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Principal Investigator: Nan-ping Peter Weng
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2020
Award: $275,992
Funding agency: National Institute on Aging
Maintenance of telomeres is essential for preserving T cell proliferative responses yet the precise role of telomerase in human T cell differentiation, function and aging is not fully understood. Here we analyzed human telomerase reverse transcriptase (hTERT) expression and telomerase activity in six T cell subsets from 111 human adults and found that levels of hTERT mRNA and telomerase activity had an ordered decrease from nave (TN) to central memory (TCM) to effector memory (TEM) cells and were higher in CD4+ than their corresponding CD8+ subsets. This differentiation-related reduction of hTERT mRNA and telomerase activity was preserved after activation. Furthermore, the levels of hTERT mRNA and telomerase activity were positively correlated with the degree of activation-induced proliferation and survival of T cells in vitro. Partial knockdown of hTERT by an anti-sense oligo in nave CD4+ cells led to a modest but significant reduction of cell proliferation. Finally, we found that activation-induced levels of telomerase activity in CD4+ TN and TCM cells were significantly lower in old than in young subjects. These findings reveal that hTERT/telomerase expression progressively declines during T cell differentiation and age-associated reduction of activation-induced expression of hTERT/telomerase mainly affects nave CD4+ T cells and suggest that enhancing telomerase activity could be a strategy to improve T cell function in the elderly.
Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes.
Terms: <21+ years old><Active Follow-up><Adult><Adult Human><Affect><Age><Aging><Anti-Sense Oligonucleotides><Antinuclear Antibodies><Antinuclear Factors><Antisense Agent><Antisense Oligonucleotides><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Baltimore><Biological><Blood Cells><Blood monocyte><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><Cell Aging><Cell Body><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Process><Cell Proliferation><Cell Senescence><Cell physiology><Cells><Cellular Aging><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular Senescence><Confidence Intervals><Cross Sectional Analysis><Cross-Product Ratio><Cross-Sectional Analyses><Cross-Sectional Studies><Cross-Sectional Survey><DNA blotting><Disease Frequency Surveys><EC 2.7.7.49><Elderly><General Population><General Public><Goals><Human><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunodeficiency and Immunosuppression Disorders><Immunofluorescence><Immunofluorescence Immunologic><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><In Vitro><Incidence><Individual><Influenza Vaccines><LYT3><Length><Logistic Regressions><Longitudinal Studies><Lymphocyte><Lymphocyte Function><Lymphocytic><Marrow monocyte><Measures><Memory><Messenger RNA><Modern Man><Molecular><Odds Ratio><PBMC><Peripheral Blood Cell><Peripheral Blood Mononuclear Cell><Prevalence><Process><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Race><Racial Group><Racial Stocks><Relative Odds><Replicative Senescence><Reverse Transcriptase><Revertase><Risk Ratio><Role><Southern Blotting><Subcellular Process><T cell differentiation><T-Cell Proliferation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><Telomerase><Telomere Maintenance><Time><active followup><adulthood><advanced age><aged><ages><anti-DNA autoantibody><anti-Sm><anti-sense agent><anti-sense oligo><antiDNA autoantibody><antisense oligo><autoimmune disorder><cell age><elders><flu vaccine><flu virus vaccine><follow up><follow-up><followed up><followup><geriatric><host response><immunoresponse><improved><in vivo><influenza virus vaccine><knock-down><knockdown><late life><later life><long-term study><longitudinal analysis><longitudinal outcome studies><longterm study><lymph cell><mRNA><monocyte><older adult><older person><preservation><response><senior citizen><seropositive><sex><social role><southern hybridization><telomere><thymus derived lymphocyte><vaccine against flu><vaccine against influenza>