Decreased epidermal lipid synthesis accounts for altered barrier function in aged mice

The epidermis of aged mice displays decreased stratum corneum (SC) lipid content and decreased extracellular bilayers, which result in impaired barrier recovery following the solvent treatment or tape stripping. We assessed the role of altered lipid synthesis as the cause of the abnormal barrier and lipid content in aged epidermis, both under basal conditions and in response to acute barrier perturbations. In aged epidermis ( > or = 18 months), synthesis of one of the three key lipid classes (cholesterol) is decreased under basal conditions, and sterologenesis fails to attain the levels reached in young epidermis following comparable acute perturbations. In contrast, fatty acid and sphingolipid synthesis in aged epidermis increase sufficiently to approach the levels attained in stimulated young epidermis. The abnormalities in sterologenesis in aged epidermis are paralleled by a decrease in activity of its rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, under basal conditions, and enzyme activity also fails to increase as much as in young epidermis after barrier disruption. That defective lipid generation contributes to the barrier defect is shown directly by the ability of either a cholesterol-containing mixture of SC lipids or cholesterol alone to enhance barrier recovery. Finally, lipid-induced acceleration of barrier recovery in aged epidermis correlates with repletion of the extracellular spaces with normal lamellar structures. Thus, a deficiency in lipid synthesis, particularly in cholesterologenesis, accounts for the barrier abnormality in aged epidermis.