Aging is a functional debility of the cellular process observed in most biological species. This decline in cellular function results in susceptibility to age-associated diseases such as diabetes, fatty liver,
cardiovascular diseases, neurodegeneration, and muscular diseases.
Recent research indicates that the association of Nicotinamide adenine dinucleotide (NAD+) with aging makes it significant as its levels decrease with age in certain tissues(5).
The discrepancy between NAD+ production and degradation leads to age-induced changes in numerous biological processes(1).
NAD+ is involved in reduction-oxidation (redox) reactions by transferring electrons between an oxidized form of NAD+ and a reduced form of NADH. Therefore, NAD+ mediates cellular processes through redox reactions(1).
NADPH, which is a phosphorylated form of NADH, functions as a reductant to convert an oxidized
glutathione into a reduced glutathione (GSH) and is involved in the antioxidant system(2).
NAD+ also acts as a co-substrate for various NAD+ consuming enzymes, which play a crucial role in signaling pathways. Thus, NAD+ is involved in several biological functions, including cellular bioenergetics, DNA repairing, metabolic homeostasis, genomic stability, mitochondrial biogenesis, and cell survival(3).
Essentially, NAD+ is an important molecule for cellular processing as summarized in the figure below.
 Fig. 1: Physiological functions of NAD+. NAD+ is a beneficial coenzyme that plays a vital role in many biological processes. NAD+ is a critical element in maintaining optimal cellular health and function(4). |
Supplementation of NAD+ precursors have been extensively used in preclinical models. Boosting NAD+ levels via NAD+ precursors has demonstrated advantageous effects in animal models of aging-associated diseases(6).
After these successful rodent studies, worldwide clinical investigations have effectively translated NAD+ precursors into human subjects. Although several studies have been completed, the efficacy of NAD+ precursors in humans were much less than that in animal studies.
It is critical to understand the reason for this gap between rodent and human results. Recent evidence indicates a role of
the gut microbiome in the absorption of NAD+ precursors, providing new insight for discovering their significant in clinical translation(7).
NAD+ homeostasis is essential for proper cellular processing and functioning. NAD+ is synthesized from dietary NAD+ precursors like nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and an amino acid known as tryptophan.
Therapeutical Efficacy of NAD + Precursors
Reduced NAD+ levels impair NAD+ dependent cellular processes and accelerate numerous age-related diseases(8). NAD+ replenishment is attracting attention as an anti-aging intervention. Supplementation of NAD+ precursors can be beneficial in maintaining normal cellular metabolism regulated by NAD+ and NAD+-dependent enzymes.
NAD+ precursors, such as nicotinic acid, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide, provide beneficial effects in various preclinical disease models of age-induced deficits, including
metabolic disorders, cardiovascular, neurodegenerative diseases, and musculoskeletal diseases
(see figure below).
 Fig: Replenishment of NAD + precursors ameliorate age-related pathologies in preclinical and clinical studies(4). |
Besides animal studies, several clinical studies of NAD+ precursors have been reported. The therapeutic benefits of nicotinic acid have been widely recognized for a long time in clinical settings.
Due to its lipid-lowering effect, nicotinic acid is a well-known treatment option for dyslipidemia(9).
Researchers have explored alternative precursors such as nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide after experiencing side effects of nicotinic acid. Clinical trials have been conducted to evaluate the safety of nicotinamide riboside and nicotinamide mononucleotide when taken orally. Studies have unequivocally reported no serious adverse effects following treatment with nicotinamide riboside and nicotinamide mononucleotide(10).
Based on these investigations, the highest safe dose of nicotinamide riboside is 2000 mg per day(11), while nicotinamide mononucleotide has been confirmed to be safe at a maximum recorded dose of 1250 mg per day(12).
These findings indicate that NAD+ precursors are safe to use.
Nicotinamide riboside supplementation raised the NAD+ concentration in the blood. Like nicotinamide riboside, nicotinamide mononucleotide also has an impact on NAD+ metabolism. According to various studies, nicotinamide mononucleotide raises NAD+ dose-dependently in the blood and peripheral blood mononuclear cells. Several clinical trials of NAD+ precursors showed beneficial effects in pathological conditions outlined in the table below.
 Table. Therapeutic potential of NAD + precursors in clinical trials of age-associated diseases(4). |
Recent Advancements in NAD + Metabolism
The latest research in NAD+ metabolism indicate the role of the gut interaction with orally administered NAD+ precursors(13)
(see figure below)
 Figure. The fate of orally administered NAD + precursors and involvement of gut microbiome in NAD + metabolism(4). |
NAD+ precursors that are orally administered can enter the gut in two distinct phases:
- – The first route is the direct absorption of nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide from the small intestine. These precursors subsequently enter the systemic circulation, providing a direct route to contribute to the synthesis of NAD+.
- – The second route involves the conversion of nicotinamide riboside and nicotinamide mononucleotide into nicotinamide in the small intestine’s lumen before progressing towards the large intestine.
In the large intestine, gut microbiota converts nicotinamide into nicotinic acid, which is then transported to the liver via portal circulation and synthesized into NAD+. Further, the liver synthesizes nicotinamide from NAD+ and distributes it to other organs,
including the gut, to maintain the continual supply of nicotinamide required for the salvage pathway in each distal tissue for their optimal physiological function.
Research has shed new light on NAD+ precursors indicating that dietary nicotinamide was directly absorbed into the circulation at the upper gut and did not reach at the lower gut. The results of investigations on oral supplementation of NAD+ intermediates have demonstrated a significant link with gut microbes. It has been established that the NAD+ intermediates require conversion into nicotinic acid to effectively elevate NAD+ levels.
Research on the impact of human NAD+ metabolism indicates that supplementing with oral nicotinamide riboside leads to an increase in deamidated NAD+ metabolites in the blood, indicating the involvement of the gut, as shown in preclinical studies(14).
Similarly, nicotinamide mononucleotide treatment also shows a similar findings, an increase in nicotinic acid mononucleotide levels, indicating that the gut microbiome plays a crucial role in the oral intake of these compounds(15).
These outcomes suggest a correlation between the NAD+ metabolism of the host and gut microbiome. Additional research is needed to determine how the gut microbiota affects human clinical outcomes and NAD+ metabolism.
Summary
NAD+ has a versatile role in physiological processes in the body, and numerous pre-clinical trials have proved the therapeutic potential of NAD+ precursor replenishment therapy against age-related pathologies. However, these precursors have shown a minimal effect in clinical studies compared to pre-clinical studies.
Nicotinamide riboside and nicotinamide mononucleotide treatment demonstrated beneficial results in preclinical studies. Recently, it was discovered that nicotinamide riboside reduced form dramatically raises the NAD+ levels in plasma after oral administration and is stable in
blood circulation more than nicotinamide riboside, suggesting that the reduced form of nicotinamide riboside is more potent than nicotinamide riboside(16).
The current progress in NAD+ metabolism demonstrates that the gut microbiome breaks down nicotinamide into nicotinic acid, emphasizing the role of the microbiome in the oral metabolism of NAD+ precursors(7).
It is essential to consider how
the gut microbiome affects NAD+ metabolism, and changes in microbiome composition may affect the availability of NAD+ precursors.
Future research should conduct a comparative analysis of different precursors, and the role of gut microbiomes related to various intermediaries. Assessment of how NAD+ precursors affect microbiota and how their interaction with NAD+ metabolism benefits the physiological condition is essential for future preclinical and clinical studies.
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References:
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3. Imai S-i, Guarente L: NAD+ and sirtuins in aging and disease. Trends in cell biology 24:464-471, 2014
4. Iqbal T, Nakagawa T: The therapeutic perspective of NAD(+) precursors in age-related diseases. Biochem Biophys Res Commun 702:149590, 2024
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8. Gomes AP, Price NL, Ling AJ, et al: Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155:1624-1638, 2013
9. Mouchiroud L, Houtkooper RH, Moullan N, et al: The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430-441, 2013
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11. Dollerup OL, Chubanava S, Agerholm M, et al: Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin‐resistant men. The Journal of physiology 598:731-754, 2020
12. Fukamizu Y, Uchida Y, Shigekawa A, et al: Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Scientific reports 12:14442, 2022
13. Kim LJ, Chalmers TJ, Madawala R, et al: Host–microbiome interactions in nicotinamide mononucleotide (NMN) deamidation. FEBS letters 597:2196-2220, 2023
14. Brakedal B, Dölle C, Riemer F, et al: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell metabolism 34:396-407. e6, 2022
15. Okabe K, Yaku K, Uchida Y, et al: Oral administration of nicotinamide mononucleotide is safe and efficiently increases blood nicotinamide adenine dinucleotide levels in healthy subjects. Frontiers in nutrition 9:868640, 2022
16. Yang Y, Zhang N, Zhang G, et al: NRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase. Nature metabolism 2:364-379, 2020
