Imbalanced redox dynamics induce fibroblast senescence leading to impaired stem cell pools and skin aging

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Skin function depends on a meticulously regulated dynamic interaction of distinct skin compartments such as the epidermis and dermis. Adaptive responses at the molecular and cellular level are essential for these interactions – and if dysregulated – drive skin aging and other pathologies. After defining the role of redox homeodynamics in physiology and aging pathology, we focus on the redox distress-dependent aging of dermal fibroblasts including their progenitors. We here discuss the prime role of senescent fibroblasts in the control of their own endogenous niche and stem cell niches for epidermal stem cells, hair follicle stem cells, adipocyte precursors and muscle stem cells. We here review that redox imbalance induced reduction in Insulin-like Growth Factor-1 drives skin aging by the depletion of stem cell pools. This IGF-1 reduction is mediated via the redox-sensitive transcription factor JunB and also by the redox-dependent changes in sphingolipid-metabolism, among others. In addition, we will discuss the changes in the extracellular matrix of the skin affecting cellular senescence and the skin integrity and function in aging. The aim is a deeper understanding of the two main redox-dependent hubs such as JunB-induced depletion of IGF-1, and the sphingolipid-mediated remodeling of the cell membrane with its impact on IGF-1, fibroblast heterogeneity, function, senescence and plasticity in skin aging. • ROS induce JunB with IGF-1 suppression and increases p16INK4a expression in skin fibroblasts. • ROS affect sphingolipid structure, composition and function. • This results in fibroblast cellular senescence with SASP, apoptosis resistance, reduced IGF-1 signaling and expression. • Loss of fibroblast heterogeneity disturbed stem cell niche homeostasis and stem cell function, contributing to skin aging.