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.