ABSTRACT
INTRODUCTION Normal embryonic development requires discrete concentrations of retinoic acid during specific stages and at precise loci (1,2). Retinoid deficiency during these times results in birth defects; yet excess retinoic acid during the same times or in inappropriate loci causes teratogenic defects in the central nervous system, face, and limbs. In the adult, retinoic acid regulates differentiation status either by ···-·--····,., terminal differentiation or, depending on the cell type, preventing terminal differentiation, thereby maintaining cells in a differentiation stage between primitive stem cells and terminally differentiated cells. The precise effect of retinoic acid depends on the specific cell type. In differentiated cells, retinoic acid also regulates the transcription of genes that support the mission of the cell, a function distinct from its role in inducing the global transcription changes preced-
differentiation (3-5). Other than from deficiency or excess, no diseases are known to be
caused by in situ to generate rctinoic acid or by its overproduction. Establishing such a causal relationship, however, probably is just a matter of time. Three considerations support such an expectation: an inverse relationship exists between vitamin A nutriture and the incidence of spontaneous and chemically induced cancer (6); exogenous retinoids have beneficial effects on several diseases, including carcinomas and skin diseases and retinoic acid reverses the manifestations of aging in skin (8). The corrective effects of retinoic acid on skin
aging are noteworthy. If retinoic acid can correct age-related defects in skin, why not in other retinoid-responsive tissues as well? Age-related decreases in retinoic acid synthesis, or increases in its catabolism, or both, may be partially but universally responsible for age-associated degeneration of organ function.
