Study examines link between folate and one-carbon metabolism to reduced epigenetic age deviation in older adults

A recently published study¹ examined the effects of nutrition on aging, specifically how one-carbon metabolism (OCM) influences certain biomarkers. As the study explains, OCM is a biochemical pathway that relies on micronutrients including B vitamins, noting that imbalances are associated with an increased risk of age-related diseases and possibly influences biomarkers related to aging. The study, “One-carbon metabolism-related compounds are associated with epigenetic aging biomarkers: results from the cross-sectional National Health and Nutrition Examination Survey 1999–2002,” was published in The American Journal of Clinical Nutrition in August 2025.

The researchers studied data from 2,346 participants aged 50 – 85 years old, examining epigenetic age deviation (EAD) and associations of serum folate, red blood cell folate, vitamin B₁₂, homocysteine (Hcy), and methylmalonic acid (MMA) concentrations. Several epigenetic aging biomarkers were included, such as PhenoAge, GrimAge2, and Dunedin Pace-of-Aging (DunedinPoAm).

As explained in an August 12 press release² from Balchem, the researchers used machine learning tools known as “epigenetic clocks” to analyze the associations. “Epigenetic clocks examine the levels of DNA methylation at specific points on the genome that change with age to help quantify variations in biological versus chronological aging,” explained Eric Ciappio, PhD, RD, senior manager, nutrition science, Balchem HNH. “This difference is known as epigenetic age deviation (EAD). This recent study was particularly interesting as it tested for associations between EAD and nutritional biomarkers associated with one-carbon metabolism. This essential biochemical pathway supports many physiological processes, including balanced methylation.”

Highlighted results listed in the study include¹:

• Higher concentration of Hcy, an indicator of OCM deficiencies, is associated with greater PhenoAge and GrimAge2 EAD and DunedinPoAm, and this was seen even after adjusting for factors including smoking status, alcohol intake, and renal function
• Serum folate concentration was associated with lower GrimAge2 EAD and DunedinPoAm and greater DNA methylation telomere length (DNAmTL) EAD

“In a nationally representative sample of United States adults, higher concentration of folate, a carbon donor, was associated with lower EAD, and higher concentration of Hcys, an indicator of OCM deficiencies, was associated with greater EAD,” the researchers concluded. Additional studies on this topic would need to focus on high-risk populations, they suggested, which may benefit from nutritional intervention.

“These findings underscore the importance of folate in epigenetic health,” stated Ciappio. “Folate plays an essential role, supplying methyl groups to be used in DNA methylation, a fundamental process which regulates gene expression and supports genomic stability. As we age, our global DNA methylation levels decrease. This is where folate’s methyl-donor function comes into play – helping to maintain cellular health and optimize the integrity of our genetic material.”

“This study signals the potential for folate to drive innovation in this space through its methyl-donor function,” added Lauren Eisen, senior marketing and business development manager, minerals, and nutrients at Balchem. “The key point here is that every methyl counts. That’s why we developed our first-of-its-kind, choline-enriched folate salt, Optifolin+, which delivers seven times the methyl groups found in other folate products – uniquely positioning the ingredient to promote balanced and effective methylation throughout life.”

References

1. Bozack, AK.; Khodasevich, D.; Nwanaji-Enwerem, JC.; Gladish, N.; Shen, H.; Daredia, S.; Gamble, M.; Needham, BL.; Rehkopf, DH.; Cardenas, A. The American Journal of Clinical Nutrition, 122(2). 2025. DOI: 10.1016/j.ajcnut.2025.05.029.
2. Balchem. New Study Shows Association of Serum Folate Levels to “Epigenetic Age Deviation" https://balchem.com/news/association-of-serum-folate-levels-to-epigenetic-age-deviation/ (accessed 2025-08-12).