Nicotinamide Adenine Dinucleotide (NAD)

Nicotinamide Adenine Dinucleotide (NAD) is a vital coenzyme found in every cell of our bodies and has become a focal point in the field of longevity and aging research. NAD+ plays a central role in energy metabolism and is essential for the function of several enzymes that are associated with aging and DNA repair.

NAD exists in two main forms: NAD+ and NADH. NAD+ is the oxidized form of the compound and is essential for various cellular processes, including DNA repair, gene expression, and calcium signaling. When NAD+ accepts electrons during metabolic reactions, it becomes reduced and transforms into NADH. NADH, the reduced form, primarily functions in the production of ATP, the cell's primary energy currency, through the electron transport chain. The dynamic interconversion between these two forms, NAD+ and NADH, is fundamental to the cell's energy production and overall function.

The Role of NAD+ in the Cell

NAD+ is involved in several crucial biological processes:

Energy Production: NAD+ helps in converting nutrients into energy within the mitochondria, the powerhouse of cells.
DNA Repair: It's essential for the function of enzymes like PARPs and sirtuins, which are involved in DNA repair and have links to longevity.
Cell Signaling: As a substrate for various enzymes, it plays a role in cellular communication and adaptations to stress.

CD38/NADase increases during aging, and causes NAD decline and subsequent mitochondrial dysfunction.

NAD+ Decline with Age

A significant finding in the field of aging research is that NAD+ levels naturally decline as we age. This reduction has been associated with:

A decrease in mitochondrial function, leading to reduced energy output.
Reduced activity of sirtuins, proteins linked to lifespan extension in various organisms.
Enhanced vulnerability of DNA to damage.
Increased susceptibility to age-related diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases.

A gradual increase in CD38 has been implicated in the decline of NAD+ with age.^[1]^[2] Treatment of old mice with a specific CD38 inhibitor, 78c, prevents age-related NAD+ decline.^[3] CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,^[4] with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).^[5] On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction.^[4]

Boosting NAD+ Levels

Given the importance of NAD+ in various cellular functions and its decline with age, researchers have been exploring ways to replenish or boost NAD+ levels in the body. Several methods are under investigation:

Nicotinamide Mononucleotide (NMN): A precursor to NAD+ that, when supplemented, has shown potential in increasing NAD+ levels in various studies, mainly in animals.
Nicotinamide Riboside (NR): Another NAD+ precursor that can elevate NAD+ levels in the body.
Caloric Restriction: It has been observed to enhance NAD+ levels and activate sirtuins.
NAD+ Infusions: Direct infusion of NAD+ is being explored as a method, although it's still in the early stages of research.

⇒ see NAD+ Booster

Safety and Implications for Longevity

While initial studies, primarily on animal models, have shown promise in boosting NAD+ levels for promoting health and extending lifespan, it's essential to approach the findings with caution. Comprehensive human trials are needed to understand:

The long-term effects of boosting NAD+.
The effective dosages and potential side effects.
The real impact on human longevity.

Todo

2021, NAD⁺ metabolism and its roles in cellular processes during ageing ^[6]
2022, Efficient Assay and Marker Significance of NAD⁺ in Human Blood ^[7]
2021, Age-Dependent Decline of NAD⁺-Universal Truth or Confounded Consensus? ^[8]

References

↑ Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN (June 2016). "CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism". Cell Metabolism. 23 (6): 1127–1139. doi:10.1016/j.cmet.2016.05.006. PMC 4911708. PMID 27304511.
↑ Schultz MB, Sinclair DA (June 2016). "Why NAD(+) Declines during Aging: It's Destroyed". Cell Metabolism. 23 (6): 965–966. doi:10.1016/j.cmet.2016.05.022. PMC 5088772. PMID 27304496.
↑ Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN (May 2018). "A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline". Cell Metabolism. 27 (5): 1081–1095.e10. doi:10.1016/j.cmet.2018.03.016. PMC 5935140. PMID 29719225.
↑ ^4.0 ^4.1 Cambronne XA, Kraus WL (2020). "Location, Location, Location: Compartmentalization of NAD + Synthesis and Functions in Mammalian Cells". Trends in Biochemical Sciences. 45 (10): 858–873. doi:10.1016/j.tibs.2020.05.010. PMC 7502477. PMID 32595066.
↑ Kang BE, Choi J, Stein S, Ryu D (2020). "Implications of NAD + boosters in translational medicine". European Journal of Clinical Investigation. 50 (10): e13334. doi:10.1111/eci.13334. PMID 32594513. S2CID 220254270.
↑ Covarrubias AJ et al.: NAD⁺ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021. (PMID 33353981) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.
↑ Balashova NV et al.: Efficient Assay and Marker Significance of NAD⁺ in Human Blood. Front Med (Lausanne) 2022. (PMID 35665345) [PubMed] [DOI] [Full text] Oxidized nicotinamide adenine dinucleotide (NAD+) is a biological molecule of systemic importance. Essential role of NAD+ in cellular metabolism relies on the substrate action in various redox reactions and cellular signaling. This work introduces an efficient enzymatic assay of NAD+ content in human blood using recombinant formate dehydrogenase (FDH, EC 1.2.1.2), and demonstrates its diagnostic potential, comparing NAD+ content in the whole blood of control subjects and patients with cardiac or neurological pathologies. In the control group (n = 22, 25-70 years old), our quantification of the blood concentration of NAD+ (18 μM, minimum 15, max 23) corresponds well to NAD+ quantifications reported in literature. In patients with demyelinating neurological diseases (n = 10, 18-55 years old), the NAD+ levels significantly (p < 0.0001) decrease (to 14 μM, min 13, max 16), compared to the control group. In cardiac patients with the heart failure of stage II and III according to the New York Heart Association (NYHA) functional classification (n = 24, 42-83 years old), the blood levels of NAD+ (13 μM, min 9, max 18) are lower than those in the control subjects (p < 0.0001) or neurological patients (p = 0.1). A better discrimination of the cardiac and neurological patients is achieved when the ratios of NAD+ to the blood creatinine levels, mean corpuscular volume or potassium ions are compared. The proposed NAD+ assay provides an easy and robust tool for clinical analyses of an important metabolic indicator in the human blood.
↑ Peluso A et al.: Age-Dependent Decline of NAD⁺-Universal Truth or Confounded Consensus?. Nutrients 2021. (PMID 35010977) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

[1] Camacho-Pereira J, Tarragó MG, Chini CC, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN (June 2016). "CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism". Cell Metabolism. 23 (6): 1127–1139. doi:10.1016/j.cmet.2016.05.006. PMC 4911708. PMID 27304511.

[2] Schultz MB, Sinclair DA (June 2016). "Why NAD(+) Declines during Aging: It's Destroyed". Cell Metabolism. 23 (6): 965–966. doi:10.1016/j.cmet.2016.05.022. PMC 5088772. PMID 27304496.

[3] Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, de Oliveira GC, Rud M, Samani A, Hein KZ, Huang R, Jurk D, Cho DS, Boslett JJ, Miller JD, Zweier JL, Passos JF, Doles JD, Becherer DJ, Chini EN (May 2018). "A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline". Cell Metabolism. 27 (5): 1081–1095.e10. doi:10.1016/j.cmet.2018.03.016. PMC 5935140. PMID 29719225.

[pmid32595066-4] 4.0 ^4.1 Cambronne XA, Kraus WL (2020). "Location, Location, Location: Compartmentalization of NAD + Synthesis and Functions in Mammalian Cells". Trends in Biochemical Sciences. 45 (10): 858–873. doi:10.1016/j.tibs.2020.05.010. PMC 7502477. PMID 32595066.

[pmid32594513-5] Kang BE, Choi J, Stein S, Ryu D (2020). "Implications of NAD + boosters in translational medicine". European Journal of Clinical Investigation. 50 (10): e13334. doi:10.1111/eci.13334. PMID 32594513. S2CID 220254270.

[pmid33353981-6] Covarrubias AJ et al.: NAD⁺ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021. (PMID 33353981) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.

[pmid35665345-7] Balashova NV et al.: Efficient Assay and Marker Significance of NAD⁺ in Human Blood. Front Med (Lausanne) 2022. (PMID 35665345) [PubMed] [DOI] [Full text] Oxidized nicotinamide adenine dinucleotide (NAD+) is a biological molecule of systemic importance. Essential role of NAD+ in cellular metabolism relies on the substrate action in various redox reactions and cellular signaling. This work introduces an efficient enzymatic assay of NAD+ content in human blood using recombinant formate dehydrogenase (FDH, EC 1.2.1.2), and demonstrates its diagnostic potential, comparing NAD+ content in the whole blood of control subjects and patients with cardiac or neurological pathologies. In the control group (n = 22, 25-70 years old), our quantification of the blood concentration of NAD+ (18 μM, minimum 15, max 23) corresponds well to NAD+ quantifications reported in literature. In patients with demyelinating neurological diseases (n = 10, 18-55 years old), the NAD+ levels significantly (p < 0.0001) decrease (to 14 μM, min 13, max 16), compared to the control group. In cardiac patients with the heart failure of stage II and III according to the New York Heart Association (NYHA) functional classification (n = 24, 42-83 years old), the blood levels of NAD+ (13 μM, min 9, max 18) are lower than those in the control subjects (p < 0.0001) or neurological patients (p = 0.1). A better discrimination of the cardiac and neurological patients is achieved when the ratios of NAD+ to the blood creatinine levels, mean corpuscular volume or potassium ions are compared. The proposed NAD+ assay provides an easy and robust tool for clinical analyses of an important metabolic indicator in the human blood.

[pmid35010977-8] Peluso A et al.: Age-Dependent Decline of NAD⁺-Universal Truth or Confounded Consensus?. Nutrients 2021. (PMID 35010977) [PubMed] [DOI] [Full text] Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

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