ABSTRACT: Ageing is associated with profound remodelling of white adipose tissue, yet the cell-intrinsic molecular mechanisms underlying visceral fat dysfunction remain poorly understood. Here, we performed integrated transcriptomic, DNA methylation, and lipidomic profiling of purified pre-adipocytes and mature adipocytes from visceral fat of young (3-month) and aged (18-month) mice. Bulk RNA sequencing revealed extensive, largely cell type–specific transcriptional reprogramming with age, including shared induction of inflammatory pathways and erosion of cellular identity, particularly in adipocytes, consistent with age-associated de-differentiation. Whole-genome bisulphite sequencing uncovered distinct ageing-associated DNA methylation landscapes in the two cell types, with predominant hypomethylation in pre-adipocytes and hypermethylation in adipocytes. Ageing-differentially methylated regions (ageing-DMRs) were enriched at promoters, super-enhancers, and distal regulatory elements, and their presence significantly increased the likelihood of associated genes becoming ageing-differentially expressed genes (ageing-DEGs). Notably, ageing-DMRs located near ageing-DEGs displayed higher CpG and GC content, active chromatin features, and enrichment for motifs of ageing-relevant transcription factors compared with ageing-DMRs as a whole. Targeted lipidomic analysis of adipocytes revealed pronounced, cell-intrinsic remodelling of the lipidome, including selective depletion of triglycerides and accumulation of ceramides, largely uncoupled from systemic lipid changes. Integration of lipidomic and transcriptomic data highlighted coordinated downregulation of glycerolipid biosynthesis and lipolysis genes alongside upregulation of sphingolipid and ceramide metabolism pathways, frequently accompanied by ageing-associated DNA methylation changes. Collectively, our findings demonstrate that ageing drives coordinated epigenetic, transcriptional, and metabolic rewiring across visceral adipose cell types, linking loss of cellular identity and ceramide accumulation to intrinsic adipose ageing and metabolic dysfunction
