Frailty reflects declining physiological reserve and is a major barrier to healthy longevity. Methyl-donor nutrients, which serve as substrates and cofactors in one-carbon metabolism, are involved in several biological processes relevant to aging, including the regulation of oxidative stress. However, their association with frailty and the potential role of oxidative stress in this relationship remain unclear.

To examine the association between a composite Methyl-Donor Nutrient Quality Index (MNQI) and frailty and to evaluate whether oxidative stress may contribute to this association in middle-aged and older adults.

Cross-sectional data from NHANES 2005–2018 were analyzed among 13,528 adults aged ≥40 years. Frailty was assessed using a 53-item deficit accumulation frailty index categorized as robust, prefrail, or frail. The MNQI was calculated from seven methyl-donor and cofactor nutrients. The oxidative stress index (OSI) was derived from gamma-glutamyl transferase, uric acid, albumin, and bilirubin. Survey-weighted multinomial logistic regression examined MNQI and OSI associations with frailty, and exploratory mediation analyses evaluated the indirect effect through OSI.

Higher MNQI was associated with 33% lower odds of frailty (OR = 0.67; 95% CI: 0.52–0.88; P = 0.004), with a significant dose–response relationship. Higher OSI was associated with 113% greater odds of frailty (OR = 2.13; 95% CI: 1.92–2.36; P < 0.001). Exploratory mediation analyses indicated a significant indirect effect through oxidative stress, accounting for approximately 29% of the MNQI–frailty association.

Higher dietary intake of methyl-donor nutrients was associated with lower odds of frailty and may support physiological processes relevant to healthy longevity, with oxidative stress potentially representing one pathway underlying this association. Longitudinal studies and randomized trials are needed to confirm these relationships and clarify the underlying mechanisms.