Hepatic SIRT6 Deficiency Accelerates Female-Specific Aging Through SULT1E1-Mediated Estrogen Depletion

Sexual dimorphism is a fundamental feature of aging, yet the liver-centric mechanisms underlying sex-specific aging trajectories remain incompletely understood. SIRT6, a NAD+-dependent deacetylase, is a master regulator of genome stability, metabolic homeostasis, and longevity. However, its cell-type- and sex-specific functions in aging have not been fully characterized. Here, we generated hepatocyte-specific Sirt6 knockout (HKO) mice of both sexes and evaluated longitudinal lifespan, comprehensive metabolic profiling, hepatic histopathology, and transcriptomic profiles. Female HKO mice exhibited an acceleration of aging and a 17.60% reduction in median lifespan, characterized by severe systemic gerometabolic decline, visceral adiposity, and advanced metabolic-associated fatty liver disease (MAFLD). In stark contrast, aged male HKO mice displayed an enhanced catabolic state and lipid-clearing phenotype via the compensatory reprogramming. Mechanistically, hepatic Sirt6 deficiency in females exclusively hyperactivated the expression of estrogen sulfotransferase SULT1E1, resulting in reduced circulating estradiol levels. This hormonal collapse triggered a self-amplifying pathological triad of de novo lipogenesis, genomic instability, and cellular senescence. Crucially, pharmacological SIRT6 activation using the small-molecule activator MDL-800 suppressed Sult1e1 expression, restored estrogen homeostasis, and successfully rescued the gerometabolic phenotypes in aged female mice. Collectively, these findings demonstrate that hepatic SIRT6 regulates female lifespan and healthspan by safeguarding estrogen homeostasis, defining the druggable SIRT6-SULT1E1 axis as a sex-stratified therapeutic target against age-related metabolic decline.