Homocysteine and related B-vitamins throughout our International Conferences: a historical perspective.

In this invited keynote review, I reflect on biochemical, clinical, and epidemiological evidence on the role of folate and vitamin B12 in one-carbon metabolism and their relationship with homocysteine, integrating over five decades of research. One-carbon metabolism represents a central biochemical network linking folate-dependent one-carbon transfer reactions with vitamin B12-dependent remethylation of homocysteine to methionine. Disruptions in this pathway result in elevated homocysteine concentrations and impaired methylation capacity, providing a mechanistic link between micronutrient status and chronic disease. Early work demonstrated that folate is a major determinant of plasma homocysteine levels, supporting folic acid fortification policies that significantly reduced neural tube defects worldwide. Research in my laboratory in older adults shifted the paradigm of deficiency from inadequate intake to impaired bioavailability. Elevated homocysteine has been associated with cardiovascular disease, stroke, and cognitive decline, although intervention trials have yielded mixed results, suggesting that homocysteine is best interpreted as a marker of metabolic dysfunction, but when elevated, a potential target for mitigating cognitive decline. Recent advances in epigenetics and gene-nutrient interactions have expanded the relevance of one-carbon metabolism, highlighting its role in DNA methylation and gene regulation. Future research in precision nutrition may refine strategies for preventing chronic disease and promoting healthy aging.