What is nicotinamide riboside

Nicotinamide riboside is a unique member of the vitamin B3 (also known as Niacin) family and was originally identified as a nutrient in milk ¹. The body converts nicotinamide riboside into Nicotinamide Adenine Dinucleotide (NAD+) which is an essential molecule found in every living cell. Baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin (vitamin B3 or nicotinic acid and nicotinamide), which consists of nicotinic acid and/or nicotinamide ². However, nicotinic acid (vitamin B3) is associated with undesirable flushing at therapeutic doses ³ and nicotinamide does not reliably activate (and may even inhibit) sirtuins despite raising concentrations of NAD+ ⁴. Therefore, administration of nicotinic acid or nicotinamide is unlikely to be widely adopted for maintaining health and function with aging.

In contrast to these compounds, oral supplementation with either of the NAD+ metabolites, nicotinamide mononucleotide (NMN) or nicotinamide riboside, increases levels of NAD+ and improves multiple physiological functions in animal models ⁵. Recently scientists demonstrated that supplementation of nicotinamide mononucleotide (NMN) in the drinking water improved cardiovascular function in old mice ⁶ . Moreover, chronic calorie restriction increases concentrations of nicotinamide riboside and NAD+ and restores normal circadian gene transcription in the liver, further suggesting that nicotinamide riboside may act as a chronic calorie restriction mimetic ⁷. Thus, nicotinamide mononucleotide (NMN) and nicotinamide riboside are NAD+ boosting compounds that hold promise for enhancing cardiovascular health and physiological function with aging ⁸.

Nicotinamide riboside is a useful compound for elevation of NAD+ (Nicotinamide Adenine Dinucleotide or the oxidized form of NADH) levels in humans. NAD+ is the oxidized form of NADH ⁹. NAD+ and NADH participate in reactions such as glycolysis, the tricarboxylic acid cycle (citric acid cycle), and oxidative phosphorylation, participating in multiple redox reactions in cells ¹⁰. Nicotinamide riboside has recently been discovered to be an NAD(+) precursor that is converted to nicotinamide mononucleotide (NMN) by specific nicotinamide riboside kinases, Nrk1 and Nrk2. It has been shown that exogenous nicotinamide riboside promotes Sirtuins (silent information regulator 2 or Sir2)-dependent repression of recombination, improves gene silencing, and extends the lifespan of certain animal models without calorie restriction ¹¹. Supplementation of nicotinamide riboside in mammalian cells and mouse tissues increases NAD(+) levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities ¹². Indeed, supplementation with NAD+ precursors can extend the lifespan of worms, return tissue functionality to a more youthful state in mice, and rescue mitochondrial dysfunction in some DNA repair disorders ¹³. Interestingly, the NAD+-dependent deacetylase SIRT1 is required for these effects ¹³. Recent data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis ¹⁴. Nicotinamide riboside kinase has an essential role for phosphorylation of nicotinamide riboside and the cancer drug tiazofurin ¹ .

Figure 1. NADH redox reaction

Figure 2. NADH and NAD+ redox metabolism

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in all living cells. NAD+ (nicotinamide adenine dinucleotide) 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 and poly(adenosine diphosphate–ribose) polymerases ¹⁵. Cellular NAD+ concentrations change during aging, and modulation of NAD+ usage or production can prolong both health span and life span.

The NAD⁺/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb’s cycle (also known as tricarboxylic acid cycle or citric acid cycle), and fatty acid oxidation ¹⁶. Intracellular NAD⁺ is synthesized de novo from L-tryptophan, although its main source of synthesis is through salvage pathways from dietary vitamin B3 (Niacin) as precursors. NAD⁺ is utilized by various proteins including sirtuins (silent information regulator 2), poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases. The NAD⁺ pool is thus set by a critical balance between NAD⁺ biosynthetic and NAD⁺ consuming pathways. Raising cellular NAD⁺ content by inducing its biosynthesis or inhibiting the activity of poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases via genetic or pharmacological means lead to sirtuins activation. Sirtuins (silent information regulator 2) modulate distinct metabolic, energetic and stress response pathways, and through their activation, NAD⁺ directly links the cellular redox state with signaling and transcriptional events. NAD⁺ levels decline with mitochondrial dysfunction and reduced NAD⁺/NADH ratio is implicated in mitochondrial disorders, various age-related pathologies as well as aging.

Sirtuins (silent information regulator 2 or Sir2) proteins are a family of evolutionarily conserved nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacylases harboring lysine deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity ¹⁷ or an ADP-ribosyltransferase activity ¹⁸. Mammals contain seven sirtuins (SIRT1–7) that are locacted in different subcellular compartments i.e. nucleus (SIRT1, SIRT6 and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3, SIRT4 and SIRT5) ¹⁹ and are implicated in a wide variety of biological functions including control of cellular metabolism and energy homeostasis, aging and longevity, transcriptional silencing, cell survival, proliferation, differentiation, DNA damage response, stress resistance, and apoptosis ²⁰. Since sirtuins are NAD⁺-dependent enzymes, the availability of NAD⁺ is one of the key mechanisms that regulate their activity. Sirtuins therefore serve as “metabolic sensors” of the cells as their activity is coupled to changes in the cellular NAD⁺/NADH redox state, which is largely influenced by the availability and breakdown of nutrients ²¹. Thus, NAD⁺ is not only a vital cofactor/coenzyme but also a signaling messenger that can modulate cell metabolic and transcriptional responses. Changes in cellular NAD⁺ levels can occur due to modulation of pathways involved in NAD⁺ biosynthesis and consumption. Reduced NAD⁺ levels have been reported in mitochondrial and age-related disorders, and NAD⁺ levels also decline with age ²². Boosting cellular NAD⁺ levels serves as a powerful means to activate sirtuins, and as a potential therapy for mitochondrial as well as age-related disorders.

It is known, as aging progresses, nicotinamide adenine dinucleotide (NAD⁺) levels decrease and are involved in age-related metabolic decline and mitochondrial dysfunction ²³. Elevated NADH to NAD+ ratio further suggests that older individuals of both sexes are unable to utilize NADH as effectively as the younger adults. This observation has direct bearing on the mitochondrial oxidation. NADH is perhaps not oxidized efficiently in the older and female adults than the younger individuals, i.e. less of the energy pool (ATP) in the older adults. Recent studies have shown that a reduction in NAD⁺ is a key factor for the development of age-associated metabolic decline. Increased NAD⁺ levels in vivo results in activation of pro-longevity and health span-related factors. Also, it improves several physiological and metabolic parameters of aging, including muscle function, exercise capacity, glucose tolerance, and cardiac function in mouse models of natural and accelerated aging.

It has been shown that the cellular NAD⁺ pool is determined by a balance between the activity of NAD-synthesizing and NAD-consuming enzymes ²⁴. In previous publications, it was demonstrated that expression and activity of the NADase CD38 increases with age and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity (see Figure 3 below) ²⁵. It was also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo. That indicates that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases ²⁵. CD38 was originally identified as a cell-surface enzyme that plays a key role in several physiological processes such as immune response, inflammation, cancer, and metabolic disease ²⁶.

Type 2 diabetes has become an epidemic due to calorie-rich diets overwhelming the adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD⁺ biosynthesis and the NAD⁺-dependent protein deacetylase SIRT1. The results presented in this study in mice demonstrated that nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD⁺ biosynthesis is severely compromised by high fat diet and aging, contributing to the pathogenesis of type 2 diabetes ²⁷. Strikingly, nicotinamide mononucleotide (NMN), a product of the nicotinamide phosphoribosyltransferase (NAMPT) reaction and a key NAD⁺ intermediate, ameliorates glucose intolerance by restoring NAD⁺ levels in high fat diet-induced type 2 diabetes mice. Nicotinamide mononucleotide (NMN) also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD⁺ and NAMPT levels show significant decreases in multiple organs during aging, and nicotinamide mononucleotide (NMN) improves glucose intolerance and lipid profiles in age-induced type 2 diabetes mice ²⁷.

The recent development of potent and specific CD38 inhibitors ²⁸, together with the novel findings highlighting the role of NAD⁺ replacement therapy and CD38 in age-related diseases such as hearing loss and Alzheimer’s ²⁹, indicate that CD38 inhibition combined with NAD precursors may serve as a potential therapy for metabolic dysfunction and age-related diseases.

Figure 3. NAD decline due to increases in CD38/NADase during aging

[Source ²³]

NAD+ biosynthesis, consumption and compartmentalization

The mammalian NAD⁺ biosynthesis occurs via de novo and salvage pathways, and involves four major substrates including the essential amino acid l-tryptophan (Trp), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide riboside (NR) ³⁰. De novo biosynthesis of NAD⁺ starts from dietary L-tryptophan (Trp) which is catalytically converted to N-formylkynurenine by either indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO) and is the first rate limiting step. N-formylkynurenine is then converted by a series of four enzymatic reactions to α-amino-β-carboxymuconate-ε-semialdehyde (ACMS) which is unstable and hence undergoes either complete enzymatic oxidation or non-enzymatic cyclization to quinolinic acid (see Figure 4). The second rate limiting step involves the catalytic conversion of quinolinic acid to nicotinic acid mononucleotide (NAMN) by quinolinate phosphoribosyl transferase (QPRT). Next, NAMN is converted to nicotinic acid adenine dinucleotide (NAAD) by one of the three isoforms of nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme. The human NMNAT1 is localized in the nucleus, NMNAT2 is found in the Golgi and cytosol, whereas NMNAT3 is localized in both mitochondria and cytosol ³¹. The final step of de novo biosynthesis is the amidation of NAAD by NAD synthase (NADS) enzyme (see Figure 4) ³⁰. The de novo pathway contributes only a minor fraction to the total NAD⁺ pool, however, its importance is stressed by the human disease pellagra which is caused by dietary deficiency of Trp and NAM intermediate, leading to diarrhea, dermatitis, dementia and ultimately death ³². However, pellagra is easily treated by dietary supplementation of L-tryptophan (Trp) or niacin (vitamin B3) (i.e. nicotinic acid, nicotinamide and nicotinamide riboside). The primary source of NAD⁺ biosynthesis is the salvage or Preiss-Handler pathway which utilizes dietary niacin as precursors (Figure 4). The salvage pathway involves catalytic conversion of nicotinic acid to nicotinic acid mononucleotide by nicotinic acid phosphoribosyltransferase (NAPT), which is subsequently converted to NAD⁺ by the action of nicotinamide mononucleotide adenylyltransferase (NMNAT) and NAD synthase (NADS) enzymes. The nicotinamide and nicotinamide riboside are converted to nicotinamide mononucleotide (NMN) by the action of nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside kinase (NRK) enzymes respectively. Finally, nicotinamide mononucleotide (NMN) is enzymatically converted to NAD⁺ by nicotinamide mononucleotide adenylyltransferase (NMNAT).

The cellular abundance of NAD⁺ is also regulated by its breakdown since NAD⁺ serves as a degradation substrate for multiple enzymes including sirtuins, poly ADP-ribose polymerases (PARPs) and cyclic ADP (cADP) ribose synthases which cleave NAD⁺ to produce nicotinamide and an ADP-ribosyl product ³³. For instance, the deacetylase activity of mammalian sirtuins uses NAD⁺ to cleave the acetyl group from ε–acetyl lysine residues of target proteins to generate nicotinamide and 2′O-acetyl-ADP-ribose. Sirtuins are activated in response to nutrient deprivation or energy deficit which triggers cellular adaptations to improve metabolic efficiency. Poly ADP-ribose polymerases’s are activated in response to DNA damage (e.g. DNA strand breaks) and genotoxic stress, and use NAD⁺ to catalyze a reaction in which the ADP ribose moiety is transferred to a substrate protein. The cADP-ribose synthases (e.g. CD38 and CD157) use NAD⁺ to generate cADP-ribose which serves as an intracellular second messenger. The members of poly ADP-ribose polymerases and cADP-ribose synthase family show increased affinity and lower K_m for NAD⁺ compared to sirtuins, indicating that their activation critically impacts intracellular NAD⁺ levels and determines if it reaches a permissive threshold for sirtuin activation ³⁴. Multiple studies also suggested that PARP activity constitutes the main NAD⁺ catabolic activity, which drives cells to synthesize NAD⁺ from de novo or salvage pathways ³⁵.

The intracellular NAD⁺ levels are typically between 0.2 and 0.5 mM in mammalian cells, and change during a number of physiological processes ³⁴. Since the nucleus, cytosol and mitochondria are equipped with NAD⁺ salvage enzymes, the compartment-specific NAD⁺ production activates distinct sirtuins to trigger the appropriate physiological response. The NAD⁺/NADH levels also vary with the availability of dietary energy and nutrients. For instance, tissue NAD⁺ levels decrease with energy overload such as high-fat diet ³⁶ and display circadian oscillations with a 24 hour rhythm in the liver, which is regulated by feeding ³⁷. During energetic stress such as exercise, calorie restriction and fasting in mammals, the NAD⁺ levels increase leading to sirtuin activation, which is associated with metabolic and age-related health benefits (Figure 5) ³⁸. Decreased sirtuins (e.g. SIRT1 and SIRT3) expression is associated with various age-related pathologies ³⁹ and their overexpression has been reported to enhance overall mitochondrial and metabolic health in age-related disorders as well as mitochondrial diseases ⁴⁰.

Figure 4. NAD⁺ biosynthesis

Footnotes: Schematic representation of de novo and salvage pathways for NAD⁺ biosynthesis. In mammals, the de novo biosynthesis starts from l-tryptophan (Trp) which is enzymatically converted in a series of reactions to quinolinic acid (QA). Through quinolinate phosphoribosyltransferase (QPRT) enzyme activity, QA is converted to nicotinic acid mononucleotide (NAMN), which is then converted to nicotinic acid adenine dinucleotide (NAAD) by nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme. The final step in de novo biosynthesis is the amidation of NAAD by NAD synthase (NADS) which generates NAD⁺. The salvage pathway involves NAD⁺ synthesis from its precursors, i.e. Nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR). NA is catalytically converted to NAMN by the action of nicotinic acid phosphoribosyltransferase (NAPT). NAM is converted by nicotinamide phosphoribosyltransferase (NAMPT) to nicotinamide mononucleotide (NMN), which is also the product of phosphorylation of NR by nicotinamide riboside kinase (NRK) enzyme. Finally, NAMN is converted to NAD by the action of NMNAT and NADS enzymes, whereas NMN is converted to NAD by the NMNAT enzyme. Multiple enzymes break-down NAD⁺ to produce NAM and ADP-ribosyl moiety, however only sirtuins are depicted in this figure

[Source ⁴¹]

Figure 5. Boosting NAD+ levels is beneficial for health and lifespan

Footnotes: NAD⁺ is a rate-limiting cofactor for the enzymatic activity of sirtuins. Boosting intracellular NAD⁺ levels by physiological (e.g. exercise, calorie restriction, fasting) or pharmacological [e.g. resveratrol, sirtuin activating compounds (STACs)] interventions, and inducing NAD⁺ biosynthesis through supplementation with precursors (e.g. NA, NAM, NR) or inhibition of NAD⁺ consuming enzymes (e.g. PARP-1, CD38) leads to activation of sirtuins (e.g. SIRT1, SIRT3). SIRT1 deacetylates and activates transcriptional regulators (e.g. PGC-1α, FOXO1), whereas SIRT3 deacetylates and activates multiple metabolic gene targets (e.g. succinate dehydrogenase, superoxide dismutase 2), which in turn regulate mitochondrial biogenesis and function. Supplementation with NR or PARP inhibitors extends lifespan in worms by inducing the UPR^mt stress signaling response via Sir-2.1 activation, which then triggers an adaptive mitohormetic response to stimulate mitochondrial function and biogenesis. Improved mitochondrial function associated with mitohormesis or metabolic adaptation can attenuate the impact of mitochondrial diseases, aging as well as age-related metabolic and neurodegenerative disorders. The physiological and pharmacological interventions that boost NAD⁺ levels are highlighted in yellow and pink respectively whereas the pathways that produce and consume/decrease NAD⁺ levels are highlighted in green and red respectively

[Source ⁴¹]

Increased NAD+ levels protects against mitochondrial and age-related disorders

Mitochondrial disorders represent one of the most common forms of heritable metabolic disease in children ⁴². Reduced NAD⁺/NADH ratio is strongly implicated in mitochondrial disorders and, age-related disorders including diabetes, obesity, neurodegeneration and cancer ⁴³. NAD⁺ levels also decline during aging in multiple models including worms, rodents and human tissue ⁴⁴. Increasing evidence suggests that boosting NAD⁺ levels could be clinically beneficial, as it activates the NAD⁺/sirtuin pathway which yields beneficial effects on multiple metabolic pathways.

Pharmacological activation of NAD⁺ production has recently been used to treat mouse models of mitochondrial diseases. For instance, treatment of cytochrome c oxidase (COX) deficiency caused by SURF1, SCO2 or COX15 genetic mutations in mice, with AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), partially rescued mitochondrial dysfunction and improved motor performance ⁴⁵. These findings could be explained by the fact that AMPK stimulates NAD⁺ production, consequently activating SIRT1 which promotes energy production and homeostasis ³⁹. Oral administration of NAD⁺ precursor, NR in mitochondrial myopathy mice harboring a pathogenic mutation in the mtDNA helicase—Twinkle, effectively delayed myopathy progression, by increasing mitochondrial biogenesis, preventing mitochondrial ultrastructural abnormalities, mtDNA deletion formation and activating the mitochondrial unfolded protein (UPR^mt) response ⁴⁶. In addition, NR supplementation and reduction of NAD⁺ consumption by a specific PARP inhibitor significantly improved mitochondrial respiratory chain defect and exercise intolerance, in a mouse model of COX deficiency caused by SCO2 mutation ⁴⁰.

Besides improving mitochondrial function, boosting NAD⁺ levels with resveratrol, nicotinamide riboside or nicotinamide mononucleotide (NMN) also corrects metabolic disturbances in mice caused by high fat diet ³⁹. Nicotinamide mononucleotide (NMN) administration ameliorates glucose intolerance and insulin resistance in diet- and age-induced type 2 diabetic mice ⁴⁷ and rectifies glucose-stimulated insulin secretion and glucose intolerance in NAMPT-deficient animals, by restoring NAD⁺ levels ⁴⁸. Interventions using NAD⁺ precursors or poly ADP-ribose polymerase inhibitors were also shown to be neuroprotective. For instance treatment with nicotinamide mononucleotide (NMN) or nicotinamide riboside precursors, protected against axonal degeneration and hearing loss in mice ⁴⁹. Raised NAD⁺ levels after calorie restriction, nicotinamide or nicotinamide riboside treatment attenuated increase in β-amyloid content and oxidative damage, preventing cognitive decline and neurodegeneration in rodent models of Alzheimer’s disease ⁵⁰. PARP-1 (poly ADP-ribose polymerase 1) activation also occurs in neurodegenerative DNA repair disorders including xeroderma pigmentosum group A (XPA) and Cockayne syndrome group B, and treatment with specific PARP inhibitors rescues defective phenotypes in XPA mutant worms and Cockayne syndrome group B mutant mice respectively ⁵¹. However, PARP-2 (poly ADP-ribose polymerase 2) deleted mice were glucose intolerant and exhibited pancreatic dysfunction, implying that these results may interfere with other beneficial consequences of PARP inhibition, and hence warrant further investigation on the safe clinical use of these inhibitors ⁵². Because poly ADP-ribose polymerase inhibitors enhance oxidative metabolism and improve metabolic flexibility, these compounds are being tested in phase III trials as anti-cancer agents ⁵³.

Increasing NAD⁺ levels by treatment with nicotinic acid and nicotinamide precursors has been shown to inhibit metastasis and breast cancer progression in response to mitochondrial complex I defect in mice ⁵⁴. However, reducing NAD⁺ bioavailability is reported to have an antineoplastic effect in various tumor cell types, as cancer cells rely on increased central carbon metabolism and biomass production to sustain an unrestricted growth ⁵⁵. The exact role of sirtuins in cancer remains controversial with dichotomous functions being reported, for example multiple studies have shown that SIRT1, SIRT3 and SIRT5 can act as tumor promoters or tumor suppressors under different cellular conditions, tumor stage and tissue of origin ⁵⁶. However, SIRT4 is only shown to have a tumor suppressor function ⁵⁷. Further research is needed to understand why and how certain sirtuins have both oncogenic or tumor-suppressive roles, and how this dual action may be best exploited for cancer management.

Declining NAD⁺ levels during aging compromise mitochondrial function in multiple model organisms, which can be restored via NAD⁺ precursor supplementation or poly ADP-ribose polymerase inhibition. For instance, nicotinamide mononucleotide or nicotinamide riboside administration in aged mice or worms respectively, reversed mitochondrial dysfunction by restoring NAD⁺ levels ⁵⁸. Moreover, nicotinamide riboside administration or poly ADP-ribose polymerase inhibition in worms extended lifespan by activating the UPR^mt response via Sir-2.1 (worm SIRT1 ortholog) and mitonuclear protein imbalance, which in turn induced a mitohormetic response to improve mitochondrial function (Figure 5) ⁵⁹. Inducing UPR^mt genes such as Hsp60 paralogs in Drosophila also prevented mitochondrial and age-dependent muscle dysfunction, thereby promoting longevity ⁶⁰.

Modulation of NAD+ levels by pharmacological compounds

Besides physiological processes, NAD⁺ levels can be modulated pharmacologically. Resveratrol—a polyphenolic compound found in red wine has been shown to indirectly stimulate NAD⁺ production by activating the energy sensor AMP-activated protein kinase (AMPK) ⁶¹. Increased NAD⁺ subsequently stimulates SIRT1 activity, which in turn activates PGC-1α and FOXO family of proteins that govern mitochondrial biogenesis and function (Figure 5) ⁶¹. SIRT1 is also amenable to intervention by small molecules such as SIRT1-activating compounds (STACs) that exert beneficial effects on age-related metabolic abnormalities ³⁹. NAD⁺ levels can be directly raised by supplying NAD⁺ biosynthetic precursors/intermediates, or by inhibiting NAD⁺ consuming enzymes with specific inhibitors (Figure 5). For instance, supplementation of nicotinic acid, nicotinamide riboside or nicotinamide mononucleotide compounds increase NAD⁺ levels in both cultured cells and mouse tissues³⁹. Because nicotinamide riboside can be metabolized both in the nucleus and mitochondria, its supplementation raises the nuclear and mitochondrial NAD⁺ levels, thereby activating nuclear SIRT1 and mitochondrial SIRT3 respectively ³⁹. Pharmacological activation of NAD⁺ thus stimulates the activity of multiple sirtuin in a compartment-specific manner to exert its beneficial effects on multiple metabolic pathways which is in contrast to SIRT1 activating compounds’s that specifically stimulate the activity of SIRT1 pathway. Treatment of mice or cultured cells with poly ADP-ribose polymerase and CD38 specific inhibitors has also been shown to induce NAD⁺ levels that activate sirtuins ⁵³.

Summary

Based on the current evidence, both NAD⁺ precursors and poly ADP-ribose polymerase inhibitors seem as promising candidates for boosting NAD⁺ levels in cell culture and animal models. However, there are several key questions that remain unanswered ⁶².

1. First, whether different pharmacological, genetic and physiological manipulations that boosts NAD⁺ production lead to enhanced activity of all sirtuin enzymes or whether only a few family members are activated, especially considering the fact that some sirtuins may have opposing actions?
2. Second, how sirtuins located in different subcellular compartments differ in their enzyme kinetics towards NAD⁺ availability?
3. Third, what may be the optimal dosages, routes of administration, efficacy and bioavailability of compound drugs that raise intracellular NAD⁺ levels for human application?

Future studies that are directed towards understanding these would be highly relevant in designing therapeutic strategies aimed at selective activation of specific sirtuins, and would also aid in translating the results for human clinical application. It is possible that some of the NAD⁺ boosting drugs show adverse side effects in humans which could preclude their use and/or may be acceptable for only those inherited conditions that are highly devastating. It is also important to determine if nicotinamide riboside could be valid substitute to avoid undesirable side effects of other NAD⁺ precursors such as nicotinic acid and nicotinamide, for instance when used as lipid lowering drugs ⁶³.

In addition, future studies are required to examine the UPR^mt pathway in vivo in mammalian models to identify key signaling molecules involved in mitochondrial protective mechanisms, which will further advance our understanding of the diseases associated with mitochondrial dysfunction, and will allow discovery of new targets to modulate this pathway. Finally, it remains to be determined whether or not boosting NAD⁺ levels could extend lifespan in higher organisms. Although much remains to be done, based on the steadily growing evidence, the pharmacological modulation of NAD⁺ levels via NAD⁺ precursors and poly ADP-ribose polymerase inhibitors appears to be an attractive and valid strategy to enhance oxidative metabolism and mitochondrial biogenesis, and holds a significant therapeutic potential in the clinical management of mitochondrial and age-related disorders.

Nicotinamide riboside supplement

Nicotinamide riboside chloride is intended for use as a source of vitamin B3 in vitamin waters, protein shakes, nutrition bars, gum and chews at a maximum use level is 0.027% by weight ⁶⁴. A 100 mg of nicotinamide riboside chloride provides 88 mg of nicotinamide riboside. Nicotinamide riboside is involved in nicotinate and nicotinamide metabolism. In 2016 the U.S. Food and Drug Administration (FDA) granted generally recognized as safe (GRAS) status for nicotinamide riboside as a food ingredient in enhanced water products, protein shakes, nutrition bars, gum and chews at no more than 0.027% of nicotinamide riboside chloride by weight ⁶⁵. In rodents studies, the No-Observed-Adverse-Effect Level (NOAEL) is 300 mg/kg/day and the Lowest Observed Adverse Effect Level (LOAEL) is  1,000 mg/kg/day ⁶⁵.

These terms refer to the actual doses used in human clinical or experimental animal studies. They are defined as follows:

• NOAEL (No-Observed-Adverse-Effect Level) — Highest dose at which there was not an observed toxic or adverse effect.
• LOAEL (Lowest Observed Adverse Effect Level) — Lowest dose at which there was an observed toxic or adverse effect.

Oral nicotinamide riboside supplementation at 500 mg, 2×/day for 6 weeks, effectively elevated levels of NAD+ in circulating peripheral blood mononuclear cells by ~60% compared with placebo (mean change = 6.2 pmol per mg protein) ⁶⁶. The mean level of NADP+ also increased, but did not reach statistical significance (mean change = 1.2 pmol per mg protein) ⁶⁶. Of note, nicotinamide riboside also elevated levels of nicotinic acid adenine dinucleotide (NAAD) nearly fivefold above the placebo condition (mean change = 1.1 pmol per mg protein), ⁶⁶ confirming a previous report that NAAD is a highly sensitive and reliable biomarker of increased NAD+ metabolism and a product of nicotinamide riboside utilization in humans ⁶⁷. Nicotinamide riboside also elevated the mean concentration of nicotinamide (NaM), but this was not statistically significant (mean change = 106.5 pmol per mg protein) ⁶⁶. An increase in nicotinamide would suggest an increase in the activity of NAD+-consuming enzymes, which catalyze the breakdown of NAD+ into nicotinamide and ADP-Ribose ⁶⁸. Though not significant, the study authors also observed an ~1.5-fold increase in nicotinamide mononucleotide (NMN) (mean change = 0.72 pmol per mg protein), which may indicate the possible conversion of nicotinamide riboside to nicotinamide mononucleotide (NMN) by nicotinamide riboside kinase (nicotinamide ribosideK) enzymes or further metabolism of nicotinamide into nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT) ⁶⁸.

Nicotinamide riboside dosage

A small randomized, placebo-controlled, crossover clinical trial of nicotinamide riboside supplementation (500 mg, 2×/day) to assess its overall tolerability and efficacy vs. placebo for raising levels of NAD+-related metabolites in healthy middle-aged and older men and women ⁶⁶. The results demonstrate that 6 weeks of nicotinamide riboside supplementation at this dose is well-tolerated in humans and effectively increases blood cellular NAD+ concentrations ⁶⁶.

Nicotinamide riboside side effects

All self-reported side effects were mild in severity ⁶⁶. The reported symptoms included nausea, flushing, leg cramps and increased bruising during the nicotinamide riboside condition, and headache, skin rash, flushing, fainting and drowsiness during the placebo condition ⁶⁶. Only 2 out of the 30 enrolled subjects (<10%) dropped out of the study due to a complaint of side effects, both occurring while subjects were in the placebo phase (headache and skin rash); no subject dropped out during the nicotinamide riboside treatment condition.

Nicotinamide Niacin food sources

Niacin (also known as vitamin B3 or or nicotinic acid and nicotinamide) is found in:

• Milk
• Eggs
• Enriched breads and cereals
• Rice
• Fish
• Lean meats
• Legumes
• Peanuts
• Poultry

A deficiency of niacin causes pellagra. The symptoms include:

• Digestive problems
• Inflamed skin
• Mental impairment

Large doses of niacin can cause:

• Increased blood sugar (glucose) level
• Liver damage
• Peptic ulcers
• Skin rashes

Even normal doses can be associated with feeling warmth, redness, itching or tingling of the face, neck, arms or upper chest. This is called “flushing”. In most cases, this problem will get better after taking niacin on a regular basis for a while. To prevent flushing, do not drink hot beverages or alcohol at the same time you take niacin. New forms of nicotinic acid reduce this side effect.

Nicotinamide does not cause these side effects.

Table 1. Foods rich in Niacin (vitamin B3 or or nicotinic acid and nicotinamide) from highest to low

Description	Niacin (mg) Value Per 100 grams
Yeast extract spread	127.5
Cereals ready-to-eat, RALSTON Enriched Wheat Bran flakes	90.57
Beverages, Orange-flavor drink, breakfast type, low calorie, powder	80
Beverages, fruit-flavored drink, powder, with high vitamin C with other added vitamins, low calorie	80
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON Double Chocolate Nut Bar	45.25
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON Honey Nut Oat Bar	45.25
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON Energy Bar, all flavors	45.25
Leavening agents, yeast, baker’s, active dry	40.2
Beverages, UNILEVER, SLIMFAST Shake Mix, powder, 3-2-1 Plan	38.46
Beverages, UNILEVER, SLIMFAST Shake Mix, high protein, whey powder, 3-2-1 Plan,	38.44
Formulated bar, LUNA BAR, NUTZ OVER CHOCOLATE	37.1
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON Chewy Chocolate Peanut Bar	36.36
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON MULTIGRAIN CRUNCH BAR	36.36
Babyfood, cereal, oatmeal, with honey, dry	36.29
Cereals ready-to-eat, rice, puffed, fortified	35.3
Cereals ready-to-eat, wheat, puffed, fortified	35.3
Rice bran, crude	33.99
Formulated bar, POWER BAR, chocolate	32.6
Cereals ready-to-eat, MALT-O-MEAL, CORN BURSTS	32.25
Babyfood, rice cereal, dry, EARTHS BEST ORGANIC WHOLE GRAIN, fortified only with iron	31.24
Cereals ready-to-eat, RALSTON CRISP RICE	28.97
Beverages, coffee, instant, regular, half the caffeine	28.17
Beverages, coffee, instant, regular, powder	28.17
Beverages, coffee, instant, decaffeinated, powder	28.07
Incaparina, dry mix (corn and soy flours), unprepared	27
Peanut flour, defatted	27
Cereals ready-to-eat, MALT-O-MEAL, Fruity DYNO-BITES	26.5
Beverages, chocolate powder, no sugar added	25.6
Beverage, instant breakfast powder, chocolate, sugar-free, not reconstituted	25.6
Babyfood, cereal, rice with pears and apple, dry, instant fortified	25.24
Cereals ready-to-eat, MALT-O-MEAL, GOLDEN PUFFS	25.17
Beverages, nutritional shake mix, high protein, powder	25
Formulated bar, MARS SNACKFOOD US, SNICKERS MARATHON Protein Performance Bar, Caramel Nut Rush	25
Cereals ready-to-eat, RALSTON Crispy Hexagons	24.14
Cereals ready-to-eat, QUAKER, Cap’n Crunch’s OOPS! All Berries Cereal	23.96
Babyfood, cereal, high protein, with apple and orange, dry	23.83
Cereals ready-to-eat, MALT-O-MEAL, OAT BLENDERS with honey & almonds	23.51
Babyfood, cereal, rice, with bananas, dry	23.32
Babyfood, cereal, rice, dry fortified	23.01
Salmon, red (sockeye), filets with skin, smoked (Alaska Native)	22.75
Fish, tuna, yellowfin, fresh, cooked, dry heat	22.07
Meat extender	22.02
Cereals ready-to-eat, RALSTON Corn Biscuits	21.83
Cereals ready-to-eat, QUAKER, Christmas Crunch	21.74
Beverages, coffee, instant, with chicory	21.67
Cereals ready-to-eat, QUAKER, CAP’N CRUNCH	21.46
Babyfood, cereal, oatmeal, dry fortified	21.35
Formulated bar, SLIM-FAST OPTIMA meal bar, milk chocolate peanut	21.2
Cereals ready-to-eat, RALSTON Corn Flakes	21.03
Cereals ready-to-eat, QUAKER, CAP’N CRUNCH with CRUNCHBERRIES	20.75
Cereals ready-to-eat, SUN COUNTRY, KRETSCHMER Toasted Wheat Bran	20.62
Babyfood, cereal, mixed, with bananas, dry	20.56
Cereals ready-to-eat, QUAKER, CAP’N CRUNCH’S Halloween Crunch	20.56
Cereals ready-to-eat, QUAKER, QUAKER CRUNCHY BRAN	20.39
Cereals ready-to-eat, QUAKER, SWEET CRUNCH/QUISP	20.38
Cereals ready-to-eat, QUAKER, CAP’N CRUNCH’S PEANUT BUTTER CRUNCH	20.36
Cereals, MALT-O-MEAL, chocolate, dry	20.31
Formulated bar, ZONE PERFECT CLASSIC CRUNCH BAR, mixed flavors	20
Babyfood, rice and apples, dry	20
Fish, anchovy, european, canned in oil, drained solids	19.9
Cereals, MALT-O-MEAL, Farina Hot Wheat Cereal, dry	19.77
Cereals ready-to-eat, MALT-O-MEAL, Blueberry MUFFIN TOPS Cereal	19.64
Snacks, KELLOGG, KELLOGG’S, NUTRI-GRAIN Cereal Bars, fruit	19.27
Cereals ready-to-eat, MALT-O-MEAL, HONEY GRAHAM SQUARES	18.97
Fish, tuna, skipjack, fresh, cooked, dry heat	18.76
Cereals ready-to-eat, POST, FRUITY PEBBLES	18.52
Cereals ready-to-eat, POST, GOLDEN CRISP	18.5
Fish, tuna, fresh, yellowfin, raw	18.48
Cereals ready-to-eat, QUAKER, QUAKER Honey Graham LIFE Cereal	18.42
Cereals ready-to-eat, QUAKER, QUAKER OAT CINNAMON LIFE	18.22
Beverages, rich chocolate, powder	18.18
Beverages, OVALTINE, Classic Malt powder	18.18
Beverages, OVALTINE, chocolate malt powder	18.18
Cereals ready-to-eat, GENERAL MILLS, CHEERIOS	17.9
Cereals ready-to-eat, QUAKER, Maple Brown Sugar LIFE Cereal	17.87
Cereals ready-to-eat, RALSTON TASTEEOS	17.86
Cereals, CREAM OF WHEAT, instant, dry	17.86
Cereals ready-to-eat, POST, HONEY BUNCHES OF OATS, honey roasted	17.8
Beverages, coffee substitute, cereal grain beverage, powder	17.66
Cereals ready-to-eat, frosted oat cereal with marshmallows	17.64
Cereals ready-to-eat, chocolate-flavored frosted puffed corn	17.64
Snacks, crisped rice bar, almond	17.64
Beef, variety meats and by-products, liver, cooked, braised	17.52
Beef, variety meats and by-products, liver, cooked, pan-fried	17.48
Cereals ready-to-eat, MALT-O-MEAL, Honey BUZZERS	17.24
Cereals ready-to-eat, MALT-O-MEAL, Cocoa DYNO-BITES	17.23
Cereals ready-to-eat, POST, COCOA PEBBLES	17.2
Cereals ready-to-eat, POST, GRAPE-NUTS Flakes	17.2
Cereals ready-to-eat, POST, HONEY BUNCHES OF OATS, pecan bunches	17.2
Cereals ready-to-eat, QUAKER, QUAKER OAT LIFE, plain	17.18
Cereals, MALT-O-MEAL, Maple & Brown Sugar Hot Wheat Cereal, dry	17.12
Cereals ready-to-eat, QUAKER, KING VITAMAN	16.84
Seeds, sisymbrium sp. seeds, whole, dried	16.82
Cereals ready-to-eat, POST, ALPHA-BITS	16.7
Cereals ready-to-eat, POST Bran Flakes	16.7
Cereals ready-to-eat, Post, Waffle Crisp	16.7
Cereals ready-to-eat, POST HONEY BUNCHES OF OATS with cinnamon bunches	16.7
Lamb, variety meats and by-products, liver, cooked, pan-fried	16.68
Cereals ready-to-eat, MALT-O-MEAL, MARSHMALLOW MATEYS	16.67
Cereals ready-to-eat, MALT-O-MEAL, COCO-ROOS	16.67

[Source ⁶⁹]

Table 2. Foods high in tryptophan (ordered from highest to low)

Description	Tryptophan (g) Value Per 100 gramm
Egg, white, dried, stabilized, glucose reduced	1.43
Egg, white, dried, powder, stabilized, glucose reduced	1.27
Egg, white, dried, flakes, stabilized, glucose reduced	1.18
Soy protein isolate	1.12
Soy protein isolate, potassium type	1.12
Seeds, sesame flour, low-fat	1.1
Egg, white, dried	1
Seaweed, spirulina, dried	0.93
Seeds, sesame flour, partially defatted	0.88
Soy protein concentrate, produced by alcohol extraction	0.83
Soy protein concentrate, produced by acid wash	0.83
Whale, beluga, meat, dried (Alaska Native)	0.8
Egg, whole, dried	0.78
Egg, whole, dried, stabilized, glucose reduced	0.77
Winged beans, mature seeds, raw	0.76
Seeds, cottonseed flour, low fat (glandless)	0.75
Tofu, dried-frozen (koyadofu)	0.75
Tofu, dried-frozen (koyadofu), prepared with calcium sulfate	0.75
Seeds, cottonseed meal, partially defatted (glandless)	0.74
Seeds, sunflower seed flour, partially defatted	0.73
Beverages, Protein powder soy based	0.72
Fish, cod, Atlantic, dried and salted	0.7
Soy flour, defatted	0.68
Seeds, sesame flour, high-fat	0.67
Soy meal, defatted, raw	0.65
Pork, fresh, variety meats and by-products, pancreas, cooked, braised	0.62
Seeds, cottonseed flour, partially defatted (glandless)	0.62
Mollusks, whelk, unspecified, cooked, moist heat	0.62
Soybeans, mature seeds, raw	0.59
Seeds, pumpkin and squash seed kernels, dried	0.58
Soybeans, mature seeds, dry roasted	0.57
Meat extender	0.57
Seeds, pumpkin and squash seed kernels, roasted, without salt	0.57
Seeds, pumpkin and squash seed kernels, roasted, with salt added	0.57
Cheese, parmesan, shredded	0.56
Cheese, mozzarella, low moisture, part-skim	0.55
Cheese, cheddar (Includes foods for USDA’s Food Distribution Program)	0.55
Game meat, elk, cooked, roasted	0.55
Leavening agents, yeast, baker’s, active dry	0.54
Parsley, freeze-dried	0.52
Cheese, mozzarella, whole milk	0.52
Soybeans, mature seeds, roasted, salted	0.51
Soybeans, mature seeds, roasted, no salt added	0.51
Milk, dry, nonfat, regular, without added vitamin A and vitamin D	0.51
Milk, dry, nonfat, regular, with added vitamin A and vitamin D	0.51
Peanut flour, defatted	0.51
Soy flour, full-fat, roasted	0.51
Soy flour, full-fat, raw	0.5
Milk, dry, nonfat, calcium reduced	0.5
Milk, dry, nonfat, instant, with added vitamin A and vitamin D	0.49
Milk, dry, nonfat, instant, without added vitamin A and vitamin D	0.49
Seeds, cottonseed kernels, roasted (glandless)	0.49
Milk, buttermilk, dried	0.48
Cheese, parmesan, hard	0.48
Spices, parsley, dried	0.47
Pork, cured, bacon, cooked, microwaved	0.46
Game meat, caribou, cooked, roasted	0.46
Seeds, chia seeds, dried	0.44
Game meat, rabbit, wild, cooked, stewed	0.44
Cheese, romano	0.43
Cheese, gruyere	0.42
Lamb, shoulder, arm, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	0.41
T.G.I. FRIDAY’S, classic sirloin steak (10 oz)	0.41
Game meat, elk, raw	0.41
CRACKER BARREL, grilled sirloin steak	0.41
Pork, ground, 96% lean / 4% fat, cooked, pan-broiled	0.41
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.41
Pork, fresh, variety meats and by-products, pancreas, raw	0.41
Pork, cured, bacon, pre-sliced, cooked, pan-fried	0.41
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.41
Beef, round, top round, separable lean only, trimmed to 0″ fat, choice, cooked, braised	0.41
Beef, round, top round, separable lean only, trimmed to 0″ fat, select, cooked, braised	0.41
Chicken, broiler or fryers, breast, skinless, boneless, meat only, cooked, braised	0.4
Goose, domesticated, meat only, cooked, roasted	0.4
Seeds, safflower seed meal, partially defatted	0.4
Game meat, goat, cooked, roasted	0.4
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	0.4
Cheese, swiss	0.4
Game meat, rabbit, domesticated, composite of cuts, cooked, stewed	0.4
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.4
Duck, young duckling, domesticated, White Pekin, leg, meat only, bone in, cooked without skin, braised	0.4
Beef, plate steak, boneless, inside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.4
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, choice, cooked, braised	0.4
Beef, round, top round, separable lean and fat, trimmed to 0″ fat, select, cooked, braised	0.4
Lamb, Australian, imported, fresh, shoulder, arm, separable lean only, trimmed to 1/8″ fat, cooked, braised	0.4
Cereals ready-to-eat, wheat germ, toasted, plain	0.4
Lamb, New Zealand, imported, frozen, shoulder, whole (arm and blade), separable lean only, cooked, braised	0.4
Seeds, sesame butter, paste	0.4
Pork, ground, 96% lean / 4% fat, cooked, crumbles	0.39
Beef, round, top round steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, grilled	0.39
Lamb, cubed for stew or kabob (leg and shoulder), separable lean only, trimmed to 1/4″ fat, cooked, braised	0.39
Seeds, sesame butter, tahini, from unroasted kernels (non-chemically removed seed coat)	0.39
Restaurant, family style, sirloin steak	0.39
Spices, fenugreek seed	0.39
Egg, yolk, dried	0.39
Chicken, broilers or fryers, breast, meat only, cooked, fried	0.39
Seeds, watermelon seed kernels, dried	0.39
Seeds, sesame butter, tahini, from raw and stone ground kernels	0.39
Beef, top loin filet, boneless, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	0.39
Seeds, sesame seeds, whole, dried	0.39
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, select, cooked, braised	0.39
Beef, loin, top loin steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	0.39
Chicken, stewing, light meat, meat only, cooked, stewed	0.39
Pork, fresh, loin, tenderloin, separable lean only, cooked, broiled	0.39
Beef, loin, top loin steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.39
Chicken, broiler or fryers, breast, skinless, boneless, meat only, cooked, grilled	0.39
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, all grades, cooked, braised	0.39
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	0.39
Beef, round, eye of round steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.39
Game meat, rabbit, domesticated, composite of cuts, cooked, roasted	0.38
Cheese, parmesan, grated	0.38
Chicken, broilers or fryers, light meat, meat only, cooked, fried	0.38
Lamb, shoulder, whole (arm and blade), separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	0.38
Beef, loin, top sirloin petite roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.38
Beef, round, top round, separable lean and fat, trimmed to 1/8″ fat, choice, cooked, braised	0.38
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	0.38
Beef, rib, back ribs, bone-in, separable lean only, trimmed to 0″ fat, select, cooked, braised	0.38
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	0.38
Duck, young duckling, domesticated, White Pekin, breast, meat only, boneless, cooked without skin, broiled	0.38
Game meat, boar, wild, cooked, roasted	0.38
DENNY’S, top sirloin steak	0.38
Lamb, shoulder, blade, separable lean only, trimmed to 1/4″ fat, choice, cooked, braised	0.38
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, select, cooked, braised	0.38
Beef, rib eye steak, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, grilled	0.38
Beef, rib eye steak, boneless, lip off, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.38
Beef, shank crosscuts, separable lean only, trimmed to 1/4″ fat, choice, cooked, simmered	0.38
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, roasted	0.38
Pork, fresh, loin, tenderloin, separable lean and fat, cooked, broiled	0.38
Snacks, soy chips or crisps, salted	0.38
Fish, roe, mixed species, cooked, dry heat	0.38
Beef, rib eye roast, boneless, lip-on, separable lean only, trimmed to 1/8″ fat, select, cooked, roasted	0.38
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, grilled	0.38
Pork, fresh, leg (ham), whole, separable lean only, cooked, roasted	0.37
Pork, fresh, loin, center rib (chops), boneless, separable lean only, cooked, broiled	0.37
Pork, fresh, composite of trimmed retail cuts (loin and shoulder blade), separable lean only, cooked	0.37
Beef, plate steak, boneless, outside skirt, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.37
Chicken, broilers or fryers, giblets, cooked, fried	0.37
Beef, chuck for stew, separable lean and fat, choice, cooked, braised	0.37
Turkey, retail parts, wing, meat only, cooked, roasted	0.37
Chicken, broiler or fryers, breast, skinless, boneless, meat only, with added solution, cooked, grilled	0.37
Ham and cheese spread	0.37
Seeds, sesame butter, tahini, from roasted and toasted kernels (most common type)	0.37
Veal, leg (top round), separable lean only, cooked, braised	0.37
Beef, chuck for stew, separable lean and fat, all grades, cooked, braised	0.37
Milk, dry, whole, with added vitamin D	0.37
Milk, dry, whole, without added vitamin D	0.37
Seeds, sesame seeds, whole, roasted and toasted	0.37
Seeds, sesame seed kernels, toasted, without salt added (decorticated)	0.37
Seeds, sesame meal, partially defatted	0.37
Seeds, sesame seed kernels, toasted, with salt added (decorticated)	0.37

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