Telomere length and aging‐related outcomes in humans: A Mendelian randomization study in 261,000 older participants

Abstract

Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging‐related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40–70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow‐up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate‐adjusted p‐values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92–0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06–1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age‐related health outcomes. Telomere lengthening may offer little gain in later‐life health status and face increasing cancer risks.

Assessing the Relationship Between Leukocyte Telomere Length and Cancer Risk/Mortality in UK Biobank and TCGA Datasets With the Genetic Risk Score and Mendelian Randomization Approaches

“…Although the molecular mechanism remains unclear, some prior studies implied that both short and long telomere length played an important role in the etiology of cancers (Cui et al, 2012;Cheng et al, 2017;Nelson and Codd, 2020). Cells with longer telomere lengths have greater proliferative potential and more probability of accruing mutations (Hanahan and Weinberg, 2011); therefore, telomere shortening is generally considered to be a protective mechanism against tumorigenesis (Rode et al, 2016;Zhang et al, 2017;Kuo et al, 2019). However, it has been proposed that telomere shortening can generally give rise to end-to-end chromosome fusions and attenuates DNA damage response, thus increasing genomic instability and finally initiating carcinogenesis (Wu et al, 2003).…”

Aerobic capacity and telomere length in human skeletal muscle and leukocytes across the lifespan

“…TL is associated with some, but not all, ageing and disease-related traits [13,14]. Literature is inconsistent regarding TL and all-cause mortality with some [7,15] but not all studies [16,17] finding that a shorter TL is associated with increased risk of all-cause mortality.…”

“…While in cancer the literature is conflicted regarding risk of cancer and TL [7,[21][22][23] with suggestions that perhaps a "Ushaped" risk association may exist between very short and very long telomeres and risk of different types cancer [12,22,24,25]. In two recent papers, there was no association between TL and cognitive function, grip strength, frailty and sarcopenia [13,26]; suggesting that telomere length may not be a marker of all ageing and disease-related traits.…”

Age-associated changes in the circulating human antibody repertoire are upregulated in autoimmunity

“…This predictive score could then be compared to chronological age to estimate "accelerated ageing" of the antibody repertoire, or immune age. Similar "biological age" metrics based on cell counts, gene expression, cytokine expression, blood and leukocyte epigenetics, telomere length, and genetic predispositions thereof have been found to be predictive of health, disease, and even all-cause mortality [33][34][35][36][37][38][39][40][41], suggesting that molecular correlates of age can be useful biomarkers.…”