Age and sex influence transcriptomic responses to statin therapy that control liver aging during systemic metabolic dysfunction

BACKGROUND AND AIMS: Older age increases susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined. APPROACH AND RESULTS: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use is strongly associated with suppression of senescence-related pathways. Statin use is also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort. CONCLUSIONS: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.