Telomere diminution as a cause of immune failure in old age: an unfashionable demurral

The hypothesis that cellular proliferation leads to telomere shortening, wh ich in turn leads to replicative failure, which in turn leads to a failure of immune function in aged individuals, is here evaluated against the publi shed evidence about the nature and pace of immune decline in animals and hu mans. Although the evidence is strong that telomere shortening in late-pass age human lymphocyte and non-lymphocytic cell lines induces a state in whic h the cells can no longer divide, there is no compelling evidence to sugges t that replicative senescence of this kind is an important contributor to i mmune deficiency in old age. On the contrary, the accelerated pace of immun e decline in mice and rats, whose telomeres are much longer than those of h umans, argues strongly that the factors that pace age-dependent immune decl ine do not include telomere shortening. In addition, three subsidiary argum ents - (a) the decline with age in naive T cell proliferation despite their relatively long telomeres; (b) the preservation of T cell proliferation in Werner's syndrome patients despite their cell lines' proclivity to replica tive senescence in vitro; and (c) the ability of PMA and ionomycin to stimu late proliferation in T cells from old donors, but not in late-passage T ce ll lines - all support the conclusion that aging of the immune system in li ving animals is not a consequence of the kind of replicative senescence typ ically caused by short telomeres in vitro.