Role of Telomere In Human Lymphocyte Function and Aging

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Telomeres are end structure of chromosome and essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within individuals with age have not been fully addressed. Here, we report a longitudinal analysis of telomere length in PBMCs, lymphocytes and monocytes of two hundred and sixteen human subjects aged from 20s to 90s assessed at zero, five- and twelve- year follow-up. For the 5- and 12-year follow-up, telomere length in PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47%, and increased in 10% and 7% of the subjects, respectively. The rate of telomere change was distinct for T-, B-cells and monocytes for any given subject. Telomerase activity declined with age in resting T- and B cells and activated T cells. Finally, a significant portion of telomere attrition in T cells with age was explained by a decline in telomerase activity, decreased naive cells and the change in physiological conditions such as elevated blood glucose and IL-6 levels. These findings show that changes in telomere length of PBMCs with age in vivo occur at different rates in different individuals and cell types, and reveal that changes in telomere length in T cells with age is influenced by telomerase activity, nave T cell percentage and changes in health conditions. Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown. To understand the role of telomere length in the age-associated decline of immune function in vivo. We compared immune responses against influenza in 22 healthy older adults who had relatively short or long telomere lengths in peripheral blood mononuclear cells (PBMCs). B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte-derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8+ T cells. Vaccination did not increase M1-specific CD8+ T cells in blood, however, M1-specific CD8+ T cells from the long telomere group exhibited significantly better expansion in vitro compared to those from the short telomere group. Finally, M1-specific CD8+ T cells that underwent more expansions had significantly longer telomeres compared to cells with fewer divisions. Telomere length is positively associated with a robust lymphocyte response and telomere attrition may contribute to the age-associated decline of adaptive immunity. Ionizing radiation (IR) is a major source of cellular damage. Despite recent progress in understanding the mechanisms of the immediate cellular response, the long term impact of IR on cell function and its relationship with aging are not well studied. Here, we report a study of the long term effects of IR exposure resulting from the atomic bombing at Hiroshima during WWII on telomere length in leukocytes and its change with age in 415 survivors with two time points (50-58 years after exposure as first sample and 60-68 years as second sample). We measured telomere lengths of leukocytes in an observer-blind manner by the Southern blot method and found that telomere length was inversely correlated with the dose of IR (p=0.008), and this effect was more profound in survivors who were exposed at younger ages, specifically <12 years old (p=0.0004). Even though a dose-related retardation of telomere shortening with age was observed in the cross-sectional data, our longitudinal follow-up of 11-years did not show IR exposure-related alteration of the rate of telomere shortening with age. In addition, IR diminished the associations between telomere length and selected biomarkers that were observed in survivors with no dose. Such biomarkers included uric acid metabolism, cytokines (IL-1&#61538;, IL-10, IL-6 and TNF-&#61537;), and T cell counts in blood. Together, these findings showed that the long lasting detrimental effects of IR on telomere length in leukocytes were both dose- and age-dependent, and included alteration of biomarkers that are associated with telomere length in leukocytes.