DECREASED EPIDERMAL LIPID-SYNTHESIS ACCOUNTS FOR ALTERED BARRIER FUNCTION IN AGED MICE

The epidermis of aged mice displays decreased stratum corneum (SC) lip id content and decreased extracellular bilayers, which result in impai red 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 ep idermis (greater than or equal to 18 months), synthesis of one of the three key lipid classes (cholesterol) is decreased under basal conditi ons, and sterologenesis fails to attain the levels reached in young ep idermis following comparable acute perturbations. In contrast, fatty a cid and sphingolipid synthesis in aged epidermis increase sufficiently to approach the levels attained in stimulated young epidermis. The ab normalities in sterologenesis in aged epidermis are paralleled by a de crease in activity of its rate-limiting enzyme, 3-hydroxy-3-methylglut aryl-coenzyme A reductase, under basal conditions, and enzyme activity also fails to increase as much as in young epidermis after barrier di sruption. That defective lipid generation contributes to the barrier d efect is shown directly by the ability of either a cholesterol-contain ing mixture of SC Lipids or cholesterol alone to enhance barrier recov ery. Finally, lipid-induced acceleration of barrier recovery in aged e pidermis correlates with repletion of the extracellular spaces with no rmal lamellar structures. Thus, a deficiency in lipid synthesis, parti cularly in cholesterologenesis, accounts for the barrier abnormality i n aged epidermis.