In muscle biopsies from 137 men, NAD+ and NADPH, molecules involved in energy production and cellular protection, were more strongly associated with muscle function than with age
In muscle biopsies from 137 men, NAD+ and NADPH, molecules involved in energy production and cellular protection, were more strongly associated with muscle function than with age
On August 28, the authors of a preprint reported measurements of six metabolites involved in cellular metabolism in muscle biopsies from 137 men aged 20 to 93 years. The total NAD(H) and NADP(H) pools did not change significantly with age. After adjustment for age, NAD+ and NADPH remained associated with walking performance, leg power, muscle mass, and the abundance of mitochondria, the structures that produce energy for cells.
NAD+ participates in reactions that allow cells to obtain energy. NADPH is required to synthesize molecules and regenerate glutathione, which protects cells from oxidation. One hypothesis attributes age-related muscle decline to NAD+ depletion. The authors therefore also measured related metabolites, including NADP and glutathione.
Previous human findings have been inconsistent. In a 2022 study, NAD+ levels were lower in older adults, particularly among those who performed worse on physical tests, while levels in trained older adults approached those observed in younger people. A May analysis of whole-blood NAD+ across seven human cohorts also found little change with age. Blood is convenient to measure, but these findings did not resolve what happens in muscle itself.
The authors collected biopsies from the vastus lateralis, part of the quadriceps muscle, and simultaneously measured two forms of NAD, two forms of NADP, and two forms of glutathione. The same participants completed walking, step-up, and chair-rise tests. The researchers also measured leg strength and power, muscle mass, and mitochondrial respiration, meaning oxygen consumption that indicates how mitochondria produce energy. Age was included separately in the statistical model to test whether the metabolites were associated with these outcomes independently of age.
The total NAD(H) and NADP(H) pools and the ratios between their respective forms showed no statistically significant correlations with age. After adjustment for age, NAD+ remained associated with walking, step-up and chair-rise performance, leg strength and power, muscle mass, and maximal mitochondrial oxygen consumption. NADPH remained associated with walking, leg power, muscle mass, mitochondrial respiration, and mitochondrial abundance. In contrast, both forms of glutathione increased in parallel with age, while their ratio remained stable.
The authors separately examined whether these associations reflected mitochondrial abundance or mitochondrial respiratory capacity. Citrate synthase activity in muscle serves as a marker of mitochondrial abundance. NAD+ and NADPH were associated with both citrate synthase activity and maximal respiration. The associations disappeared when respiration was normalized to citrate synthase activity. The authors therefore consider mitochondrial abundance the most direct explanation for the observed associations.
“Measures of NAD(P) metabolism reflect preserved muscle health more strongly than muscle aging,” the authors write.
Interventions that alter NAD levels should be evaluated by determining whether the biochemical change is accompanied by a change in the function of the specific tissue.