Within this century, there has been a marked increase in the average lifespan and the proportion of the population that is elderly. This demographic shift has focused attention on the physiologic changes occuring in all organ systems with age that may predispose to injury and/or disease and hence, to increased health care cost for the elderly. In the skin, aging is known to be associated with decreases epidermal turnover, rate of wound healing, immune recognition, inflammatory response, thermoregulation, sensory perception, barrier function and vitamin D synthetic capacity. These physiological losses are attributable, in part, to age-associated anatomic changes in the skin but are largely unexplained at a molecular level. A better understanding of skin aging is warranted both by the substantial burden of dermatologic disease in the elderly and by the general applicability of many cutaneous findings to other organ systems. We propose a series of studies to investigate the mechanisms involved in the aging process in different skin cell types, the fibroblast and the keratinocyte. We will investigate the effects of specific mitogens on fibroblast proliferation and protooncogene expression in a serum free tissue culture system in an effort to understand the relevance of specific signals to the decreased proliferative capacity associated with the aged human dermal fibroblast. We will also elucidate the mechanism underlying recent findings, in the keratinocyte, of an age-associated decreased expression of c-myc and increased expression of the differentiation marker involucrin by studies of transcription and mRNA stability, as well as further these studies by studying other growth regulated as well as differentiation associated genes. Finally, we will attempt to correlate our in vitro findings with the actual in vivo situation by performing in situ hybridization on whole skin sections. In this way, we will begin to provide a framework for understanding the molecular basis of the aging process in human skin.
NIH ExPorter
NIH ExPorter