Research Paper Volume 11, Issue 6 pp 1874—1899

DNA methylation in genes of longevity-regulating pathways: association with obesity and metabolic complications

Francisca Salas-Pérez1, , Omar Ramos-Lopez1, , María L. Mansego2, , Fermín I. Milagro1,3,4, , José L. Santos4, , José I. Riezu-Boj1,3,4, , J. Alfredo Martínez1,3,5,6, ,

  • 1 Department of Nutrition, Food Science and Physiology; Center for Nutrition Research, University of Navarra, Pamplona 31008, Spain
  • 2 Department of Bioinformatics, Making Genetics S.L, Pamplona 31002, Spain
  • 3 CIBERobn, Fisiopatología de la Obesidad y la Nutrición, Carlos III Health Institute, Madrid 28029, Spain
  • 4 IdiSNA, Navarra Institute for Health Research, Pamplona 31008, Spain
  • 5 Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
  • 6 Institute IMDEA Food, Madrid 28049, Spain
* Equal contribution

Received: November 20, 2018       Accepted: March 20, 2019       Published: March 29, 2019
How to Cite

Copyright: © 2019 Salas-Pérez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Aging is the main risk factor for most chronic diseases. Epigenetic mechanisms, such as DNA methylation (DNAm) plays a pivotal role in the regulation of physiological responses that can vary along lifespan. The aim of this research was to analyze the association between leukocyte DNAm in genes involved in longevity and the occurrence of obesity and related metabolic alterations in an adult population. Subjects from the MENA cohort (n=474) were categorized according to age (<45 vs 45>) and the presence of metabolic alterations: increased waist circumference, hypercholesterolemia, insulin resistance, and metabolic syndrome. The methylation levels of 58 CpG sites located at genes involved in longevity-regulating pathways were strongly correlated (FDR-adjusted< 0.0001) with BMI. Fifteen of them were differentially methylated (p<0.05) between younger and older subjects that exhibited at least one metabolic alteration. Six of these CpG sites, located at MTOR (cg08862778), ULK1 (cg07199894), ADCY6 (cg11658986), IGF1R (cg01284192), CREB5 (cg11301281), and RELA (cg08128650), were common to the metabolic traits, and CREB5, RELA, and ULK1 were statistically associated with age. In summary, leukocyte DNAm levels of several CpG sites located at genes involved in longevity-regulating pathways were associated with obesity and metabolic syndrome traits, suggesting a role of DNAm in aging-related metabolic alterations.


ADCY: adenylate cyclase; APOE: apolipoprotein E; AMP: adenosine monophosphate; ATP: adenosine triphosphate; BMI: body mass index; CpG: cytosine-phosphate-guanine site; CREB5: CAMP responsive element binding protein 5; DNAm: DNA methylation; DXA: dual-energy X-ray absorptiometry; FDR: false discovery rate; FOXO1: forkhead box protein O1; GEO: gene expression omnibus database; GHR: growth hormone receptor; GWAS: genome-wide association study; HDL-c: high-density lipoprotein cholesterol; HOMA-IR: homeostatic model assessment-insulin resistance index; HT: hypertension; IGF1: insulin-like growth factor 1; IG1R: insulin-like growth factor 1 receptor; INS: insulin; IR: insulin resistance; KEGG: Kyoto encyclopedia of genes and genomes; LARS: least-angle regression; LDL-c: low-density lipoprotein cholesterol; LIMMA: linear models for microarray data; MENA: methyl epigenome network association project; MetS: Metabolic syndrome; mTOR: mammalian target of rapamycin; NFκB: nuclear factor κB; PathDIP: pathway data integration portal; PBMC: peripheral blood mononuclear cell; PCR: polymerase chain reaction; PRKAG2: 5´-AMP-activated protein kinase subunit gamma-2; r: regression, r2: squared regression; RELA: transcription factor p65; SBP: systolic blood pressure; SNP: single nucleotide polymorphism; SPSS: statistical package for the social sciences; TC: total cholesterol; TG: triglycerides; TSC1: hamartin; TSS: transcription start site; ULK1: Unc-51 like autophagy activating kinase; UTR: untranslated region; WC: waist circumference.