Longitudinal associations of one-carbon metabolism biomarkers with biological and epigenetic aging in older adults in India

Abstract Circulating folate, vitamin B12, and homocysteine reflect one-carbon (1-C) metabolism, a pathway central to methylation and cellular maintenance, but longitudinal evidence linking these biomarkers to biological aging remains limited, particularly in low- and middle-income populations. We examined associations of 1-C biomarkers with clinical biomarker-based Phenotypic Age and DNA methylation-based measures of accelerated biological aging among adults aged ≥ 60 years in the Longitudinal Aging Study in India Diagnostic Assessment of Dementia (LASI-DAD), with repeated measures over 4.5 years. Higher serum folate level was associated with slower biological aging, whereas higher homocysteine was associated with faster aging. Longitudinally, each doubling in homocysteine was associated with ~ 3.2 years faster Phenotypic Age acceleration, whereas each doubling in folate was associated with ~ 1.1 years slower aging. Transition to folate deficiency and persistent hyperhomocysteinemia were associated with accelerated aging across Phenotypic Age and DNA methylation–based aging measures, with folate exhibiting the strongest inverse associations with DunedinPACE and SystemsAge. These findings provide longitudinal evidence that 1-C metabolism, particularly folate status and homocysteine, is associated with trajectories of biological aging in older adults in India.