Brown adipocyte Acss1 restoration ameliorates redox-metabolic dysfunction and systemic metabolic decline during aging

Aging disrupts the coupling between redox homeostasis and energy metabolism in brown adipose tissue (BAT), but the molecular nodes linking BAT redox-metabolic deterioration to systemic metabolic dysfunction remain unclear. Using aging mouse BAT time-course transcriptomics, we prioritized Acss1, encoding mitochondrial acetyl-CoA synthetase 1 (ACSS1), as a progressively age-decreased mitochondrial metabolic candidate. Acss1 expression correlated positively with BAT metabolic programs and negatively with oxidative stress and senescence-associated programs. Age-series single-nucleus transcriptomics further localized Acss1 mainly to adipocytes and classified BAT adipocyte nuclei into Acss1-high and Acss1-low transcriptional states. Acss1-high adipocytes retained thermogenic, oxidative phosphorylation and fatty acid oxidation programs, whereas Acss1-low adipocytes were enriched for stress- and senescence-related programs, with this divergence increasing with age. To test Acss1 function, we locally injected 18-month-old mouse BAT with an adeno-associated virus expressing Acss1 under the adipocyte-specific adiponectin (Adipoq) promoter. BAT-local Acss1 restoration attenuated redox imbalance, restored thermogenic programs and reduced senescence-associated injury. This local intervention also improved glucose and lipid metabolism, energy substrate utilization, motor performance and plasma antioxidant capacity, and was associated with improved histological and stress-related features in distal metabolic tissues. Matched BAT transcriptomic and plasma metabolomic profiling showed that Acss1 restoration shifted BAT redox-metabolic programs and was associated with spermidine-related circulating metabolic remodeling. In human BAT, ACSS1 expression correlated positively with oxidative phosphorylation and negatively with reactive oxygen species metabolic processes. These findings support brown adipocyte Acss1 as a regulator of redox-metabolic homeostasis in aged BAT, whose restoration is associated with improved local BAT state, improved systemic metabolic phenotypes and spermidine-related circulating metabolic remodeling.