Telomere length and telomerase activity in T cells are biomarkers of high‐performing centenarians

Abstract

It is generally recognized that the function of the immune system declines with increased age and one of the major immune changes is impaired T‐cell responses upon antigen presentation/stimulation. Some “high‐performing” centenarians (100+ years old) are remarkably successful in escaping, or largely postponing, major age‐related diseases. However, the majority of centenarians (“low‐performing”) have experienced these pathologies and are forced to reside in long‐term nursing facilities. Previous studies have pooled all centenarians examining heterogeneous populations of resting/unstimulated peripheral blood mononuclear cells (PBMCs). T cells represent around 60% of PBMC and are in a quiescence state when unstimulated. However, upon stimulation, T cells rapidly divide and exhibit dramatic changes in gene expression. We have compared stimulated T‐cell responses and identified a set of transcripts expressed in vitro that are dramatically different in high‐ vs. low‐performing centenarians. We have also identified several other measurements that are different between high‐ and low‐performing centenarians: (a) The amount of proliferation following in vitro stimulation is dramatically greater in high‐performing centenarians compared to 67‐ to 83‐year‐old controls and low‐performing centenarians; (b) telomere length is greater in the high‐performing centenarians; and (c) telomerase activity following stimulation is greater in the high‐performing centenarians. In addition, we have validated a number of genes whose expression is directly related to telomere length and these are potential fundamental biomarkers of aging that may influence the risk and progression of multiple aging conditions.

Transient introduction of human telomerase mRNA improves hallmarks of progeria cells

“…Senescent cells secrete a variety of inflammatory cytokines, known as the senescence‐associated secretory phenotype (SASP), triggered by persistent DNA damage (Rodier et al, ; Tedone et al, ). Vascular inflammation, calcification, and the progression of atherosclerosis are also associated with SASP (Csoka et al, ).…”

Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution

“…mtDNA levels during T cell stimulation decrease with age, but healthy centenarians escape this decline Previously, we identified genes and pathways potentially involved in the process of healthy human immune cell aging and longevity through the study of stimulated PBMCs from a well-characterized population of 114 individuals aged 23-113 yr (Tedone et al 2019). PBMCs are a heterogeneous cell population mainly consisting of T cells, a major component of human immune responses.…”

Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single cell resolution: a focus on aging and cancer

“…Interestingly, healthy centenarians appeared to retain more mtDNA molecules and less major mtDNA deletions, suggesting mtDNA copy number and maintenance during immune cell stimulation is a potential biomarker of healthy aging. In addition, previous studies have shown mtDNA to be a critical player in the NLRP3 inflammation pathway (Zhou et al 2011;Zhong et al 2018) and we recently reported involvement of the NLRP3 inflammasome in centenarian longevity and healthy aging (Tedone et al 2019). Additional studies are required to better understand the contribution that mtDNA plays in chronic inflammation and aging, not only for its role in metabolism but also as a signaling molecule.…”

“…Previously, we identified genes and pathways potentially involved in the process of healthy human aging and longevity through the study of stimulated peripheral blood mononuclear cells In contrast, upon antigen-specific activation T cells rapidly divide and exhibit dramatic changes in gene expression (Zhao et al 2014;Tedone et al 2019) and metabolic features (Dimeloe et al 2017). Activated T cells initiate immune responses such as discriminating between healthy and abnormal (e.g.…”

“…Human PBMC were obtained from 61 donors in accordance with the Institutional Review Board (IRB)-approved protocol (certification number STU 042014-016) (Tedone et al 2019). Subjects affected by cancer, infections or autoimmune diseases or on immunosuppressive treatment at the time of enrollment were excluded from the study.…”