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 molecule 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.

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.

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.

[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.

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