NAD+ sits at the center of how your cells make energy and fix damage, and its levels reliably drop as you get older. That decline has fueled a wave of products - pills like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), plus IV drips - that promise to restore youthful NAD+ levels. Animal studies are genuinely exciting: mice live longer, recover better, and develop less age-related disease when researchers boost their NAD+. Human research is catching up. It shows these pills are safe and do raise NAD+ in the body, but proof that this translates into feeling or functioning better is still thin and mixed.
How strong is the evidence?
This is one of the most heavily discussed topics in aging science, but most of that attention is theory and mouse data, not proof in people. Of the 40 papers reviewed here, the large majority are reviews and lab or animal studies explaining how NAD+ works and why researchers are excited about it. Only a handful are real human trials - a 21-day trial of nicotinamide riboside in older men and a 10-week NMN trial in prediabetic women are the clearest examples. A large 2026 systematic review pooling 113 studies (33 of them in humans, 28 randomized) found that oral NAD+ boosters reliably raise NAD+ levels in the body and are generally safe, but their effects on how people actually feel or function were 'heterogeneous and often null.' IV NAD+ has essentially no controlled human outcome data behind it at all - only one small non-randomized safety study. Bottom line: solid biology, encouraging animal data, and safe-but-unproven results in people.
Uses
What people use it for
Anti-aging / longevity support
TheoryThe main reason people take NAD+ boosters. The idea is to refill a molecule that naturally declines with age and is tied to energy, DNA repair, and inflammation control.
Metabolic and blood sugar support
Some human dataStudied in people with prediabetes to see if it improves how the body handles insulin and blood sugar.
General energy and fatigue
TheoryMarketed for energy because NAD+ is central to how cells burn fuel, but no trial in this file tested self-reported energy or fatigue as an outcome.
Cognitive and neurodegenerative disease support
Animal / labBeing researched for Alzheimer's, Parkinson's, and glaucoma because low NAD+ shows up in aging, damaged brain and nerve cells. So far this is animal and lab evidence, not proven in people.
Potential benefits
What it may help with
May improve insulin sensitivity in prediabetes
Some human dataIn a 10-week randomized, placebo-controlled trial, postmenopausal women with prediabetes who were overweight or obese took NMN (a building block the body turns into NAD+). Their muscles got better at pulling sugar out of the blood after NMN, but not after placebo. This is a real controlled human trial, not just a lab finding.
Studies:33888596May raise muscle NAD+ and calm inflammation in older adults
Some human dataIn a 3-week trial, older men who took 1 gram of nicotinamide riboside (NR) a day saw their muscle NAD+ building blocks go up and their blood levels of inflammatory markers go down. Muscle strength or performance wasn't measured, so this shows a change in body chemistry, not a felt result.
Studies:31412242Tracks with muscle strength in aging and sarcopenia
Some human dataPeople with age-related muscle loss (sarcopenia) tend to have lower blood levels of trigonelline, a natural NAD+ building block, and higher levels line up with better muscle strength. This is an observed pattern in people, not proof that taking a supplement fixes muscle loss.
Studies:38504132Early hints of broader benefits in small human studies
Some human dataA major review of early human research found hints that NAD+ boosting may modestly lower blood pressure, improve cholesterol, help prevent a common skin cancer, protect kidneys in at-risk patients, and calm inflammation in Parkinson's disease and COVID-19. These are early, small findings that still need to be confirmed in larger trials.
Studies:37364580Protects brain cells from inflammation and damage (animal research)
Animal / labIn mice bred to develop Alzheimer's-like disease, boosting NAD+ with nicotinamide riboside cut brain inflammation, reduced DNA damage, and improved memory and learning. This hasn't been tested in people with Alzheimer's.
Studies:34497121May protect against age-related vision loss (animal research)
Animal / labIn mice prone to glaucoma, giving vitamin B3 (a building block for NAD+) by mouth stopped the disease from developing in 93% of eyes at the highest dose tested. This is one of the most striking animal results in NAD+ research, but it hasn't been tested in people with glaucoma.
Studies:28209901May extend lifespan and refresh stem cells (animal research)
Animal / labIn mice, restoring NAD+ with nicotinamide riboside rejuvenated aging muscle, brain, and skin stem cells and extended how long the animals lived. This is a foundational study behind the whole NAD+ trend, but mouse lifespan results don't automatically carry over to people.
Studies:27127236May help aging eggs and fertility (animal research)
Animal / labIn older female mice, restoring NAD+ with NMN improved egg quality and fertility and reversed some effects of reproductive aging. Human studies haven't confirmed this.
May help joint health in osteoarthritis (early lab research)
Animal / labA specially designed NAD+-releasing gel injected directly into joints reduced joint aging and inflammation in mice with osteoarthritis. This is very early-stage research using an experimental delivery method, not something tested or available for people.
Studies:40315404
What to watch for
Side effects & risks
- Mild
Appears safe and well tolerated in short-term studies
Across human trials lasting weeks to months, people taking oral NAD+ building blocks like NMN and NR haven't shown serious safety problems. Researchers who reviewed the field describe these compounds as generally safe and well tolerated at the doses studied.
- Moderate
- Moderate
IV/injectable NAD+ hasn't actually been tested in controlled human trials
Despite IV NAD+ infusions being popular at wellness clinics, a 2026 systematic review of the entire field found no controlled outcome trials of intravenous or intramuscular NAD+ - just one small non-randomized safety and biomarker study. People commonly report flushing, nausea, or chest tightness during rapid IV infusions, but that's clinic experience, not published trial data.
Dosing
Dosing — what studies used
There's no single proven dose of NAD+. Almost all human research has actually tested NAD+'s precursor building blocks - nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) - taken as daily oral pills, not NAD+ itself. The best-documented human dose is 1 gram of NR per day for 3 weeks. Another key human trial tested NMN over 10 weeks for insulin sensitivity, but the published abstract doesn't spell out the exact milligram dose used. IV NAD+, despite being popular at wellness clinics, has essentially no published controlled-trial dosing data behind it at all - a major 2026 review found no outcome trials of the injectable form. Treat any dose you see online as a starting point for a conversation with a doctor, not an established medical standard.
Muscle NAD+ and inflammation in older men (research setting)
Human trial1 gram nicotinamide riboside (NR)
Once daily · 21 days · Oral
Placebo-controlled, randomized, double-blind crossover trial in 12 healthy older men. Raised muscle NAD+ building blocks and lowered inflammatory markers, but didn't test strength, symptoms, or function.
Insulin sensitivity in prediabetic women (research setting)
Human trialNot specified in the published abstract
Daily · 10 weeks · Oral
Randomized, placebo-controlled trial of NMN in postmenopausal women with prediabetes who were overweight or obese. The exact milligram dose isn't stated in the abstract (registered as ClinicalTrials.gov NCT03151239).
IV or injectable NAD+ (as offered at wellness clinics)
Community reportsNot established
Not established · Not established · Intravenous
A 2026 systematic review of the field found zero controlled human outcome trials of IV or intramuscular NAD+. Clinic protocols and doses currently in use are not derived from published clinical evidence.
Dosing in human trials of NAD+ precursors has varied widely across studies, and published abstracts often don't give exact milligram amounts (see PMID 37068054, which reviews this inconsistency directly). Nothing in this file should be read as an approved medical dose.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Every cell in your body uses NAD+ like a rechargeable battery for turning food into usable energy. It also fuels a group of repair proteins called sirtuins that help fix damaged DNA, control inflammation, and keep your cell's energy factories (mitochondria) running well. As you age, NAD+ levels naturally fall, and low NAD+ has been linked to slower repair, more inflammation, and weaker mitochondria. The idea behind NAD+ supplements is to refill the tank. Pills like NMN and NR are 'precursor' molecules - raw materials your cells convert into NAD+ once absorbed. IV drips deliver NAD+ itself straight into the bloodstream, skipping digestion, though it's unclear how much of it actually gets inside the cells where it's needed.
Who should avoid it
- Pregnant or breastfeeding people (no safety data exists)
- Anyone with active cancer or a cancer history, without their oncologist's sign-off, since NAD+ pathways are involved in cell growth and DNA repair and are an active area of cancer research
- Children (no pediatric data)
- Anyone expecting dramatic, fast anti-aging results - current human evidence doesn't support that expectation
Interactions to know
- No confirmed drug interactions have been established in human studies to date
- Caution advised if you're undergoing chemotherapy or other cancer treatment, since NAD+ pathways are tied up in cell growth and DNA repair - check with your oncologist first
- Talk to your doctor before combining with diabetes medication, since early data suggests NAD+ precursors can affect insulin sensitivity and blood sugar
- Nicotinic acid (a niacin-type NAD+ precursor, different from NMN/NR) is known to interact with statins and blood pressure medicines and can cause a hot, flushed feeling - know which form you're taking
The papers that matter most
Key studies
Pooling 113 studies (33 in humans, 28 randomized), oral NAD+ boosters reliably raise NAD+ and are safe, but effects on real-world function were often null. No controlled outcome trials of IV/IM NAD+ exist at all.
NAD+ supplementation for anti-aging and wellness: A PRISMA-guided systematic review of preclinical and clinical evidence
A 10-week RCT in overweight/obese prediabetic women found NMN improved how muscle responds to insulin - one of the clearest positive human results in this file.
Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women
1 g/day of NR for 21 days raised muscle NAD+ building blocks and lowered inflammatory markers in older men, but didn't test strength or symptoms.
Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures
Reviews human trials of NAD+ precursors: supplementation is safe and raises NAD+ levels, but doses and study lengths vary widely and small sample sizes limit what can be concluded about real benefits.
Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions
Foundational mouse study showing NR restored aging stem cells and extended lifespan - a major reason the NAD+ field took off, though it's mouse data, not human proof.
NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice
Cautions that age-related NAD+ decline has only been confirmed in a limited number of human studies, and that human trials of NAD+ precursors have shown limited efficacy so far.
NAD+ precursor supplementation in human ageing: clinical evidence and challenges
Bottom line
NAD+ boosting is backed by real biology and looks safe to try, but don't expect a proven anti-aging fix - the best human trials show it raises NAD+ levels in the body without reliably changing how people feel or function, and IV versions have essentially no controlled trial evidence behind them at all.
Research papers
Studies we have on file for NAD+. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
NAD+ metabolism and its roles in cellular processes during ageing.
Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.
NAD+ and sirtuins in aging and disease.
Nicotinamide adenine dinucleotide (NAD(+)) is a classical coenzyme mediating many redox reactions. NAD(+) also plays an important role in the regulation of NAD(+)-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD(+) biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD(+) levels decline during the aging process and may be an Achilles' heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD(+) by supplementing NAD(+) intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.
The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update.
The importance of nicotinamide adenine dinucleotide (NAD+) in human physiology is well recognized. As the NAD+ concentration in human skin, blood, liver, muscle, and brain are thought to decrease with age, finding ways to increase NAD+ status could possibly influence the aging process and associated metabolic sequelae. Nicotinamide mononucleotide (NMN) is a precursor for NAD+ biosynthesis, and in vitro/in vivo studies have demonstrated that NMN supplementation increases NAD+ concentration and could mitigate aging-related disorders such as oxidative stress, DNA damage, neurodegeneration, and inflammatory responses. The promotion of NMN as an antiaging health supplement has gained popularity due to such findings; however, since most studies evaluating the effects of NMN have been conducted in cell or animal models, a concern remains regarding the safety and physiological effects of NMN supplementation in the human population. Nonetheless, a dozen human clinical trials with NMN supplementation are currently underway. This review summarizes the current progress of these trials and NMN/NAD+ biology to clarify the potential effects of NMN supplementation and to shed light on future study directions.
NAD⁺ in aging, metabolism, and neurodegeneration.
Nicotinamide adenine dinucleotide (NAD(+)) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate-ribose) polymerases. Cellular NAD(+) concentrations change during aging, and modulation of NAD(+) usage or production can prolong both health span and life span. Here we review factors that regulate NAD(+) and discuss how supplementation with NAD(+) precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases.
NAD metabolism: Role in senescence regulation and aging.
The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD+ can promote the development of senescence. On the other hand, the low NAD+ state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD+ metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.
NAD+ homeostasis in health and disease.
The conceptual evolution of nicotinamide adenine dinucleotide (NAD+) from being seen as a simple metabolic cofactor to a pivotal cosubstrate for proteins regulating metabolism and longevity, including the sirtuin family of protein deacylases, has led to a new wave of scientific interest in NAD+. NAD+ levels decline during ageing, and alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. In preclinical settings, various strategies to increase NAD+ levels have shown beneficial effects, thus starting a competitive race to discover marketable NAD+ boosters to improve healthspan and lifespan. Here, we review the basics of NAD+ biochemistry and metabolism, and its roles in health and disease, and we discuss current challenges and the future translational potential of NAD+ research.
Nicotinamide mononucleotide (NMN) as an anti-aging health product - Promises and safety concerns.
Elderly population has been progressively rising in the world, thus the demand for anti-aging heath products to assure longevity as well as to ameliorate age-related complications is also on the rise. Among various anti-aging health products, nicotinamide mononucleotide (NMN) has been gaining attentions of the consumers and the scientific community. This article intends to provide an overview on the current knowledge on promises and safety concerns of NMN as an anti-aging health product. Nicotinamide adenine dinucleotide (NAD+) levels in the body deplete with aging and it is associated with downregulation of energy production in mitochondria, oxidative stress, DNA damage, cognitive impairment and inflammatory conditions. However, NMN, as the precursor of NAD+, can slow down this process by elevating NAD+ levels in the body. A number of in vivo studies have indicated affirmative results of therapeutic effects for various age-induced complications with NMN supplementation. One preclinical and one clinical study have been conducted to investigate the safety concerns of NMN administration while a few more human clinical trials are being conducted. As there is a large influx of NMN based anti-aging products on the market, proper clinical investigations are urgently needed to find out the effectiveness and safety of NMN supplementation.
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential.
Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.
The kynurenine pathway: a finger in every pie.
The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.
NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR.
Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.
Sirtuin family in autoimmune diseases.
In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation and immune responses by influencing the epigenome, which can lead to abnormal autoimmune responses in the body. Currently, an increasing number of studies have emphasized the important role of epigenetic modification in the progression of autoimmune diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and SIRT-mediated deacetylation is an important epigenetic alteration. The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus. SIRTs are key regulators of various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, immune response, oxidative stress, and mitochondrial function. We discuss the association between SIRTs and common autoimmune diseases to facilitate the development of more effective therapeutic strategies.
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence.
Nicotinamide adenine dinucleotide (NAD), the cell's hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.
Molecular mechanisms of dietary restriction promoting health and longevity.
Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.
Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current Knowledge and Future Directions.
Advancing age and many disease states are associated with declines in nicotinamide adenine dinucleotide (NAD+) levels. Preclinical studies suggest that boosting NAD+ abundance with precursor compounds, such as nicotinamide riboside or nicotinamide mononucleotide, has profound effects on physiological function in models of aging and disease. Translation of these compounds for oral supplementation in humans has been increasingly studied within the last 10 years; however, the clinical evidence that raising NAD+ concentrations can improve physiological function is unclear. The goal of this review was to synthesize the published literature on the effects of chronic oral supplementation with NAD+ precursors on healthy aging and age-related chronic diseases. We identified nicotinamide riboside, nicotinamide riboside co-administered with pterostilbene, and nicotinamide mononucleotide as the most common candidates in investigations of NAD+-boosting compounds for improving physiological function in humans. Studies have been performed in generally healthy midlife and older adults, adults with cardiometabolic disease risk factors such as overweight and obesity, and numerous patient populations. Supplementation with these compounds is safe, tolerable, and can increase the abundance of NAD+ and related metabolites in multiple tissues. Dosing regimens and study durations vary greatly across interventions, and small sample sizes limit data interpretation of physiological outcomes. Limitations are identified and future research directions are suggested to further our understanding of the potential efficacy of NAD+-boosting compounds for improving physiological function and extending human health span.
Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.
In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling [phosphorylation of protein kinase AKT and mechanistic target of rapamycin (mTOR)] increased after NMN supplementation but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor β and other genes related to muscle remodeling. These results demonstrate that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese (clinicaltrial.gov NCT03151239).
T cells with dysfunctional mitochondria induce multimorbidity and premature senescence.
The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-α signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.
Sarcopenia and Muscle Aging: A Brief Overview.
The world is facing the new challenges of an aging population, and understanding the process of aging has therefore become one of the most important global concerns. Sarcopenia is a condition which is defined by the gradual loss of skeletal muscle mass and function with age. In research and clinical practice, sarcopenia is recognized as a component of geriatric disease and is a current target for drug development. In this review we define this condition and provide an overview of current therapeutic approaches. We further highlight recent findings that describe key pathophysiological phenotypes of this condition, including alterations in muscle fiber types, mitochondrial function, nicotinamide adenine dinucleotide (NAD+) metabolism, myokines, and gut microbiota, in aged muscle compared to young muscle or healthy aged muscle. The last part of this review examines new therapeutic avenues for promising treatment targets. There is still no accepted therapy for sarcopenia in humans. Here we provide a brief review of the current state of research derived from various mouse models or human samples that provide novel routes for the development of effective therapeutics to maintain muscle health during aging.
NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS-STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS-STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS-STING in neuroinflammation and cellular senescence in AD.
Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes.
Advanced maternal age is highly associated with a decline in oocyte quality, but effective approaches to improve it have still not been fully determined. Here, we report that in vivo supplementation of nicotinamide mononucleotide (NMN) efficaciously improves the quality of oocytes from naturally aged mice by recovering nicotinamide adenine dinucleotide (NAD+) levels. NMN supplementation not only increases ovulation of aged oocytes but also enhances their meiotic competency and fertilization ability by maintaining the normal spindle/chromosome structure and the dynamics of the cortical granule component ovastacin. Moreover, single-cell transcriptome analysis shows that the beneficial effect of NMN on aged oocytes is mediated by restoration of mitochondrial function, eliminating the accumulated ROS to suppress apoptosis. Collectively, our data reveal that NMN supplementation is a feasible approach to protect oocytes from advanced maternal age-related deterioration, contributing to the improvement of reproductive outcome of aged women and assisted reproductive technology.
Role of NAD+ in regulating cellular and metabolic signaling pathways.
Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders. Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD+ levels using NAD+ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets. An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within cells, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation.
NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.
Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals.
CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism.
Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging 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. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.
Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns.
Recent research has unveiled an expansive role of NAD+ in cellular energy generation, redox reactions, and as a substrate or cosubstrate in signaling pathways that regulate health span and aging. This review provides a critical appraisal of the clinical pharmacology and the preclinical and clinical evidence for therapeutic effects of NAD+ precursors for age-related conditions, with a particular focus on cardiometabolic disorders, and discusses gaps in current knowledge. NAD+ levels decrease throughout life; age-related decline in NAD+ bioavailability has been postulated to be a contributor to many age-related diseases. Raising NAD+ levels in model organisms by administration of NAD+ precursors improves glucose and lipid metabolism; attenuates diet-induced weight gain, diabetes, diabetic kidney disease, and hepatic steatosis; reduces endothelial dysfunction; protects heart from ischemic injury; improves left ventricular function in models of heart failure; attenuates cerebrovascular and neurodegenerative disorders; and increases health span. Early human studies show that NAD+ levels can be raised safely in blood and some tissues by oral NAD+ precursors and suggest benefit in preventing nonmelanotic skin cancer, modestly reducing blood pressure and improving lipid profile in older adults with obesity or overweight; preventing kidney injury in at-risk patients; and suppressing inflammation in Parkinson disease and SARS-CoV-2 infection. Clinical pharmacology, metabolism, and therapeutic mechanisms of NAD+ precursors remain incompletely understood. We suggest that these early findings provide the rationale for adequately powered randomized trials to evaluate the efficacy of NAD+ augmentation as a therapeutic strategy to prevent and treat metabolic disorders and age-related conditions.
NAD+ Metabolism in Cardiac Health, Aging, and Disease.
Nicotinamide adenine dinucleotide (NAD+) is a central metabolite involved in energy and redox homeostasis as well as in DNA repair and protein deacetylation reactions. Pharmacological or genetic inhibition of NAD+-degrading enzymes, external supplementation of NAD+ precursors, and transgenic overexpression of NAD+-generating enzymes have wide positive effects on metabolic health and age-associated diseases. NAD+ pools tend to decline with normal aging, obesity, and hypertension, which are all major risk factors for cardiovascular disease, and NAD+ replenishment extends healthspan, avoids metabolic syndrome, and reduces blood pressure in preclinical models. In addition, experimental elevation of NAD+ improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, or dilated cardiomyopathies, as well as different modalities of heart failure. Here, we critically discuss cardiomyocyte-specific circuitries of NAD+ metabolism, comparatively evaluate distinct NAD+ precursors for their preclinical efficacy, and raise outstanding questions on the optimal design of clinical trials in which NAD+ replenishment or supraphysiological NAD+ elevations are assessed for the prevention or treatment of major cardiac diseases. We surmise that patients with hitherto intractable cardiac diseases such as heart failure with preserved ejection fraction may profit from the administration of NAD+ precursors. The development of such NAD+-centered treatments will rely on technological and conceptual progress on the fine regulation of NAD+ metabolism.
Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.
Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.
NAD+ Repletion Rescues Female Fertility during Reproductive Aging.
Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.
Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.
Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure.
Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.
SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.
Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia.
Niacin.
Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precursors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are important cofactors for most cellular redox reactions, and as such are essential to maintain cellular metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified to date are important genetic and epigenetic regulators, e.g., poly(ADP-ribose)polymerases and sirtuins. There is rapidly growing knowledge of the close connection between dietary niacin intake, NAD(P) availability, and the activity of NAD(P)-dependent epigenetic regulator enzymes. It points to an exciting role of dietary niacin intake as a central regulator of physiological processes, e.g., maintenance of genetic stability, and of epigenetic control mechanisms modulating metabolism and aging. Insight into the role of niacin and various NAD-related diseases ranging from cancer, aging, and metabolic diseases to cardiovascular problems has shifted our view of niacin as a vitamin to current views that explore its potential as a therapeutic.
Roles of Sirtuins in Cardiovascular Diseases: Mechanisms and Therapeutics.
Cardiovascular diseases (CVDs) are experiencing a rapid surge and are widely recognized as the leading cause of mortality in the current aging society. Given the multifactorial etiology of CVDs, understanding the intricate molecular and cellular mechanisms is imperative. Over the past 2 decades, many scientists have focused on Sirtuins, a family of nicotinamide adenine dinucleotide-dependent deacylases. Sirtuins are highly conserved across species, from yeasts to primates, and play a crucial role in linking aging and diseases. Sirtuins participate in nearly all key physiological and pathological processes, ranging from embryogenic development to stress response and aging. Abnormal expression and activity of Sirtuins exist in many aging-related diseases, while their activation has shown efficacy in mitigating these diseases (eg, CVDs). In terms of research, this field has maintained fast, sustained growth in recent years, from fundamental studies to clinical trials. In this review, we present a comprehensive, up-to-date discussion on the biological functions of Sirtuins and their roles in regulating cardiovascular biology and CVDs. Furthermore, we highlight the latest advancements in utilizing Sirtuin-activating compounds and nicotinamide adenine dinucleotide boosters as potential pharmacological targets for preventing and treating CVDs. The key unresolved issues in the field-from the chemicobiological regulation of Sirtuins to Sirtuin-targeted CVD investigations-are also discussed. This timely review could be critical in understanding the updated knowledge of Sirtuin biology in CVDs and facilitating the clinical accessibility of Sirtuin-targeting interventions.
Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation.
Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD+ derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD+ synthesis depleted NAD+, suppressed mitochondrial NAD+-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD+ synthesis by limiting the conversion of downstream quinolinate to NAD+, a profile recapitulated in aging macrophages. Increasing de novo NAD+ generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD+ operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD+ synthesis may underlie declining NAD+ levels and rising innate immune dysfunction in aging and age-associated diseases.
Nicotinamide Adenine Dinucleotide-Loaded Lubricated Hydrogel Microspheres with a Three-Pronged Approach Alleviate Age-Related Osteoarthritis.
Chondrocyte senescence, synovitis, and decreased level of lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (AROA). However, there are currently no effective therapeutic interventions capable of altering the progression of OA until it reaches advanced stages, necessitating joint replacement. In this study, lubricious and drug-loaded hydrogel microspheres were designed and fabricated by utilizing microfluidic technology for radical polymerization of chondroitin sulfate methacrylate and incorporating nicotinamide adenine dinucleotide (NAD)-loaded liposomes modified with lactoferrin that are positively charged. Mechanical, tribological, and drug release analyses demonstrated enhanced lubrication properties and an extended drug dissemination time for the NAD@NPs@HM microspheres. In vitro assays unveiled the ability of NAD@NPs@HM to counteract chondrocyte senescence. RNA sequencing analysis, untargeted metabolomics analysis, and in vitro experiments on macrophages revealed that NAD@NPs@HM can regulate the metabolic reprogramming of synovial macrophages, promoting their repolarization from the M1 to M2 phenotype, thereby alleviating synovitis. Intra-articular injection of NAD@NPs@HM in aged mice reduced the mechanisms associated with AROA. These results suggest that NAD@NPs@HM may provide extended drug release, improved joint lubrication leading to better gait, and attenuation of AROA pathogenic processes, indicating its potential as a therapeutic approach for AROA.
Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline.
Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD+) catabolism primarily feeds systemic organs for NAD+ synthesis. We surprisingly found that, despite blunted hepatic NAD+ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD+ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD+ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD+, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD+ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD+ decline and kidney dysfunction.
LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.
Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.
Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice.
Glaucomas are neurodegenerative diseases that cause vision loss, especially in the elderly. The mechanisms initiating glaucoma and driving neuronal vulnerability during normal aging are unknown. Studying glaucoma-prone mice, we show that mitochondrial abnormalities are an early driver of neuronal dysfunction, occurring before detectable degeneration. Retinal levels of nicotinamide adenine dinucleotide (NAD+, a key molecule in energy and redox metabolism) decrease with age and render aging neurons vulnerable to disease-related insults. Oral administration of the NAD+ precursor nicotinamide (vitamin B3), and/or gene therapy (driving expression of Nmnat1, a key NAD+-producing enzyme), was protective both prophylactically and as an intervention. At the highest dose tested, 93% of eyes did not develop glaucoma. This supports therapeutic use of vitamin B3 in glaucoma and potentially other age-related neurodegenerations.
NAD⁺ supplementation for anti-aging and wellness: A PRISMA-guided systematic review of preclinical and clinical evidence.
Nicotinamide adenine dinucleotide (NAD⁺) declines with age, motivating "NAD⁺-boosting" strategies ranging from lifestyle interventions to supplementation with NAD⁺ precursors (e.g., nicotinamide riboside [NR], nicotinamide mononucleotide [NMN]) and, in some wellness settings, parenteral NAD⁺ administration. We conducted a PRISMA-guided systematic review of peer-reviewed human and rodent intervention studies (January 2010-October 2025) evaluating NAD-related compounds administered orally or parenterally. We identified 113 eligible studies: 33 human intervention studies (28 randomized; 5 nonrandomized) and 80 rodent studies. In rodent models, NAD⁺ augmentation was frequently associated with improvements in metabolic, mitochondrial, inflammatory, and functional outcomes, although effects varied across models and endpoints. In humans, oral NR and NMN consistently demonstrated biochemical target engagement (circulating (plasma/whole blood) or cellular (e.g., PBMC) NAD-related metabolites) and were generally well tolerated over weeks to months; however, effects on functional, metabolic, vascular, and other healthspan-relevant outcomes were heterogeneous and often null or endpoint-specific. No eligible outcomes trials evaluated intravenous or intramuscular NAD⁺ itself for anti-aging or wellness indications. One nonrandomized intravenous NMN study met inclusion criteria and primarily contributed short-term safety and biomarker information. An intravenous NAD⁺ pharmacokinetic pilot lacking eligible clinical outcomes was identified as contextual evidence only. Overall, NAD⁺ augmentation shows clear biological activity, but clinical effectiveness for anti-aging or wellness outcomes remains inconclusive. Larger, well-designed randomized trials with longer follow-up and prespecified clinically meaningful endpoints are needed, particularly for parenteral approaches.
Biological properties, synthetic pathways and anti-aging mechanisms of nicotinamide mononucleotide (NMN): Research progress and challenges.
The increasing global population aging has made the prevention and control of aging-related diseases a major public health challenge in the twenty-first century. Nicotinamide mononucleotide (NMN), as a precursor of nicotinamide adenine dinucleotide (NAD+), has garnered significant attention in recent years for its anti-aging potential. This review comprehensively reviews the metabolic pathways and molecular mechanisms of NMN, comparing the technical characteristics and industrialization prospects of chemical synthesis, microbial fermentation, and enzyme-catalyzed synthesis. The molecular targets and networks of NMN in core aging mechanisms, such as DNA damage repair, mitochondrial function regulation, inflammatory response balance, gut microbiota remodeling, and autophagy pathway activation, are analyzed. The molecular mechanism of NMN in slowing down the aging process through multi-target synergistic effects is elucidated. However, critical issues such as age-stratified dosage modeling, long-term safety, and efficacy of NMN still require in-depth research. This review provides a theoretical basis and research direction for translational research and precise anti-aging strategies of NMN.
Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.
Nicotinamide adenine dinucleotide (NAD+) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.
Quick links (PubMed)
- PMID 33353981 — 2021 · NAD+ metabolism and its roles in cellular processes during ageing.
- PMID 24786309 — 2014 · NAD+ and sirtuins in aging and disease.
- PMID 37619764 — 2023 · The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human…
- PMID 26785480 — 2015 · NAD⁺ in aging, metabolism, and neurodegeneration.
- PMID 37424179 — 2024 · NAD metabolism: Role in senescence regulation and aging.
- PMID 32694684 — 2020 · NAD+ homeostasis in health and disease.
- PMID 35499054 — 2022 · Nicotinamide mononucleotide (NMN) as an anti-aging health product - Prom…
- PMID 33028824 — 2020 · NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential.
- PMID 30980044 — 2020 · The kynurenine pathway: a finger in every pie.
- PMID 29249689 — 2018 · NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR.
- PMID 37483618 — 2023 · Sirtuin family in autoimmune diseases.
- PMID 29514064 — 2018 · Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Eviden…
- PMID 34518687 — 2022 · Molecular mechanisms of dietary restriction promoting health and longevi…
- PMID 37068054 — 2023 · Dietary Supplementation With NAD+-Boosting Compounds in Humans: Current …
- PMID 33888596 — 2021 · Nicotinamide mononucleotide increases muscle insulin sensitivity in pred…
- PMID 32439659 — 2020 · T cells with dysfunctional mitochondria induce multimorbidity and premat…
- PMID 33397034 — 2020 · Sarcopenia and Muscle Aging: A Brief Overview.
- PMID 34497121 — 2021 · NAD+ supplementation reduces neuroinflammation and cell senescence in a …
- PMID 32755581 — 2020 · Nicotinamide Mononucleotide Supplementation Reverses the Declining Quali…
- PMID 33609766 — 2021 · Role of NAD+ in regulating cellular and metabolic signaling pathways.
- PMID 27127236 — 2016 · NAD⁺ repletion improves mitochondrial and stem cell function and …
- PMID 27304511 — 2016 · CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction thro…
- PMID 37364580 — 2023 · Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applicatio…
- PMID 34843394 — 2021 · NAD+ Metabolism in Cardiac Health, Aging, and Disease.
- PMID 33199924 — 2020 · Senescent cells promote tissue NAD+ decline during ageing via the activa…
- PMID 32049001 — 2020 · NAD+ Repletion Rescues Female Fertility during Reproductive Aging.
- PMID 41083806 — 2025 · NAD+ precursor supplementation in human ageing: clinical evidence and ch…
- PMID 38504132 — 2024 · Trigonelline is an NAD+ precursor that improves muscle function during a…
- PMID 40394194 — 2025 · Age-associated nicotinamide adenine dinucleotide decline drives CAR-T ce…
- PMID 38908209 — 2024 · SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential t…
- PMID 29477227 — 2018 · Niacin.
- PMID 40014680 — 2025 · Roles of Sirtuins in Cardiovascular Diseases: Mechanisms and Therapeutic…
- PMID 30478397 — 2019 · Macrophage de novo NAD+ synthesis specifies immune function in aging and…
- PMID 40315404 — 2025 · Nicotinamide Adenine Dinucleotide-Loaded Lubricated Hydrogel Microsphere…
- PMID 40315855 — 2025 · Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging…
- PMID 38636518 — 2024 · LXR/CD38 activation drives cholesterol-induced macrophage senescence and…
- PMID 28209901 — 2017 · Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma i…
- PMID 41655607 — 2026 · NAD⁺ supplementation for anti-aging and wellness: A PRISMA-guided…
- PMID 40550930 — 2025 · Biological properties, synthetic pathways and anti-aging mechanisms of n…
- PMID 31412242 — 2019 · Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metab…