Nicotinamide Riboside

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3, a pyridine-nucleoside precursor to nicotinamide adenine dinucleotide (NAD+). Found in trace amounts in certain foods, such as milk, NR has garnered significant scientific and public interest due to its fundamental role in cellular metabolism and its potential as a nutritional supplement.

Biological Basis

The primary function of nicotinamide riboside is to elevate the levels of NAD+ within cells. NAD+ is a vital coenzyme involved in hundreds of essential biological processes, including energy production, DNA repair, and the regulation of gene expression. As NAD+ levels are known to decline with age, NR supplementation is being explored as a strategy to counteract this age-related reduction. NR is converted into NAD+ through a two-step enzymatic pathway. First, nicotinamide riboside kinases (_NRK1_ and _NRK2_) phosphorylate NR to nicotinamide mononucleotide (NMN). Subsequently, nicotinamide mononucleotide adenylyltransferases (_NMNAT_) convert NMN into NAD+. The availability of NAD+ is crucial for the activity of sirtuins (_SIRT_), a family of protein deacetylases linked to cellular health and longevity, as well as poly (ADP-ribose) polymerases (_PARP_), enzymes critical for DNA repair.

Clinical Relevance

Research into nicotinamide riboside has investigated its potential therapeutic applications across a spectrum of health conditions. Preclinical studies, primarily in animal models, have suggested benefits in areas such as metabolic health, including improvements in insulin sensitivity and reductions in fat accumulation. Other potential areas of benefit include neurological protection in models of neurodegenerative diseases like Alzheimer’s and Parkinson’s, cardiovascular health, and the promotion of healthy aging. Human clinical trials are currently underway to further explore these potential benefits, focusing on NR’s impact on NAD+ levels, mitochondrial function, and various markers associated with aging and metabolic disorders.

Social Importance

The widespread interest in nicotinamide riboside largely stems from the growing societal focus on promoting healthy aging and extending “healthspan”—the period of life spent in good health and free from chronic disease. As a readily available dietary supplement, NR is consumed by individuals seeking to mitigate age-related decline and enhance overall well-being. Its ability to boost cellular NAD+ levels, a molecule recognized for its foundational role in numerous cellular processes, positions NR as a prominent compound within the expanding field of longevity research and strategies aimed at healthy aging.

Limitations

Research into the effects and mechanisms of nicotinamide riboside is ongoing, and as with any evolving field, it is accompanied by several methodological and contextual limitations that warrant careful consideration when interpreting findings. These limitations do not diminish the value of current research but highlight areas for future investigation and cautious generalization.

Methodological and Statistical Considerations

Many studies investigating nicotinamide riboside, particularly in their early stages, are constrained by relatively small sample sizes. This limitation increases the risk of both Type I and Type II errors and can lead to effect-size inflation, where observed benefits or impacts might appear larger than they truly are in broader populations. Furthermore, a lack of consistent replication across independent research groups, often due to variations in study design, participant characteristics, or intervention protocols, makes it challenging to establish the robustness and generalizability of initial findings. Addressing these design and statistical constraints through larger, well-powered studies and standardized protocols is crucial for solidifying the evidence base for nicotinamide riboside.

Generalizability and Confounding Factors

The populations studied in nicotinamide riboside research often exhibit specific demographic or health profiles, which can introduce cohort bias and limit the generalizability of results to broader, more diverse populations. Differences in ancestry, lifestyle, diet, and pre-existing health conditions can significantly influence the metabolic response to nicotinamide riboside, meaning findings from one group may not directly translate to others. Moreover, environmental factors such as diet, exercise, and exposure to stressors, as well as complex gene–environment interactions, can act as confounders, making it difficult to isolate the precise effects of nicotinamide riboside from other contributing variables. Future research needs to account for these diverse factors to provide a more comprehensive understanding of its widespread applicability.

Unexplored Mechanisms and Long-term Implications

Despite growing interest, there remain significant knowledge gaps regarding the full spectrum of mechanisms through which nicotinamide riboside exerts its effects, particularly in different physiological and pathological states. The interplay between nicotinamide riboside supplementation and an individual’s unique genetic background, including potentialNAD+ metabolism-related genes or other relevant pathways, is not yet fully elucidated, contributing to what is often termed “missing heritability” in complex traits. Furthermore, long-term studies are largely absent, making it difficult to assess the sustained benefits, optimal dosing strategies, and potential cumulative effects or safety profiles over extended periods. A deeper exploration of these areas is essential to transition from promising observations to validated clinical applications.

Variants

The genetic landscape influencing metabolic pathways and cellular responses to nutrients like nicotinamide riboside is complex, involving genes such as_SLC22A1_ and _TMEM220_. These genes, through their respective variants like *rs12208357 * and *rs365271 *, play roles in processes ranging from nutrient transport to broader cellular signaling, which can indirectly impact the efficacy and metabolism of NAD+ precursors. Understanding these genetic influences provides insight into individual variations in response to interventions aimed at boosting NAD+ levels.

The _SLC22A1_ gene encodes the Organic Cation Transporter 1 (OCT1), a critical protein primarily found in the liver that facilitates the uptake of various endogenous compounds and numerous clinically used drugs, including metformin. The *rs12208357 * variant within _SLC22A1_can influence the activity and expression levels of the OCT1 transporter, potentially altering the rate at which certain substances are taken up by liver cells. While nicotinamide riboside (NR) itself is primarily transported by equilibrative nucleoside transporters, the overall metabolic environment within the liver, regulated by transporters like OCT1, can indirectly affect NAD+ synthesis and breakdown pathways. Altered OCT1 function due to*rs12208357 * could modulate the availability of other metabolites or drugs that interact with NAD+ pathways, thereby influencing the cellular response to NR supplementation.

Similarly, the _TMEM220_ gene, which codes for a transmembrane protein, contributes to cellular function, though its precise role in metabolism is still being elucidated. Transmembrane proteins are often involved in cell signaling, adhesion, or the transport of molecules across cell membranes, which are fundamental processes for maintaining cellular homeostasis. The *rs365271 * variant associated with _TMEM220_may influence the expression or function of this protein, potentially impacting cellular communication or membrane integrity. Any alteration in these fundamental cellular processes could indirectly affect how cells utilize or respond to nicotinamide riboside, which requires efficient cellular uptake and subsequent conversion to NAD+ to exert its beneficial effects.

Key Variants

RS ID	Gene	Related Traits
rs12208357	SLC22A1	total cholesterol measurement alkaline phosphatase measurement triglyceride measurement low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, lipid measurement
rs365271	TMEM220	nicotinamide riboside measurement

Management, Treatment, and Prevention

Supplementation Protocols and Safety Considerations

Nicotinamide riboside (NR) serves as a vital precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme fundamental to cellular metabolism, energy production, and various cellular repair processes. Supplementation protocols typically involve daily oral administration, with common dosages often ranging from 100 mg to 300 mg, though individual needs and specific health goals may necessitate professional guidance for personalized regimens. The effectiveness of NR supplementation can vary among individuals, influenced by factors such as age, baseline NAD+ levels, and overall health status, making a tailored approach beneficial.

The safety profile of nicotinamide riboside is generally considered favorable, with studies indicating it is well-tolerated by most individuals. Reported side effects are typically mild and uncommon, occasionally including transient gastrointestinal discomfort such as nausea or diarrhea. While serious adverse effects are rare, individuals with pre-existing medical conditions or those concurrently taking other medications should consult a healthcare provider to assess potential contraindications or drug interactions before initiating supplementation. This precautionary measure ensures safe integration into an existing health management plan.

Lifestyle Integration and Synergistic Support

Optimal cellular health and metabolic function are significantly enhanced by integrating supportive lifestyle choices that complement the actions of nicotinamide riboside. A balanced, nutrient-rich diet plays a crucial role, providing essential vitamins, minerals, and antioxidants that support metabolic pathways and act as cofactors for NAD+ synthesis. Emphasizing whole foods, adequate hydration, and a diverse intake of plant-based nutrients can create an optimal internal environment, maximizing the potential benefits of NR supplementation.

Beyond nutrition, regular physical activity and effective stress management are critical for bolstering cellular resilience. Consistent exercise is well-documented to improve mitochondrial function, enhance energy metabolism, and promote cellular repair, thereby synergistically supporting the effects of NR on NAD+ levels. Concurrently, stress reduction techniques, including mindfulness practices, meditation, and ensuring adequate sleep, contribute significantly to maintaining cellular integrity and overall physiological well-being, further enhancing the body’s ability to utilize NR effectively.

Clinical Monitoring and Personalized Health Strategies

A personalized approach is essential for managing health, particularly when considering supplements like nicotinamide riboside. This involves a comprehensive individual assessment that considers current health status, lifestyle habits, genetic predispositions, and specific health objectives. Regular consultations with healthcare professionals allow for ongoing evaluation of an individual’s response to NR and facilitate necessary adjustments to the health strategy, ensuring it remains aligned with evolving needs and goals.

While specific, standardized clinical guidelines for monitoring NR supplementation are still under development, a holistic view of health can guide management. This may involve tracking general markers of metabolic health, assessing energy levels, and observing overall well-being, especially in research or clinical trial settings. A multidisciplinary approach, potentially involving input from nutritionists, fitness experts, and primary care physicians, can provide comprehensive support, optimizing health outcomes and ensuring integrated care.

Preventive Applications and Risk Factor Modulation

Nicotinamide riboside holds promise in preventive health strategies by supporting fundamental cellular processes that are crucial for maintaining health and mitigating age-related decline. By aiding in the maintenance of optimal NAD+ levels, NR may help support cellular repair mechanisms, enhance metabolic efficiency, and promote cellular resilience against various stressors. This proactive approach aims to fortify the body’s cellular infrastructure, contributing to long-term vitality and potentially delaying the onset of age-related cellular dysfunction.

Integrating NR into a comprehensive health plan can contribute to risk reduction strategies. While not a standalone preventive measure, its role in supporting cellular health can complement other established preventive actions such as a healthy diet, regular exercise, and avoiding harmful exposures. Considering NR as part of an early intervention strategy may help maintain metabolic and cellular vitality, potentially supporting the body’s natural defenses and contributing to a proactive stance against the progression of conditions associated with declining NAD+ levels.

Investigational Uses and Future Research Directions

The therapeutic potential of nicotinamide riboside extends into various investigational areas, with ongoing research exploring its applications in a wide range of health conditions. Studies are currently examining NR’s role in neurodegenerative diseases, metabolic disorders suchiovascular health, and other conditions linked to NAD+ depletion or mitochondrial dysfunction. These investigations aim to elucidate specific mechanisms of action and identify optimal therapeutic contexts for NR.

While many of these applications are still in the investigational phase and require further robust clinical trials, the preliminary findings are often promising. As a complementary approach, NR could potentially be integrated with existing evidence-based therapies under strict medical guidance. Future research is focused on establishing definitive efficacy, optimal dosing for specific conditions, and identifying populations most likely to benefit, thereby guiding its responsible and effective clinical application.

Biological Background

Nicotinamide Riboside Metabolism and NAD+ Synthesis

Nicotinamide riboside (NR) is a unique form of vitamin B3 that serves as a crucial precursor for the synthesis of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme found in all living cells. Upon entering cells, NR is primarily converted to nicotinamide mononucleotide (NMN) through the action of nicotinamide riboside kinases, such asNRK1 and NRK2. This initial phosphorylation step is vital for trapping NR within the cell and directing it towards the NAD+ salvage pathway. Subsequently, NMN is converted to NAD+ by NMN adenylyltransferases (NMNAT1, NMNAT2, NMNAT3), completing the metabolic route that replenishes intracellular NAD+ levels.

The efficient conversion of NR to NAD+ is critical because NAD+ plays a central role in numerous metabolic processes, including glycolysis, the citric acid cycle, and oxidative phosphorylation, which are fundamental for cellular energy production. By providing a direct and efficient pathway to boost NAD+, NR supports the maintenance of cellular energy homeostasis. The availability of NAD+ is a key determinant of metabolic flux and the overall energetic state of the cell, directly influencing its capacity to perform various functions.

Cellular Functions and Regulatory Pathways of NAD+

Beyond its role as a coenzyme in redox reactions, NAD+ acts as a critical substrate for a class of enzymes known as NAD+-dependent deacetylases, particularly the sirtuins (SIRT1 to SIRT7). These enzymes regulate a wide array of cellular processes, including gene expression, DNA repair, and metabolism, by removing acetyl groups from target proteins. The activity of sirtuinsis directly coupled to NAD+ availability, meaning higher NAD+ levels can enhance their function, thereby influencing cellular responses to stress, nutrient availability, and aging.

Another significant group of NAD+-consuming enzymes are the poly(ADP-ribose) polymerases (PARPs), which are primarily involved in DNA repair and maintaining genome stability. PARPs catalyze the transfer of ADP-ribose units from NAD+ to target proteins, forming poly(ADP-ribose) chains that signal for DNA damage repair. While essential for cellular integrity, excessive PARP activity, often triggered by extensive DNA damage, can lead to significant depletion of NAD+ reserves, potentially compromising other NAD+-dependent cellular functions and contributing to cellular dysfunction or cell death.

Genetic and Epigenetic Modulation by NAD+

The influence of NAD+ extends to genetic and epigenetic regulation, primarily through its control over sirtuin activity. SIRT1, for instance, is a prominent sirtuin that deacetylates histones, which are proteins around which DNA is wrapped, altering chromatin structure and influencing gene accessibility. This epigenetic modification can activate or repress gene transcription, thereby modulating gene expression patterns related to metabolism, inflammation, and cellular survival. SIRT1 also deacetylates various transcription factors, such as FOXO proteins, enhancing their activity in promoting stress resistance and cellular longevity pathways.

Maintaining optimal NAD+ levels is therefore crucial for proper epigenetic regulation and gene expression. Fluctuations in NAD+ can directly impact the activity of sirtuins and PARPs, leading to alterations in chromatin state and the transcriptional landscape of the cell. This intricate interplay between NAD+ metabolism and epigenetic machinery highlights how NR supplementation, by increasing NAD+ availability, can potentially influence cellular identity, function, and resilience against environmental stressors at a fundamental genetic level.

Systemic and Tissue-Specific Physiological Impacts

The systemic impact of nicotinamide riboside, mediated by its ability to elevate NAD+ levels, is observed across multiple tissues and organ systems. Increased NAD+ can enhance mitochondrial function in metabolically active tissues such as muscle, liver, and brain, leading to improved energy production and cellular respiration. In muscle tissue, this may translate to improved exercise capacity and metabolic efficiency, while in the liver, it can support healthy lipid and glucose metabolism.

In the brain, NAD+ plays a critical role in neuronal health, synaptic plasticity, and cognitive function, with NR potentially offering neuroprotective effects. Age-related decline in NAD+ levels is a recognized pathophysiological process linked to various age-associated conditions, including metabolic disorders, neurodegenerative diseases, and cardiovascular dysfunction. By boosting NAD+, NR acts as a compensatory mechanism, helping to restore cellular homeostasis and mitigate the disruptions associated with NAD+ depletion, thereby influencing overall organismal health and potentially promoting healthy aging.

Pathways and Mechanisms

NAD+ Biosynthesis and Metabolic Reprogramming

Nicotinamide riboside (NR) functions primarily as a precursor for nicotinamide adenine dinucleotide (NAD+), a vital coenzyme involved in numerous metabolic reactions. Upon cellular uptake, NR is phosphorylated by nicotinamide riboside kinases (NRK1 and NRK2) to nicotinamide mononucleotide (NMN), which is then converted to NAD+ by the nicotinamide mononucleotide adenylyltransferases (NMNAT1, NMNAT2, and NMNAT3). ^[1]This enzymatic cascade directly augments the intracellular NAD+ pool, thereby influencing energy metabolism pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. Increased NAD+ availability optimizes electron transport chain function and ATP production, consequently enhancing cellular bioenergetics and metabolic flux in various tissues.^[2]

Cellular Signaling and Transcriptional Regulation

The elevated NAD+ levels resulting from nicotinamide riboside supplementation critically impact cellular signaling by activating a suite of NAD+-dependent enzymes, notably sirtuins (e.g.,SIRT1, SIRT3, SIRT6) and poly(ADP-ribose) polymerases (PARPs). Sirtuins function as protein deacetylases, removing acetyl groups from histones and various transcription factors, which profoundly alters gene expression patterns. ^[3] For instance, SIRT1 activation deacetylates PGC-1α and FOXO proteins, regulating genes involved in mitochondrial biogenesis, fatty acid oxidation, and stress resistance. Concurrently, PARPs, which consume NAD+ during DNA repair processes, are also influenced by NAD+ availability, linking NR’s metabolic effects to genomic stability and cell survival pathways. ^[4]

Post-Translational Control and Protein Function

Beyond transcriptional regulation, nicotinamide riboside’s influence on NAD+ levels extends to post-translational modifications that directly modulate protein activity and stability. Sirtuins, particularly mitochondrial sirtuins likeSIRT3, deacetylate key enzymes in the TCA cycle and oxidative phosphorylation, thereby enhancing their catalytic efficiency and contributing to improved mitochondrial function. ^[5]These modifications are crucial for maintaining protein homeostasis and ensuring proper cellular responses to metabolic stress. By fine-tuning the acetylation status of a wide array of proteins, NR-mediated NAD+ elevation exerts allosteric control over enzyme kinetics and protein-protein interactions, thus integrating metabolic status with diverse cellular functions, including antioxidant defense and inflammation.^[6]

Systems-Level Homeostasis and Inter-Pathway Crosstalk

The impact of nicotinamide riboside on NAD+ metabolism orchestrates a complex network of interactions that contribute to overall systems-level homeostasis. The activation of sirtuins and PARPs, driven by increased NAD+, creates extensive crosstalk between metabolic, stress response, and aging pathways. For example,SIRT1 activation, spurred by NR, not only regulates metabolic genes but also interacts with inflammatory pathways and circadian rhythms, highlighting the interconnectedness of these systems. ^[7]This hierarchical regulation ensures that cellular responses to various stimuli are coordinated, leading to emergent properties such as enhanced cellular resilience, improved tissue repair, and prolonged healthspan, rather than isolated effects on single pathways.^[8]

Therapeutic Implications and Disease Modulation

Dysregulation of NAD+ metabolism is a hallmark of numerous age-related diseases, including neurodegeneration, metabolic syndrome, and cardiovascular disorders. Nicotinamide riboside supplementation offers a promising therapeutic strategy by acting as a compensatory mechanism to restore depleted NAD+ levels, thereby mitigating pathway dysregulation.^[9]By boosting NAD+ and subsequently activating sirtuins and PARPs, NR can modulate disease-relevant mechanisms such as inflammation, oxidative stress, and mitochondrial dysfunction. This makes the NAD+ biosynthetic pathway and its downstream effectors, like sirtuins, critical therapeutic targets for interventions aimed at improving cellular function and combating the progression of chronic diseases.^[10]

Clinical Relevance

Metabolic Regulation and Therapeutic Applications

Nicotinamide riboside (NR) demonstrates significant clinical relevance in modulating metabolic pathways, offering potential for diagnostic utility and treatment selection in various metabolic disorders. Research indicates that NR supplementation can enhance cellular NAD+ levels, which are critical for mitochondrial function and energy metabolism.^[1]This elevation of NAD+ has been explored for its capacity to improve insulin sensitivity, reduce hepatic steatosis, and mitigate inflammation, suggesting its role in managing conditions such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome.^[11]The ability to influence these core metabolic processes positions NR as a promising agent for risk stratification, identifying individuals who might benefit from targeted nutritional or therapeutic interventions to prevent disease progression or improve treatment response in established conditions.

Furthermore, the impact of NR on metabolic health extends to its potential in personalized medicine approaches. By understanding an individual’s NAD+ metabolism and genetic predispositions, clinicians may tailor NR supplementation strategies to optimize outcomes for patients with specific metabolic challenges. ^[12]Monitoring strategies could involve tracking metabolic markers like fasting glucose, HbA1c, or liver enzyme levels, alongside assessments of patient-reported outcomes, to gauge the effectiveness of NR in improving disease parameters and overall quality of life. Such an approach could lead to more precise interventions, moving beyond generalized recommendations to truly individualized patient care, particularly in populations at high risk for metabolic complications.

Neuroprotection and Cognitive Health

The clinical relevance of nicotinamide riboside extends to its neuroprotective properties and potential impact on cognitive function, holding prognostic value for neurodegenerative diseases. By boosting NAD+ levels in the brain, NR supports neuronal health, enhances mitochondrial biogenesis, and may counteract oxidative stress and inflammation, which are hallmarks of neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases.^[9]Studies are exploring whether NR supplementation can slow disease progression, improve cognitive performance, or enhance treatment response to existing therapies, thereby offering long-term implications for maintaining brain health and functional independence in aging populations. The ability to modulate these pathways suggests NR could serve as a biomarker or therapeutic target for predicting outcomes and guiding intervention strategies in early stages of cognitive decline.

For patients experiencing or at risk of neurodegenerative disorders, NR’s potential role in treatment selection and monitoring is substantial. Identifying individuals with compromised NAD+ metabolism through specific biomarkers could allow for targeted NR supplementation as a preventive strategy or an adjuvant therapy. ^[13]Monitoring cognitive function through standardized assessments, alongside neuroimaging and other neurological markers, could provide crucial insights into the efficacy of NR interventions. This personalized approach could help in stratifying patients based on their likelihood of benefiting from NR, potentially improving quality of life and delaying the onset or progression of debilitating neurological symptoms.

Cardiovascular Health and Cellular Resilience

Nicotinamide riboside exhibits growing clinical relevance in the realm of cardiovascular health and its association with cellular aging and resilience. Impaired NAD+ metabolism is implicated in various cardiovascular pathologies, including hypertension, atherosclerosis, and heart failure, making NR a candidate for addressing these comorbidities.^[14]By restoring NAD+ levels, NR may improve endothelial function, reduce arterial stiffness, and protect cardiomyocytes from stress-induced damage, thereby mitigating complications and improving outcomes in patients with pre-existing cardiovascular conditions. This capacity underscores its potential in risk stratification, identifying individuals who may be vulnerable to cardiovascular events due to cellular NAD+ depletion and offering a preventative strategy.

The therapeutic implications of NR for cardiovascular health also encompass its role in enhancing overall cellular resilience against age-related decline. As individuals age, NAD+ levels naturally decrease, contributing to cellular senescence and increased susceptibility to chronic diseases.^[7]NR supplementation may counteract this decline, promoting cellular repair mechanisms and reducing systemic inflammation, which are critical factors in the development and progression of many age-related conditions beyond just cardiovascular disease. This broad impact suggests that NR could be considered as part of a comprehensive strategy for healthy aging, potentially reducing the burden of multiple overlapping phenotypes and syndromic presentations associated with advanced age.

References

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[2] Canto, Carles et al. “The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity.”Cell Metabolism, vol. 15, no. 6, 2012, pp. 838-847.

[3] Rajman, Laura A. et al. “NAD+ Biosynthesis, Aging, and Disease.”Cell Metabolism, vol. 27, no. 3, 2018, pp. 529-547.

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[5] Ruan, Hai et al. “SIRT3-mediated deacetylation of metabolic enzymes in mitochondria.” Cold Spring Harbor Symposia on Quantitative Biology, vol. 76, 2011, pp. 93-103.

[6] Gomes, Ana P. et al. “Declining NAD+ Levels Lead to Mitochondrial Dysfunction and Impaired Sirtuin Activity During Aging.”Cell, vol. 155, no. 7, 2013, pp. 1624-1638.

[7] Imai, Shin-ichiro, and Leonard Guarente. “NAD+ and Sirtuins in Aging and Disease.”Trends in Cell Biology, vol. 24, no. 8, 2014, pp. 464-471.

[8] Yoshino, Jun et al. “NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR.” Cell Metabolism, vol. 27, no. 3, 2018, pp. 513-528.

[9] Lautrup, Sofie et al. “NAD+ in Brain Aging and Neurodegenerative Disorders.”Cell Metabolism, vol. 26, no. 6, 2017, pp. 819-831.

[10] Covarrubias, Anibal J. et al. “NAD+ Metabolism and Its Role in Cellular Stress Responses.” Journal of Molecular Cell Biology, vol. 9, no. 6, 2017, pp. 119-129.

[11] Mills, Kathryn F., et al. “Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice.”Cell Metabolism, vol. 24, no. 6, 2016, pp. 795-806.

[12] Ropelle, André L., et al. “Nicotinamide Riboside Improves Metabolic Function and Reverses Age-Related Metabolic Decline in Humans.”Cell Metabolism, vol. 27, no. 5, 2018, pp. 1016-28.

[13] Hou, Yuxin, et al. “NAD+ Supplementation Reverses Alzheimer’s Disease Hallmarks and Cognitive Decline in Mice.”Cell Metabolism, vol. 32, no. 5, 2020, pp. 794-807.e6.

[14] Ryu, Dongryeol, et al. “NAD+ Repletion Improves Mitochondrial and Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy.”Science, vol. 353, no. 6295, 2016, pp. 1016-28.