# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 3 Effects of NR on Metabolism and Age-Associated Pathophysiology
### Effects on Neurodeinsorders  
Neurodegenerative disorders are associated with DNA damage and oxidative stress, which accumulate with age [85] leading to impaired mitochondrial function [86]. In addition, NAD\({}^{+}\) depletion was observed during the aging process in multiple animals, including humans, and is considered the major risk factor for Alzheimer's disease (AD) [87]. When administered in AD mouse models, NR displays beneficial effects on both oxidative stress and DNA repair by increasing NAD\({}^{+}\) levels [88]. Additionally, NR can improve other aspects of AD neuropathology including pTau, amyloid-\(\beta\), neurogenesis, neuroinflammation, hippocampal synaptic plasticity, and cognition [89; 90]. Specifically, NR treatment reduce neuroinflammation and amyloidogenesis in the whole brain of high-fat diet (HFD)-fed mice, by decreasing amyloid-\(\beta\) levels and several inflammatory markers (NLRP3, CASP1, IL-1, TNF-\(\alpha\), and IL-6) [91]. Since brain inflammation is closely related to cognitive impairment [92; 93; 94], cognitive function and recognition memory could be attenuated by NR treatment in only 6 weeks [91]. Furthermore, increased PARylation, another hallmark of AD, could be decreased in AD mice with NR supplementation [90]. Increased PARylation has also been detected in several other neurodegenerative disorders that involve DNA repair defects, including Cockayne syndrome, xeroderma pigmentosum and ataxia-telangiectasia. Nevertheless, PARP-mediated NAD\({}^{+}\) depletion was recently confirmed to play a major role in the pathogenesis of these disorders. Despite the \begin{table}
\begin{tabular}{c c} \hline \hline \multirow{2}{*}{SIRT1} & Heart cell growth and development, mediation of cardiac hypertrophy, protection from ischemic injury; partial deficiency protects from pressure overload-induced hypertrophy and failure \\ \hline SIRT2 & Mediating ischemic injury due to attenuated programmed apoptosis \\ \hline SIRT3 & Protection from age-induced hypertrophy, fibrosis and contractile dysfunction, prevents susceptibility to cardiac hypertrophic stimuli \\ \hline SIRT6 & Protection from cardiac hypertrophy and heart failure \\ \hline SIRT7 & Protection from spontaneous cardiac hypertrophy and inflammatory cardiomyopathy \\ \hline SIRT1 & Low to moderate overexpression attenuates age-dependent decline in cardiac functions in mice, while high overexpression induces cardiac hypertrophy and heart failure \\ \hline SIRT3 & Cardiac-specific overexpression protects the heart from hypertrophic stimuli by preserving mitochondrial function \\ \hline SIRT6 & Cardiac-specific overexpression protects the heart from hypertrophic stimuli by blocking activation of Akt signaling at the level of chromatin \\ \hline \hline \end{tabular}
\end{table} 
Table 2: The roles of sirtuins in heart failure development acquired from experiments on knock-out and transgenic mice (adapted from [PERSON] et al., [84]). underlying DNA repair deficiencies, NR could dramatically improve the phenotype of each of these conditions in mouse models, while prolonging survival by more than three times in atax mice [95; 96]. Another early event that occurs in acute cerebral injury and in chronic neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, is axonal degeneration [97; 98; 99; 100]. In such cases, axonal degeneration is caused by excitotoxicity, which is another feature implicated in most neurodegenerative disorders that affect the central nervous system. Interestingly, a strong NAD\({}^{+}\) depletion in neurons has been revealed during excitotoxicity [101; 102; 103; 104], whereas mice injected with NR were protected from excitotoxicity-induced axonal degeneration [105]. Among three tested NAD\({}^{+}\) precursors (NA, NAM, and NR) including NAD\({}^{+}\), only NR could prevent axonal degeneration by altering the local NR metabolism within the axon [105; 106].