# Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies
## 1 Introduction  
The nicotinamide adenine dinucleotide molecule (NAD+) is a redox coenzyme in electron transfer during oxidation-reduction reactions in mitochondria to generate ATP [1] and as a cofactor for NAD+-dependent enzymes, such as sirtuins (SIRT1-7 in mammals), poly (ADP-ribose) polymerases (PARPs), COOH-terminal binding protein (CtBP), cyclic ADP-ribose (ADPR) synthetases, glycoproteins CD38 and CD157, and many other NAD+-dependent enzymes [2; 3]. NAD+ is required for over 500 enzymatic reactions and is involved in numerous evolutionarily conserved signaling pathways that include DNA repair, apoptosis, genomic signaling, endocrine signaling, senescence, proliferation, inflammation, mitochondrial function, lipid and glucose homeostasis [3].  
NAD+ levels decrease during aging because of decreased synthesis and increased consumption of NAD+ due to (i) increased DNA damage and damage repair (activation of PARPs and sirtuins), (ii) increased secretion of inflammatory factors and inflammatory processes that activate CD38 or cause a defect in the enzyme nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis [4; 5], and (iii) alcohol metabolism, resulting in an overall tissue-specific depletion in the concentration of NAD+ [6; 7; 8; 9; 10; 11; 12; 13; 14]. NAD+ is also used during NAD+ kinase phosphorylation where NADP+ is generated, which in turn is reduced by dehydrogenases to generate NADPH [15]. In summary, NAD+ levels decrease with age due to increased DNA damage, oxidative stress, and chronic inflammation, which dysregulate NAD metabolism by activating CD38 and PARPs or by inhibiting NAMPT [10; 16]. As a result of decreased NAD+ levels, a reduction in cellularenergy production and DNA repair, as well as altered genomic signaling, leads to aging and an increased incidence of chronic diseases [2; 7; 8; 9]. Indeed, during aging and in many age-associated diseases, a decreased NAD+ availability was observed [6; 7; 8; 9]. On the other hand, by increasing the availability of NAD+ and by preventing NAD+ degradation, aging and age-associated diseases could be modulated, delayed, and perhaps even reversed [6; 7; 8; 9]. Scientific studies reports imply that besides life extension [17; 18; 19; 20] and phenotypes consistent with an aging delay [21], rising NAD+ levels influence a number of different diseases and conditions, including metabolic syndrome, type 2 diabetes, and/or insulin sensitivity [5; 17; 22; 23], cancer [24; 25; 26; 27; 28], cardiovascular disease [29; 30; 31; 32; 33; 34], neurodegeneration [35; 36; 37], renal function [38; 39], Alzheimer's disease [40; 41], and reduce inflammation [18; 42; 43], as well as help to prevent obesity [5; 44; 45; 22; 46]. NAD+ depletion was reported in neurological diseases as an increase in the ratio of NMN to NAD+ triggers axonal degeneration due to Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) hydrolyzilation of NAD+ [47]. Namely, SARM1 is a neuronally expressed NAD+ glycohydrolase whose activity is increased in response to stress resulting in degeneration and programmed axon death (Wallerian degeneration) [48; 49; 50]. NAD+ deficiency is also associated with retinal degeneration and human vision impairment as deficits in NAD+ bioavailability promote senescence in retinal cells [51; 52].