Zerong Zhang, Yong Liao
Traditional theories of early skin aging have established a robust foundation by elucidating the accumulation of molecular damage, such as inflammation, oxidative stress, epigenetic drift, and telomere shortening, and related extracellular matrix (ECM) changes. While these biochemical perspectives remain central to our understanding, increasing attention has been paid to the degeneration of the physical microenvironment of the dermal ECM and the concomitant dysfunction of core cellular functions during aging. This article aims to propose and substantiate an integrative framework for the early mechanisms of skin aging. Aging is not initiated by isolated molecular events but rather represents a tissue-level structural and functional degenerative process involving three coupled and progressively amplified dimensions: dermal fluid dynamics decay (characterized by decreased interstitial fluid pressure and impaired interstitial flow), mechanical unloading of fibroblasts (resulting from ECM fragmentation leading to diminished mechanical tension), and cellular nutrient-sensing dysfunction (involving dysregulation of the mechanistic target of rapamycin/AMP-activated protein kinase/sirtuin 1 pathways). Signaling axes, such as integrin-YAP/TAZ, constitute a core bridge linking these physical microenvironmental changes to intracellular biochemical responses. Based on this coupling framework, a progressively reinforced positive feedback loop model is further constructed, and its clinical implications for developing multitargeted, tissue-level skin aging intervention strategies are elaborated.