In the field of anti-aging research, the role of NAD+ has been gaining increasing attention. This molecule, which is widely present within cells, is not only a central player in energy metabolism but also plays a key role in maintaining cellular homeostasis and responding to age-related damage. As people age, the decline in NAD+ levels is closely linked to various physiological deteriorations, and boosting NAD+ through scientific approaches has become an important research direction for slowing the aging process.

However, as “NAD+ and anti-aging” becomes a hot topic and related supplements flood the market, many questions arise: Why do some people experience a noticeable increase in energy after taking NAD+ precursors, while others see little effect? Does the so-called “optimal dosage” truly apply to everyone? Are the underlying scientific principles solid, and what precautions should be taken?

Recently, independent researcher Faruk Alpay published a paper on July 23, 2025, titled “Boosting NAD+ for Anti-Aging: Mechanisms, Interventions, and Opportunities.” This paper systematically reviewed the central role of nicotinamide adenine dinucleotide (NAD+) in the aging process, along with the scientific basis and practical strategies for delaying aging by modulating NAD+ levels. It may provide authoritative insights to help answer these questions and allow us to view this anti-aging trend with greater clarity.


1. The Biological Functions of NAD+ and Its Link to Aging

NAD+ is a highly conserved coenzyme within cells, with two core functions. First, it acts as a key participant in redox reactions, transferring electrons during glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, thereby providing the foundation for ATP energy production. Second, it serves as a substrate for several enzyme families—including sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38—that regulate gene expression, DNA repair, immune responses, and other critical physiological processes.

The sirtuin family (SIRT1–SIRT7) relies on NAD+ to function. For example, SIRT1 influences mitochondrial activity by regulating metabolism-related gene expression, while SIRT3 helps maintain mitochondrial homeostasis and reduce oxidative damage. Both are directly linked to slowing down aging. PARPs primarily detect and repair DNA damage; when cells are exposed to oxidative stress or radiation, PARPs are activated and consume large amounts of NAD+ to initiate repair mechanisms. CD38, a major NAD+-consuming enzyme in immune cells, becomes significantly more active under chronic inflammation, accelerating NAD+ degradation.

Aging leads to a marked decline in NAD+ levels. Research shows that by middle age, NAD+ levels in blood and various tissues drop by about 50% compared to youth, and continue to decrease with advancing age. This decline is the result of multiple factors: accumulated DNA damage chronically activates PARPs, increasing NAD+ consumption; age-related chronic inflammation (also known as inflammaging) induces high CD38 expression in immune cells, further depleting NAD+; meanwhile, activity of key enzymes in NAD+ synthesis pathways, such as NAMPT, decreases with age, reducing biosynthetic capacity. In addition, aging of the gut microbiome may lower the supply of NAD+ precursors, creating a vicious cycle.

Falling NAD+ levels trigger a cascade of negative effects: insufficient sirtuin activity reduces cellular stress resistance and disrupts mitochondrial function; PARP-mediated DNA repair efficiency declines, leading to greater genomic instability; and metabolic dysfunction promotes oxidative stress and inflammatory factor release, which further stimulate CD38 expression. Together, these changes exacerbate aging-related phenotypes such as insulin resistance, muscle weakness, and cognitive decline. Experimental evidence confirms that artificially lowering NAD+ levels in young animals can induce premature aging-like physiological traits.


2. Strategies to Increase NAD+ Levels

Given the age-related decline in NAD+ levels, several intervention strategies have been developed, including supplementation with precursors, lifestyle modifications, and inhibition of NAD+-consuming enzymes.

2.1 Supplementing with NAD+ Precursors

NAD+ precursor supplementation is one of the most direct and effective approaches. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are the most extensively studied precursors.

NR is a derivative of vitamin B3 that can be absorbed and converted into NAD+ through the salvage pathway. Animal studies show that supplementing older mice with NR improves muscle endurance, neural stem cell function, and lifespan, extending median lifespan by about 5%. Human clinical trials confirm that daily supplementation of 500–2000 mg of NR increases blood NAD+ levels by 60%–200%, with good safety. Some participants also reported lowered blood pressure and reduced inflammatory markers.

NMN, an intermediate in NAD+ biosynthesis, has shown high efficiency as well. Researchers have identified a specific NMN transporter (Slc12a8) in the intestine, enabling effective absorption. Long-term NMN supplementation in mice improved insulin sensitivity, boosted energy metabolism, delayed bone density loss, and preserved vision. In human studies, prediabetic women taking 250 mg of NMN daily for 10 weeks showed a 25% improvement in muscle insulin sensitivity, while healthy middle-aged adults experienced enhanced aerobic capacity and VO₂ max.


2.2 Lifestyle Interventions

Lifestyle modifications also play an important role in regulating NAD+ metabolism.

Caloric restriction (20%–40% fewer calories) upregulates NAMPT expression, enhances NAD+ recycling, and activates sirtuins, mimicking longevity effects.

Exercise increases muscle consumption of NADH, raises the NAD+/NADH ratio, and stimulates NAMPT activity, thereby boosting NAD+ levels in muscle tissues. Studies have shown that individuals who exercise regularly express more NAD+-related genes in muscle, supporting youthful metabolic profiles.

Dietary composition also matters. Diets high in sugar and fat lower tissue NAD+ levels, whereas foods rich in polyphenols (such as apigenin and quercetin) inhibit CD38 activity, reducing NAD+ consumption. Compounds like resveratrol, while not directly boosting NAD+, activate sirtuins and may work synergistically with NAD+ precursors.


2.3 Inhibiting NAD+-Consuming Enzymes

Another strategy involves reducing NAD+ breakdown.

CD38 inhibitors, such as the small molecule 78c, have shown promise in animal studies, restoring NAD+ levels, improving metabolic health, and extending median lifespan by about 10% in male mice.

However, since CD38 plays an important role in calcium signaling within immune cells, long-term inhibition may impair immune function. Future approaches may include developing tissue-specific inhibitors or intermittent treatment protocols.


2.4 Potential Benefits of Direct NAD+ Supplementation

In addition to precursor supplementation, recent studies have also explored the feasibility and effects of direct oral or intravenous NAD+ supplementation. Although the NAD+ molecule is relatively large and its oral absorption in the gut is limited, some animal and preliminary human studies suggest that direct NAD+ intake can still increase blood and tissue NAD+ levels in the short term, bringing certain health benefits:

Rapid boost in energy metabolism: Clinical observations indicate that oral NAD+ supplements may raise blood NAD+ concentrations within hours to days, with some users reporting improvements in energy and stamina.

Better sleep and cognitive function: Early trials suggest that NAD+ supplementation may influence circadian rhythm regulation, with some individuals experiencing enhanced sleep quality and improved concentration.

Neuroprotective effects: Intravenous NAD+ administration has been tested in clinical settings, showing potential in supporting cognitive performance and reducing fatigue.

Cell repair and detoxification support: Direct NAD+ supplementation has been linked to enhanced activity of enzymes involved in DNA repair and liver detoxification.

That said, the bioavailability of oral NAD+ remains a subject of debate, as much of it may be degraded in the digestive tract, with only a fraction converted into usable forms. To overcome this limitation, researchers are investigating advanced delivery methods such as liposomal formulations, sublingual administration, and intravenous infusions to improve effectiveness.

Overall, while direct NAD+ supplementation is still in the early stages of research, it has emerged as a promising complement or alternative to precursor-based approaches and is drawing increasing interest from both scientists and consumers.


3. Health Effects of NAD+ Interventions

Increasing NAD+ levels has demonstrated anti-aging benefits across multiple physiological systems.

Metabolic Regulation: NAD+ precursors activate SIRT1 and SIRT3, promoting fatty acid oxidation and improving insulin signaling. Animal studies show that NR and NMN supplementation can alleviate high-fat diet-induced insulin resistance and fatty liver. In human trials, NMN improved blood glucose control in prediabetic patients, while NR reduced triglyceride levels in obese individuals.

Cardiovascular Benefits: Boosting NAD+ improves vascular endothelial function. In aged mice, NMN supplementation restored carotid artery dilation to levels close to young mice, mediated by SIRT1 activation of endothelial nitric oxide synthase (eNOS). In humans, middle-aged men taking NR experienced a 5 mmHg reduction in systolic blood pressure and decreased arterial stiffness. Long-term use may reduce cardiovascular disease risk by approximately 25%.

Neuroprotective Effects: NAD+ interventions support nervous system health. In Alzheimer’s disease mouse models, NMN and NR reduced tau protein phosphorylation and neuroinflammation, preserved synaptic structure, and improved memory. Parkinson’s patients taking NR showed increased NAD+ in cerebrospinal fluid and improved mitochondrial biomarkers. In rare ataxia-telangiectasia patients, NR supplementation alleviated neurological symptoms and enhanced immune function.

Muscle and Immune System Support: Aged mice receiving NR showed enhanced muscle stem cell proliferation and repair capacity, resulting in improved exercise endurance. In humans, NR supplementation reduced pro-inflammatory markers (IL-6, IL-5, etc.) by 50%–70%, demonstrating immune-modulatory potential.

It is important to note that NAD+ interventions are not a “cure-all” for aging. Aging involves multiple mechanisms, including telomere shortening and stem cell exhaustion, with NAD+ representing only one aspect. Future strategies may be most effective when combined with senolytics, mTOR inhibitors, and other anti-aging approaches to create a comprehensive intervention.


4. Conclusion

Research on NAD+ metabolism has identified important targets for anti-aging interventions. Current evidence indicates that supplementing precursors, modifying lifestyle, or inhibiting NAD+-consuming enzymes can safely and effectively increase NAD+ levels, improving the function of metabolic, cardiovascular, and nervous systems. Although questions remain regarding optimal dosages and long-term safety, NAD+ interventions have demonstrated significant potential.

Future studies should focus on: determining the best intervention strategies for different populations (e.g., varying ages and genotypes); exploring the synergistic effects of NAD+ with other anti-aging targets; and assessing the impact of long-term interventions on healthspan. As research progresses, NAD+ modulation is likely to become a routine clinical approach for slowing aging and preventing age-related diseases, helping people not only live longer but also live healthier and higher-quality lives.