The rising global life expectancy and the demographic shift towards an aging population have significantly increased the prevalence of age-related disorders, including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer. These conditions are closely associated with a systemic decline in nicotinamide adenine dinucleotide (NAD+) levels, a coenzyme essential for energy metabolism, DNA repair, and maintaining cellular homeostasis. Nicotinamide mononucleotide (NMN), a key precursor in NAD+ biosynthesis, has emerged as a potent therapeutic candidate to counteract the deleterious effects of aging and manage age-associated pathologies. Studies show NMN's wide-ranging potential, including its ability to replenish NAD+ levels, improve mitochondrial function, and reduce inflammation and oxidative stress, thereby mitigating many hallmarks of aging (1) (2) (3) (4).

NAD+ Decline and Aging

NAD+ levels decrease significantly with age, primarily due to the heightened activity of NAD+-dependent enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38. This decline not only leads to impaired mitochondrial function and disrupted cellular metabolism but also exacerbates systemic inflammation and genomic instability—both hallmarks of aging— significantly affecting tissue functionality and organismal health (1) (4). NMN supplementation has been shown to counteract these effects by replenishing NAD+ levels and restoring cellular homeostasis. Research indicates that NMN enhances mitochondrial bioenergetics, reduces oxidative stress, and mitigates inflammation, presenting it as a robust therapeutic tool against age-associated cellular impairments and systemic decline (4).

Fig 1. NMN increases NAD+, activates sirtuins, leading to delaying of aging (3).

NMN Biosynthesis and Mechanisms of Action

NMN is synthesized through the salvage pathway of NAD+ biosynthesis, wherenicotinamide is converted to NMN by nicotinamide phosphoribosyltransferase (NAMPT). NMN is subsequently converted to NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). This process is essential for maintaining cellular energy metabolism and counteracting age-related NAD+ depletion. NMN supplementation elevates intracellular NAD+ levels, thereby enhancing mitochondrial function, promoting efficient DNA repair, and activating sirtuins, which regulate critical pathways related to metabolism, stress response, and aging. Studies have demonstrated these mechanisms, reinforcing NMN’s potential as a therapeutic agent to mitigate aging and its associated physiological decline (1) (2).

FIG. 2 NADþ levels are maintained by 3 independent pathways. The salvage pathway is the major source of NADþ. 3-HAA, 3-hydroxyan- thranilic acid; ACMS, 2-amino-3-carboxymuconate-6- semialdehyde; cADPR, cyclic ADP-ribose; IDO, indoleamine 2,3-dioxygenase; L-kin, L- kinurenine; NAAD, nicotinic acid adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NADS, NADþ synthase; NAM; nicotinamide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyltransferase; NRK, nicotinamide riboside kinase; PARP, poly(adenosinediphosphate-ribose) po- lymerase; PRPP, 5-phosphoribosyl-1-pyrophosphate; TDO, tryptophan 2,3-dioxygenase (2)

Recent research also indicates that NMN directly enters cells via the transporter SLC12A8, which is primarily expressed in the small intestine and certain other tissues, enabling rapid replenishment of NAD+ pools. This transporter plays a crucial role in mediating NMN's bioavailability and its efficient absorption into cells (3) (4). The ability to bypass the conversion of NMN to nicotinamide riboside (NR) before cellular uptake further solidifies its position as a direct and potent precursor for NAD+ synthesis, enhancing its therapeutic potential in aging and related diseases.

Preclinical and Clinical Evidence

Numerous animal studies have demonstrated the therapeutic potential of NMN. In aged mice, NMN supplementation has been shown to improve insulin sensitivity, restore mitochondrial function, and reverse cognitive decline (1) (3) (4). For instance, NMN administration in Alzheimer’s disease models reduced amyloid-beta deposition, enhanced synaptic plasticity, and improved cognitive performance (4). NMN also ameliorates vascular aging by increasing capillary density and enhancing endothelial function (1) (4).

Clinical trials have begun to confirm NMN’s safety and efficacy in humans. Short-term studies have shown that NMN supplementation increases blood NAD+ levels without adverse effects. A trial involving older adults reported improved muscle strength and aerobic capacity, suggesting NMN’s potential to counteract age-related physical decline (2) (3) (4).

Anti-Aging Potential

The anti-aging effects of NMN are mediated by its ability to:

1. Enhance Mitochondrial Function: NMN restores NAD+ levels, facilitating the recovery of oxidative phosphorylation and ATP production, both of which decline with age. By replenishing NAD+, NMN supports mitochondrial dynamics and bioenergetics, reducing age-associated energy deficits in vital tissues such as the brain, liver, and skeletal muscle. These findings emphasize its role in mitigating mitochondrial dysfunction, a cornerstone of aging and related metabolic decline (1) (4).
2. Facilitate DNA Repair: By activating PARPs, NMN improves the cell's ability to repair DNA damage, a critical factor in mitigating aging and preventing cancer. NMN enhances the recruitment of DNA repair enzymes to sites of damage, stabilizes genomic integrity, and alleviates the accumulation of mutations associated with cellular senescence and tumorigenesis. These effects underline its therapeutic potential in maintaining genome stability across aging tissues (4).
3. Reduce Inflammation: NMN suppresses chronic inflammation by modulating the activity of sirtuins, which regulate inflammatory pathways and cellular stress responses. It also reduces oxidative stress by enhancing the activity of antioxidant enzymes and decreasing the production of reactive oxygen species (ROS). These mechanisms emphasize NMN's potential to mitigate inflammation- related damage, particularly in tissues affected by aging and chronic disease (2) (4).4.
4. Improve Cognitive and Physical Function: NMN supplementation has been associated with enhanced neurovascular health, reduced neuroinflammation, and better physical performance. Studies highlight NMN's role in supporting cerebral blood flow and reducing vascular aging, which directly contributes to improved cognitive function (3). Additionally, evidence indicates that NMN reduces oxidative stress in neurons and enhances synaptic plasticity, resulting in better memory retention and learning capabilities. Physical performance improvements, including increased muscle strength and endurance, are attributed to NMN's ability to restore mitochondrial function and enhance energy metabolism in skeletal muscles (4).

Fig. 3 Causes for reducing NAD+ levels when aging and mechanism underlying anti-aging activity of NMN. DNA damage, chronic inflammation, oxidative stress and increasing NAD+ consuming enzymes (sirtuins, CD38/ CD157, PARP, TNKS and BST) accelerate NAD degradation. The reduced levels of NAD+ cause downregulation of energy production in mitochondria, leading to aging and various age-associated diseases. NMN supplementation can reinstate NAD+ levels in the body through biosynthesis pathways, reversing the aging process and preventing age-associated diseases (1).

Safety and Regulatory Challenges

While NMN is widely marketed as a dietary supplement, concerns regarding its long-term safety and regulatory approval persist. The U.S. FDA recently raised issues about NMN’s status as a health supplement, prompting further investigations into its safety and efficacy (2). Preclinical toxicology studies suggest that NMN is well-tolerated, with no significant adverse effects observed at high doses in animal models. However, large-scale, long-term human trials are needed to establish safe dosing guidelines (1) (2).

Future Directions

Further research should focus on optimizing NMN’s bioavailability and understanding its long-term impact on human health. Investigating NMN’s role in managing specific age-related diseases, such as cardiovascular disorders and neurodegeneration, could expand its therapeutic applications. Additionally, developing cost-effective and sustainable production methods for NMN will be crucial for its widespread adoption (3) (4).

Conclusion

NMN represents a groundbreaking intervention in the field of anti-aging and age-related disease management. By restoring NAD+ levels, NMN addresses multiple aging hallmarks, including mitochondrial dysfunction, genomic instability, and systemic inflammation. Studies highlight its ability to enhance metabolic pathways, such as oxidative phosphorylation and energy production, improve DNA repair mechanisms by activating sirtuins and PARPs, and reduce oxidative stress by lowering reactive oxygen species (ROS) levels (1) (4). Furthermore, clinical findings discussed demonstrate significant improvements in physical endurance, muscle strength, and cognitive performance, including better memory retention and neurovascular health (2). This evidence reinforces NMN’s potential as a cornerstone therapy for aging and age-related diseases. Continued research into optimizing NMN's bioavailability, investigating its role in specific conditions like neurodegeneration and metabolic disorders, and ensuring long-term safety through extensive clinical trials will be critical to unlocking its full therapeutic potential and integrating it effectively into clinical practice.

References

1. Nadeeshani H, Li J, Ying T, Zhang B, Lu J. Nicotinamide mononucleotide (NMN) as an anti-aging health product - Promises and safety concerns. J Adv Res. 2021 Aug 11;37:267-278. doi: 10.1016/j.jare.2021.08.003. PMID: 35499054; PMCID: PMC9039735.
2. Song Q, Zhou X, Xu K, Liu S, Zhu X, Yang J. The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update. Adv Nutr. 2023 Nov;14(6):1416-1435. doi: 10.1016/ j.advnut.2023.08.008. Epub 2023 Aug 22. PMID: 37619764; PMCID:PMC10721522.
3. Rahman SU, Qadeer A, Wu Z. Role and Potential Mechanisms of Nicotinamide Mononucleotide in Aging. Aging Dis. 2024 Apr 1;15(2):565-583. doi: 10.14336/AD.2023.0519-1. PMID: 37548938; PMCID: PMC10917541.
4. Johnson S, Imai SI. NAD + biosynthesis, aging, and disease. F1000Res. 2018 Feb 1;7:132. doi: 10.12688/f1000research.12120.1. PMID: 29744033; PMCID: PMC5795269.