Document text
Principal Investigator: Nan-ping Peter Weng
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2019
Award: $446,172
Funding agency: National Institute on Aging
A number of hallmarks of immune aging have been identified but underpinning causes are not fully understood. We analyzed three parameters (telomere length, inflammatory cytokines, and antibody titer to CMV) of immune system aging through a longitudinal analysis of 465 subjects ranging in age from 21 to 88 at the first visit, with an average of 13 years (7-19 years) follow-up. A highly variable rate of change in telomere length of PBMCs with a relatively slow average rate of telomere shortening (-16 bp/year) was observed. Similarly, there were significant increases with age in vivo in three inflammatory-related cytokines (IFN-, IL-6 and IL-10) and in anti-CMV IgG titer, which varied widely across individuals as well. Although there were positive correlative changes among different inflammatory cytokines, we did not observe significant correlations among the rate of changes in telomere length, inflammatory cytokines, and anti-CMV IgG titers, indicating age-related trajectories of telomere attrition, elevated circulating inflammatory cytokines, and anti-CMV IgG are independent. Immune aging processes are complex and vary across individuals, and the use of multiple biomarkers is essential to evaluation of biological aging of the immune system.
To understand the role of telomerase in T cell differentiation and function, we analyzed human telomerase reverse transcriptase (hTERT) mRNA expression and telomerase activity in six T cell subsets from 85 healthy human donors (aged 17-82 years old). We found that levels of hTERT mRNA and telomerase activity were higher in CD4 T cell subsets as compared to corresponding CD8 T cell subsets and decreased from nave (TN) to memory (central, TCM and effector, TEM). In all six subsets, in vitro activation with anti-CD3/CD28 antibody led to increased amounts of hTERT mRNA as well as telomerase enzymatic activity, while the differences in hTERT amounts and telomerase activity among subsets remained in the same order observed prior to stimulation. Next, we compared activation-induced proliferation in vitro over the course of a 15-day culture and found that expansion and survival were most robust in CD4 TN and poorest in CD8 TEM, correlating with their respective levels of hTERT mRNA and telomerase activity. Finally, we tested directly of the role of telomerase in T cell proliferation by knock-down hTERT mRNA by an anti-sense DNA oligo of hTERT. We found that knock-down hTERT in CD4 TN cells reduced hTERT mRNA, telomerase activity and cell proliferation in response to anti-CD3 and anti-CD28 stimulation. These findings suggest that greater hTERT expression and telomerase activity promote T cell proliferative potential, and that differentiation is associated with a loss of proliferative potential in T cells.
Terms: <21 year old><21 years of age><7S Gamma Globulin><Active Follow-up><Age><Aging><Anti-Sense DNA><Antibodies><Antibody titer measurement><Antisense DNA><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BCDF><BSF-2><BSF2><Biological Aging><Biological Markers><Blood Cells><Blood monocyte><CD28><CD28 gene><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CMV><CSIF><CSIF-10><Cell Body><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Process><Cell Proliferation><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Complex><Cytokine Synthesis Inhibitory Factor><Cytomegalovirus><EC 2.7.7.49><Elderly><Evaluation><Goals><HCMV><HHV 5><HHV5><HPGF><Hepatocyte-Stimulating Factor><Human><Human Herpesvirus 5><Hybridoma Growth Factor><IFN><IFN-beta 2><IFNB2><IL-10><IL-6><IL10><IL10A><IL6 Protein><IgG><Immune><Immune response><Immune system><Immunes><Immunoglobulin G><Immunological response><In Vitro><Individual><Inflammatory><Influenza Vaccines><Interferons><Interleukin 10 Precursor><Interleukin-10><Interleukin-6><LYT3><Length><Lymphocyte><Lymphocyte Function><Lymphocytic><MGI-2><Marrow monocyte><Measures><Memory><Messenger RNA><Modern Man><Molecular><Myeloid Differentiation-Inducing Protein><OKT3 antigen><Oligo><Oligonucleotides><PBMC><Peripheral Blood Cell><Peripheral Blood Mononuclear Cell><Plasmacytoma Growth Factor><Process><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Reverse Transcriptase><Revertase><Role><Salivary Gland Viruses><Subcellular Process><T cell differentiation><T-Cell Proliferation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T3 Antigens><T3 Complex><T3 molecule><T4 Cells><T4 Lymphocytes><T44><T8 Cells><T8 Lymphocytes><Telomerase><Telomere Shortening><Testing><Visit><active followup><advanced age><age 21><age 21 years><age dependent><age related><aged><ages><allergic/immunologic body system><allergic/immunologic organ system><antibody titering><bio-markers><biologic marker><biomarker><cytokine><cytomegalovirus group><elders><flu vaccine><flu virus vaccine><follow up><follow-up><followed up><followup><geriatric><host response><immunoresponse><in vivo><influenza virus vaccine><interferon beta 2><knock-down><knockdown><late life><later life><longitudinal analysis><lymph cell><mRNA><mRNA Expression><monocyte><older adult><older person><oligos><rate of change><response><senior citizen><social role><telomere><thymus derived lymphocyte><twenty-one year old><twenty-one years of age><vaccine against flu><vaccine against influenza>