T cell replicative senescence: pleiotropic effects on human aging





R.B. Effros

Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA



Elderly persons have been exposed to a myriad of pathogens over their lifespan. This life-long immunological history leads, in many cases, to the generation of expanded populations of memory T cells that have reached the end stage of replicative senescence. Studies on CD8 T cells (the subset that controls viral infection) in cell culture show that repeated rounds of antigen-driven proliferation leads to irreversible cell cycle arrest, permanent loss of gene expression of the essential costimulatory signaling molecule (CD28), apoptosis resistance, poor stress response, altered cytokine profiles, loss of telomerase upregulation, and shortened telomeres. Clinical studies have shown that high proportions of CD8 T cells with markers of senescence are correlated with such diverse organ system outcomes as a reduced antibody response to influenza vaccination and increased osteoporotic fractures. Moreover, increased numbers of senescent CD8 T cells also constitute an immune risk marker for all-cause mortality in elderly persons, suggesting that the immune system constitutes one of the most dramatic examples of the pleiotropic deleterious effects of replicative senescence on organismic ageing and longevity. Gene therapy of virus-specific CD8 T cells with the catalytic component of telomerase (hTERT) corrects many of the cell cycle-related defects, and leads to telomere maintenance and restoration of anti-viral cytotoxic functions. Thus, the immune system, which undergoes dramatic decline during aging, is a potent model system in which to explore the effects of aging at both the cellular and organismic level, using a cell type in which intrinsic telomerase is stringently regulated.



Key words: T cells, immune system, telomerase, replicative senescence







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