The Ageing Adipose Paradox: Implications for Metabolic Health

ABSTRACT Background Preadipocyte commitment to the adipogenic lineage declines markedly with advancing age, while triglyceride accumulation in hypertrophied existing adipocytes persists or expands. This creates a dissociation between adipogenic capacity and lipid‐buffering demand, progressively weakening depot metabolic competence and contributing to systemic insulin resistance. Objective This review examines the molecular mechanisms linking impaired adipose tissue plasticity during ageing to metabolic decline, and appraises therapeutic strategies that may restore adipose progenitor competence or limit downstream metabolic dysfunction. Key Findings Ageing adipose tissue is characterized by four interlocking defects. First, transcriptional reprogramming, including induction of the inhibitory CCAAT/enhancer‐binding protein β‐LIP isoform through CUG triplet repeat‐binding protein 1, together with reduced C/EBPα and peroxisome proliferator‐activated receptor γ activity, shifts progenitors away from differentiation and toward hypertrophic lipid storage. Second, SIRT7 opposes SIRT1 in regulating adipogenic commitment, implicating sirtuin and NAD + dysregulation in the age‐related adipogenic deficit. Third, nuclear lamina remodelling restricts chromatin accessibility at adipogenic loci. Fourth, senescent cells accumulate in ageing depots and generate a senescence‐associated secretory phenotype enriched in interleukin‐6, tumour necrosis factor‐α, and matrix metalloproteinases, sustaining local inflammation and inhibiting preadipocyte differentiation. These changes occur alongside redistribution of fat from subcutaneous depots toward visceral, hepatic, muscular, and perivascular compartments, accelerating insulin resistance, Type 2 diabetes, and cardiovascular disease. Sex‐specific depot trajectories diverge, and rodent models reproduce these patterns only partly. Therapeutic Implications Senolytics, NAD + precursors, and incretin‐based agents, including GLP‐1 and dual GIP/GLP‐1 receptor agonists, are reviewed together with still‐preclinical stem cell and CRISPR approaches, ranked by translational readiness. Conclusion Restoring adipose progenitor competence while preserving depot‐specific metabolic identity may help slow age‐related metabolic deterioration and prolong healthspan.