Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in all living cells. NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other a nicotinamide. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins, CD38 and poly(adenosine diphosphate-ribose) polymerases (PARP).
Cellular NAD+ concentrations change during aging, and modulation of NAD+ usage or production has been proposed to prolong both healthspan and lifespan in animal models.
The latest study from the ITP (Interventions Testing Program), which tests for the reproducibility of the lifespan effects from a range of compounds, showed that NAD+ supplementation had no effect in very old mice lifespan of either sex. However, there is evidence that NAD+ might have beneficial effects in health in rather old mice. For example, a potent and selective CD38 inhibitor, 78c, has been shown to restore low NAD+ levels in mouse models of aging, and thus protect against aging-induced health loss in aged male mice, resulting in an increase in lifespan (average by 17% and maximal by 14%).
A bit of history
Links between NAD+ levels and health were established almost a century ago. In 1923-1936, Otto Warburg isolated, from an enzyme required for fermentation of sugar by yeast, two substrates: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) and demonstrated theirs critical roles as indispensable cosubstrates in hydrogen transfer during fermentation. In 1937, Conrad Elvehjem discovered that the disease pellagra (popularly known as Asturian leprosy or “mal de la rosa”, due to dermatitis with the reddish color of the skin rashes in areas of sun exposure, and also characterized by diarrhoea, dementia and other manifestations of premature aging) resulted in low NAD+ and its phosphorylated counterpart NADP+ levels. He also found that this disease is caused by a dietary deficiency of the Pellagra preventing factors (PPF) which turned out to be niacin, also known as nicotinic acid or Vitamin B3. Proteins rich in the amino acid tryptophan may also protect against pelagra, although the activity of tryptophan was 50 times lower than that of niacin.
Later, low NAD+ levels were linked to multiple disease states, including metabolic and neurodegenerative diseases, and lower NAD+ levels are now known to correlate with ageing in rodents and humans. 
Importance in aging
NAD+ is an indispensable participant in the most important processes of energy metabolism, such as mitochondrial electron transport, glycolysis, and citric acid cycle. Moreover, NAD+ is a rate-limiting substrate for many signalling enzymes such as sirtuin proteins SIRT1 and SIRT3, the poly (ADP-ribose) polymerase (PARP) proteins PARP1 and PARP2, a COOH-terminal binding proteins (CtBP transcriptional regulators), cyclic ADP-ribose (ADPR) synthetases CD38 and CD157, and many other NAD+ dependent enzymes. These enzymes are involved in important cellular processes, such as DNA repair, stress response, genomic stability, chromatin remodelling, circadian rhythm regulation, cell cycle progression, insulin secretion and sensitivity, and expression of the inflammatory cytokines, thus translating changes in energy status into metabolic adaptations.
Given their critical role as mediators of cellular responses to metabolic perturbations, it is unsurprising that dysregulation of NAD and NADP metabolism has been associated with the pathobiology of many chronic human diseases and aging. 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.
NAD+ and NADP+
NAD+ and NADP+ are vital cofactors for most cellular oxidation/reduction reactions. Cellular NAD exists in two forms, oxidized (NAD+) and reduced (NADH). The NAD+/NADH couple primarily drives oxidation reactions, while the NADP+/NADPH couple drives reductive reactions.
The mitochondrial tricarboxylic acid cycle (TCA) is a major location for the reduction of NAD+ into NADH molecules. Mitochondrial NADH can be re-oxidized to NAD+ by Complex I of the mitochondrial electron transport chain. The subsequent two electrons gained by Complex I will then be an initial step to generate a proton gradient that provides the chemiosmotic force to drive the oxidative phosphorylation of ADP to ATP. These processes highlight the intimate link between NAD+ and cellular ATP synthesis.
By accepting and donating hydride ions (H−), NAD+, as an oxidoreductase cofactor, plays a central role in metabolism, supporting myriad biochemical reactions including of glycolysis, oxidative phosphorylation, and β-oxidation. At the same time, ATP generated via glycolytic reactions is critical for NAD+ regeneration from NADH by mitochondrial complex I of the electron transport chain (ETC). Through this process, mitochondria can communicate with the rest of the cell and thereby regulate physiological and pathophysiological outcomes. Senescent cells have been shown to be less efficient in producing ATP due to the decrease in the efficiency of oxidative phosphorylation (OXPHOS), characterized by less H+ in the intermembrane space, i.e. with a reduction of mitochondrial membrane potential. While decrease in mitochondrial membrane potential was associated with increased production of ROS (reactive oxygen species), suggesting that mitochondria in senescent cells are dysfunctional. Many types of senescent cells show increased mitochondrial mass per cell. But this does not compensate enough for the decrease in the functionality of aged mitochondria. However, treatment with KB1541 that enhances the efficiency of OXPHOS is accompanied by amelioration of senescent phenotypes, rendering targeting mitochondrial metabolic reprogramming as a potential treatment method for senescence.
The remarkably conserved enzymes throughout evolution from archaebacteria to eukaryotes named sirtuins have been defined as a family of nicotinamide adenine dinucleotide-dependent enzymes that deacetylate lysine residue on various proteins. Certain sirtuins have in addition an ADP-ribosyltransferase activity. Their exceptional conservation indicates that these proteins play vital physiological roles. Sirtuins are the major players in delaying biological aging. Sirtuins depend on NAD+ for their activity. Therefore, the availability of NAD+ is a boost for the action of sirtuins. However, how NAD deficiency may affect longevity through the sirtuins inhibition is not entirely clear. On the one hand brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females and phenotypes consistent with a delay in aging, Inhancing the function of SIRT6 also improves the healthspan in mice, while on the other hand, male, but not female, Sirt7 knockout mice exhibited an extension of mean and maximum lifespan, displayed better glucose tolerance with improved insulin sensitivity and a delay in the age-associated mortality rate compared with wild-type mice. Such opposite roles in aging of SIRT1/SIRT6 and SIRT7 may actually be associated with different dynamics of the amount of SIRT7 in different organs. Since, significant reductions in SIRT7 levels have been reported in most organs and tissues of human and animal models as a consequence of aging, including the heart, liver, lungs, colon, skin, subcutaneous white adipose tissue (WAT) depots, hair follicles, and blood, while, there are some tissues in which SIRT7 levels increase with aging, such as in the frontal lobe of the brain and retroperitoneal WAT depots.
CtBP family of NADH-dependent transcriptional regulators
CtBP (C-terminal binding protein) is an evolutionarily conserved NAD(H)-dependent transcriptional corepressor, whose activity has been shown to be regulated by the NAD/NADH ratio. Increasing cellular NADH/NAD+ ratio, like under hypoxia condition, promotes CtBP1 repression activity leading to transcriptional repression of the target genes. Loss of CtBP either by depletion or mutation triggered an extended life span in C. elegans.
Mammalian genomes encode two CtBPs, CtBP1 and CtBP2, which function as both corepressors and coactivators in different biological processes ranging from apoptosis to inflammation and osteogenesis. Their overexpression in tumors is associated with malignant behavior, such as uncontrolled cell proliferation, migration, and invasion, as well as with an increase in the epithelial-mesenchymal transition.
Since CtBP1 and CtBP2 do not bind directly to DNA, they regulate cellular processes through binding transcription factors and recruiting chromatin remodeling enzymes such as histone deacetylases, methyl transferases, and demethylases to targeted promoters by developing dimers with DNA-binding proteins.
Studies in model organisms have demonstrated that CtBP is indispensable for embryonic development and adult lifespan regulation. The homozygous mutation of mCtBP2 in mouse leads to developmental defects and embryonic death, while mCtBP1 homozygous deletion reduces their offsprings’ life span.
CtBP plays a prominent role in repression of E-cadherin, which suppresses tumorigenesis by restricting tumor cell motility and invasion. Protocatechuic aldehyde, a natural compound in the root of a traditional Chinese herb, Salvia miltiorrhiza, that inhibited the proliferation and migration of breast cancer cells, could be a potential CtBP1 inhibitor, due to its ability to directly attach to the CtBP1 and specifically attenuate the repression activity of CtBP1 on p21 and E-cadherin.
The protein NAMPT, encoded by the NAPMT gene, is present in intracellular form of NAMPT (iNAMPT) and as secreted by cells and referred to as extracellular NAMPT (eNAMPT also known as Visfatin and as PBEF (pre-B-cell colony-enhancing factor), and was initially described as an adipokine.
NAMPT/Visfatin/PBEF (nicotinamide phosphoribosyltransferase) catalyses the transfer of a phosphoribosyl group from PRPP (5-phosphoribosyl-1-pyrophosphate) to nicotinamide, forming NMN (nicotinamide mononucleotide) and PPi (pyrophosphate). NMN is then converted to NAD by Nmnat (nicotinamide mononucleotide adenylyltransferase).
NAMPT is the main bottleneck in NAD+ biosynthetic pathway making it a regulator of the intracellular NAD pool. Thus, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism.
Ways of boosting NAD+ in aging
Although NAD+/NADH in most people declines in aged tissues, specifically in the brain, skeletal muscles and plasma, no reduced NAD+/NADH levels were found in centenarians in the plasma when compared to young individuals. Many studies and clinical trials are currently being carried out increasing the levels of NAD+ in the organisms, both using precursors to increase its levels by intake (NR, NMN and Vitamin B3), or inhibiting NAD+ consumption by inhibiting NAD+ consuming enzymes (e.g. PARP and CD38) to limit its depletion.
Counteracting NAD+ deficiency with NAD+ precursors
Boosting intracellular NAD+ content has been suggested as a potential anti-aging strategy. Despite limited conclusive evidence, supplements of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), aimed at increasing NAD+ levels are becoming increasingly popular.
While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.
NAD regulation by microbiome
NAD precursors obtained from the diet are complemented by NA synthesized by a healthy gut microbiome. The gut microbiota uses host-derived nicotinamide to generate NAD and in return, produces nicotinic acid for host NAD biosynthesis. Furthermore, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome.
Poly(ADP-ribose) polymerases (PARPs), also known as ADP-ribosyltransferases (ARTs), are a family of proteins that catalyzes either mono-ADP-ribose (MAR) or poly ADP-ribose (PAR) to target proteins using NAD+ as a donor; this process is also termed MARylation or PARylation, respectively. PARP is an abundant ADP-ribosyltransferase that functions as a DNA nick-sensor and contributes to DNA repair, chromatin remodeling, and genomic stability. In particular, PARP1 and PARP2 play a role in the base excision repair (BER) pathway, while PARP3 senses double-strand breaks (DSBs) and is involved in double-strand break repair (DSBR).
In response to age-dependent accumulation of DNA damage, PARPs consume more NAD+ resulting in reduced cellular/tissue NAD+. In particular, PARP1 uses NAD+ to generate large amounts of poly(ADP-ribose), which promotes the recruitment of DNA repair factors. However, excessive activation of PARP1 causes depletion of intracellular NAD+ and ATP levels, eventually leading to cell death. PARP1 activation allows the recruitment of DNA repair proteins to repair damaged DNA. Although PARP1 activation is crucial for genomic maintenance, hyperactivation of PARP1 can cause a reduction in NAD+ levels.
CD38 and CD157
CD38 is an enzyme critical for the regulation of NAD+ levels. Senescent cells promote tissue NAD+ decline during ageing mainly via the activation of CD38+ macrophages.
CD38 and its sister molecule CD157 belong to a family with ADP-ribosyl cyclase activity involved in the regulation of calcium mobilization processes from ryanodine receptors to intracellular Ca2+ pools by cyclic ADP-ribose (cADPR). They are involved in the formation of cADPR from NAD+. The ADP-ribosyl cyclase activity of CD157 is weaker than that of CD38. The function of CD157 is mediated solely by the second messenger cyclic ADP-ribose and not nicotinic acid adenine dinucleotide phosphate (NAADP). While CD38 is known to have a robust ability to catalyze cADPR as well as NAADP formation, that plays an important role in insulin secretion.
Many studies have reported that a flavonoid compound cyanidin-3-O-glucoside (C3G), a natural inhibitor of CD38, that prevent CD38 from consuming NAD+ exerts anti-tumor, anti-inflammatory and antioxidant effects.
- ↑ 1.0 1.1 Poljšak, B., Kovač, V., Špalj, S., & Milisav, I. (2023). The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation. International Journal of Molecular Sciences, 24(3), 2959. https://doi.org/10.3390/ijms24032959
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