Molecular Aspects of Skin Aging

Abstract

The past two decades have seen significant strides, not only in our understanding of the pathobiology of human skin aging, but also in the search for targeted modalities to treat or possibly prevent some of the changes that come with this process. Human skin aging can be categorized as either (a) chrono-logic/intrinsic aging or (b) extrinsic aging, of which photoaging is a major component [1-5]. Chronologic skin aging is a slow, progressive, cumulative, and degradative process, similar to aging at noncutaneous sites, and is influenced by several factors, including genetic predisposition, diet, lifestyle (i.e., smoking), and hormone levels [1-5]. It is characterized by a number of molecular and cellular events in the skin, such as replicative senescence, telomere shortening, decreased proliferative capacity, cell cycle and apoptosis alterations, oxidative damage, mitochondrial dysfunction, mutations in mitochondrial DNA (mtDNA), reduced DNA repair mechanisms, matrix metalloproteinase dysregulation, decreased responses to mitogenic stimuli, and changes in stem cell function [1-8]. Aged skin is less resistant to shearing forces, shows increased fragility and a limited capacity to regenerate, and is at risk of chronic wound formation (see Chap. 17) [9]. The study of "progeroid" syndromes, such as Werner syndrome, Hutchinson-Gilford progeria syndrome , and xeroderma pigmentosum, has been helpful in our understanding of the skin aging process [10-12]. These inherited premature aging disorders are characterized by defects in DNA transcription, replication, recombination, and repair [10-12]. A recent gene expression profiling study demonstrated that transcription alterations in Werner syndrome were similar to those seen in chronologic aging [11]. Up to 91% of genes displayed comparable expression changes in both groups, suggesting that Werner syndrome is characterized by an acceleration of normal aging mechanisms [11]. Extrinsic aging is primarily the result of environmentally induced changes, superimposed on the physiologic manifestations of chronologic aging. While exposure to ultraviolet (UV) radiation is regarded as the most important exogenous factor ("photoaging"), additional environmental insults include other forms of ionizing/nonionizing radiation, trauma, air pollutants, chemicals, and infectious agents [1]. UV radiation leads to skin damage through a variety of mechanisms, including the upregulation of immune responses [13]. It is known that high levels of and/or long-term UV exposure induce persistent single strand nuclear DNA breaks, pyrimidine dimer formation, UV-signature mutations in TP53, CDKN2A/p16, RAS and PTCH genes, mtDNA aberrations, and other types of DNA lesions in human skin