© 2005 Blackwell Publishing • Journal of Cosmetic Dermatology, 4, 237–244 237 Review Article Blackwell Publishing Inc Proposed mechanisms of action for retinoid derivatives in the treatment of skin aging Olivier Sorg, Stéphane Kuenzli, Gürkan Kaya & Jean-Hilaire Saurat Department of Dermatology, University Hospital, Geneva, Switzerland Summary Skin aging (intrinsic aging) and photoaging (extrinsic aging) involve a similar process that leads to the typical creased appearance of the skin, with the progressive loss of its physical and biologic properties. Photoaging is a premature skin aging caused by long- term exposure to the ultraviolet B radiations of the sun, and is more frequently associated to skin cancer than intrinsic aging. Retinoids are natural and synthetic vitamin A derivatives. They are lipophilic molecules and penetrate the epidermis easily. Their biologically active forms can modulate gene expression by binding to nuclear receptors and then to specific DNA sequences. Because of their ability to modulate genes involved in cellular differentiation and proliferation, they appear as good candidates to treat and prevent photoaging. Hyaluronate and collagen, two major constituents of the dermis, are progressively decreased and altered during aging. Various retinoids were shown to increase their synthesis and concentration in the skin and reduce their rate of degradation. Furthermore, retinoids share a common chemical structure containing several conjugated double bonds that enable them to trap free radicals and absorb UV radiations from the sun, thereby protecting cellular targets such as DNA, lipid membranes, or proteins by preventing direct photochemical damage or UV-induced oxidative stress. Therefore, retinoids may be beneficial in treating skin aging and photoaging because of their biologic, chemical, and physical properties, which act at several levels. Keywords : aging, photoaging, retinoids, sunlight, vitamin A Aging and photoaging Aging is a natural, ineluctable, and complex process that reverses biological characteristics acquired during development and leads to cellular death. Two main theories explain the process of aging. According to the genetic theory, a fully differentiated organism is able to perform elaborate actions, but this is realized to the detriment of the renewal of tissues, and leads to general aging; thus the pursuit of life opposes development and differentiation. 1–3 On the other hand, the damage- accumulation theory, which was introduced by Denham Harman, explains aging by the accumulation of alterations of the biomolecules that the organism cannot repair or eliminate completely. 4–6 Skin aging begins with a redistribution of fat, a decreased dermal elasticity, and a loss of bone mass, resulting in gravitational changes such as enhanced nasolabial fold, 7 and continues with a progressive impairment of the regeneration of connective tissue components such as collagen and hyaluronate. 8–10 Finally, the aging skin loses its immunological defenses and its capacity to repair Abbreviations: RAR, retinoic acid receptor; RARE, retinoic acid response element; RXR, retinoid X receptor. Correspondence: Olivier Sorg, PhD, Clinique de Dermatologie, Hôpital Cantonal Universitaire, 24 rue Micheli-du-Crest, 1211 Genève 14, Switzerland, E-mail: olivier.sorg@hcuge.ch Accepted for publication June 25, 2005