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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000756-16
Application #
8736615
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2013
Total Cost
$304,529
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Lustig, Ana; Shterev, Ivo; Geyer, Susan et al. (2016) Long term effects of radiation exposure on telomere lengths of leukocytes and its associated biomarkers among atomic-bomb survivors. Oncotarget 7:38988-38998
Kajimura, Junko; Kyoizumi, Seishi; Kubo, Yoshiko et al. (2016) Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors. Mutat Res Genet Toxicol Environ Mutagen 802:59-65
Najarro, Kevin; Nguyen, Huy; Chen, Guobing et al. (2015) Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults. J Infect Dis 212:1261-9
Lin, Yun; Damjanovic, Amanda; Metter, E Jeffrey et al. (2015) Age-associated telomere attrition of lymphocytes in vivo is co-ordinated with changes in telomerase activity, composition of lymphocyte subsets and health conditions. Clin Sci (Lond) 128:367-77
Wang, Meng C; Oakley, Holly D; Carr, Christopher E et al. (2014) Gene pathways that delay Caenorhabditis elegans reproductive senescence. PLoS Genet 10:e1004752
Ratts, Robert B; Weng, Nan-Ping (2012) Homeostasis of lymphocytes and monocytes in frequent blood donors. Front Immunol 3:271
Yao, Xu; Hamilton, Robert G; Weng, Nan-ping et al. (2011) Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. Vaccine 29:5015-21
Kiecolt-Glaser, Janice K; Gouin, Jean-Philippe; Weng, Nan-Ping et al. (2011) Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. Psychosom Med 73:16-22
Xu, Dongyi; Muniandy, Parameswary; Leo, Elisabetta et al. (2010) Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication. EMBO J 29:3140-55
Weng, Nan-Ping; Akbar, Arne N; Goronzy, Jorg (2009) CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol 30:306-12