Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules.

Tumor necrosis factor-alpha (TNF-alpha) induces apoptosis predominantly via TNF-receptor I (TNF-RI). We have examined the molecular and biochemical pathways of TNF-alpha-induced apoptosis in T cells from aged and young subjects. Aged subjects show absolute lymphopenia and decreased numbers of both CD4+ and CD8+ T cells. T cells from aged subjects show increased sensitivity to TNF-alpha-induced apoptosis that is associated with increased expression of TNF-RI and decreased expression of TNF-RII in both CD4+ and CD8+ T cells. Agonistic TNF-RI also induced greater apoptosis in T cells from aged subjects as compared to young subjects, suggesting that increased TNF-alpha-induced apoptosis in aging is predominantly mediated via TNF-RI. There was an increased expression of FADD and increased activation of caspase 8 and caspase 3 in lymphocytes from aged humans as compared to young subjects. A role of impaired TNF-RII-mediated signaling in increased apoptosis in aged subjects is also discussed.