Abstract
Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer. The present studies tested the hypothesis that pro-energetics creatine monohydrate (Cr) and nicotinamide (NAM) can protect normal dermal human fibroblasts (DHF) against experimentally induced senescence. To that end, we used an experimental model of senescence in which primary DHF are treated with hydrogen peroxide (H2O2) in vitro, with senescence measured by staining for beta-galactosidase activity, p21 protein expression, and senescence associated secretory phenotype cytokine mRNA levels. We also determined the effect of H2O2 on IGF-1 mRNA and protein expression. Our studies indicate that pretreatment with Cr or NAM protects DHF from the H2O2-induced cell senescence. Treatment with pro-energetics post-H2O2 had no effect. Moreover, these agents also inhibited reactive oxygen species generation from H2O2 treatment. These studies suggest a potential strategy for protecting fibroblasts in geriatric skin from undergoing stress-induced senescence, which may maintain IGF-1 levels and therefore limit carcinogenesis in epidermal keratinocytes.
Highlights
Senescence is defined as the state of a cell when a series of degenerative events occur, followed by maturation, and is associated with the process of aging [1]
Young fibroblasts secrete connective tissues and other metabolic signals, one of them being insulin-like growth factor-1 (IGF-1) [32]. This growth factor binds to its transmembrane receptors present on the keratinocytes, activating several pathways responsible for cell proliferation/metabolism/apoptosis
Data derived from using keratinocytes in culture as well as human clinical studies have provided significant premise for the novel paradigm that the increased susceptibility of aged skin to non-melanoma skin cancer involves fibroblast senescence [15]
Summary
Senescence is defined as the state of a cell when a series of degenerative events occur, followed by maturation, and is associated with the process of aging [1]. Certain inflammatory cytokines including IL-6, IL-8, and TNF-α, termed the senescence-associated secretory phenotype (SASP), are expressed in large amounts in the senescent cell [9]. When these cytokines are released in the microtissue environment, they attract immune cells to specific locations to potentially eliminate senescent cells [10]. This phenomenon is not commonly seen in geriatric tissues which potentially leads to increased numbers of senescent cells in the geriatric microenvironment. As mentioned, determine the fate of a cell and in certain conditions accelerate senescent cell formation
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