Fellowship (Dotson): Glutathione-Dependent Regulation of Neutral Sphingomy Elinase II Activity During Aging

Sfl SpllEIfl4flins-2 (nSt..2) S. kld.rr.ttokbi; .nn". that S! tiydrofles aphingorryelin to ceranide, a bioacthie ipid n~tabolile. Transient activation of nstMse-2 is essential for rsadiation of cellular signaling in response to pro-irlflan'.ralot'y n'ediators and contributes to the induction of various stress respcnses in cells including; apoptosis, growth arrest, and in the case of liver, the expression of acute phase proteins. ~Jring aging, the basal activiW of nSf.~se-2 is constitutive~y upregulated and causes hyperresponsivness to IL-1β, a najor pro-inflarmetory cytoldne. This hyperresponaiveness is nanifested by the fact that hepstocytes isolated from old antn'ols respond to nbch lower doses of IL- 1β and weh a slgnificant~ higher anplltude than hepatocytes isolated from young aninets causing substantial increases in acute phase response proteins in the elders' and the onset of pro-inflarmatory environnant. A state of chronic, low- grade inflanrration is an intrinsic conponent of the aging process and rrany aging- associated diseases ike cardiovascular disease, arthritis, sarcopenia, and lype II diabetes. The nechanisns regulating the activation of nSl,~se-2, however, are largely unknown, Revious reporls have suggested lhst severe depletion of intracellular glutathione (GSH) content, during vsrious conditions associated w th oxidatwe stress, nay activate the enryno as 051-I acts scan inhibtor of nSttse-2 aclivity These data have shown that nSftse-2 acts as a focal point of integration of systenic pro-inflarTn'atory signals (IL-1β) and inlracelular signals sensing the redox state of cells (GSI-l). The objective of this research is to understand the