Nicotinamide adenine dinucleotide (NAD⁺) is central to energy metabolism, redox reactions, and cellular signaling. However, human evidence linking circulating NAD⁺ concentrations to frailty remains limited. We examined the association of whole-blood NAD⁺ concentration with frailty in community-dwelling older adults. This cross-sectional analysis included community-dwelling adults aged ≥ 65 years from the 2025 Itabashi Longitudinal Study on Aging. Frailty was assessed using the revised Japanese Cardiovascular Health Study Criteria. Multivariable linear and logistic regression models adjusted for age, sex, and fasting time assessed the association. Restricted cubic spline, Firth penalized-likelihood logistic regression, and hematological sensitivity analyses were also performed. Among 529 participants (54.3% women), 32 (6.0%) had frailty. Median whole-blood NAD⁺ concentration was lower among participants with frailty than among those without frailty (24.00 vs. 25.00 µmol/L; P = 0.007). After adjustment for age, sex, and fasting time, higher whole-blood NAD⁺ concentration was associated with lower odds of frailty (OR per 1 µmol/L increase, 0.871; 95% CI, 0.780-0.970; P = 0.013). Restricted cubic spline analysis showed no clear evidence of nonlinearity. The association persisted after broader covariate adjustment using the Firth regression (OR, 0.880; 95% CI, 0.782-0.986) but was attenuated after additional adjustment for hematocrit (OR, 0.911; 95% CI, 0.800-1.034). Lower whole-blood NAD⁺ concentration was associated with frailty in community-dwelling older adults. Attenuation after hematocrit adjustment suggests that blood cell composition may partly explain this association. Further studies using cell- and tissue-specific measurements are needed to clarify the relationship between NAD⁺ metabolism and frailty.
