Effects of Nicotinamide Riboside in Hyperammonemia: Preclinical Findings

Synopsis

Excess ammonia in the body disrupts metabolism and contributes to cellular aging (senescence) by damaging mitochondria and disturbing the NAD+/NADH redox balance, which is vital for energy production. This study found that hyperammonemia (elevated ammonia levels) reduced the activity of SIRT3, an NAD+-dependent mitochondrial enzyme, leading to protein hyperacetylation, oxidative stress, and senescence in skeletal muscle cells. Although nicotinamide riboside (NR), an NAD+ precursor, raised NAD+ levels, it did not restore mitochondrial function or reverse aging effects. Instead, treatment with a mitochondria-targeted NADH oxidase (MitoLbNOX), which helps convert excess NADH back to NAD+, successfully restored mitochondrial activity, ATP production, and cellular redox balance, preventing ammonia-induced dysfunction. The results reveal that impaired NADH oxidation, rather than NAD+ depletion alone, drives ammonia-related muscle aging and that targeting the redox imbalance may be a better therapeutic strategy than NAD+ supplementation.

Journal

Aging Cell