Emerging Strategies, Applications, and Challenges of Targeting NAD⁺ in the Clinic: A Review

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A notable 2025 Nature Aging review outlines current and future approaches to targeting nicotinamide adenine dinucleotide (NAD⁺) in human disease, emphasizing both its therapeutic promise and the hurdles of translating NAD⁺ biology into clinical medicine.

 

Once regarded as a simple coenzyme required for energy production, NAD⁺ is now recognized as a master regulator of health, supporting DNA repair, epigenetic programming, immune responses, and mitochondrial function. The steady decline of NAD⁺ with age has been linked to multiple chronic diseases, driving a surge of interest and clinical research into strategies to restore it.

Key Points

  • NAD⁺ is a central regulator of DNA repair, mitochondrial function, immune balance, and aging biology.

  • Early clinical trials show safety and efficacy of NAD⁺ precursors in improving metabolic and cardiovascular outcomes.

  • Broader disease applications including cancer, neurodegeneration, and cardiovascular disorders, are being explored with promise.

  • Implementing clinical strategies remains challenging due to a variety of uncertainties.

  • Researchers are actively pursuing next-generation strategies

NAD⁺ is no longer seen as merely a metabolic cofactor. As a regulator of DNA repair, mitochondrial health, stress resistance, and cellular metabolism, NAD⁺ sits at the heart of efforts to combat age-related decline and chronic disease. Declining NAD⁺ contributes to inflammation and mitochondrial dysfunction, causing a loss of resilience across nearly every organ system.

"Extensive research has demonstrated that NAD⁺ levels decline with age across multiple species, correlating with various hallmarks of aging including mitochondrial dysfunction, genomic instability and altered cellular communication."

This has made restoring NAD⁺ one of the most promising anti-aging strategies in modern medicine, and early clinical work shows improvements across systems and even lifespan. For a comprehensive overview of recent developments, see latest breakthroughs in NAD+ research for 2025. Turning this promise into clinical therapies is now a central focus of geroscience.

NAD⁺ as a Clinical Target

NAD⁺ supports health in two major ways: it helps keep our cells' energy and repair systems in balance, and it powers key enzymes, like sirtuins and PARPs, that protect DNA and help cells respond to stress. As NAD⁺ levels fall, these defenses weaken, creating a cascade of inflammation, mitochondrial decline, and increased disease risk.

"The growing understanding of NAD⁺ biology and its decline with age has prompted investigation into therapeutic strategies to restore NAD⁺ levels."

"Two primary strategies have emerged: precursor supplementation … or inhibiting major NAD⁺-consuming enzymes like CD38 and PARPs to maintain higher steady-state NAD⁺ levels."

This biology makes NAD⁺ a unique therapeutic target, not just for individual conditions, but for the fundamental processes of aging itself. Rather than treating symptoms later on, NAD⁺ therapies aim to restore the body's core resilience, supporting healthier function over time.


Disease Applications

A growing body of research is revealing how NAD⁺ decline contributes to many of the most common and devastating age-related diseases. Efforts to restore NAD⁺ are now being tested in conditions ranging from neurodegeneration to heart disease, with early results pointing toward broad potential. Early results are promising, pointing to a strategy that could impact both individual illnesses and the aging process as a whole.

Neurodegenerative Diseases

The nervous system is especially dependent on NAD⁺ for maintaining nerve cell connections, mitochondrial energy, and DNA repair. In animal models of Alzheimer's and Parkinson's, replenishing NAD⁺ reduces symptoms and improves cognition. Inhibiting the NAD⁺-consuming enzyme SARM1 has been particularly promising at protecting nerve connections from degeneration.

"NAD⁺ dysregulation intersects with key disease mechanisms, including aberrant proteostasis, mitochondrial dysfunction and neuroinflammation, highlighting its potential role in PD pathogenesis."

"An NR-containing supplementation improved memory, slowed reduction of hippocampal volumes, increased cortical thickness and improved glutathione metabolism."

Human studies with NAD⁺ infusions and oral precursors have demonstrated enhanced NAD⁺ availability in the brain and encouraging biomarker shifts, but large-scale studies are still needed. For a detailed analysis of the evidence, see our comprehensive review on NAD+ as a multi-target therapy for neurodegenerative diseases.

Cardiovascular Health

Healthy blood vessels depend on NAD⁺-driven repair and sirtuin activity. With aging, declining NAD⁺ contributes to endothelial senescence and vascular stiffness with preclinical studies show that boosting NAD⁺ improves vessel function and lowers cardiovascular risk factors.

"A 30-day NMN supplementation (800 mg daily) elevated peripheral blood mononuclear cell NAD⁺ levels by 43% while reducing both systolic and diastolic blood pressure."

"The landmark Coronary Drug Project demonstrated that NA therapy led to a 26% reduction in recurrent myocardial infarction, with long-term follow-up revealing an 11% reduction in all-cause mortality."

Initial human trials echo these findings, with NAD⁺ precursors supporting endothelial responsiveness and improving blood pressure markers. Given the scale of cardiovascular disease worldwide, NAD⁺ restoration represents an exciting new tool for prevention and resilience.

"High dietary intake of naturally occurring NAD⁺ precursors was associated with lower blood pressure and reduced risk of cardiac mortality."

Metabolic Health

Metabolic disorders such as type 2 diabetes and fatty liver disease are closely tied to age-related NAD⁺ decline. Human data suggest supplementation with precursors like NR and NMN has reliably raised NAD⁺ levels in humans and improved insulin sensitivity and fat cell metabolism.

"A targeted investigation of NMN supplementation (250 mg per day for 10 weeks) in postmenopausal women with prediabetes demonstrated significant improvement in muscle insulin sensitivity and signaling."

While outcomes vary across trials, the overall trend points to a shift toward healthier metabolic profiles. These findings support NAD⁺ restoration as a promising strategy for metabolic disease, with the potential for greater benefit when combined with diet and exercise.

"Both type 1 diabetes and type 2 diabetes show disrupted NAD⁺ homeostasis… Results across studies highlight the need for more targeted approaches that consider the specific pathophysiology of different metabolic disorders and patient subgroups."

Cancer

NAD⁺ biology in cancer is complex. Some tumors depend on NAD⁺ for survival, while healthy cells require it for repair and stability. This has led to dual strategies: restricting NAD⁺ in tumors while restoring it in normal tissue to improve resilience.

The important takeaway is that NAD⁺ science is already influencing oncology. The future of oncology may hinge on precision targeting to determine where boosting or blocking NAD⁺ delivers the greatest benefit.

Aging and Longevity

Perhaps the most transformative application is targeting aging itself. In mice, NAD⁺ boosters extend lifespan and improve multiple hallmarks of health. Human studies already show reliable NAD⁺ increases and encouraging effects on muscle function, fatigue, and inflammation.

The field is now moving toward long-term clinical trials that can confirm what preclinical science already suggests: that supporting NAD⁺ may help sustain resilience, delay chronic disease, and extend the healthy years of life.

Strategies and Limitations

NAD⁺ exists in multiple forms and pools (nuclear, cytosolic, mitochondrial), with metabolism that is highly tissue specific, which brings its own challenges to medicine translation. Raising blood NAD⁺ does not necessarily guarantee increases in the brain, heart, muscles, or other places where it really matters. Current strategies include:

  • Precursors: Supplementation with NMN, NR, and their reduced forms (NRH, NMNH) feeds directly into the salvage pathway and reliably raises NAD⁺ levels in blood and many tissues.

  • Direct delivery: Intravenous and liposomal NAD⁺ bypass precursor metabolism. Liposomal formulations, in particular, show enhanced bioavailability and ~30% greater penetration than free NAD⁺ in skin models, suggesting value where rapid or targeted restoration is needed.

  • Inhibiting breakdown: Enzymes such as CD38, which rise with age and inflammation, accelerate NAD⁺ depletion. Inhibiting CD38 has improved mitochondrial function and tissue health in preclinical models.

  • Stimulating biosynthesis: Boosting NAMPT, the rate-limiting enzyme that recycles nicotinamide back to NMN, may sustain intracellular NAD⁺ more effectively than precursors alone.

"In CD8⁺ T cells, inhibition of the NAD⁺-consuming CD38 protein reinvigorated cellular defense capacity against virus infection … via mitophagy induction and the maintenance of mitochondrial homeostasis."

Most clinical studies are small and short in duration, making it difficult to define efficacy, optimal dosing, or long-term outcomes. Similarly, lack of standardized biomarkers remain a major obstacle as blood NAD⁺ measurements do not always reflect tissue status or functional improvements.

"Although these early results show promise, the field faces substantial limitations … short treatment periods, small participant numbers and use of combination therapies … complicates data interpretation."

In terms of safety, NAD+ therapies are generally well tolerated but without enough clinical data, questions still remain. Sustained elevation of reduced NADH could, under certain conditions, impair glycolysis or contribute to oxidative stress. Long-term human data are still lacking, underscoring the need for larger and longer trials.

"Current clinical trials have demonstrated that oral administration of NR and NMN … showed no obvious adverse effects within the designated treatment periods."


The Future of Clinical NAD⁺

The science of NAD⁺ has advanced from niche biochemistry to the center of translational medicine. Precursors consistently raise NAD⁺ in humans, early trials show benefits across metabolic, neurological, and cardiovascular systems, and next-generation approaches are poised to amplify these effects.

Looking forward, several strategies are likely to define the next decade of NAD⁺ therapeutics:

  • Combination Therapies: Pairing precursors (NMN, NR) with CD38 or SARM1 inhibitors may sustain higher NAD⁺ levels, while adding sirtuin activators could enhance downstream effects on mitochondrial health, DNA repair, and inflammation control. These "stacked" approaches may address multiple aging pathways simultaneously.

  • Advanced Delivery Systems: Liposomal formulations improve bioavailability, while organ-targeted carriers and nanoparticle-based delivery may direct NAD⁺ restoration to the brain, heart, or muscles where it is most needed.

  • Large-Scale Clinical Trials: Current studies are limited by small cohorts and short durations. Well-powered, long-term trials will be essential to move beyond biomarkers and demonstrate real clinical outcomes in aging and chronic disease.

  • Precision NAD⁺ Medicine: Tailoring interventions to genetics, metabolic state, age, and baseline NAD⁺ levels could maximize benefit while minimizing risk, aligning with broader trends in personalized medicine.

NAD⁺ boosters sit at the intersection of pharmaceuticals and metabolic therapies, and their regulatory gray zone complicates trial design and approval. Even so, research momentum is accelerating, and the optimism is well founded.

NAD⁺ has become one of the most promising molecular targets for extending healthspan. What began as a simple coenzyme has evolved into a central focus of clinical medicine. With ongoing advances being explored, NAD⁺ therapeutics could redefine preventive medicine, helping people not only live longer, but live better.

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Olivia Harrier

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Olivia is a longevity writer and researcher passionate about making science easy to understand and apply. She focuses on metabolic health, integrative wellness, and the everyday habits that support better aging. With backgrounds in biochemistry and fitness, her work explores the intersection of molecular biology and lifestyle, blending evidence-based research with practical tools for feeling good and living well.

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