Choong Kim

Effect of age on molecular signaling of TNF-α-induced apoptosis in human lymphocytes

Aging in humans is associated with progressing decline in T cell numbers and functions. In addition, there is an increased production of tumor necrosis factor-α (TNF-α) during human aging. TNF-α mediates both survival and cell death signals. TNF-α exerts its biological effects via TNFR-I and TNFR-II. Here we discuss signaling pathways induced by TNF-α and the effect of age on TNF-α-induced apoptosis in T cells and T cell subsets. T cells and T cell subsets from aged humans are more sensitive to TNF-α-induced apoptosis, which appears to be due to both an increased apoptotic signaling and decreased survival signals.

A Role of Fas-Associated Death Domain (FADD) in Increased Apoptosis in Aged Humans

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-α-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.