL8 as a previously unrecognized regulator of adipose tissue aging through integrative analyzes of human cohorts, animal models, transcriptomics, and cellular studies. In a large human cohort, circulating ANGPTL8 levels were strongly associated with biological aging and mortality risk and significantly improved machine learning–based models for age and survival prediction. Consistent with these findings, genetic deletion of Angptl8 in mice extended lifespan, attenuated aging‐associated functional decline, and reduced senescence markers in adipose tissue. Transcriptomic analyzes revealed age‐dependent upregulation of ANGPTL8 in adipocytes accompanied by activation of pro‐senescent transcriptional programs. Mechanistically, ANGPTL8 directly interacted with AKT2 and activated the AKT–mTOR–S6K signaling pathway, thereby promoting cell‐autonomous adipocyte senescence. Genetic or pharmacological inhibition of this pathway abolished the pro‐senescent effects of ANGPTL8. Collectively, our findings identify ANGPTL8 as an endocrine regulator linking metabolic dysfunction to adipose tissue senescence and systemic aging, highlighting the ANGPTL8–AKT2–mTOR axis as a potential therapeutic target for delaying age‐associated functional decline.