## 4 Nicotinamide Riboside for Healthy Aging and Longevity
### Brain Aging, Cognitive Impairment, and Neurodeine Diseases  
Supplements of NAD\({}^{+}\) precursors (NR, NRH, NMN) are a potential way to prevent cognitive decline within aging-associated diseases, such as neurodegenerative disorders [199; 200; 201]. For example, in models of murine dementia, NRS decreased neuroinflammation, DNA damage, and apoptosis while contributing to maintaining synaptic plasticity, integrity of the blood-brain barrier (BBB), and gut microbiota functionality. It also improved hippocampal synaptic plasticity, learning, and memory in AD. A\(\beta\) forming in the brain can be prevented by NRS partly through the upregulation of ubiquitination and proteasomal degradation of PGC-1\(\alpha\)-mediated beta-secretase 1 (BACE1) [202; 203]. These studies have extended for over a decade. For example, in Tg2576 mice, NR dietary supplementation (250 mg/kg/day) for three months significantly alleviated cognitive damage, increased the NAD\({}^{+}\)/NADH ratio in the cerebral cortex, and reduced A\(\beta\) production [26]. A further study examines DNA repair-deficient 3 xTgAD/Pol\(\beta^{+/-}\) mice that exhibited cognitive impairment, synaptic dysfunction, phosphorylated _tau_ (p-_tau_) pathologies, and neuronal death, the main characteristics of human AD. Here, NRS decreased neuroinflammation, DNA damage, and hippocampal neurons' apoptosis, increased SIRT3 activity in the brain, improved cognitive function, and restored hippocampal synaptic plasticity [204]. NRS (2.5 g/kg in food for three months) in APP/PS1 transgenic AD and aged mice inhibited serum NAMPT elevation, astrocyte activation, neuroinflammation, senescence, A\(\beta\) accumulation, and astrocyte migration to A\(\beta\), as well as improving locomotor activity, cognitive function, behavior, and dementia progression [205; 206]. Inhibition of CD38 and NRS alleviated LPS-induced microglial and astrocytic neuroinflammation/neurodegeneration by increasing NAD\({}^{+}\) levels in mice brains and by suppressing the NF-kB signaling pathway at the microglia level [207]. In APP/PS1 transgenic (AD) mice, NRS for eight weeks normalized gut dysbiosis for _Adlercretuzia_, _Akkemansia_, _Bacteroides_, _Bifidobacterium_, _Butyricicoccus_, _Desulfovibrio_, _Lactobacillus_, _Olsenella_, and _Oscillospira_ microbiota species [208]. In late-onset AD patients, NR and caffeine co-administration partially restores diminished NAD\({}^{+}\) availability but does not alter bioenergetic metabolism [209]. In a randomized, double-blinded, PLA-controlled, phase II clinical trial, combined metabolic activators (CMAs) administered in a single dose during the first 28 days and twice daily between days 28 and 84 significantly increased the cognitive capacity and alleviated NAD\({}^{+}\) plasma levels and GSH metabolism of AD patients. CMA complex included 12.35 g L-serine (61.75%), 3.73 g L-carnitine tartrate (18.65%), 2.55 g \(N\)-acetyl-L-cysteine (12.75%), and 1 g NR (5%) [210]. NR food supplementation for 28 days rescues Ang II-induced cerebral small vessel disease (CSVD) in C57 BL/6 mice. NRS significantly reduced glial activation, neuroinflammation, and white matter injury that is associated with cognitive dysfunction. It also supported BBB integrity and vascular remodeling, and improved Ang II-induced CSVD [211]. Further, treatment with NAD\({}^{+}\) precursor NRS rescues MT defects in induced pluripotent stem cells (iPSCs) and aging-associated dopaminergic neuronal loss and motor decline and _Drosophila_ models of glucocerebrosidase (GBA)-related Parkinson's disease (PD) [212]. In a randomized, PLA-controlled, phase I clinical trial in 30 newly diagnosed, treatment-naive PD patients (NADPARK study), oral NRS 1 g for 30 days significantly increased the level of NAD\({}^{+}\) and its related metabolites in the CSF and decreased the inflammatory cytokines amounts also in serum and CSF [213].