title: Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin.
abstract: The growing incidence of non-melanoma skin cancer (NMSC) necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV) wavelengths of sunlight and age. Whereas UV radiation (UVR) has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1) by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC.
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, OH 45435, USA. mike.kemp@wright.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kemp
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dspanda@iu.edu.|Department of Biochemistry and Molecular Biology Indiana University School of Medicine, Indianapolis, IN 46202, USA. dspanda@iu.edu.
authors.forename: Dan F
authors.initials: DF
authors.lastname: Spandau
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, OH 45435, USA. jeffrey.travers@wright.edu.|Dayton Veterans Affairs Medical Center, Dayton, OH 45428, USA. jeffrey.travers@wright.edu.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation / Q000528:radiation effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000528:radiation effects*; D013472:Sunlight
chemical_list: C583557:IGF1 protein, human; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: DNA damage; DNA damage response; DNA repair; DNA replication; Skin cancer; UV light; dermal wounding; genomic instability; insulin-like growth factor-1; keratinocyte