Dr. David Sinclair, Co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School is considered one of TIMES Magazine “Most Influential People in the World”.
Dr. Sinclair discovered a link to aging and degenerative disease and the secret weapon to reversing it.
He and his team took a closer look into our cells and determined that as we age, our cells become less and less efficient due to the lack of a very important and essential metabolite called NAD+.
Low levels of NAD+ cause you to feel less energized, less focused, excess mental fog and mental loss, excess weight gain especially in your mid section and other issues and illnesses related to aging.
This is commonly known as mitochondrial dysfunction.
WHAT IS NAD+
NAD+ stands for nicotinamide adenine dinucleotide. It is an enzyme found in every cell of every living organism.
NAD+ acts a a kind of signaling mechanism that is required for our mitochondria to burn glucose to power the basic functions of all our cells.
Low NAD+ levels impair mitochondria function and are implicated in perhaps all age related health problems such as cancer, diabetes, heart disease, immune problems, and disease.
What is Nicotinamide Riboside?
Nicotinamide Riboside is a pyridine-nucleoside form of vitamin B3 that functions as a precusor to nicotinamide adenine dinucleotide or NAD+. Nicotinamide Riboside is naturally found in food, such as milk but the body does not get enough of it, especially as we age and NAD+ levels naturally decline.
A 2015 study showed a single 100mg dose of Nicotinamide Riboside was effective in raising NAD+ levels by 30%; 300mg and 1000mg dosages showed a 50% increase in NAD+ levels.
The benefits of restoring NAD+ levels are:
- Optimized Mitochondrial Function
- Improve Metabolism
- Cardiovascular Health
- Mental Clarity and Focus
- Heightened Energy Level
Low NAD+ Results in faster Aging
In mitochondria of young people, NADH can readily donate its electrons to generate NAD+. During the aging process, increased DNA damage reduces NAD+, leading to reduced SIRT1 activity and reduced mitochondrial function (R).
The more NAD+ levels increase, the more SIRT1 is active (on the other hand, Nicotinamide blocks SIRT1 activity) (R).
Low NAD+ reduces Sirt1 activity, which ages the body.
Can increased NAD+ Prevent Aging?
There is reason to think that NAD+ can at least slow the aging process. Now, to be clear, the research is in the early phases but the results are promising so far.
A recent study was done at Harvard in which mice were bred with a defect in SIRT1. As you might expect, these mice aged rapidly and showed significant problems with their mitochondria.
When these mice were 22 months old, they were given increased levels of NAD+, and the results were marked:
- Less insulin resistance
- Less inflammation
- Less muscle wasting
Suddenly, it appeared that these mice were approximately 6 months old.
Here’s a brief video explaining the research:
This suggests that increasing overall NAD+ levels in humans can potentially slow the aging process and give us more time.
In other words, things are looking good for NAD+, but we don’t have all the results in yet. Yes, things definitely improved with the mice, but we need to see more data when this is tested on humans.
No, NAD+ isn’t some sort of fountain of youth that will turn you into an immortal being. But if you can increase the levels of NAD+ in your body, you may be able to stay healthy longer, which could be a huge benefit.
How Can You Increase NAD+ In Your Body?
There are a number of ways that you may be able to increase NAD+ in you body.
Putting yourself on a restricted calorie diet has been shown to increase NAD+ levels in the body. The reason is a bit complex, but has to do with the ratio of NAD+ to other compounds in your body.
When you restrict your calories, it allows your body to properly balance this ratio by increasing NAD+ production.
Exercise puts your body in a similar state to calories reduction. It causes a favorable ratio of NAD+ to other compounds in the body.
You could consider taking a supplement such as nicotinamide riboside, which supports healthy NAD+ levels in the body. In fact, all the way back in 1953, the Connecticut State Medical Journal reported that Niacin can help slow and reverse some of the aging process.
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 . 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 .
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 . 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 . 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 .
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 .
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 .
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 . 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 .
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 .
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) . 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 .
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 . Replenishing NAD+ stores with dietary NR supplementation improved muscle function in these mice through better mitochondrial function .
Additionally, enhanced NAD+ concen- trations by NR are apparently beneficial for some neurodegenerative diseases , as well as in noise-induced hearing loss . 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 . 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 . 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 .
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 . 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  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 . 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 . 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 . Hence, NR is taken up by the cells and intracellularly phosphorylated firstly into NMN by NRKs and then, converted into NAD+ by NMNATs  (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 .
Interestingly, mice injected with NMN had increased NAM in their plasma that may come after initial conversion of NMN into NR . However, degradation of NR into NAM could only be observed when cells were cultured in media supplementing with 10% FBS . Finally, it is important to note that NR is stably associated with protein fractions in milk with a lifetime of weeks .
Notably, as reported above, NMN may be degraded by CD38 in older mice promoting NAD+ decline and mitochondrial dysfunctions , 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 . 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 .
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 . 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 
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 .
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 . Other recent reports suggest that NAMPT downregulation could be beneficial in treating pancreatic ductal adenocarcinoma [69,70] and colorectal cancer .
Recent findings show that Duchenne muscular dystrophy was accompanied by reduced levels of NAMPT in mice . 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 . 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  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 .
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 .
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 .
Interestingly, effects of NMN supplementation and exercise on glucose tolerance in HFD-treated mice are very similar . 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 . 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 .
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 (see Outstanding Questions), NAD+ deficits may be part of the answer unifying the aging process to its associated pathologies.
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 [150,151].
An increased human lifespan without any health problems still remains a fundamental challenge in our society and, finding new NAD+ boosters with better efficacy and stability would be an interesting perspective in the future
Things are looking good for NAD+. If researchers can find ways to dramatically increase the NAD+ levels in humans, much like they did in mice, we may be able to dramatically slow the aging process.
Trying to increase your levels certainly won’t hurt you. And it might just have a big impact on your overall health as you get older.
RESTORNG NAD+ LEVELS EXTENDS HEALTHSPAN – RESEARCH
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).
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).
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.,
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).
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).
- Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans (Meydayni, 2016)
- A high-fat, ketogenic diet induces a unique metabolic state in mice. (Kennedy, 2007)
- Ketone body metabolism and cardiovascular disease.(Cotter, 2013)
- Ketone bodies as signaling metabolites(Newman, 2014)
- The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease(Youm, 2015)
- The effect of the Spanish Ketogenic Mediterranean Diet on nonalcoholic fatty liver disease: a pilot study.(Guisado, 2011)
- β-Hydroxybutyrate: A Signaling Metabolite in starvation response(Morales, 2016)
- Physiological roles of ketone bodies as substrates and signals in mammalian tissues(Robinson, 1980)
- Ketone bodies mimic the life span extending properties of caloric restriction (Veech, 2017)
- Novel ketone diet enhances physical and cognitive performance(Murray, 2016)
- Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.
- Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes(Cox, 2013)
- Neuroendocrine Factors in the Regulation of Inflammation: Excessive Adiposity and Calorie Restriction (Fontana, 2009)
- Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice(August, 2017)
- A randomized trial of a low-carbohydrate diet for obesity(Foster, 2003)
- β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation(Bae, 2016)
- The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. (Maalouf, 2009)
- AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation (Han, 2016)
- Regulation of AMP-activated protein kinase by natural and synthetic activators (Hardie, 2015)
- Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)
- NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy (Yang, 2016
- )NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. (Zhang, 2016)
- Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (Mills, 2016)
- Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)b
- NAD+ metabolism and the control of energy homeostasis – a balancing act between mitochondria and the nucleus (Canto, 2015)
- Modulating NAD+ metabolism, from bench to bedside (Auwerx, 2017)
- Aspects of Tryptophan and Nicotinamide Adenine Dinucleotide in Immunity: A New Twist in an Old Tale. (Rodriguez, 2017)
- Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes (Strasser, 2016)
- PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation(Bai, 2011)
- Carbohydrate restriction regulates the adaptive response to fastingCarbohydrate restriction regulates the adaptive response to fasting (Klein, 1992)
- Interventions to Slow Aging in Humans: Are We Ready? (longo, 2015)
- Extending healthy life span–from yeast to humans (longo, 2010)
- Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)
- Dietary restriction with and without caloric restriction for healthy aging (Lee, 2016)
- AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity (Cato, 2009)
- A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan (Longo, 2015)
- Diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms (Longo, 2016
- Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle (Porter, 2015)
- Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice (Newman, 2017)
- NAD+ and sirtuins in aging and disease (Imai, 2014)
- The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. (Mouchiroud, 2013)
- Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)
- NAMPT- mediated NAD(+) biosynthesis is essential for vision in mice (Lin, 2016)
- Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice (Williams, 2017)
- NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair( Fang, 2016 )
- Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease (Gariani, 2017 )
- Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle(Canto, 2010)
- AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity(Canto, 2009 )
- The NAD (+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity(Canto, 2012 )
- Nicotinamide riboside is uniquely and orally bioavailable in mice and humans(Trammell, 2016a )
- Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice(Trammell, 2016b )
- NAD blocks high glucose induced mesangial hypertrophy via activation of the sirtuins-AMPK-mTOR pathway (Zhuo, 2011)
- NAMPT-mediated NAD biosynthesis as the internal timing mechanism: In NAD+ World, time is running in its own way (Poljsak, 2017)
- THE EFFECT OF DIFFERENT EXERCISE REGIMENS ON MITOCHONDRIAL BIOGENESIS AND PERFORMANCE (Philander, 2014)