Impaired Neovascularization in Aging.

Significance: The skin undergoes an inevitable degeneration as an individual ages. As intrinsic and extrinsic factors degrade the structural integrity of the skin, it experiences a critical loss of function and homeostatic stability. Thus, aged skin becomes increasingly susceptible to injury and displays a prolonged healing process. Recent Advances: Several studies have found significant differences during wound healing between younger and older individuals. The hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathway has recently been identified as a major player in wound healing. Hypoxia-inducible factors (HIFs) are pleiotropic key regulators of oxygen homeostasis. HIF-1α is essential to neovascularization through its regulation of cytokines, such as SDF-1α (stromal cell-derived factor 1-alpha) and has been shown to upregulate the expression of genes important for a hypoxic response. Prolyl hydroxylase domain proteins (PHDs) and factor inhibiting HIF effectively block HIF-1α signaling in normoxia through hydroxylation, preventing the signaling cascade from activating, leading to impaired tissue survival. Critical Issues: Aged wounds are a major clinical burden, resisting modern treatment and costing millions in health care each year. At the molecular level, aging has been shown to interfere with PHD regulation, which in turn prevents HIF-1α from activating gene expression, ultimately leading to impaired healing. Other studies have identified loss of function in cells during aging, impeding processes such as angiogenesis. Future Directions: An improved understanding of the regulation of molecular mediators, such as HIF-1α and PHD, will allow for manipulation of the various factors underlying delayed wound healing in the aged. The findings highlighted in this may facilitate the development of potential therapeutic approaches involved in the alteration of cellular dynamics and aging. Copyright 2020, Mary Ann Liebert, Inc., publishers.