Sebacic Acid as a Potential Age-Related Biomarker of Liver Aging: Evidence Linking Mice and Human

The aging process is complicated and involves diverse organ dysfunction; furthermore, the biomarkers that are able to reflect biological aging are eagerly sought after to monitor the system-wide decline associated with the aging process. To address this, we performed a metabolomics analysis using a longitudinal cohort study from Taiwan (N = 710) and established plasma metabolomic age using a machine learning algorithm. The resulting estimation of age acceleration among the older adults was found to be correlated with HOMA-insulin resistance. In addition, a sliding window analysis was used to investigate the undulating decrease in hexanoic and heptanoic acids that occurs among the older adults at different ages. A comparison of the metabolomic alterations associated with aging between humans and mice implied that ω-oxidation of medium-chain fatty acids was commonly dysregulated in older subjects. Among these fatty acids, sebacic acid, an ω-oxidation product produced by the liver, was significantly decreased in the plasma of both older humans and aged mice. Notably, an increase in the production and consumption of sebacic acid within the liver tissue of aged mice was observed, along with an elevation of pyruvate-to-lactate conversion. Taken together, our study reveals that sebacic acid and metabolites of ω-oxidation are the common aging biomarkers in both humans and mice. The further analysis suggests that sebacic acid may play an energetic role in supporting the production of acetyl-CoA during liver aging, and thus its alteration in plasma concentration potentially reflects the aging process.