Some sources make cautious statements, such as „may support cellular energy”, while others present much more far-reaching claims, for example „reverses the ageing process”. This article focuses on what published research on cells, animal models and human clinical trials actually shows. The evidence has been organised according to biological mechanisms, with a clear distinction between well-documented processes and benefits demonstrated in humans. The findings discussed here reflect scientific data and should not be interpreted as confirmed medical claims.
What do studies actually link to NAD+ levels?
Before discussing the individual categories of potential benefits, it is important to establish the proper scientific context. NAD+ is a coenzyme involved in hundreds of cellular reactions, which is why research linking it to health-related processes covers a very broad scope of biology, including energy metabolism, DNA repair, gene regulation and other cellular functions.
Such a broad biological role is one of the reasons why claims regarding NAD+ can seem very extensive. However, the strength of the evidence varies considerably depending on the specific claim. Some relationships, such as the role of NAD+ in energy metabolism, belong to long-established biochemistry. Other issues, such as whether increasing NAD+ through supplementation provides specific clinical benefits in humans, are much newer, less certain and often supported by ambiguous results [1,2].
These two types of evidence should not be treated as equivalent. Demonstrating that NAD+ is essential for a specific biological process is not the same as proving that NAD+ precursor supplementation improves a specific health outcome in humans. We maintain this distinction throughout the article.
Cellular energy and mitochondrial function
The biological foundations in this area are well established. NAD+ plays a crucial role in the processes by which cells convert nutrients into ATP, the primary form of usable cellular energy. It participates in electron transfer during glycolysis, the citric acid cycle and the mitochondrial electron transport chain [1]. This is a fundamental element of cellular biochemistry.
Clinical evidence from human studies linking NAD+ precursor supplementation to functional energy-related effects is more limited, although some studies have reported measurable changes.
In one randomised, placebo-controlled, dose-ranging study, 80 middle-aged and older healthy individuals received 300 mg, 600 mg or 900 mg of NMN daily for 60 days. Participants in the higher-dose groups showed improvements in 6-minute walk test performance compared to baseline. This result may be related to changes in energy metabolism, but the researchers treated it as an exploratory finding requiring confirmation in larger and more targeted studies [3].
In another study, 12 older men were given nicotinamide riboside for 21 days. The intervention significantly altered the NAD+ metabolome in muscle and induced transcriptional patterns associated with reduced inflammatory signalling in skeletal muscle. However, no significant improvement was observed in grip strength, relative strength, or parameters of skeletal muscle mitochondrial bioenergetics, including complex I- and II-dependent oxidative phosphorylation and mitochondrial content [4].
This is an important example of a broader pattern observed in NAD+ research. Increasing the level of NAD+ or related metabolites in the blood or tissues does not automatically lead to a measurable improvement in every functional outcome that can theoretically be linked to these pathways.
DNA repair and maintenance of cellular functions
The mechanistic link between NAD+ and DNA repair is well documented.
PARP enzymes, namely poly(ADP-ribose) polymerases, are involved in the detection and repair of DNA damage. These enzymes use NAD+ as a substrate in the repair process, meaning that DNA repair activity directly consumes cellular NAD+ [5].
This dependence is one of the reasons why the age-related increase in DNA damage is considered a potential contributing factor to the decline in NAD+ availability with ageing. Greater activation of PARP-dependent repair pathways may increase NAD+ consumption [2].
Patient-derived cell studies also analysed how DNA repair complexes form and break down at damage sites. These results suggest that interactions between PARP activity, NAD+ availability and the NAD+-dependent enzyme SIRT6 can influence the timing and regulation of repair processes [5].
These are detailed mechanistic studies in the field of cell biology. Direct clinical data in humans showing that NAD+ precursor supplementation improves overall DNA repair capacity, reduces DNA damage, or leads to clinically significant effects related to DNA repair, however, remain significantly less developed than the basic molecular evidence.
Activation of sirtuins and the link to longevity
The relationship between NAD+ and sirtuins is one of the main reasons for the interest in NAD+ in ageing and longevity research.
Sirtuins are a family of seven enzymes, from SIRT1 to SIRT7, which require NAD+ as a substrate. They remove acetyl groups from proteins and are involved in processes related to gene regulation, mitochondrial function, inflammation, metabolism and the cellular response to stress [1,2].
Since NAD+ is essential for sirtuin activity, the amount of NAD+ available in the cell can influence these enzymatic processes. This forms the main biological basis for research into whether changes in NAD+ availability can affect pathways related to ageing and the maintenance of normal cellular functions.
Animal studies have yielded significant results in this area. In one frequently cited study, the administration of nicotinamide riboside to mice activated the mitochondrial unfolded protein response and was associated with an extended lifespan and improved muscle stem cell function. This study significantly increased scientific interest in NAD+ precursors as potential modulators of biological processes associated with ageing.
However, these results come from an animal model. No clinical study in humans has directly demonstrated that NAD+ precursor supplementation extends human lifespan. Lifespan itself is also a difficult endpoint to study directly in clinical interventions, as such studies would require an extremely long follow-up period.
In the Phase I NADPARK trial, oral nicotinamide riboside was administered to people with Parkinson's disease. The trial showed that NR increased brain NAD+ levels and was associated with changes in cerebrospinal fluid biomarkers related to inflammation and disease-related processes, as well as minor clinical changes [6].
These results provide early human trial data indicating that increasing NAD+ can induce measurable biological effects in a population of individuals with a neurological condition. However, this was a phase I study designed primarily to evaluate safety, feasibility and biological activity. It was not intended to provide conclusive evidence of disease-modifying activity.
The most precise interpretation is therefore that the link between NAD+ and sirtuins is well established at the molecular level, animal studies have produced several important findings regarding further biological effects, and early human studies have shown biological and clinical signals in selected contexts. However, it has not been demonstrated in clinical trials that increasing NAD+ activates sirtuins in a way that leads to an extension of human lifespan.
What has been established and what is still being investigated?
Analysing all the evidence discussed above, it is worth separating the results according to the level of their scientific confirmation.
Well-established biochemical foundations include the role of NAD+ as an electron carrier in cellular energy metabolism, its function as an essential substrate for sirtuins and PARPs, the existence of the NAD+ salvage pathway, which enables the reuse of nicotinamide, and observations indicating that NAD+ levels decrease with age in blood and several tissues [1,2].
Human clinical trials provide fairly consistent evidence that oral nicotinamide riboside and NMN can increase blood NAD+ levels, often in a dose-dependent manner, as demonstrated in numerous randomised placebo-controlled trials [3,4]. A meta-analysis of 40 studies involving 14,750 people also showed a statistically significant reduction in triglyceride, total cholesterol and LDL cholesterol concentrations in the NAD+ precursor interventions analysed together [7].
Human evidence regarding functional effects is less consistent. Some studies have reported improvements in parameters such as walking performance [3], whilst others have shown no significant changes in strength or skeletal muscle mitochondrial bioenergetics despite a clear increase in NAD+-related metabolites [4].
The results of the phase I Parkinson’s disease study also remain preliminary. The NADPARK study demonstrated changes in brain NAD+ levels and disease-related biomarkers, but larger confirmatory studies are needed before drawing conclusions regarding clinical efficacy [6].
Other claims remain primarily at a mechanistic or preclinical level. This applies, among other things, to the direct improvement of DNA repair capacity in humans as a clinical endpoint and to the extension of lifespan or healthspan. These concepts are biologically plausible and supported by laboratory or animal studies, but have not been directly demonstrated in human studies [5].
Benefits depending on the form: do injections and supplements differ?
The mode of delivery is often discussed as if it alone determines the effectiveness of a NAD+-related intervention. The available evidence does not support such an assumption.
Oral NR and NMN have the largest body of randomised, placebo-controlled human trials among the administration forms discussed here. Numerous studies have consistently demonstrated that these oral precursors can increase circulating levels of NAD+ and related metabolites [3,4,7].
Direct administration of NAD+ via injection or intravenous infusion has a significantly smaller base of controlled clinical trials. A 2026 systematic review found no qualifying controlled outcome trials regarding intravenous or intramuscular NAD+ specifically for general anti-ageing or wellness purposes, despite the widespread commercial use of these forms [8].
This does not mean that injectable or intravenous NAD+ is ineffective. It does mean, however, that the quantity and quality of currently available controlled evidence from human studies are considerably greater for oral NAD+ precursors than for injectable or intravenous NAD+ in general wellness applications.
Claims that one route of administration is inherently better should therefore be treated with caution, unless supported by direct, human head-to-head clinical trials evaluating the same outcomes.
Limitations of current evidence
- Much of the mechanistic and longevity-related evidence discussed in this article, particularly concerning the link between sirtuins, NAD+ metabolism and lifespan, comes from cellular studies and animal models. Human research has focused primarily on safety, biomarkers and selected functional outcomes, rather than lifespan or the full range of effects suggested by preclinical studies [2,6].
- Human studies consistently show that NAD+ precursors can increase NAD+ levels in the blood, yet functional outcomes such as strength, mitochondrial bioenergetics and cognitive function have been mixed. Some studies demonstrate measurable improvements, whereas others find no significant effect within the same general outcome category [3,4].
- Evidence from meta-analyses indicating an improvement in lipid parameters combines several different NAD+ precursors, including NR, NMN, niacin, and nicotinamide. These results cannot therefore be automatically attributed to one specific compound [7].
- The quantity and quality of evidence vary significantly depending on the route of administration. Oral precursor capsules have considerably greater support from controlled clinical trials than injectable or intravenous NAD+ used for general wellness purposes [8].
- Changes in NAD+ concentration, metabolites, gene expression patterns or other biomarkers do not automatically mean an improvement in symptoms, disease outcomes, lifespan or overall health.
- The fact that NAD+ is required in a specific biological pathway does not prove that increasing its levels above physiological values will improve the functioning of this pathway or yield a clinical benefit.
- Results of cell and animal studies should not be presented as confirmed effects in humans unless they have been replicated in appropriately designed clinical trials.
Disclaimer
The article is purely educational in nature and summarises scientific research. It does not constitute medical advice, a diagnosis, therapeutic recommendations, or a recommendation to use NAD+, NAD+ precursors, supplements, injections, or intravenous therapies.
NAD+ and its precursors should not be presented as FDA- or EMA-approved methods for the prevention, treatment or cure of diseases, unless referring to a specific approved medicinal product and indication.
The evidence summarised here includes basic biochemistry, cellular studies, animal research and human clinical trials at various stages of development. Results regarding biomarkers, molecular pathways or animal models should not be interpreted as confirmed medical benefits in humans. You should consult a qualified healthcare professional before starting any new supplement or therapy, particularly during pregnancy or breastfeeding, when managing a chronic condition, or while taking prescription medications.
References
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[2] Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. *Nature Reviews Molecular Cell Biology*, 22(2), 119–141. https://doi.org/10.1038/s41580-020-00313-x
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[5] Koczor, C. A., Saville, K. M., Andrews, J. F., Clark, J., Fang, Q., Li, J., Al-Rahahleh, R. Q., Ibrahim, M., McClellan, S., Makarov, M. V., Migaud, M. E., & Sobol, R. W. (2021). Temporal dynamics of base excision/single-strand break repair protein complex assembly/disassembly are modulated by the PARP/NAD+/SIRT6 axis. *Cell Reports*, 37(5), 109917. https://doi.org/10.1016/j.celrep.2021.109917
[6] Brakedal, B., Dölle, C., Riemer, F., Ma, Y., Nido, G. S., Skeie, G. O., Craven, A. R., Schwarzlmüller, T., Brekke, N., Diab, J., Sverkeli, L., Skjeie, V., Varhaug, K., Tysnes, O.-B., Peng, S., Haugarvoll, K., Ziegler, M., Grüner, R., Eidelberg, D., & Tzoulis, C. (2022). The NADPARK study: A randomised phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. *Cell Metabolism*, 34(3), 396–407.e6. https://doi.org/10.1016/j.cmet.2022.02.001
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