Ovarian-derived signals reprogram hepatic lipid metabolism in aging: Implications for therapeutic targeting of metabolic dysfunction.

BACKGROUND AND AIM: Aging in mammals is a complex, multifaceted process involving the progressive decline of physiological functions, in which energy metabolism plays a pivotal role. β-oxidation-the primary pathway for converting fatty acids into energy-is tightly linked to aging and to female reproductive senescence. In the present study, we investigated how ovarian tissue remodels hepatic proteins central to the β-oxidation pathway.

METHODS

Liver proteomes were analyzed in CBA/J control mice at 4, 13, 23, and 27 months of age and compared with those of 23-month-old mice that received transplants of young ovarian tissue at 13 months. β-oxidation proteins were quantified using high-resolution mass spectrometry. Serum triglycerides were measured enzymatically, and metabolic cage analyses were performed to assess substrate utilization and energy balance.

RESULTS

Ovarian tissue transplantation substantially modulates the expression of β-oxidation-related proteins and reduces systemic lipid accumulation in aged mice. These proteomic shifts are consistent with enhanced metabolic efficiency and decreased oxidative stress-mechanisms well-established as drivers of extended health span and longevity. Results apply to menopause dyslipidemia, insulin resistance, metabolic syndrome, NAFLD, and aging. Transplants reduce β-oxidation proteins and triglycerides, improving hepatic lipid clearance and steatosis risk. Identifying ovarian signals enables non-surgical mimics via peptides or modulators. Changes align with PPARα agonists, CPT1 modulators, mitochondria-targeted antioxidants (MitoQ), and NAD+/sirtuin pathways-offering testable routes to replicate ovarian benefits.

CONCLUSIONS

Ovarian-derived signals induce metabolic reprogramming in aged mice, characterized by reduced β-oxidation protein expression, decreased triglyceride accumulation, and improved metabolic efficiency. These findings provide a molecular framework for understanding how ovarian-derived factors may govern metabolism and organismal health during aging, with potential implications for interventions targeting age-related metabolic decline.