Female mice with hepatocyte-specific SIRT6 knockout suffered a 17.6% reduction in median lifespan alongside visceral adiposity, metabolic-associated fatty liver disease, genomic instability, and accelerated cellular senescence — none of which appeared in male knockouts. The mechanistic driver was exclusive hyperactivation of SULT1E1, a sulfotransferase enzyme that inactivates estradiol, triggering a pathological triad of de novo lipogenesis, DNA damage, and senescence. Critically, the small-molecule SIRT6 activator MDL-800 suppressed SULT1E1, restored circulating estradiol, and reversed the aging phenotype in aged female mice.
This finding reframes the liver not merely as a metabolic organ but as an active regulator of systemic sex-hormone homeostasis and, by extension, female longevity. SIRT6 has long been recognized as a longevity gene — its whole-body overexpression extends murine lifespan — but this is among the first studies to isolate a sex-dimorphic, cell-type-specific mechanism explaining why SIRT6 biology diverges between males and females. The SIRT6→SULT1E1→estradiol axis dovetails with established epidemiology linking estrogen decline at menopause to accelerated metabolic aging and fatty liver risk in women. Limitations are real: this is an animal model with artificially complete hepatic SIRT6 deletion, and translating MDL-800 to clinical use requires human pharmacokinetic and safety data. Still, the identification of a druggable, sex-stratified hepatic axis is genuinely paradigm-shifting, offering a mechanistic rationale for sex-specific interventions in metabolic aging rather than one-size-fits-all approaches.