Investigating the impact of metabolic syndrome traits on telomere length: a Mendelian randomization study

Abstract

Objective: Observational studies have reported bidirectional associations between metabolic syndrome (MetS) traits and short leukocyte telomere length (LTL), a TL marker in somatic tissues and a proposed risk factor for age-related degenerative diseases. However, in Mendelian randomization studies, longer LTL has been paradoxically associated with higher MetS risk. This study investigated the hypothesis that shorter LTL might be a consequence of metabolic dysfunction.Methods: This study undertook univariable and multivariable Mendelian randomization. As instrumental variables for MetS traits, all of the genome-wide significant independent signals identified in genome-wide association studies for anthropometric, glycemic, lipid, and blood pressure traits conducted in European individuals were used. Summary-level data for LTL were obtained from a genome-wide association study conducted in the UK Biobank. Results: Higher BMI was associated with shorter LTL (β = À0.039, 95% CI: À0.058 to À0.020, p = 5 Â 10 À5 ) equivalent to 1.70 years of age-related LTL change. In contrast, higher low-density lipoprotein cholesterol was associated with longer LTL (β = 0.022, 95% CI: 0.007 to 0.037, p = 0.003) equivalent to 0.96 years of agerelated LTL change. Mechanistically, increased low-grade systemic inflammation, as measured by circulating C-reactive protein, and lower circulating linoleic acid levels might link higher BMI to shorter LTL. Conclusions: Overweight and obesity might promote the development of agingrelated degenerative diseases by accelerating telomere shortening.

The association between telomere length and blood lipids: a bidirectional two-sample Mendelian randomization study

“…The second step of our MR analysis provided evidence that a genetically predicted lower BMI was associated with longer TL. Several published MR studies have reported causal evidence for BMI as a risk factor for TL or related phenotypes ( 86 , 87 ), consistent with the estimations from the second step of our mediation analysis. Mechanistically, obesity-related metabolic dysregulation leads to oxidative stress, resulting in telomere shortening ( 88 ).…”

Causal association of obesity with epigenetic aging and telomere length: a bidirectional mendelian randomization study

“…Hence, the observed disparity in their outcomes could be attributed to the aforementioned factors. Loh et al [ 28 ] found a significant negative correlation between BMI and telomere length through Mendelian randomization (MR) analysis; however, when it came to waist-to-hip ratio (WHR), the causal association with telomere length was not statistically significant. Notably, there existed a failure to investigate the inverse relationship in that study, with WC and other biological age indicators not being taken into account.…”

17-year follow-up of association between telomere length and all-cause mortality, cardiovascular mortality in individuals with metabolic syndrome: results from the NHANES database prospective cohort study

“…These associations persist even after a six-year follow-up [ 12 ]. Mendelian randomization study revealed a paradoxical association between LTL (leukocyte telomere length) and the risk of metabolic syndrome [ 14 ]. It was observed that higher BMI (body mass index) was linked to shorter LTL, while higher levels of low-density lipoprotein cholesterol were associated with longer LTL [ 14 ].…”

“…Mendelian randomization study revealed a paradoxical association between LTL (leukocyte telomere length) and the risk of metabolic syndrome [ 14 ]. It was observed that higher BMI (body mass index) was linked to shorter LTL, while higher levels of low-density lipoprotein cholesterol were associated with longer LTL [ 14 ]. Obesity may be linked to shorter LTL through the mechanisms of increased subclinical inflammation and lower circulating levels of linoleic acid [ 14 ].…”

“…It was observed that higher BMI (body mass index) was linked to shorter LTL, while higher levels of low-density lipoprotein cholesterol were associated with longer LTL [ 14 ]. Obesity may be linked to shorter LTL through the mechanisms of increased subclinical inflammation and lower circulating levels of linoleic acid [ 14 ]. In another Mendelian randomization study, it was found that longer LTL was associated with a higher waist-to-hip ratio adjusted for body mass index, elevated blood pressure, and increased risk of metabolic syndrome [ 15 ].…”