Evolutionary Conservation of Lipid-Associated Epigenetic Signatures and Their Distinct Roles in Tissue Identity and Mammalian Aging

Background/Objectives: Lipid metabolism is fundamental to energy homeostasis and cellular structural integrity, and its dysregulation is a hallmark of biological aging. While DNA methylation clocks are well-established, it remains unclear whether epigenetic sites associated with specific lipid markers—High-Density Lipoprotein (HDL), Total Cholesterol (TCH), and Triglycerides (TGY)—are evolutionarily conserved across mammals and how they manifest across different metabolic tissues. Methods: We identified lipid-associated CpG sites in humans using the Korean Genome and Epidemiology Study (KoGES) cohort and projected these sites onto the Mammalian Methylation Consortium (GSE223748) dataset. Using the Hybrid Pi (HyPi) score, we selected robust markers to analyze their evolutionary conservation, tissue specificity, and age-related dynamics across over 300 mammalian species. Specifically, we examined the phylogenetic concordance between blood and three major metabolic organs (Liver, Adipose, Muscle) in five representative species. Results: Lipid-related CpGs were highly conserved across diverse mammals. t-SNE analysis revealed that these epigenetic signatures clustered samples by tissue identity and species. Methylation levels of these CpGs showed significant correlations with maximum lifespan and distinct aging rates across tissues. Notably, phylogenetic tanglegram analysis revealed a high degree of concordance between blood and key metabolic organs, suggesting that blood methylation profiles mirror the evolutionary trajectory of internal metabolic tissues. Furthermore, these patterns were consistent between sexes, indicating a fundamental, non-dimorphic regulation of lipid epigenetics. Conclusions: Our findings suggest that epigenetic mechanisms governing lipid metabolism are deeply conserved to maintain tissue identity and regulate biological aging, with blood serving as a reliable evolutionary proxy for internal metabolic states.