Introduction
In recent years, the demand for anti-aging products has surged, driven primarily by the increasing global population of individuals aged 65 and over. The number of elderly individuals is projected to rise from 702.9 million in 2019 to 1548.9 million by 2050, exacerbating the global socioeconomic and medical burden associated with age-related diseases such as hypertension, osteoarthritis, neurodegenerative disorders, diabetes mellitus, and various cancers. Among the myriad of products designed to mitigate aging effects, nicotinamide mononucleotide (NMN) has attracted substantial interest due to its purported potential in reversing mitochondrial decay and increasing nicotinamide adenine dinucleotide (NAD+) levels, both key factors implicated in the aging process.
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Nicotinamide Mononucleotide (NMN)
NMN is a bioactive nucleotide crucial for NAD+ biosynthesis in organisms. It exists in α and β forms, with the β form being active. NMN forms naturally through the action of nicotinamide phosphoribosyltransferase on a nucleoside containing nicotinamide (a form of vitamin B3) and ribose. With a molecular weight of 334.22 g/mol, NMN is water-soluble and moderately acidic. It is found in the nucleus, mitochondria, cytoplasm, placenta tissue, blood, and urine, as well as in fruits, vegetables, raw beef, and shrimp. NMN levels vary (0.06–1.88 mg/100 g) across these sources.
Fig. 1 Chemical structure of nicotinamide mononucleotide (NMN) (Nadeeshani H., et al. 2022).
Functionally, NMN serves as a precursor in the synthesis of NAD+, a vital co-enzyme in metabolic reactions. NAD+ influences numerous biological processes like aging, gene expression, and DNA repair, crucial for overall health and longevity. Studies indicate that NMN supplementation can compensate for NAD+ deficiency, offering therapeutic potential in conditions like type 2 diabetes, Alzheimer's disease, and cardiovascular ailments.
Mechanism of NMN's Anti-Aging Activity
The aging process involves a natural decline in cellular energy production within organs such as the brain, adipose tissue, and liver, primarily due to reduced levels of NAD+. NAD+ is depleted as enzymes like CD38/CD157, PARP, and sirtuins consume it for functions like DNA repair and metabolic regulation. Nicotinamide mononucleotide (NMN) serves as an intermediary in NAD+ biosynthesis via the salvage pathway, where it is synthesized from nicotinamide and 5-phosphoribosyl-1-pyrophosphate by NAMPT and converted to NAD+ by NMNAT enzymes. This pathway is crucial as it efficiently replenishes NAD+ levels crucial for cellular functions and longevity.
Chronic inflammation and oxidative stress associated with aging inhibit NAD+ biosynthesis mediated by NAMPT. Depletion of nuclear NAD+ disrupts mitochondrial function, leading to impaired oxidative phosphorylation and cellular dysfunction resembling hypoxia. This disruption can be countered by restoring NAD+ levels, which also helps mitigate cognitive decline, DNA damage, and the inactivation of sirtuin genes linked to aging.
NMN supplementation has emerged as a promising strategy to boost NAD+ levels and enhance cellular functions. Studies show that NMN can activate SIRT1, a key regulator of mitochondrial biogenesis and cellular homeostasis. Insufficient NAD+ levels compromise SIRT1's ability to regulate cellular communication, leading to mitochondrial dysfunction and age-related ailments. NMN administration as a precursor to NAD+ helps restore this communication and mitochondrial function, potentially reversing age-related complications.
Research and Promises of NMN as an Anti-Aging Health Product
Numerous studies have explored NMN's potential as an anti-aging health product through cell cultures, animal models, and clinical investigations. In animal studies, NMN supplementation has shown promising results in boosting NAD+ levels and improving various age-related conditions. For instance, NMN administration enhanced insulin secretion, sensitivity, and lipid profiles in diabetic mice, while restoring gene expression related to circadian rhythm and inflammatory responses. It also increased NAD+ levels in liver tissues significantly, activating SIRT1 and improving metabolic functions.
Further studies demonstrated NMN's ability to restore vascular function, reduce oxidative stress, and protect against kidney injuries by elevating NAD+ and SIRT1 levels. In neurodegenerative disease models, NMN improved cognitive functions, reduced amyloid plaque burden, and enhanced neuronal survival. Additionally, NMN enhanced mitochondrial bioenergetics, protected against ischemic injuries, and attenuated age-related hearing loss in various animal models.
These findings underscore NMN's potential as a therapeutic agent for combating age-related disorders and promoting overall health by restoring cellular NAD+ levels and enhancing mitochondrial functions. Ongoing research continues to explore its broader applications and optimize its effectiveness as an anti-aging intervention.
Safety Concerns and Challenges
Despite the promising results, the safety and efficacy of NMN supplementation remain under scrutiny. Most commercially available NMN products range from 50 to 500 mg per capsule, and their safety cannot be fully assured as comprehensive toxicological and safety profiles have yet to be established. The lack of regulatory oversight further complicates this issue, raising concerns about potential health risks associated with unregulated high-dose NMN consumption.
Preclinical studies indicate that NMN is absorbed rapidly in the small intestine and mainly metabolized within the body without causing significant adverse effects. However, rigorous clinical trials are essential to confirm these findings in humans and to establish a comprehensive safety profile.
Concerns regarding the potential long-term side effects of NMN supplementation are valid, especially considering the possible adverse outcomes such as exacerbating senescence-associated secretory phenotypes (SASP) responsible for age-related pathologies. Moreover, while NMN shows promising pharmacological actions, its long-term safety must be investigated through well-designed clinical trials focusing on various health parameters.
Conclusion
NMN serves as a promising NAD+ precursor with significant potential to combat age-related decline and diseases by restoring NAD+ levels. Preclinical studies have demonstrated various health benefits, ranging from metabolic improvements to neuroprotection and enhanced fertility. However, translating these findings into safe and effective human applications requires extensive long-term clinical trials to establish NMN's safety and efficacy profiles comprehensively.
With the increasing market availability of NMN supplements, it is imperative that manufacturers support research to validate their products' efficacy and safety, ensuring consumer well-being. As we advance, the collaboration between the scientific community, regulatory agencies, and the nutraceutical industry will be crucial in harnessing NMN's full potential as a reliable anti-aging intervention.
References
- Nadeeshani H., et al. Nicotinamide mononucleotide (NMN) as an anti-aging health product–promises and safety concerns. Journal of Advanced Research. 2022, 37: 267-278.
- de Picciotto N. E., et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell. 2016, 15(3): 522-530.
- Johnson S., et al. CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. NPJ Aging and Mechanisms of Disease. 2018, 4(1): 10.
- Guan Y., et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1–dependent manner. Journal of the American Society of Nephrology. 2017, 28(8): 2337-2352.
- Long A. N., et al. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurology. 2015, 15: 1-14.
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