Adipocytes as core drivers of skin aging and novel targets for regeneration.

Skin aging has traditionally been attributed to alterations in the epidermis and dermis, including keratinocyte senescence, extracellular matrix (ECM) degradation, and fibroblast dysfunction. In contrast, the role of skin-associated adipose tissue (SAAT), particularly dermal white adipose tissue (dWAT), has been largely overlooked and considered a passive structural filler. Emerging evidence indicates that adipocyte aging is not merely a consequence of skin aging but may serve as a critical upstream driver that shapes the local microenvironment. Age-related functional decline of adipocytes, including the senescence-associated secretory phenotype (SASP), metabolic reprogramming, and altered adipokine secretion, can promote dermal ECM deterioration, perturb fibroblast function, and promote chronic low-grade inflammation. Furthermore, regional heterogeneity of dWAT across anatomical sites contributes to the spatial variability of skin aging patterns, influencing both the timing and severity of structural changes. Mechanistically, an adipocyte-immune-fibroblast tri-cellular network integrates signals from senescent adipocytes, immune cells, and fibroblasts, thereby amplifying tissue-level aging phenotypes. Current anti-aging interventions, which largely target epidermal or dermal compartments or focus on restoring tissue volume, often fail to address adipocyte dysfunction and its downstream effects. Here, we propose a conceptual framework in which adipocyte aging functions as an initiating event in skin aging, and we discuss the potential of adipocyte-targeted strategies, including senolytics, senomorphics, and functional reprogramming, to restore skin homeostasis and delay aging. This adipocyte-centered perspective reframes the pathophysiology of skin aging and highlights novel therapeutic opportunities for regenerative dermatology.