The association between methylmalonic acid, a biomarker of mitochondria dysfunction, and phenotypic age acceleration: A population-based study.

Phenotypic age acceleration (PAA) is a sensitive marker of biological aging. Circulating methylmalonic acid (MMA) is a novel biomarker of mitochondrial dysfunction and has been associated with age-related disorders. Our study aimed to investigate to what extent circulating MMA was associated with PAA, and whether the association was independent of vitamin B12 status and renal function in the general population. We analyzed cross-sectional data from 13,023 participants across a wide age range (mean age: 38.9 years, range: 12 - 85 years, 51.1% women) from the US National Health and Nutrition Examination Survey (NHANES). PAA was calculated based on the published algorithm. Linear regression models were performed to assess the association between circulating MAA and PAA. Only 31% of the variation in MMA levels was explained by age, sex, race/ethnicity, social economic status, vitamin B12 status, and renal function. Per unit increase in circulating MAA (1.0 nmol/L) was associated with 1.59 years increase in PAA (β = 1.59, 95% CI: 1.17, 2.00, p < 0.001) after adjusting for multiple confounders. Importantly, PAA increased with circulating MMA levels independent of vitamin B12, creatine, and homocysteine levels. The association was more pronounced in subgroups of age ≥ 65 years, women, underweight, vitamin B12 < 400 μmol/L, and homocysteine ≥ 10 μmol/L. The association was much stronger among participants with cardiovascular diseases (CVDs) than without CVDs. In conclusion, our current population-based study showed that mitochondria-derived circulating MMA was associated with increased phenotypic age acceleration in the general population.