Nicotinamide Adenine Dinucleotide (NAD): Difference between revisions

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 == 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]]
-Disruption of proper NAD+ levels and the loss of protective sirtuin activity have emerged as prime targets for NAD+-based interventions{{pmid|28537485}}. Administration of NAD+ precursors, such as Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN), has shown potential in alleviating age-related NAD+ decline and associated pathologies, particularly in the context of age-related diseases{{pmid|28899755}}{{pmid|29883761}}{{pmid|27825999}}. Aging is associated with a decreased NAD+/NADH ratio in human plasma, mainly due to the deterioration of NAD+ stores, rather than an increase in NADH{{pmid|30124109}}. Replenishing NAD+ has been shown to rescue mitochondrial regulatory function from NAD+ induced pseudohypoxic mitochondrial stress during aging{{pmid|24360282}}.
+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.
-SIRT1, a member of the sirtuin protein family involved in cellular response to stress, has been implicated in longevity, although results are mixed and context-dependent. High-level athletes, for instance, exhibit higher telomere length and reduced insulin resistance, correlating with higher levels of SIRT1 expression{{pmid|34256387}}. SIRT1's beneficial activity may depend on the deacetylation and activation of Forkhead transcription factors like FoxO and PGC1α{{pmid|26831453}}{{pmid|14976264}}. FoxOs are involved in stress resistance, cell cycle arrest, apoptosis, and tumor suppression, and their activation has been linked with longevity in worms and flies{{pmid|16288288}}{{pmid|35004893}}. The insulin/insulin-like growth factor signaling (IIS) pathway, which regulates growth, development, metabolism, reproduction, and longevity, extends neuronal activity and longevity under low IIS conditions through FoxO activity{{pmid|26675724}}{{pmid|21443682}}. PGC1α, influencing mitochondrial biogenesis, is important in metabolic diseases, and its overexpression has been linked to improved insulin sensitivity in muscle{{pmid|23583953}}{{pmid|24559845}}{{pmid|23086035}}. Additionally, AMPK, involved in energy expenditure, exhibits a bidirectional interplay with SIRT1 and inhibits mTOR, a process linked to longevity; it also activates SIRT1 by increasing available NAD+ stores{{pmid|19262508}}. Furthermore, nuclear factor κB (NF-κB) signaling, involved in innate immunity, can be inhibited by SIRT1 activity to reduce prolonged inflammatory signaling{{pmid|23770291}}. The availability of NAD+ in the body makes SIRT1 an interesting target in manipulating age-related pathways to promote longevity{{pmid|29883761}}{{pmid|33460497}}{{pmid|33609766}}{{pmid|32124104}}. Maintaining adequate NAD+ levels for optimal SIRT1 activity during aging may be a key factor in regulating longevity.
 ==NAD+ and Circadian Rhythm==
 NAD+ plays a vital role in regulating the circadian metabolic clock. Research has shown that older mice, with lower levels of NAD+, exhibit prolonged repression of CLOCK/BMAL1 transcription compared to younger mice with higher NAD+ levels, leading to disrupted and dampened mitochondrial and transcriptional oscillation{{pmid|32369735}}. Supplementation and restoration of NAD+ in circadian mutant mice have demonstrated the ability to re-establish proper respiratory oscillations and circadian metabolic regulation, especially through the regulatory activity of SIRT3{{pmid|24051248}}. An ample supply of NAD+ and proper sirtuin activation are essential for maintaining the integrity of various endogenous clocks. Supplementing with NAD+ precursors may potentially alleviate age-related disturbances in these circadian processes{{pmid|24657895}}. Deficiencies in NAD+ are observed in numerous age-related diseases, and NAD+-based interventions are being explored to address this common issue shared by these diseases{{pmid|34743990}}{{pmid|31953124}}{{pmid|29295624}}{{pmid|34720589}}.