# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 3 Effects of NR on Metabolism and Age-Associated Pathophysiology
### Effects on Neurodeinsorders
Namely, NR prevented nuclear condensation and axonal degeneration in neurons of Nmrk2-KO mice, by inducing Nmrk1 [105], which suggests that Nmrk1 might be the key mediator of the neuroprotective activity of NR. This neuroprotective effect depends on both mitochondrial and axonal NAD\({}^{+}\) content [78]. At present, two possible mechanisms of neuroprotection have been proposed: increasing mitochondrial NAD\({}^{+}\) to support SIRT3 [77] and preserving axonal NAD\({}^{+}\) to supply damage-induced SARM1 activation [107]. Via SIRT3 activation, a NR-induced increase in NAD\({}^{+}\) levels can have additional beneficial and possible therapeutic effects. Specifically, NR has been shown to prevent noise-induced hearing loss and neurite retraction from hair cells in the inner ear through a SIRT3-dependent mechanism [77]. Moreover, SIRT3 and 5 are both critical for the health of retinal photoreceptors [108]. SIRT3 activity is sensitive to the reduction of NAD\({}^{+}\) content that has been detected in multiple disorders with retinal degeneration, including age-associated dysfunction, diabetic retinopathy, and light-induced degeneration in mice [108]. This suggests a potential therapeutic treatment with NR for a variety of disorders that include photoreceptor degeneration. Furthermore, a general decrease in NAD\({}^{+}\) levels has been observed in neuromuscular diseases which are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration [38]. Increasing NAD\({}^{+}\) content with NR can stimulate energy production and improve mitochondria function.NR has been shown to have therapeutic effects in several muscle disorders in mouse models. Although supplementation with NR could not correct the underlying genetic defects, it could improve mitochondrial abundance and function in two different mitochondrial myopathies [109; 110]. Furthermore, NR could reverse the progressive wasting syndrome in skeletal muscle in mice lacking Nampt whilst restoring endurance, in as little as 1 week of treatment [111]. Accordingly, NR was found to confer increased endurance and improved cold tolerance in the HFD-fed mice. However, whether NR has significant benefits in lean, healthy muscle is less clear, as only a nonsignificant trend toward increased endurance was observed in regular chow-fed mice [37]. Interestingly, decreased NAD\({}^{+}\) levels and Nampt expression were also observed in [PERSON]'s muscular dystrophy (DMD), a condition histologically and transcriptionally similar to progressive wasting syndrome [112; 113]. DMD is also characterized by increased PARP activity, fibrosis, and muscular degeneration. NR was found to improve muscular function and heart pathology in mdx mice models of DMD and decrease PARylation, inflammation, and fibrosis [112]. Moreover, NR treatment has been shown to improve stem cell function and thereby ameliorate the muscle wasting phenotype in mdx mice, supporting the use of NR for the human condition [38; 112]. Improvement in stem cell function appears to be a general phenomenon during NR treatment and has been suggested to underlie a small, but significant extension of lifespan in mice [38]. Altogether, these findings support that NR could be effective in managing the progression of muscular dystrophy and degeneration, by improving muscular strength, rejuvenating senescent muscle stem cells, and reducing levels of inflammation and fibrosis.