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

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.