Fas-associated death domain (FADD) is an adapter protein that is recruited to the death-inducing signaling complex (DISC) during signaling via death receptors. FADD is a common conduit in both CD95-mediated and TNF-R-mediated apoptosis. In aging, T cells show increased susceptibility to death receptor-induced apoptosis. Therefore, in this investigation, we have examined the role of FADD in increased TNF-alpha-induced apoptosis of lymphocytes from aged humans. Our study shows that FADD expression is increased in lymphocytes from aged humans as compared to those from young subjects. Furthermore, transfection of aged lymphocytes with FADD dominant negative (FADD dn) plasmid resulted in the reduction of TNF-induced apoptosis in aged lymphocytes to a level comparable to that of young subjects. In addition, overexpression of FADD by transfection of lymphocytes from young subjects with wild-type FADD (FADD wt) resulted in increased apoptosis of young lymphocytes to a level comparable to that of young subjects. These data suggest that FADD plays an important role in increased apoptosis in aged lymphocytes signaled via TNF-R.