Nicotinamide adenine dinucleotide (NAD+) has become an area of intense research and public interest, particularly for its rapidly emerging links to aging and age-related diseases. The identification of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) as promising agents capable of restoring NAD+ levels in the body, which naturally wane with age, has opened a new avenue for potential interventions targeting markers of aging and longevity. This review unpacks the scientific evidence for NAD+ and its precursors, covering their mechanisms of action, clinical evidence from both animal and human studies, and the future directions that could shape their use in combating age-associated disorders.

Mechanisms of Action

Cellular Functions

NAD+ is a vital coenzyme present in every cell, playing a central role in fundamental biological processes. It acts as a critical electron carrier in metabolic pathways such as glycolysis and the Krebs cycle, directly influencing energy production in the form of ATP. Beyond energy metabolism, NAD+ is essential for the function of sirtuins and poly(ADP-ribose) polymerases (PARPs), which are key enzymes involved in DNA repair and cellular signaling pathways (Bhasin et al., 2023; Lautrup et al., 2023). By modulating these pathways, NAD+ helps maintain genomic stability, regulate immune responses, and manage oxidative stress, all of which are intimately linked to the processes of aging and the pathogenesis of age-related diseases.

As we age, cellular NAD+ levels decline, which disrupts these critical processes and renders cells more susceptible to damage and dysfunction. The resultant decrease in sirtuin activity, diminished DNA repair capacity, and altered cellular signaling contribute to a broad spectrum of aging phenotypes and chronic diseases. This intricate, systemic role of NAD+ underscores why restoring its levels has become a promising strategy to slow down or even reverse certain aspects of biological aging.

Restoration of NAD+ Levels

Given the central importance of NAD+, restoring its physiological levels is a tantalizing target for age-related therapies. NAD+ precursors like NR and NMN are particularly effective because they can be readily converted into NAD+ within cells. Numerous preclinical studies and recent clinical trials have shown that oral supplementation with NR and NMN leads to a measurable increase in NAD+ concentrations in blood and tissues ("Therapeutic Potential of NAD+ Precursors and Aging-related Diseases", 2022; Braidy et al., 2019). This elevation in NAD+ has been associated with enhancement in mitochondrial function, improved energy metabolism, and increased activation of sirtuins and other protective enzymes.

Mechanistically, these precursors bypass certain rate-limiting steps in the NAD+ biosynthetic pathway, allowing for a more efficient replenishment compared to niacin or nicotinamide. Evidence suggests that the efficacy of this boost may differ among individuals, depending on baseline NAD+ levels, age, and metabolic health. Still, the ability of NR and NMN to actually reach tissues and effectively raise NAD+ is central to their therapeutic promise as anti-aging interventions.

Clinical Evidence

Preclinical Success

Initial excitement around NAD+ precursors comes largely from animal research. Numerous preclinical studies have found that supplementing aging rodents with NR or NMN results in notable improvements in a wide array of conditions. These benefits include enhanced cardiac function in heart failure models, protection against neurodegeneration in Alzheimer’s disease and Parkinson’s disease models, and metabolic improvements in models of diabetes and obesity (Iqbal & Nakagawa, 2024; "Therapeutic Potential of NAD+ Precursors and Aging-related Diseases", 2022). Importantly, these effects have been linked to elevated tissue NAD+ levels and restored sirtuin activity, highlighting the mechanistic importance of the molecule.

Animal studies also suggest broader systemic benefits, such as increased physical activity, improved insulin sensitivity, and even increased lifespan under certain conditions. However, while these results are compelling, translating findings from laboratory animals to humans brings considerable complexity. The precise doses, forms, and long-term safety of NAD+ precursor administration are active fields of investigation, and animal models cannot fully capture the diversity and complexity of human aging.

Human Trials

Building on preclinical findings, early-stage clinical trials in human participants have largely focused on safety, tolerability, and evidence of NAD+ boosting. Research suggests that both NR and NMN are generally well-tolerated with minimal side effects, and supplementation reliably raises blood NAD+ levels within weeks (Bhasin et al., 2023; Lautrup et al., 2023). These findings are encouraging from a translational standpoint.

However, the more challenging question is whether these biochemical changes translate into meaningful clinical benefits for age-related diseases. To date, human trials have offered only preliminary indications. Some studies report improvements in markers of cardiovascular health, metabolic function, and even mild enhancements in cognitive performance, but results are not always consistent or robust. Larger, longer-term randomized controlled trials are needed to determine whether NAD+ precursors can delay or reverse specific age-related diseases or improve overall healthspan in humans.

Future Directions

Gut Microbiota Interaction

A novel and rapidly expanding area of NAD+ research involves its dynamic interplay with the gut microbiota. Recent studies have discovered that intestinal bacteria play a role in NAD+ metabolism, impacting how precursors are processed and how effectively they are converted into NAD+ in different tissues (Iqbal & Nakagawa, 2024). This finding opens new possibilities for understanding individual variability in response to NAD+ precursor supplementation and for designing tailored interventions that incorporate both microbiome and NAD+ metabolism.

The influence of diet, probiotics, and prebiotics on this relationship represents an exciting frontier, suggesting that optimizing gut health could enhance the efficacy of NAD+-boosting strategies. Integrative therapies that consider both the microbiota and NAD+ metabolism could, therefore, offer more personalized and effective interventions for age-related diseases.

Personalized Therapy

Looking ahead, the future of NAD+ supplementation may lie in personalized, precision medicine. Since baseline NAD+ levels and metabolism vary significantly among individuals due to age, genetics, lifestyle, and other factors, personalized approaches could maximize therapeutic benefit while minimizing risk (Braidy et al., 2019). Emerging research calls for the development of diagnostic tools that can accurately measure systemic and tissue-specific NAD+ concentrations in patients, guiding more effective dosing regimens.

Additionally, combining NAD+ precursor therapy with other interventions, such as caloric restriction or exercise, could provide synergistic benefits but also requires careful monitoring for safety and efficacy. Personalized strategies may eventually become the standard for NAD+-targeted interventions, empowering clinicians to address age-related diseases with far greater precision.

The Bottom Line

NAD+ is a molecule at the heart of cellular health, and replenishing its levels with precursors like NR and NMN presents a promising avenue for the prevention and treatment of age-related diseases. Robust preclinical evidence paints an encouraging picture, but the translation of these findings to human health remains an ongoing challenge. Interindividual variability, the role of the gut microbiota, and the need for well-controlled, large-scale clinical trials will determine whether these promising molecules can fulfill their therapeutic potential. Continued, interdisciplinary research is essential to inform the future of NAD+ supplementation as a strategy to combat the burdens of aging

Sources