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 () 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