What is NAD+ effect on disease and aging

Dr. David Sinclair, Co-Director of the  Biological Mechanisms of Aging at Harvard Medical School was named to  the Times Magazine list of “Most Influential People in the World” after his research found a key cause of aging  and a potential weapon to reverse it.

He and his team found that as we age, our cells become less and less efficient due to the lack of an essential metabolite called Nicotinamide Adenine Dinucleotide (NAD+).


NAD+ is a key co-enzyme that the mitochondria in every cell of our bodies depend on to fuel all basic functions. (3,4)

NAD+ play a key role in communicating between our cells nucleus and the Mitochondria that power all activity in our cells (5,6,7,8)

Low NAD+ levels impair mitochondria function and are implicated in  health problems such as cancer, diabetes, heart disease, immune problems, and  perhaps even aging itself (5,6,7,9,10,11,13,14,15,16).





NAD+ levels decreaseAs we age, our bodies produce less NAD+ and the communication between the Mitochondria and cell nucleus is impaired. (5,8,10).

Over time,  decreasing NAD+ impairs the cell’s ability to make energy, which leads to aging and disease (8, 5) and perhaps even the key factor in why we age (5).



“NAD+ levels drop by as much as 50% as we get older”




There is reason to think that increased  NAD+ can at least slow the aging process.

When taken orally, NAD+  does not survive the digestive system long enough to enter your cells (14)

The ground-breaking paper published by Dr Sinclair found that supplementation with Nicotinamide MonoNucleotide (NMN), the immediate precursor to NAD+,  could boosts NAD+ levels in mice and resulted in the “equivalent of a human 60 year old becoming more like a 20 year old”(8).

More importantly, their research revealed that mitochondrial dysfunction is reversible with supplementation to boost NAD+

The 2013 study by Dr Sinclair at Harvard is explained in this video below:


There are a number of lifestyle changes you can make  to increase NAD+ in you body.

It’s well known that Calorie Restriction  (CR) can extend longevity by 30–50% in many mammals (32)

CR has also been shown to increase NAD+ levels in the body , thru these pathways:

  • Lowering blood glucose levels minimizes inflammation, which consumes NAD+.
  • The ketone body BHB signals to increase AMPK to produce more NAD+
  • Burning Ketones for fuel instead of glucose requires 1/2 as much NAD+

– Ketone bodies mimic the life span extending properties of caloric restriction (veech,2017)


Ketosis is a metabolic state in which fat provides most of the fuel for the body. It occurs when there is limited access to glucose (blood sugar), which is the preferred fuel source for many cells in the body.

Ketosis can occur in many different diet plans whenever carb intake is low, but is most often associated the Ketogenic Diet, as that is a much easier method for restricting carbs (3, 4, 5, 6).

Recent research now shows  Ketosis  provides the benefit in life extension, lowering inflammation and boosting NAD+ (3,9).

Intermittent or Periodic Ketosis is also effective at extending lifespan and likely achieves much of the benefit (36,37).

Some research even shows more benefit from a cyclical rather than a full time Ketogenic Diet (71).

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice (Newman, 2017)

The Red bars in the chart at left show the increased levels of the Ketone Body BHB produced from a cyclical Keto diet, resulting in Increased NAD+ and greatly improved neurological function and health.

Read more about nutrition for boosting NAD+


Researchers are finding that 2-3  short bouts of High Intensity Interval Training  (HIIT) per week is far more effective at lowering inflammation (and increasing NAD+), especially among older adults (55)

Exercise is very effective at boosting AMPK and NAD+, especially when performed at times of low blood glucose levels  ( more about HIIT ).

Short bouts of HIIT accomplishes the goal, while avoiding overtraining from endurance workouts  which increases inflammation and consumes NAD+ (55).

Read more about exercise for boosting NAD+


In mammals, NAD+ can be created from simple elements present in the body such as Nicotinic Acid or Tryptophan thru the “de novo” pathway.

However the entire NAD+ pool is consumed 2-4 times a day and recycled thru the “salvage pathway”, which is far more important for maintaining NAD+ levels (14).

In the salvage pathway, Nicotinamide or Nicotinamide Riboside are first converted to NMN, which is then further converted to NAD+(14).

NMN is more correctly referred to as a NAD+ intermediate because NMN is the last step before conversion to NAD+

NAD+ Precursors:

  • Tryptophan
  • NA – Nicotinic Acid
  • NAM – Nicotinamide
  • NR – Nicotinamide Riboside
  • NMN – Nicotinamide Mononucleotide

The first 3 NAD+ precursors are well known and have been used for decades to treat various metabolic diseases such as dislipidemia and neurological conditions (10,11,14)

NR was discovered by Dr Charles Brenner. Like NMN, NR is being tested in mice and humans for a wide range of disease and illness.

According to Dr Brenner:
“Not every cell is capable of converting each NAD+ precursor to NAD+ at all times…the precursors are differentially utilized in the gut, brain, blood, and organs” (R).



In this 2016 study, mice were given a single dose of  NMN in water.

NMN  levels in blood showed it is quickly absorbed from the gut into blood circulation within 2–3 min and then cleared from blood circulation into tissues within 15 min



The chart at right shows levels of a double labeled NAD+ (C13-d-nad+) in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows that NMN makes its way through the liver, into muscle, and is metabolized to NAD+ in 30 minutes (23) .

According to Dr Sinclair, the speed at which the NMN is utilized implies that there may be a transporter that directly uptakes NMN into cells and tissues(8).

Orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (23).


In this 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

Read more about NMN here

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Decline of NAD+ during Aging, Age-Related Diseases, and Cancer

Several evidences suggest a decline in NAD+ levels while we age, connecting NAD+ deficits to age-related diseases and cancer.

Inflammation increases during the aging process possibly due to the presence of senescent cells [1].

CD38 and bone marrow stromal cell antigen-1 (BST- 1) may provide explanations to NAD+ decline during aging.

CD38 is a membrane-bound hydrolase implicated in immune responses and metabolism. NAD+ can be degraded through its hydrolysis, deacetylation, or by NAD+ nucleosidases (also called NAD+ hydrolases or NADases) such as CD38.

Expression and activity of CD38 increase in older mice, promoting NMN degradation in vivo, responsible for NAD+ decline and mitochondrial dysfunctions [2].

Interestingly, loss of CD38 inhibits glioma progression and extends the survival of glioma- bearing mice.

Targeting CD38 in the tumor microenvironment may clearly serve as a novel therapeutic approach to treat glioma [3].


Daratumumab, a CD38 monoclonal antibody, rep- resents a first-in-class drug for the treatment of multiple myeloma. It promotes T cell expansion through inhibition of CD38+ immunosuppressive cells, improving patients’ responses [4].

These findings suggest that NAD+ boosters should be combined with CD38 inhibitors for a more efficient antiaging therapy.


NAD+ Biosynthesis Decreases during Aging, Age-Related Diseases, and Cancer 

NAD+ increases can also occur independently of the Preiss–Handler route. NAM and NR are important NAD+ precursors first converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT) and NR kinase (NRK), respectively. NMN is then transformed into NAD+ by NMN adenylyltransferase [36].

As we age, our bodies undergo changes in metabolism, and a key part of these processes may affect de novo NAD+ synthesis, also called the L-tryptophan/kynurenine pathway (see Figure IB in Box 1). In mammals, the use of the de novo NAD+ biosynthetic pathway is limited to a few specific organs.

Finally, dysregulation of the kynurenine pathway is also linked to genetic disorders and age-related diseases such as obesity and cancer [14,15]. These age-associated changes in de novo NAD+ biosynthesis may have the potential to impact several biological processes, and thus contribute to age-related diseases and cancer in the elderly.

Animal models mimicking downregulation of NAD+ biosyn-thesis are needed to modulate its activity and understand its pathophysiological relevance in age-related pathologies and cancer.

Boosting NAD+ with Niacin in Age-Related Diseases and Cancer 

In humans, a lack of nicotinic acid (NA, also called niacin) in the diet causes the vitamin B3 deficiency disease pellagra, characterized by changes in the skin with very characteristic  pigmented sunburn-like rashes developing in areas that are exposed to sunlight. Likewise, people with chronic L-tryptophan-poor diets or malnutrition develop pellagra.

Furthermore, several epidemiologic studies in human reported an association between incidence of certain types of cancers and niacin deficiency [27].

In this regard, low dietary niacin has also been associated with an increased frequency of oral, gastric, and colon cancers, as well as esophageal dysplasia.

In some populations, it was shown that daily supplementation of niacin decreased esophageal cancer incidence and mortality. Although the molecular mechanisms of niacin deprivation and cancer incidence are not well understood, it has been recently reported that NAD+ depletion leads to DNA damage and increased tumorigenesis, and boosting NAD+ levels is shown to play a role in the prevention of liver and pancreatic cancers in mice [19,28,29].

Thus, malnutrition through inadequate amounts and/or diversity of food may affect the intra- cellular pools of nicotinamide and NAD+ thereby influencing cellular responses to genotoxic damage, which can lead to mutagenesis and cancer formation [19,27]. NAD+ boosters are therefore essential in patients at risk of exposure to genotoxic and mutagenic agents, including ionizing or UV radiations or, DNA damaging chemicals.

In addition, niacin deficiency in combination with carcinogenic agents was described to induce and increase tumorigenesis in rats and mice.

For instance, in rats, the lack of niacin together with carcinogen treatment increased tumorigenesis and death of rats [30,31]. Additionally, in mice, the incidence of skin tumours induced by UV was significantly reduced by local application of NAM or by niacin supplementation in the diet [32].

Boosting NAD+ with NAM in Age-Related Diseases and Cancer 

Recent research has focused on uncovering the consequences of a decrease in NAD+ during aging using age-related disease models. In PGC1a knockout mouse, a model of kidney failure, NAD+ levels are reportedly decreased, and boosting NAD+ by NAM improves kidney function [33].

NAM injections during four days re-establish local NAD+ levels via nicotinamide phos- phoribosyltransferase (NAmPRTase or NAMPT) activation and improve renal function in postischaemic PGC1a knockout mice [33].

Surgical resection of small renal tumors can induce kidney ischemia severely affecting the renal function. Therefore, NAD+ boosters can be beneficial to protect the organ from severe injury.

Moreover, in a model of muscular dystrophy in zebrafish, NAD+ increases, which functions as an agonist of muscle fiber–extracellular matrix adhesion, and corrects dystrophic phenotype recovering muscle architecture [34].

Boosting NAD+ with NR in Age-Related Diseases and Cancer 

Further research has extensively used NR to ameliorate the effects of NAD+ deficits in pleiotropic disorders. NR naturally occurs in milk [35,36]. NR is converted to NAD+ in two step reactions by nicotinamide riboside kinases (NRKs)-dependent phosphorylation and adenylylation by nicotinamide mononucleotide adenylyl transferases (NMNATs) [36].

It is considered to be a relevant NAD+ precursor in vivo. Evidences demonstrate the beneficial effect of NR in skeletal muscle aging [37,38] and mitochondrial-associated disorders, such as myopathies [39,40] or those characterized by impaired cytochrome c oxidase biogenesis affecting the respiratory chain [41].

In line of these findings, a mouse model of Duchenne muscular dystrophy present significant reductions in muscle NAD+ levels accompanied with increased poly-ADP-ribose polymerases (PARP) activity, and reduced expression of NAMPT [42].

Replenishing NAD+ stores with dietary NR supplementation improved muscle function in these mice through better mitochondrial function [42].

Additionally, enhanced NAD+ concen- trations by NR are apparently beneficial for some neurodegenerative diseases [43], as well as in noise-induced hearing loss [44].

NR-mediated NAD+ repletion is also protective, and even therapeutic, in certain metabolic disorders associated with cancer, such as fatty liver disease [28,45] and type 2 diabetes [28,46]. Metabolic disorders characterized by defective mitochon- drial function could also benefit from an increase in NAD+ levels.

Indeed, stimulation of the  oxidative metabolism in liver, muscle, and brown adipose tissue potentially protects against obesity [47]. Interestingly, NAMPT protein levels are not affected in chow- and high fat diet (HFD)-treated mice fed with NR, arguing that in models of obesity, NR directly increases NAD+ levels without affecting other salvage reactions [47].

Recently, diabetic mice with insulin resistance and sensory neuropathy treated with NR reportedly show a better glucose toler- ance, reduced weight gain and liver damage, and protection against hepatic steatosis and sensory and diabetic neuropathy [48].


Boosting NAD+ with NMN in Age-Related Diseases and Cancer 

NMN is also a key biosynthetic intermediate enhancing NAD+ synthesis and ameliorates various pathologies in mouse disease models [49,50].

Very recent research demonstrate that a 12- month-long NMN administration to regular chow-fed wild-type C57BL/6 mice during normal aging rapidly increases NAD+ levels in numerous tissues and blunts age-associated physio- logical decline in treated mice without any toxic effects [49]. NMN is also beneficial in treating age- and diet-induced diabetes, and vascular dysfunction associated with aging in mice [51,52].

Administration of NMN also protects the heart of mice from ischemia-reperfusion injury [53] and restores mitochondrial function in muscles of aged mice [37,54].

It has been speculated that NMN is a circulating NAD+ precursor, due to the extracellular activity of NAMPT [55]. However, the mechanisms by which extracellular NMN is converted to cellular NAD+ still remain elusive.

On the one hand, it is reported that NMN is directly trans- ported into hepatocytes [51]. On the other hand, NMN can be dephosphorylated to NR to support elevated NAD+ synthesis [56–59].

It is recently shown that NAM can be metabolized extracellularly into NMN by extracellular NAMPT. NMN is then converted into NR by CD73 [60]. Hence, NR is taken up by the cells and intracellularly phosphorylated firstly into NMN by NRKs and then, converted into NAD+ by NMNATs [60] (Figure 3).

Thus, mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis. Consistent with these findings, in murine skeletal muscle specifically depleted for NAMPT, administration of NR rapidly restored muscle mass by entering the muscles and replenishing the pools of NAD+ through its conversion to NMN [38].

Interestingly, mice injected with NMN had increased NAM in their plasma that may come after initial conversion of NMN into NR [60]. However, degradation of NR into NAM could only be observed when cells were cultured in media supplementing with 10% FBS [60].

Finally, it is important to note that NR is stably associated with protein fractions in milk with a lifetime of weeks [35].

Notably, as reported above, NMN may be degraded by CD38 in older mice promoting NAD+ decline and mitochondrial dysfunctions [2], suggesting that NR may be more efficient than NMN in elderly.

Yet, the beneficial synergistic activation of sirtuins and metabolic pathways to replenish NAD+ pools cannot be excluded. However, given its efficient assimilation and high tolerance, NR represents still the most convenient and efficient NAD+ booster.

Overall, these findings suggest that NAD+ decrease in disease models and NAD+ precursors (NAM, NR or NMN) may circumvent NAD+ decline to generate adequate levels of NAD+ during aging and thus be used as preventive and therapeutic antiaging supplements.

NMN and NR  supplementations may be equivalent strategies to enhance NAD+ biosynthesis with their own limitations.

Side-Effects of Some NAD+ Boosters 

Clearly, several intermediates of the salvage pathway can be considered to boost NAD+ levels but some have contraindications. High doses of NA given to rats are needed to robustly increase NAD+ levels [61].

Additionally, relevant and unpleasant side effects through NA-induced prostaglandin- mediated cutaneous vasodilation (flushing) affecting patient compliance are due to the activation of the G-protein-coupled receptor GPR109A (HM74A) and represent a limitation in the pharma- cological use of NA [62].

NAM is much less efficient than NA as a lipid lowering agent and has also several side effects; in particular, it causes hepatic toxicity through NAM-mediated inhibition of sirtuins [63].

The metabolism of these conventional compounds to NAD+ is also different, as NA is converted via the three-step Preiss–Handler pathway, whereas NAM is metabolized into NMN via NAMPT and then to NAD+ by NMNATs [64]

Manipulating NAD+ by Manipulating Enzyme Activity of Salvage Reactions 

Enhancing the activity of enzymes that participate in salvage reactions can also be a strategic intervention to increase NAD+ concentrations. Different studies have addressed the importance of regulating the activity of NAMPT during disease, including metabolic disorders and cancer.

NAMPT is necessary in boosting NAD+ pools via the salvage pathway.

Consequently, NAMPT deletion provokes obesity-related insulin resistance, a phenotype rescued by boosting NAD+ levels in the white adipose tissue by giving NMN in drinking water [67].

Conversely, in a mouse model for atherosclerosis, NAMPT depletion promotes macro- phage reversal cholesterol transport, a key process for peripheral cholesterol efflux during atherosclerosis reversion [68].

Other recent reports suggest that NAMPT downregulation could be beneficial in treating pancreatic ductal adenocarcinoma [69,70] and colorectal cancer [71].

Recent findings show that Duchenne muscular dystrophy was accompanied by reduced levels of NAMPT in mice [42]. Moreover, NAMPT knockout mice exhibit a dramatic decline in intramuscular NAD+ content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance.

NR treatment induced a modest increase in intra- muscular NAD+ pools but sufficient to rapidly restore muscle mass. Importantly, overexpres- sion of NAMPT preserves muscle NAD+ levels and exercise capacity in aged mice [38].

Inhibitors against NAMPT are being used in several phase II clinical trials as anticancer therapy.

Given that NAMPT activation is important to boost NAD+ levels, therapy involving NAMPT inhibition should be considered with caution. Although levels of NAD+ remain to be determined in models with NAMPT depletion, further investigation on the effects of NAMPT modulation is clearly required.

The specific mechanisms and actual benefits of regulation of NAMPT activity remain elusive, evidencing the need of more specific disease models.


Can Dietary Restriction and Protein Catabolism Maintain NAD+ Levels?
Among the questions that still remain not well understood is why DR profoundly increases lifespan? Can DR affect NAD+ levels?

It is well established that overfeeding and obesity are important risk factors for cancer in humans [129] and obesity-induced liver and colorectal cancer, among others, can shorten lifespan.

Earlier research has also shown that both increased physical activity and reduction in caloric intake (without suffering malnourishment) can extend lifespan in yeasts, flies, worms, fish, rodents, and primates [3–8].

Furthermore, a recent study pointed to the importance of the ratio of macronutrients more than the caloric intake as the determinant factor in nutrition-mediated health status and lifespan extension [9].

Although in humans it is difficult to measure the beneficial effects of DR and currently there is no reliable data that describe the consequences of significantly limiting food intake, some studies have assessed how DR affects health status.

People practicing DR seem to be healthier, at least based on risk parameters such as LDL cholesterol, triglycerides, and blood pressure [130].

Activation of the salvage pathways during DR could be turned on and glucose restriction can stimulate SIRT1 through activation of the AMPK-NAMPT pathway resulting in inhibition of skeletal myoblast differentiation [131].

Interestingly, effects of NMN supplementation and exercise on glucose tolerance in HFD-treated mice are very similar [132].

Even though these effects are tissue-specific since exercise predominantly affects muscle, whereas NMN shows major effects in liver, and that mechanism of action can be different, exercise and NMN predominantly affect mitochondrial functions and may both contribute to the boost of NAD+.

It is thus tempting to speculate that L-tryptophan concentrations and thus the de novo NAD+ biosynthesis could fluctuate during DR ameliorating the aging process.

Recent studies in humans and mice suggest that moderate exercise can increase blood NAD+ levels and decrease L-tryptophan levels [137].

A possible explanation for this phenomenon is that DR,  and/or exercise, can induce autophagy and promote the release of several metabolites and essential amino acids [138].




Aging is proposed to be responsible for diverse pathologies, however, it should be considered as a disease among other diseases that appear in time while individuals age.

Although some questions still remain unclear, NAD+ precursors may present possible therapeutic solutions for the maintenance of NAD+ levels during aging and thus may provide prophylaxis to live longer and better.

Although more research is needed to understand the efficacy as well as potential adverse side effects of NAD+ Replacement Therapies in humans, recent studies already provided some pharmacological properties, showing low toxicity and high effectiveness.



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Experiments with mice have mostly focused on treating specific disease conditions, but  in the process, some have noted increase in lifespan even though the NAD boosting therapies were commenced quite late in life (22).

Sirtuins are well-known longevity regulators, and their decreased function with age might at least be partially explained by a systemic decline in NAD+ levels upon aging  (40). Rising NAD+ content, followed by sirtuin activation, has been reported to increase lifespan in yeast, worms, and mice (22).

Administration of NR, NMN, or NAM recovered NAD+ content and protected against aging-related complications, such as mitochondrial dysfunction (24, 41, 23), decline in physical performance (23,29) and muscle regeneration (22), arterial dysfunction (42), decline in vision (43, 23), including glaucoma (44), and age-associated insulin resistance (23).

The most striking benefits of NAD+ supplementation on aging were observed in several rare diseases linked to abnormal DNA repair that are typified by accelerated aging, such as the Cockayne syndrome group B (CSB), xeroderma pigmentosum group A (XPA), or ataxia-telangiectasia (A-T).

In a mouse model of CSB, neurons show mitochondrial defects, which have an impact on the cerebellum and inner ear. Administration of PARP inhibitors or the NAD+ precursor, NR, to csb / animals attenuated many of the phenotypes of CSB and restored altered mitochondrial function in their neurons.

Another DNA damage repair disorder is XPA, which is also characterized by mitochondrial alterations and reduced NAD+-SIRT1 signaling due to the overactivation of PARP1 (45).

Treatment with NAD+ precursors, NR and NMN rescued the XPA phenotype in cells and worms.  Restoring the NAD+/SIRT1 pathway, by NR and NMN administration to C. elegans and mice, improved A-T neuropathology (45).

Metabolic disorders

The importance of NAD+ as a metabolic regulator has been demonstrated by its efficacy to attenuate many features of the metabolic syndrome, a cluster of pathologies including insulin resistance, fatty liver, dyslipidemia, and hypertension, with increased risk of developing type 2 diabetes and heart failure.

Different approaches aiming to raise NAD+ levels were shown to provide protection against obesity, such as (i) inhibition of NAD+ consumers, PARPs (29) and CD38 (Barbosa et al, 2007), (ii) administration of NAD+ precursors, such as NR (49, 45T,51) or NMN (Yoshino et al, 2011), (iii).

NAD+ boosting was also efficient to improve glucose homeostasis in obese, prediabetic, and T2DM animals (29,46,51). Likewise, reestablishing NAD+ levels with NR or PARP inhibitors also protected from non-alcoholic steatohepatitis (NASH) (46) as well as alcoholic steatohepatitis (46).

Muscle function

Increase in muscle NAD+ content, resulting from NR administration or PARP inhibition, improved muscle function and exercise capacity in mice (49), including in aged animals (22).

Interestingly, muscular dystrophy is characterized by a dramatic drop in NAD+ in the muscle (Ryu et al, 2016). NR administration to the mdx mouse, a model for muscular dystrophy, improved muscle function by enhancing bioenergetics, attenuating inflammation and fibrosis (Ryu et al, 2016), as well as, by favoring regeneration and preventing the exhaustion and senescence of muscle stem cells, typical to the mdx mice (22).

The beneficial effects of improving muscle bioenergetics are also illustrated in models of mitochondrial myopathies. Increasing muscle NAD+ levels by the administration of NR or a PARP inhibitor preserved muscle function in two different models of mitochondrial myopathy (Cerutti et al, 2014; Khan et al, 2014).

Similar benefits on mitochondrial myopathy were seen with the AMPK agonist, AICAR (Viscomi et al, 2011), which may at least in part be due to the recovery of NAD+ content upon AMPK activation.,

Cardiac function

Exposing the heart to different types of stresses was reported to result in a decline in cardiac NAD+ content (Pillai et al, 2005, 2010; Karamanlidis et al, 2013; Yamamoto et al, 2014). For instance, cardiomyocyte hypertrophy is characterized by a drop in cellular NAD+ levels. Supplementation with NAD+ was hence protective against cardiac hypertrophy in mice, and these anti-hypertrophic effects were in part attributed to the activation of SIRT3 (Pillai et al, 2010).

Cardiac ischemia is another condition causing a steep decrease in NAD+ levels. NMN administration protected the mice from ischemic injury via the recovery of cardiac NAD+ content and subsequent SIRT1 activation (Yamamoto et al, 2014).

Similarly, cardiac-specific overexpression of NAMPRT in mice increased NAD+ content and reduced the extent of myocardial infarction and apoptosis in response to prolonged ischemia and ischemia/reperfusion (Hsu et al, 2009).

Maintaining NAD+ levels in pressure-overloaded hearts is crucial for myocardial adaptation and protection from heart failure, as demonstrated by NMN administration to mice treated with the NAMPRT inhibitor FK866 (Yano et al, 2015) and to cardiac-specific mitochondrial complex I-deficient mice (Lee et al, 2016).

In a mouse model of heart failure caused by iron deficit, reconstituting NAD+ content also improved mitochondrial quality, protected cardiac function, and increased lifespan (Xu et al, 2015). Similarly, NR administration improved cardiac function in aged mdx mice, which, like muscular dystrophy patients, display cardiomyopathy (Ryu et al, 2016).

Renal function

Multiple studies demonstrated the loss of SIRT1 and SIRT3 activity as a key feature of kidney dysfunction, including kidney abnormalities linked with aging (Koyama et al, 2011,53, Morigi et al, 2015; Ugur et al, 2015; Guan et al, 2017).

Acute kidney injury (AKI) is characterized by a reduction in NAD+ content and NAMPRT expression (Morigi et al, 2015; Ugur et al, 2015). Promoting NAD+ synthesis via NAM or NMN supplementation was reported to mitigate AKI in ischemia/reperfusionand cisplatininduced mouse models of AKI (Tran et al, 2016; Guan et al, 2017).

Furthermore, administration of the AMPK agonist, AICAR, which positively impacts on NAD+ levels (48), was protective against cisplatin-induced AKI in SIRT3-dependent manner (Morigi et al, 2015). Although no NAD+ quantification was performed in this particular study, the involvement of SIRT3, as well as the increase in Namprt expression detected upon AICAR administration, points toward a potential increase in NAD+ levels (Morigi et al, 2015).

Kidney mesangial cell hypertrophy is also characterized by a depletion of NAD+ content (53) and restoring intracellular NAD+ levels via supplementation with exogenous NAD+ prevented its onset by activating SIRT1 and SIRT3 (53z).


NAD+ boosting has also been shown to be neuroprotective. Raising NAD+ levels protects against neuronal death induced by ischemic brain (Klaidman et al, 2003; Sadanaga-Akiyoshi et al, 2003; Kabra et al, 2004; Feng et al, 2006; Kaundal et al, 2006; Zheng et al, 2012) or spinal cord injuries (Xie et al, 2017).

Axonal degeneration is considered as an early pathological mechanism in this type of neurodegeneration. An accumulating amount of data indicates that axonal degeneration is not only limited to ischemic brain and spinal cord injuries, but constitutes a hallmark process, preceding neuronal death, in a much larger spectrum of disease states, including traumatic brain injury, inflammatory disorders, like multiple sclerosis, and degenerative disorders, such as Alzheimer’s and Parkinson’s diseases (Lingor et al, 2012; Johnson et al, 2013).

Degenerating axons show a decrease in NAD+ content (Wang et al, 2005; Gerdts et al, 2015), while replenishing NAD+ by supplementing NAM (Wang et al, 2005), NR and NMN (Sasaki et al, 2006), and high doses of NAD+ (Araki et al, 2004), or overexpressing enzymes involved in NAD+ biosynthesis (Araki et al, 2004; Sasaki et al, 2006) delayed axonal degeneration.

In line with this, supplementation with NAM, NMN, or NR was neuroprotective in rodent models of Alzheimer disease (Qin et al, 2006; Gong et al, 2013; Liu et al, 2013; Turunc Bayrakdar et al, 2014; Wang et al, 2016a), and supplementation with NAM or LOF of PARP were protective in Drosophila models of Parkinson’s disease (Lehmann et al, 2017).

NAD+ depletion is also involved in the neurodegeneration induced by highly toxic misfolded prion protein (Zhou et al, 2015). Replenishment of intracellular NAD+ stocks, either by providing NAD+ or NAM, rescued the neurotoxic effects of protein aggregates (Zhou et al, 2015). Importantly, restoring NAD+ content is not exclusively protecting neurons, since it has also been reported to prevent the death of astrocytes (Alano et al, 2004).

P7C3, a compound that enhances neurogenesis (Pieper et al, 2010) and that was neuroprotective in mouse models of Parkinson’s disease (De Jesus-Cortes et al, 2012), amyotrophic lateral sclerosis (Tesla et al, 2012) and brain injury (Yin et al, 2014), was subsequently identified as an NAMPRT activator (Wang et al, 2014a). Therefore, the beneficial effects of P7C3 on neuron preservation seem at least in part to be due to a NAMPRT-mediated increase in NAD+ levels (Wang et al, 2014a).

Nicotinamide riboside supplementation recovered depressed sensory and motor neuron conduction velocities and thermal insensitivity in T2DM mice (51) and alleviated chemotherapy-induced peripheral neuropathy in rats (Hamity et al, 2017), indicating that NAD+ also is beneficial in the peripheral neuronal system.

NAD+ boosting was also able to protect mice from loss of vision and hearing (Shindler et al, 2007; Brown et al, 2014). Intravitreal injections of NR in mice attenuated optic neuritis in a dose-dependent manner (Shindler et al, 2007).

Even if no NAD+ quantification was performed in this study, SIRT1 activity was necessary for the neuroprotective effects of NR, since the protection was blunted in the presence of sirtinol, a SIRT1 inhibitor (Shindler et al, 2007). Furthermore, systemic administration of NAM and overexpression of Nmnat1 had spectacular effects on vision in DBA/2J mice, which are prone to glaucoma (44).

Noise exposure results in degeneration of the neurons innervating the cochlear hair cells. Increase in NAD+ levels induced by NR administration prevented against noise-induced hearing loss and neurite degeneration (Brown et al, 2014).

In line with this, CR was shown to protect against cochlear cell death and aging-associated hearing loss in a Sirt3-dependent manner (Someya et al, 2010). It is therefore tempting to speculate that this improvement could also be associated with increased NAD+ levels uponCR, though no direct measurements of NAD+ levels were performed in this study.


Manipulations of NAD+ concentrations have demonstrated multiple beneficial effects in a large spectrum of diseases in animal models . Translating these effects into clinical benefits now becomes one of the main challenges.

The fact that the long-term administration of the NAD+ precursor molecules showed no deleterious effects in animals should be considered promising.

As such, administration of NMN for 12 months demon- strated no toxicity in mice (23).

Similarly, administrtion of NR to mice for a duration of 5–6 months (Gong et al, 2013), 10 months (22), and 12 months (Tummala et al, 2014) showed no obvious adverse effects.

Another NAD+ precursor, NAM, has also been already tested in humans and protected b-cell function in type 1 diabetes patients.

Furthermore, a slow release form of NA (acipimox) was effective in inducing mitochondrial activity in skeletal muscle of type 2 diabetic patients (van de Weijer et al, 2015).

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