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Nicotinamide Adenine Dinucleotide (NAD): Difference between revisions
Nicotinamide Adenine Dinucleotide (NAD) (view source)
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[[File:NAD oxidation reduction.svg|right|frameless]] | |||
'''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. | '''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. | 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 NAD+/NADH ratio is an important cellular indicator, reflecting the cell's metabolic state. A healthy balance between NAD+ and NADH is required for optimal function of several key enzymes, including those involved in energy production, DNA repair, and cell signaling. | |||
== The Role of NAD+ in the Cell == | |||
NAD+ is involved in several crucial biological processes: | NAD+ is involved in several crucial biological processes: | ||
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[[File:nihms790132f7.jpg|thumb|[[CD38]]/[[NADase]] increases during aging, and causes NAD decline and subsequent mitochondrial dysfunction.]] | [[File:nihms790132f7.jpg|thumb|[[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 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. | * A decrease in mitochondrial function, leading to reduced energy output. | ||
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* Enhanced vulnerability of DNA to damage. | * Enhanced vulnerability of DNA to damage. | ||
* Increased susceptibility to age-related diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. | * 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 | A gradual increase in CD38 has been implicated in the decline of NAD+ with age.<ref>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.</ref><ref>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.</ref> Treatment of old mice with a specific [[CD38]] inhibitor, [[78c]], prevents age-related NAD+ decline.<ref>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.</ref> CD38 knockout mice have twice the levels of NAD+ and are resistant to age-associated NAD+ decline,<ref name="pmid32595066">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.</ref> with dramatically increased NAD+ levels in major organs (liver, muscle, brain, and heart).<ref name="pmid32594513">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.</ref> On the other hand, mice overexpressing CD38 exhibit reduced NAD+ and mitochondrial dysfunction.<ref name="pmid32595066" /> | ||
== 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: | 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 Mononucleotide (NMN)|'''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. | # [[Nicotinamide Riboside (NR)|'''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. | # [[Caloric Restriction|'''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. | # [[NAD+ Infusions|'''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 === | === Safety and Implications for Longevity === | ||
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* The effective dosages and potential side effects. | * The effective dosages and potential side effects. | ||
* The real impact on human longevity. | * The real impact on human longevity. | ||
== NAD+ and Its Role in Aging == | |||
Nicotinamide adenine dinucleotide (NAD+) is a crucial molecule in our bodies, involved in turning nutrients into energy, adapting to stress, and maintaining our daily biological rhythms. As we age, the amount of NAD+ in our bodies decreases. This is partly due to the action of an enzyme called CD38, which breaks down NAD+, leading to lower levels in older individuals{{pmid|27304496}}. Keeping a balance of NAD+ is important for our cells to work properly, and enzymes that use NAD+ are being studied for their potential to slow down aging processes. These enzymes include CD38, sirtuins (SIRT), which are involved in cell regulation, PARP1, important for DNA repair, and SARM1, linked to nerve cell health{{pmid|28676700}}{{pmid|25908823}}. | |||
Our bodies can make NAD+ in two ways: either from scratch using certain nutrients like nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), or by recycling components from chemical reactions in our cells{{pmid|32694684}}. An enzyme on the surface of our cells, called CD73, also helps to keep NAD+ levels up by converting NMN to NR{{pmid|32389638}}. | |||
=== The Role of NNMT in NAD+ Levels === | |||
An enzyme named nicotinamide N-methyltransferase (NNMT) plays a key role in managing NAD+ levels. It changes nicotinamide, a form of vitamin B3, into a substance called methylnicotinamide (MNT). This change affects how much nicotinamide is available to make NAD+ in our cells. NNMT is linked to conditions like obesity and type two diabetes{{pmid|29483571}}. Interestingly, NNMT also helps stabilize SIRT1, an enzyme that protects cells from stress and can increase lifespan{{pmid|34153425}}{{pmid|26168293}}{{pmid|24077178}}. Researchers are looking into NNMT inhibitors as potential treatments for diseases like cancer, obesity, and liver diseases related to alcohol use{{pmid|29483571}}{{pmid|34704059}}{{pmid|34572571}}{{pmid|29155147}}{{pmid|34424711}}. The balance between NNMT, MNT, and NAD+ is important for our health, especially as we age. | |||
== NAD+, Sirtuins and Longevity-Promoting Pathway == | |||
[[File:CD38-NAD+-SIRT1 Axis.png|thumb|The CD38/NAD+/SIRT1 Axis. NAD+ levels in the body can be influenced by the supplementation of precursors nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). NAD+ levels decrease with age and are further metabolized by the activation of SIRT1, PARP1, SARM1, and CD38. Restoring NAD+ levels allows for an increase in SIRT1 activity due to increased substrate availability, resulting in the inhibition of age-promoting pathways and activation of adaptive and protective transcription factors and processes. The central lineage may be described as the CD38/NAD+/SIRT1 axis, and targeting this access with nutraceutical interventions may prevent the age-related decline of NAD+ levels in the body. Black lines indicate conversion or activation. Red lines indicate inhibitors or destroyers of the indicated target.{{pmid|36678315}}|450x450px]] | |||
Maintaining the right levels of NAD+ and the activity of sirtuin proteins is crucial in the fight against aging{{pmid|28537485}}. Taking supplements that are NAD+ precursors, like Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN), has shown promise in combating the natural decline of NAD+ that comes with aging and related diseases{{pmid|28899755}}{{pmid|29883761}}{{pmid|27825999}}. The decrease in NAD+ as we age is primarily due to its reduction in our bodies, not an increase in its counterpart, NADH{{pmid|30124109}}. Adding more NAD+ can help fix issues in mitochondria, the energy factories of our cells, that happen because of this decline{{pmid|24360282}}. | |||
SIRT1, a member of the sirtuin protein family involved in cellular response to stress, has been linked to longer life spans, though the results vary depending on the situation. For example, elite athletes, who have higher SIRT1 levels, tend to have longer telomeres (a sign of cellular aging) and are less likely to develop insulin resistance{{pmid|34256387}}. SIRT1 works by turning on certain genes, like FoxO and PGC1α, which are important for managing stress, controlling cell growth, and preventing tumors. These genes are known to contribute to longer lifespans in some animals{{pmid|26831453}}{{pmid|14976264}}{{pmid|16288288}}{{pmid|35004893}}. The IIS pathway, which influences growth, metabolism, and longevity, also promotes longer life under certain conditions by activating these genes{{pmid|26675724}}{{pmid|21443682}}. PGC1α, in particular, is key in creating mitochondria and has been linked to better insulin sensitivity in muscles{{pmid|23583953}}{{pmid|24559845}}{{pmid|23086035}}. Furthermore, AMPK, which is involved in energy management in the body, interacts with SIRT1 and can inhibit mTOR, another aging-related process. AMPK also helps increase NAD+ levels, thus boosting SIRT1 activity{{pmid|19262508}}. Additionally, SIRT1 can slow down NF-κB signaling, which is part of the immune response, helping to reduce long-term inflammation{{pmid|23770291}}. Having enough NAD+ to keep SIRT1 active is essential in manipulating the aging process and promoting longevity{{pmid|29883761}}{{pmid|33460497}}{{pmid|33609766}}{{pmid|32124104}}. Keeping NAD+ at healthy levels is key for making sure SIRT1 can do its job effectively as we age. | |||
== NAD+ and Its Influence on the Body's Biological Clock == | |||
NAD+, a crucial molecule in our body, plays an important role in keeping our biological clock, or circadian rhythm, in check. Studies involving older mice have shown that when they have less NAD+, they experience more disruptions in their biological clock compared to younger mice with more NAD+{{pmid|32369735}}. This leads to problems in how their cells handle energy and time. By increasing NAD+ levels in mice with circadian rhythm issues, researchers have been able to fix these problems, particularly through the action of a protein called SIRT3{{pmid|24051248}}. Having enough NAD+ and ensuring that sirtuin proteins (like SIRT3) are active is key to keeping our internal clocks working properly. Taking supplements that increase NAD+ levels might help fix age-related issues with these biological clocks{{pmid|24657895}}. Low NAD+ levels are a common problem in many age-related diseases, so treatments that increase NAD+ are being researched as a way to help with these issues{{pmid|34743990}}{{pmid|31953124}}{{pmid|29295624}}{{pmid|34720589}}. | |||
== See also == | == See also == | ||
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* [[NAD+ Precursor]] | * [[NAD+ Precursor]] | ||
* [[NADase]] | * [[NADase]] | ||
* | * {{SeeWikipedia|Nicotinamide adenine dinucleotide}} | ||
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== References == | == References == | ||
<references /> | <references /> | ||
[[Category:Other Longevity Compounds]] | [[Category:Other Longevity Compounds]] | ||
[[Category:Molecular and Cellular Biology]] | [[Category:Molecular and Cellular Biology]] | ||