One-carbon metabolism-related compounds are associated with epigenetic aging biomarkers: Results from National Health and Nutrition Examination Survey (NHANES) 1999-2002

Abstract

Background: One-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including folate and vitamin B12, plays an essential role in aging-related physiological processes. DNA methylation-based aging biomarkers may be influenced by OCM.

Objective: This study investigated associations of OCM-related biomarkers with epigenetic aging biomarkers in the National Health and Nutrition Examination Survey (NHANES).

Methods: Blood DNA methylation was measured in adults aged ≥50 years in the 1999-2000 and 2001-2002 cycles of NHANES. The following epigenetic aging biomarkers were included: Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, DunedinPoAm, and DNA methylation telomere length (DNAmTL). We tested for associations of serum folate, red blood cell (RBC) folate, vitamin B12, homocysteine, and methylmalonic acid concentrations with epigenetic age deviation (EAD) among 2,346 participants with epigenetic and nutritional status biomarkers using survey weighted general linear regression models adjusting for sociodemographics, BMI, and behavioral factors.

Results: A doubling of serum folate concentration was associated with -0.82 years (95% confidence interval (CI) = -1.40, -0.23) lower GrimAge EAD, -0.13 SDs (-0.22, -0.03) lower DunedinPoAm, and 0.02 kb (0.00, 0.04) greater DNAmTL EAD. Associations were attenuated after adjusting for smoking status and alcohol intake, folate antagonists. Conversely, a doubling in homocysteine concentration was associated with 1.05 years (0.06, 2.04) greater PhenoAge EAD, 1.93 years (1.16, 2.71) greater GrimAge2 EAD, and 0.26 SDs (0.10, 0.41) greater DunedinPoAm. Associations with GrimAge2 EAD and DunedinPoAm were robust to alcohol and smoking adjustment.

Conclusions: In a nationally representative sample of U.S. adults, greater folate, a carbon donor, was associated with lower EAD, and greater homocysteine, an indicator of OCM deficiencies, was associated with greater EAD; however, some associations were influenced by smoking status. Future research should focus on high-risk populations. Randomized controlled trials with long-term follow-up are also needed to established causality and investigate the clinical relevance of changes in EAD.