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Turning back the clock: retinoic acid modifies intrinsic aging changes.

Editorial In this issue of The Journal, Varani and co-workers (1) report that all-trans retinoic acid (RA) produces in organ-cultured human skin specimens and in conventional monolayer cultures of skin-derived cells the same histologic and biochemical changes previously observed in RA-treated photoaged skin in vivo; and, more surprisingly, that these changes occur comparably in sun-protected intrinsically aged skin and in sun-exposed photoaged skin, whereas different effects are observed in neonatal skin. This beneficial effect of RA in intrinsically aged skin confirms and expands the recent clinical observation of Kligman and co-workers (2) that topical application of RA 0.025% cream, versus vehicle control cream, daily for nine months to the inner thigh of women aged 68-79 years strikingly improved the skin's histologic appearance, reversing changes associated with intrinsic aging. The improvements included epidermal thickening , reconstitution of rete pegs, and deposition of new dermal matrix materials. Both Varani et al. and Kligman et al. conclude that RA affects not only photodamage, but the consequences of aging itself. Is aging truly reversible? If so, by what mechanism does RA produce this reversal? Aging is a basic biologic process that over time renders organisms progressively less able to respond to their environment and thus more vulnerable to injury and disease (3). By most definitions, aging begins in early adulthood, as development ends, and is at least to a large degree under genetic control. Aging may also be viewed as the latter stages of the same genetic program that governs embryonic and postnatal development , equivalent at the cellular level to progressive differentiation. In this intellectual framework, it is of interest that RA is among the best documented embryologic morphogens (4, 5) and has well recognized roles in the development and postnatal maintenance of many tissues throughout the body, certainly including the skin (6). Moreover, a wide variety of otherwise apparently contradictory effects of RA in vivo and in vitro can be viewed as an ability of this molecule to "normalize's cellular behaviors, rather than specifically to stimulate or inhibit them (6). Appreciation of RA's central role in embryogenesis and tissue homeostasis was greatly expanded by the discovery that its effects are mediated through binding to nuclear retinoic acid receptors (7, 8), members of a super family of nuclear receptors for steroid hormones and protein growth factors, highly conserved throughout evolution, that upon ligand binding function as transactivating elements to modulate gene transcription directly. …