Do NAD⁺ Boosters Work? What the Research Says About NR and NMN for Aging, Cognition & Muscle

Introduction

As we age, our bodies gradually lose the ability to generate the energy needed to keep cells healthy and resilient.  A key reason for this decline is the steady drop in nicotinamide adenine dinucleotide or NAD⁺, a molecule that fuels metabolism, repairs DNA, and helps cells respond to stress.  Low NAD⁺ levels have been linked to cognitive decline and an increased risk of age-related diseases. This has sparked growing interest in ways to restore NAD⁺. Two compounds, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), precursors to NAD+, have emerged as potential candidates to replenish NAD+ levels. These naturally occurring molecules act as direct building blocks for NAD⁺ and are already being explored for their ability to boost energy, support healthy aging, and enhance resilience against disease. 

In preclinical studies, supplementation with NR and NMN restored NAD⁺ levels, improved mitochondrial function, and even counteracted age-related physiological decline.  However, the results in humans have been far less consistent.  While NAD⁺ levels can be boosted, the expected improvements in health outcomes have not been clearly demonstrated.  In this article, we examine how NR and NMN supplementation influences key physiological functions, particularly focusing on mitochondrial function, cognition, and muscle mass, all of which are essential for healthy aging.  We review current literature, highlighting both the potential benefits and the limitations of boosting NAD+ with NR and NMN supplements, and discuss what their use may mean for promoting long-term health and longevity.

What is NAD+?

NAD+, also known as nicotinamide adenine dinucleotide, is a critical molecule found in all living cells and plays a vital role in energy metabolism.  Without it, life would quite literally stop. NAD⁺ participates in hundreds of reactions that move electrons—the tiny packets of energy that power metabolism. Think of it as a molecular courier, shuttling electrons between chemical partners to keep the cell’s engines running.

When NAD⁺ accepts a hydride ion—a hydrogen atom carrying an extra electron—it becomes NADH, a charged form that stores energy temporarily. NADH then feeds this energy into pathways that generate ATP, the universal fuel for cellular activity. In parallel, a phosphorylated cousin called NADP⁺ accepts electrons to create NADPH, which serves a different purpose: it protects cells from oxidative damage and supplies the reducing power needed to build essential molecules like fatty acids. [1].

Because NAD⁺ is constantly consumed in these reactions, cells must continually replenish it. Some of it is recycled from its by-product, nicotinamide (NAM), through what’s known as the salvage pathway—a biochemical form of circular economy, where the cell’s ‘recycling plant’ breaks down used components and rebuilds them into fresh NAD+. Meanwhile, the liver can also synthesize NAD⁺ from dietary nutrients, maintaining the delicate balance between energy production and cellular protection.  [1].

Beyond metabolism, NAD⁺ also fuels several families of enzymes that influence how we age. The first group, sirtuins, use NAD⁺ to modify proteins that regulate stress responses, metabolism, and even gene activity. In doing so, they help counter molecular hallmarks of aging such as inflammation, DNA damage, and mitochondrial decline. The second group, PARPs (poly-ADP-ribose polymerases), spring into action when DNA strands break, using NAD⁺ to signal repair teams. And the third, NADases such as CD38 and CD157, control immune cell communication and migration.

Enhanced activation of sirtuins has been linked to improved lifespan and healthspan.  Sirtuins act as metabolic sensors [2].  Conversely, PARPs and NADases have the opposite effect, where their excessive activation has been shown to accelerate NAD+ loss, worsening age-related decline [1].

In essence, NAD⁺ acts as the molecular thread weaving together energy production, repair, and longevity. When that thread frays, nearly every system in the body begins to feel the strain.

NAD+ and Aging

NAD+ levels naturally decline with age, disrupting the balance of enzymes involved in its synthesis and degradation.  Reduction in NAD+ levels has been observed in various tissues such as the brain, liver, and skeletal muscles.  

The evidence is striking. Studies show that plasma NAD⁺ levels fall by roughly 60% over the human lifespan—from about 50 nanomolar in adults aged 20–40 to only 20 nanomolar in those aged 60–97  [3].  Similarly, aged human skin shows several-fold lower NAD+ levels compared to newborns [4].  In the liver, approximately a 30% decline in NAD+ concentration was observed in patients > 60 years old compared to those < 45 years old [5].

Why does this happen? 

Researchers have traced much of the decline to hyperactive NAD⁺-consuming enzymes. Among the main culprits are PARPs, which draw heavily on NAD⁺ during DNA repair, and the glycohydrolases CD38 and CD157, which regulate immune signaling but also deplete NAD⁺ reserves when overactivated. Another enzyme, SARM1, accelerates NAD⁺ breakdown during cellular stress, particularly in neurons. Over time, these biochemical drains outpace the body’s ability to replenish NAD⁺, setting off a slow erosion of metabolic capacity that may contribute to aging’s most visible and invisible effects.

This steady loss of NAD⁺ is not just a biochemical curiosity; it may represent one of aging’s central bottlenecks, limiting the cell’s ability to sustain both energy and repair.

To understand how this erosion unfolds at the molecular level, we need to look at the enzymes that consume NAD⁺ most aggressively. Each plays a distinct role in cellular maintenance, and when overactive, each can hasten decline.

PARPs

PARPs are major consumers of NAD+ and are active in response to DNA damage, which is known to increase with age.  Aging is a multifaceted process in which our DNA repair systems become less efficient, contributing to genomic instability.  Over time, the efficiency of our DNA repair systems falters, and the resulting damage triggers a feedback loop that can further deplete the cell’s NAD⁺ reserves.

When activated, PARP1, the most abundant member of the family, consumes large quantities of NAD⁺ to attach ADP-ribose units to target proteins—a process called PARylation. This acts like an emergency repair signal, marking damaged DNA so the cell’s maintenance crew knows where to work [6].  Under normal conditions, this response is protective. But in the face of chronic or excessive DNA damage, PARP1 activity can spiral, draining NAD⁺ faster than it can be replenished.

Evidence across species supports this link between PARP1 overactivity and NAD⁺ decline. Elevated PARP1 expression has been observed in the muscles of both Drosophila  [7] and mice [8].  In humans, similar patterns emerge in the aging brain. Studies of Alzheimer’s disease patients show increased PARP1 activation and accumulation of PAR polymers within affected neurons—changes that correlate with the buildup of amyloid-β plaques, which can themselves further stimulate PARP1 [9].

In this way, the very enzyme that once protected our DNA may, over time, contribute to the metabolic and neurodegenerative features of aging—a molecular paradox at the heart of longevity research. The story of PARPs illustrates a recurring theme in biology: mechanisms designed for protection can, under chronic stress, become agents of decline.

While PARPs drain NAD⁺ in their attempt to patch damaged DNA, another group of enzymes quietly depletes the molecule from the cell’s surface. These enzymes, CD38 and CD157, link the biology of inflammation directly to the chemistry of aging.

CD38/CD157

While PARPs drain NAD⁺ in response to DNA damage, another set of enzymes—CD38 and its close relative CD157—quietly erode this essential molecule through a different route. Both are surface enzymes that break down NAD⁺, and their activity tends to rise as organisms age.

One reason lies in the phenomenon scientists call “inflammaging”—a state of chronic, low-grade inflammation that builds up with age. As senescent cells accumulate, they release inflammatory molecules that, among other effects, stimulate the expression of CD38 [31]. The result is a biochemical chain reaction: more inflammation leads to more CD38, which consumes more NAD⁺, further weakening the cell’s ability to repair and renew itself.

Animal studies vividly illustrate this cycle. Aging mice show increased CD38 levels that correlate with sharp drops in NAD⁺, linking the enzyme directly to metabolic decline [10].  Remarkably, when researchers used a CD38 inhibitor, they were able to restore NAD⁺ levels and reverse multiple age-related impairments, including declines in muscle endurance, heart function, exercise capacity, and glucose control [11]. 

The same enzyme has also drawn attention in neurodegenerative research. In animal models of Alzheimer’s disease, elevated CD38 expression tracks closely with disease progression and altered NAD⁺ metabolism [12, 13]. Together, these findings position CD38—and, by extension, CD157—as pivotal players in the biochemical erosion of vitality that accompanies aging, linking inflammation, metabolism, and cellular energy into one interconnected story. In this way, inflammation doesn’t just exhaust immune cells—it quietly drains the cell’s energy economy, eroding resilience from within.

Deep within the nervous system, a different NAD+ consumer can trigger a more profound outcome. When activated, it doesn’t just deplete energy—it dismantles the neuron itself.

SARM1: The Axon’s Self-Destruct Switch

Among the enzymes that consume NAD⁺, SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) stands out for its destructive potential. This protein functions as a pro-degenerative NADase, an enzyme that cleaves NAD⁺ and, when activated, can trigger a catastrophic energy collapse inside neurons. The result is axonal degeneration—the breakdown of the long, wire-like projections that carry electrical signals between nerve cells.

Under healthy conditions, SARM1 remains dormant. But when neurons experience severe metabolic stress or injury, the balance between two key molecules—NMN (nicotinamide mononucleotide) and NAD⁺—shifts. A surge in the NMN/NAD⁺ ratio acts as a molecular alarm, flipping SARM1’s internal ‘kill switch’ and triggering a cascade that drains NAD⁺, much like cutting power to a neuron’s energy grid [14].  

Although SARM1’s role in normal aging remains uncertain, its destructive activation pathway has made it a central focus of neurodegeneration research. Scientists suspect that the same mechanism that clears damaged axons after injury may, under chronic metabolic stress, contribute to the slow attrition of neuronal connections seen in aging and disease. Whether SARM1 represents a necessary cleanup mechanism or an overzealous self-destruct system remains an open question, but its sensitivity to metabolic stress underscores how tightly the brain’s survival depends on NAD⁺ balance.

Taken together, these pathways reveal how NAD⁺ is continually siphoned away as we age. The next question is whether we can restore NAD⁺ levels to rejuvenate the systems it once sustained.

Potential Benefits from NAD+ and NAD+ Precursor (NR, NMN) (NR, NMN) Supplementation

If declining NAD⁺ is one of the molecular signatures of aging, could replenishing it help turn back the biological clock? In preclinical studies, raising NAD⁺ levels has consistently improved markers of healthspan and cellular function. For instance, supplementing mice with nicotinamide riboside (NR), a precursor to NAD⁺, increased NAD⁺ concentrations in both young and old animals. The results captured the scientific community’s attention: aged mice regained muscle stem cell function, showed fewer senescent cells, and demonstrated better mitochondrial activity and tissue regeneration after injury—changes that translated into improved muscle performance and greater overall healthy longevity [15].  

Similar benefits have appeared in other species. In fruit flies, supplementing with NAD⁺ precursors slowed aging and extended lifespan. The most dramatic effects came when precursors such as nicotinamide (NAM) or NR were combined with inhibitors of the kynurenine pathway—the main route through which the amino acid tryptophan is converted into NAD⁺ [16].  

The kynurenine pathway is the main route of tryptophan degradation and serves as the source of NAD+ biosynthesis.  It also breaks down tryptophan into kynurenic acid, another neuroactive metabolite.  Alterations in this pathway are linked to aging and multiple age-associated diseases, and interventions targeting its enzymes or metabolites have extended lifespan in invertebrate models [32].  Indeed, the combination treatment with NAM led to a 30% higher average lifespan in fruit flies, whereas the combination treatment with NR resulted in a 22% higher average lifespan.  This increase in lifespan was attributed to lowered systemic levels of pro-aging kynurenine pathway metabolites, suggesting that reducing these metabolites is central to this benefit.  However, the addition of NAD precursors with kynurenine pathway inhibitors may further boost mitochondrial function and cellular resilience through increased activation of SIRT1. [16].

Although preclinical studies show promising results, translating these findings to humans has proven more challenging.  Most of the evidence in humans comes from clinical trials testing NAD+ precursors such as NR and NMN.  While oral NR supplementation consistently increased NAD+ levels across participants of different ages and health conditions, it did not lead to measurable improvements in physiological functions, such as cardiovascular health.  Similar outcomes have also been reported in clinical trials utilizing NMN supplementation.  Limitations of these studies include small sample sizes, dosing regimens, and study durations [17].

As NAD+ levels naturally decline with age, an important question arises: can this process be reversed?  More specifically, can NAD+ supplementation restore the physiological functions that decline with aging?  In the sections that follow, we examine evidence on whether NAD+ supplementation can enhance cognitive performance and mitigate age-related muscle loss. If NAD⁺ truly governs cellular renewal, then restoring it could, in theory, help reverse the fatigue of aging at its biochemical roots. Yet the leap from theory to therapy is far from guaranteed.

Because the brain is among the body’s most energy-hungry organs, it offers an ideal test case for understanding NAD⁺ restoration. If neurons benefit, the implications for aging could be profound.

NAD+ and cognition

Few organs depend more on a steady energy supply than the brain. As NAD⁺ levels fall with age, neurons may lose some of their ability to repair, regenerate, and communicate efficiently, raising the question of whether replenishing NAD⁺ could help preserve cognitive function.

Preclinical animal studies have shown that supplementation with NR and NMN can improve cognition.  A systematic review found that NAD+ displayed neuroprotective and pro-cognitive effects in preclinical models of Alzheimer’s disease.  Specifically, NAD+ improved learning and memory, reduced oxidative stress, inflammation, and apoptosis, and enhanced mitochondrial function in animal models [18].  Findings from a study using a rat model of chronic cerebral hypoperfusion (which mimics vascular dementia with related cognitive impairments) found that daily injection of NAD+ significantly improved learning and memory and decreased neuroinflammation [19].  Interestingly, these effects were due to an upregulation of the Sirtuin1 pathway, which is vital for mitochondrial biogenesis, antioxidant defense, and immune modulation [19].  As discussed previously, Sirtuins are NAD+-consuming enzymes.  Therefore, increased NAD+ levels from daily injections enhance Sirtuin activity because there is more NAD+ available as a substrate for their deacetylase activity. Thus, the increased NAD+ availability enables Sirtuins to function at a higher efficiency, thereby producing beneficial effects.

Translating these findings to humans, however, has been more challenging. Evidence on whether NAD+ precursor supplementation can raise NAD+ levels and improve cognitive function in humans is limited, and results are inconclusive.  In a recent randomized, double-masked, placebo-controlled trial, researchers tested oral NR supplementation in 20 older adults with mild cognitive impairment for 10 weeks. Participants received gradually increasing doses of NR, starting at 250 mg/day and rising to 1 g/day [20].  Cognition was evaluated using the Montreal Cognitive Assessment, a screening assessment that tests various cognitive domains, including attention, memory, language, and executive functions.  Supplementation with NR increased blood NAD+ levels by an astounding 139% as well as increased levels of NAAD (nicotinic acid adenine dinucleotide; an intermediate in the NAD+ biosynthetic pathway) and NMN.  Interestingly, neurocognitive metrics remained stable throughout the study with no differences observed between the NR and placebo group.  Furthermore, walking speed did not improve in the NR group; however, the placebo group demonstrated a significant improvement that was suggestive of a practice effect [20].  With its small sample size and short duration, the study left open the question of whether longer-term NAD⁺ restoration could yield benefits for cognition.

Other small clinical efforts have yielded similarly cautious optimism. Results from a pilot 4-week open-label clinical trial found that the effects of NAD+ supplementation could ameliorate vascular aging and cognitive decline in patients with peripheral artery disease. This disease is characterized by widespread endothelial dysfunction, which extends to the cerebrovascular system, contributing to vascular cognitive deficits.  A total of 8 older adults were included in the study and received 1000 mg/day oral NR for 4 weeks.  Prior studies have shown that daily consumption of NR at 1000mg/day can increase NAD levels by 142% within 2 weeks of starting the treatment [33].  Additionally, macrovascular endothelial function, as measured using flow-mediated dilation, was significantly enhanced from a baseline of 2.2% to 9.0% after NR supplementation.  Although not statistically significant, microvascular function demonstrated an improvement after supplementation with NR.  However, it is unclear whether NR supplementation may have any cognitive benefits, as there was only a modest improvement in cognitive performance [21].  A primary limitation of this study is the small cohort, and thus, the potential benefit of increased NAD+ on cognition remains to be determined.  Larger, randomized controlled studies are needed to validate these findings further and assess the long-term benefits.

In an older, open-label pilot trial, supplementation with NADH in 17 Alzheimer’s patients led to cognitive improvements as measured using the Mini-Mental State Examination (a screening tool to evaluate different cognitive domains, including memory, orientation, attention, language, and visuospatial skills).   The patients were on NADH supplement between 8 and 12 weeks.  However, given that this was a single-arm study (ie, no placebo group), no definitive conclusions could be made regarding NADH supplementation [22].  Interestingly, a separate research attempted to duplicate the same NADH treatment on 25 patients with mild to moderate Alzheimer’s disease, including vascular and fronto-temporal dementia.  Nineteen patients completed the study, yet no cognitive improvements were observed [23].

Taken together, these findings suggest that while boosting NAD⁺ can potentially improve brain function in animals, human data remain preliminary. The molecule’s potential as a neuroprotective intervention continues to intrigue researchers, but proving its cognitive benefits in aging humans will require larger, longer, and more rigorously controlled clinical trials. The brain’s dependence on NAD⁺ makes it a compelling target for intervention, but translating molecular restoration into measurable mental resilience remains one of the field’s greatest challenges.

If the brain relies on NAD⁺ to sustain memory and repair, the muscles depend on it for strength and endurance. The same molecular currency that powers thought also fuels movement, and its decline may underlie the physical frailty of aging.

NAD+ and muscle mass

Age-related muscle decline, commonly known as sarcopenia, can be particularly detrimental to older adults.  Because of its central role in metabolism, NAD+ is closely linked to both muscle health and exercise [37].  In skeletal muscle, roughly 85–90% of NAD⁺ is produced through the “salvage pathway,” which recycles the by-product nicotinamide (NAM) back into nicotinamide mononucleotide (NMN) and ultimately NAD⁺. This recycling process depends on nicotinamide phosphoribosyltransferase (NAMPT)—the rate-limiting enzyme that acts like a factory foreman, directing the salvage pathway and ensuring that spent molecules of NAD⁺ are efficiently rebuilt to keep the cell’s energy supply running. When NAMPT activity declines with age, NAD⁺ levels fall, driving mitochondrial dysfunction and metabolic impairment in muscle tissue [24, 25].  However, exercise appears to counteract this effect.  Indeed, studies have found that acute exercise boosts NAD+ levels [26]while resistance training can increase NAD+ and NADH concentrations [27]. 

Results from preclinical animal studies investigating NR supplementation for improving muscle mass are encouraging [28].  However, these findings have not been translated into humans, and current evidence does not support NMN or NR supplementation for maintaining muscle mass or function in older adults.  A systematic review and meta-analysis of 10 randomized controlled trials in participants aged 60 – 83 years old found that NMN or NR, compared with placebo, had minimal impact on skeletal muscle index, handgrip strength, gait speed, or the 5-time chair stand test [29].  Notably, trials with NM showed that higher doses of NM (2000 mg/day) paradoxically reduced thigh muscle mass without improving strength.  Moreover, participants with mild cognitive impairment who received NR supplementation performed worse on both the short physical performance battery and the 5-time chair stand test [29]. 

In a randomized, placebo-controlled trial, 32 adults aged 55 – 80 years old received daily supplementation with NR plus pterostilbene (PT), a potent antioxidant, or placebo for two weeks before induction of skeletal muscle injury through electrically stimulated eccentric quadriceps contractions [30].  Muscle biopsies were taken at baseline and 2 hours, 2 days, 8 days, and 30 days after the injury.  The injury protocol produced clear signs of muscle injury, including a ~25% decline in muscle strength.  While NR + PT supplementation did raise blood NAD+ levels, it did not improve muscle strength recovery as evidenced by the lack of muscle stem cell recruitment.  The intervention with the combination treatment was safe, but it failed to enhance muscle regeneration in this elderly population [30]. 

The results highlight an important lesson in longevity science: restoring a molecule is not the same as restoring function. How, when, and in whom NAD⁺ is replenished may determine whether it confers strength or simply biochemistry.

Even as clinical trials wrestle with the limits of supplementation, nature offers other ways to replenish NAD⁺. Diet, exercise, and metabolic conditioning can all influence the molecule’s delicate balance.

Actionable Strategies for Boosting NAD+ Levels

While supplementation with NAD+ precursors can boost NAD+ levels, there are also nonpharmaceutical approaches to increase NAD+ levels naturally.

Diet

A balanced diet with macro and micronutrients is fundamental for maintaining health and longevity.  A diet consisting of food rich in NAD+ precursors can naturally boost NAD+ levels.  For example, edamame, broccoli, cucumber, and cabbage contain 0.25 - 1.88 mg of NMN per 100g.  Fruits, such as avocado and tomato, also contain a similar amount of NMN, about 0.26 - 1.60 mg/100g.  Shrimp and raw beef meat have much lower levels of NMN, ranging from 0.06 to 0.42 mg/100g [34].  A diet high in fat and sugar can decrease NAD+ levels.  In fact, obesity has been linked to reductions in NAD+ across multiple tissues, including adipose tissue, skeletal muscle, liver, and hypothalamus.  The loss in NAD+ in obesity is attributed to chronic low-grade inflammation, which suppresses NAMPT, a key enzyme in the NAD+ salvage pathway [35].

Exercise

Physical activity, in conjunction with a healthy diet, also impacts the levels of NAD+.  Aerobic exercise and general physical activity enhance NAD+ levels by upregulating NAMPT in the skeletal muscles.  Human cross-sectional analysis confirmed that athletes had ~22-fold higher protein levels of NAMPT in the skeletal muscle compared to sedentary individuals, whether obese or nonobese, and those with type 2 diabetes.  A group of sedentary nonobese subjects also underwent a 3-week exercise program consisting of 13 sessions on alternating days combining interval cycling at 75 - 85% VO2 max (30-60 min) and a 50-minute aerobic protocol (70% VO2 max).  The exercise intervention led to a dramatic 127% increase in NAMPT protein expression after 3 weeks of training.  These findings indicate that exercise enhances skeletal muscle NAMPT expression, which catalyzes the rate-limiting step of the NAD+ salvage pathway, and regulates NAD+ levels.  In fact, NAMPT protein expression was also positively correlated with mitochondrial content, suggesting an increase in mitochondrial biogenesis, presumably through enhanced NAD+ after exercise. [27]

In a separate study, aerobic and resistance training were found to reverse age-dependent decline in skeletal muscle, ultimately restoring NAD+ salvage capacity.  Skeletal muscle biopsies were obtained from young (≤ 35 years old) and old (≥ 55 years old) individuals before and 40 hours after the exercise training interventions.  The exercise interventions consisted of 12 weeks of aerobic exercise with a treadmill, a stationary cycle, or an elliptical trainer at 70 - 75% VO2max, for ~180 min/week;  or 12 weeks of resistance exercise (upper and lower body exercises) for ~34 min/session, 3 times a week, with progressive overload.  Aerobic training significantly increased NAMPT protein levels by 12% in young participants and by 28% in old participants.  Resistance training also increased NAMPT levels by 25% in young individuals and 30% in old individuals.  Interestingly, higher VO2max was found to be strongly correlated with higher levels of NAMPT in the skeletal muscle, emphasizing that aerobic capacity and physical activity are key determinants of muscle NAD+ metabolism [36].

Methylene Blue and Rapamycin

Methylene blue acts as a redox mediator, effectively helping the cell pass electrons more efficiently down its metabolic conveyor belt. This process enhances NADH oxidation and raises the NAD⁺/NADH ratio, mimicking some of the cellular benefits of exercise.  In cell studies, treatment with methylene blue transiently raises the NAD/NADH ratio, which induces AMPK phosphorylation.  Activation of AMPK leads to upregulation of PGC1 and SURF1, inducers of mitochondrial biogenesis.  This improved mitochondrial function may maintain elevated NAD+ levels and reduce oxidative stress [39].

Rapamycin, an mTOR inhibitor, has been shown to extend lifespan in various model organisms and postpone age-related cellular decline through mechanisms such as autophagy induction and immune system rejuvenation.  Similar to methylene blue, rapamycin increases the NAD+/NADH ratio.  Inhibition of mTOR by rapamycin reduces the cellular energetic and anabolic demands, activating autophagy and improving mitochondrial function.  This reduces NADH consumption, resulting in higher NAD+ availability and maintaining a higher cellular NAD+/NADH ratio [38].

Although methylene blue and rapamycin are theoretically capable of raising the NAD+/NADH ratio, there are no human studies, to the best of our knowledge, that have directly measured changes in NAD+ through these interventions.

Together, these findings suggest that NAD⁺ is malleable—not just through supplementation but through daily habits. The way we eat, move, and manage stress may be as influential as any molecule we swallow.

Conclusions

NAD+ is a fundamental molecule essential for cellular energetics, DNA repair, and stress resilience.  Its age-related decline is consistently associated with impaired tissue function, neurodegeneration, and loss of muscle integrity.  Preclinical studies convincingly demonstrate that supplementation with NAD+ precursors, particularly NR and NMN, can restore NAD+ pools, enhance mitochondrial performance, and mitigate functional decline in cognition and muscle health.  These findings underscore the potential for NAD+ restoration as a strategy to support healthy aging and extend healthspan.

Translation of these findings to humans, however, remains limited and inconclusive.  Current clinical trials show that supplementation reliably elevates NAD+ levels, yet improvements in cognitive performance and muscle strength have been modest or absent.  Differences in study design, dosing regimens, trial duration, and participant characteristics likely contribute to the variability observed. 

Looking forward, rigorous, large-scale randomized controlled trials with standardized endpoints are needed to determine whether boosting NAD+ levels can translate to clinically meaningful benefits in humans.  Future studies could address dose-response relationships, long-term safety, and the potential synergy of NAD+ supplementation with lifestyle interventions such as diet and exercise.  Individual participant characteristics are also critical to better understand how specific individuals respond to NAD+ supplementation.  Additional studies are needed to better clarify whether enhancing NAD+ represents a viable approach to counteract age-related decline and promote resilience in the aging population. Ultimately, the story of NAD⁺ offers a window into aging itself: a reminder that longevity may hinge less on discovering new molecules than on preserving the ancient ones that have powered life since its beginning.