Telomeres are the tip of chromosome and serve essential function in chromosome integrity and in regulating cell replicative lifespan. Previous cross-sectional analyses of telomere length in blood leukocytes show an age-related shortening, but the actual in vivo change of telomere length and its relationship with telomerase, cell composition of leukocytes, and health conditions is not fully addressed. We have conducted a longitudinal analysis of telomere length in peripheral blood mononuclear cells (PBMCs), lymphocytes, and monocytes at zero (n=220) and at five- (n=216) and twelve- year (n=158) follow-up of the human subjects. In PBMCs, we observed telomere length of decrease in 34% and 46%, no detectable changes in 56% and 47%, and increase in 10% and 7% of all subjects for 5- and 12-year follow-up, respectively. The rate of telomere change was distinct for T- and B-cell and monocytes for an individual. Furthermore, telomerase activity declined with age in resting and activated T cells, and resting but not activated B cells. Age-related changes in percentages of naive (decrease) and CD28- (increase) T cells were positively and negatively correlated to telomere length in T cells, respectively. Finally, a significant portion of the observed telomere attrition in T cells with age was explained by declined telomerase activity, decreased naive cells, and the presence of specific health conditions such as adiposity. These findings show that reduction of telomere length of PBMC with age in vivo occurs at different rates in different subjects and that telomere length of T cells is affected by telomerase activity, nave T cell percentage, and changes in health conditions. To understand the role of telomere length in the age-associated decline of immune function in vivo. We compared immune responses against influenza in healthy older adults who had relatively short or long telomere lengths in peripheral blood mononuclear cells (PBMCs). Our findings showed that: 1) B cells from individuals with a robust antibody response to the seasonal influenza vaccine had significantly longer telomeres than those from individuals with a poor antibody response;2) monocyte derived antigen presenting cells (APC) from both short and long telomere groups were able to induce similar expansions of influenza reactive CD8+ T cells;3) influenza reactive CD8+ T cells from the long telomere group exhibited significantly better expansion in response to the influenza antigen (M1) in vitro compared to those from the short telomere group;and 4) direct measurement of telomere length of M1 reactive CD8+ T cells demonstrated that cells with significantly more divisions had significantly longer telomeres compared to cells with few divisions. Together, these findings show that telomere length is positively associated with a robust adaptive immune response and suggest that telomeres may have an important role in the age-associated decline of adaptive immunity against influenza infection.

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