759 Protection of geriatric skin from abnormal procarcinogenic UVB responses by dermal wounding strategies which upregulate IGF-1 levels

Abstract

UVB irradiation causes specific DNA-damage to keratinocytes that can lead to cancer-causing mutations if they are allowed to persist in proliferating cells. Previously, we demonstrated that the activation status of the insulin-like growth factor-1 receptor (IGF-1R) regulates the cellular response of keratinocytes to UVB exposure, both in vitro and in vivo. Briefly, geriatric skin is deficient in IGF-1 expression resulting in an aberrant IGF-1R-dependent UVB response consisting of basal keratinocytes proliferating while still harboring unrepaired DNA damage (Ki-67- and thymine dimer-co-expressing cells). This abnormal UVB response contributes to the development of aging-associated squamous cell carcinoma. As the dermal fibroblast is the source of IGF-1 in skin, and aging results in senescent fibroblasts which produce less IGF-1, we have used wounding strategies which enhance IGF-1 expression in an attempt to normalize the abnormal, pro-carcinogenic geriatric UVB response. Here we demonstrate that localized wounding of geriatric skin with fractionated laser resurfacing (FLR) or topical use of a dermaroller device results in decreased numbers of senescent fibroblasts and increased levels of IGF-1. Moreover, acute UVB treatment of previously wounded skin results in decreased numbers of basal keratinocytes co-expressing thymine dimers and the proliferative antigen Ki-67, in comparison to UVB-treated control (not wounded) skin. Long-term studies reveal that the wounding effect induced by FLR appears to be durable, in that we note statistically increased levels of IGF-1 mRNA and decreased numbers of basal keratinocytes expressing both thymine dimers and Ki-67 in geriatric subjects at one and two years post-treatment. These studies suggest that wounding procedures could protect geriatric skin from the abnormal pro-carcinogenic UVB response associated with aging.