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-Induced Apoptosis in Lymphocytes from Aged Humans: Changes in TNF- Receptor Expression and Activation of Caspases
Department of Medicine, University of California, Irvine, CA 92697
Aging is characterized by increased T cell lymphopenia, T cell
dysfunction, and increased serum TNF levels. In this study, we have
examined the role of TNF-induced apoptosis in T cell deficiency in
lymphocytes from aged humans. The constitutive expression of TNF
receptors (TNFRI and TNFRII) and the adapter molecules, including
TNFR-associated death domain protein (TRADD), TNFR-associated factor 2
(TRAF-2), and receptor interacting protein (RIP), were analyzed both at
the protein level by flow cytometry or Western blotting, and at the
mRNA level using quantitative PCR or Northern blotting in lymphocytes
from aged and young subjects. The susceptibility of T cells to undergo
TNF-induced apoptosis was analyzed using terminal
deoxynucleotidyltransferase-mediated UTP-end-labeling (TUNEL) and DNA
ladder assays. Caspase (caspase-8 and caspase-3) activation was
compared between aged and young subjects using Western blotting and
colorimetric assays. In lymphocytes from aged humans, there was an
increased susceptibility of CD4+ and CD8+ T
cells to undergo TNF-
-induced apoptosis, as observed by TUNEL assay
and DNA fragmentation ladder assay. Increased TNF--induced apoptosis
was also observed in both CD45RA+ and CD45RO+ T
cells from aging subjects. An increased constitutive expression of
TNFRI and TRADD and decreased expression of TNFRII and TRAF-2 were
observed in lymphocytes from aged as compared with young controls. In
addition, there was an early and increased activation of caspases
(caspase-8 and caspase-3) involved in TNFR/TNF signaling pathway, as
evident by early cleavage of caspase-8, poly(ADP-ribose) polymerase
(PARP), and caspase-3 substrate DEVD-p-nitroamilide
NA. These data suggest that an increased TNF--induced
apoptosis may play a role in T cell deficiency associated with human
aging.
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