Published in The American Journal of Clinical Nutrition, findings indicate that adults between the ages of 50 and 85 with higher serum folate levels are more likely to have a lower epigenetic age deviation (EAD). This is defined as the difference between a person’s biological age—as estimated by an epigenetic clock based on DNA methylation patterns—and their chronological age.
“As the application of epigenetic aging biomarkers becomes more common in research and clinical settings, it is important to understand how intervenable factors, such as nutrition, influence epigenetic aging,” the researchers wrote.
“In this study of a nationally representative sample of middle-aged and older adults, we found that homocysteine concentration is positively associated with epigenetic aging, particularly among former and current smokers. We also found evidence that serum folate is associated with lower EAD.”
The study drew on data from the cross-sectional National Health and Nutrition Examination Survey (NHANES, 1999–2002) to investigate associations of OCM-related biomarkers with epigenetic aging biomarkers.
Researchers, supported by National Institutes of Health grands and affiliated with the University of Pennsylvania, University of California, Berkeley, Columbia University and University of Michigan, also contributed to the analysis and review.
B Vitamins, one-carbon metabolism and epigenetic aging
Epigenetic aging became hot topic following the development of the Horvath Clock in 2013, which could accurately predict chronological age based on the understanding that DNA methylation patterns change with the progression of time. This breakthrough, along with the work of others like Dr. Gregory Hannum, sparked significant interest in the concept of the epigenome as a programmable marker of aging and a potential target for interventions to extend healthspan.
The researchers on the current study noted that one-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including B vitamins, plays an essential role in aging-related physiological processes and suggested that DNA methylation–based aging biomarkers may be influenced by OCM.
“OCM is dependent on diet-derived micronutrients including folate (vitamin B9) and cobalamin (vitamin B12),” they wrote. “The prevalence of folate and B12 deficiencies increases with age due to changes in diet, intestinal absorption and antagonistic therapeutic drugs. Low folate concentrations have been associated with age-related conditions, including dementia, cognitive function and cancers.”
They added that shortages in these B vitamins also increase homocysteine (Hcy) concentration, which can induce oxidative stress, inflammation and impair endothelial function, increasing risk of cardiovascular disease (CVD) incidence and mortality, cognitive impairment and decline, and all-cause mortality.
Study details
The observational study analyzed data from 2,346 participants age 50 and older with epigenetic and nutritional status biomarkers from the 1999–2002.
It used several generations of epigenetic clocks to examine associations between serum folate, red blood cell folate, vitamin B12, homocysteine (Hcy) and methylmalonic acid (MMA) concentrations with EAD.
Epigenetic aging biomarkers analyzed included Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, Dunedin Pace-of-Aging (DunedinPoAm) and DNA methylation telomere length (DNAmTL).
“In this study of a nationally representative sample of middle-aged and older adults, we found that Hcy concentration is positively associated with epigenetic aging, particularly among former and current smokers,” the researchers reported.
“We also found evidence that serum folate is associated with lower EAD. Our results suggest that changes in OCM-related biomarkers may be one mechanism through which behavioral and health factors are related to EAD.”
These potential outcomes contrast with a recent study research carried out at Texas A&M, which linked reduce folate intakes to heathier aging in animal models and attributed to metabolic flexibility.
Commenting on these findings following the study’s publication, Michael Polymenis, PhD, professor and associate head of graduate programs in the Texas A&M College of Agriculture and Life Sciences Department of Biochemistry and Biophysics said:
“Optimal folate intake may vary depending on an individual’s age. While higher folate is crucial during early life for growth and development, a lower intake later in life may benefit metabolic health and longevity.”
Acknowledging the cross-sectional nature of the data and limitations on the generalizability of findings, the Stanford-led study called for future research in high-risk populations and long-term randomized controlled trials to establish causality, investigate the long-term consequences of OCM-related epigenetic aging and evaluate the clinical relevance of changes in EAD.
Source: The American Journal of Clinical Nutrition. doi: 10.1016/j.ajcnut.2025.05.029. “One-carbon metabolism-related compounds are associated with epigenetic aging biomarkers: results from the cross-sectional National Health and Nutrition Examination Survey 1999–2002”. Authors: Anne K Bozak et al.
