Sphingomyelin and ceramide as regulators of development and lifespan

Sphingomyelin (SM) is a prominent phospholipid component of cell membranes that has evolved diverse functions in cells beyond its role in membrane str uctural organization. Cleavage of SM by acid or neutral sphingomyelinase re sults in the liberation of ceramide, an intracellular messenger that regula tes the activities of an array of kinases, phosphatases and transcription f actors. Signals that activate sphingomyelinases range from growth factors a nd cytokines. to neurotransmitters, hormones and reactive oxygen species. S tudies of experimental cell culture and animal models, and of patients with inherited defects in sphingomyelin metabolism suggest important roles for SM-ceramide signaling in the regulation of cell proliferation, differentiat ion and survival. At low concentrations SM and ceramide can stimulate cell proliferation and survival, whereas higher levels can induce cell dysfuncti on or death. Analyses of development and aging suggest a major role for SM metabolism in regulating development rate and lifespan. Several factors tha t alter the metabolism of sphingolipids, including oxidative and metabolic stress, also increase risk and progression of age-related diseases. In addi tion, recent findings have linked alterations in SM metabolism to the patho genesis of several age-related diseases including cancers and neurodegenera tive disorders. The emerging data suggest the possibility that dietary and pharmacological manipulations of SM metabolism might prove effective in ext ending lifespan and treating various age-related diseases. (C) 2001 Publish ed by Elsevier Science Ireland Ltd.