Fat metabolism is associated with telomere length in six population-based studies

Abstract

Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer, and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold pmeta = 6.5x10−4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-ce %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-ce) became significantly associated with LTL (p = 3.6x10−4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (p = 1.9x10−4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.

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

“…Mechanistically, higher circulating omega‐6 FAs and LA levels might link LDL‐C to longer LTL, although we were unable to provide support for this premise from mediation analyses, possibly because of the high genetic correlations of omega‐6 FAs and LA with LDL‐C [24]. Consistent results were reported by a cross‐sectional study investigating the relationships of 226 metabolites measured by nuclear magnetic resonance (NMR) spectroscopy in 11,775 individuals with LTL [23]. Potential links between FA metabolism and functions and LTL were discussed earlier.…”

“…Subsequently, we used the GENE2FUNCTION tool in FUMA to test whether the sets of mapped genes associated with BMI and LDL‐C are overrepresented within sets of genes mapping to signals for other GWAS catalog traits (http://www.ebi.ac.uk/gwas/). Finally, we cross‐referenced the GENE2FUNCTION gene set output with traits and indices of healthy behaviors previously shown to be cross‐sectionally associated with LTL (Supporting Information Tables S2 and S3) [19, 23]. Based on these results, we postulated that subclinical inflammation, as measured by circulating CRP [19] and omega‐6 [23] and omega‐3 FAs [19], and educational attainment [19] might mediate the links of higher BMI and/or hypercholesterolemia with altered LTL.…”

“…Finally, we cross‐referenced the GENE2FUNCTION gene set output with traits and indices of healthy behaviors previously shown to be cross‐sectionally associated with LTL (Supporting Information Tables S2 and S3) [19, 23]. Based on these results, we postulated that subclinical inflammation, as measured by circulating CRP [19] and omega‐6 [23] and omega‐3 FAs [19], and educational attainment [19] might mediate the links of higher BMI and/or hypercholesterolemia with altered LTL.…”

“…We then used the GENE2FUNCTION tool in FUMA, which performs hypergeometric tests, to test whether genes of interest are overrepresented in predefined pathways, i.e., in this instance, reported genes from the GWAS catalog (http://www.ebi.ac.uk/gwas/). Finally, we cross‐referenced the GENE2FUNCTION gene set output with traits and indices of healthy behavior previously shown to be cross‐sectionally associated with LTL [19, 23]. The latter, which are highlighted in Supporting Information Tables S2 and S3, were taken forward for further MR analyses, including mediation studies with multivariable MR (MVMR).…”

Enzymatic approaches against SARS-CoV-2 infection with an emphasis on the telomere-associated enzymes

“…Despite it is assumed that liver function enzymes (i.e. ALT and AST) are not regulating the TL directly, but fat metabolism might be associated with TL (Van der Spek et al 2022 ). Experimentally, regulation of TL was performed by Fatty Acid Elongase 3 in yeast (Ponnusamy et al 2008 ).…”