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(WikiLink:NAD+) - (Last Revision: 6/7/2022)

NAD (Nicotinamide adenine dinucleotide)

NAD+ levels decline by about 50% for each 20 years you age. These these levels are highly correlated with a number of age-related conditions and neurodegenerative diseases. A decline in NAD+ results in a decrease in energy metabolism, weakened DNA repair, and inefficient immune activation. Sirtuins, a class of longevity enzymes that regulate and control genes rely on NAD+ to function correctly.

⫸ Nicotinamide adenine dinucleotide (NAD+, 30) is an indispensable pyridine nucleotide that is used as a cofactor and substrate for many key cellular processes including DNA repair, epigenetic regulation of gene expression, oxidative phosphorylation, ATP production, intracellular calcium signal transduction, and immune function. It is well known that NAD+ con- centration increases with reduced energy load. These activities include fasting, glucose deprivation, calo- rie restriction and exercise. However, with the exception of pellagra, NAD+ levels decreased in high-fat diet animals and during aging and cellular senescence [132]. Considering that NAD+ levels increase with increased life or healthspan and decrease with accel- erated aging and/or reduced healthspan, it suggests that reduced NAD+ levels may be a major aspect in the aging process [133]. Therefore, NAD+ supplementa- tion and its precursors may be a potential therapeutic strategy that mediates protection against inflammation and the accumulation of highly volatile reactive oxygen species (ROS) during aging. Oral supplementation of NAD+ and NADH did not show a significant increase in NAD+ levels in plasma or tissue, which may be due to poor bioavailability due to the inefficiency of gut NAD+ metabolism. At present, intravenous infusion of NAD+ is clinically recognized as the only effective means to improve the level of systemic NAD+. How- ever, it is expected that some alternative NAD+ pre- cursors, including NA, NAM, NMN, NR and NAR, may provide some benefits (Scheme 4) [134].

SIRTUINS (Silent Information Regulator Proteins)

The discovery of Sirtuins, a deacetylase dependent on NAD and a deacetylase associated with longevity, has opened up a whole new field of aging research [135]. Interest in using the NAD/Sirtuin pathway to especially treat brain aging has greatly increased recently, and therapies based on this biological principle become clinically available sooner or later [136].

Recently, NR (31) has been identified as an NAD+ precursor vitamin with unique oral bioavailability in mice and humans [137]. Blood NAD+ levels have been shown to increase 2.7 times after 7 days of a sin- gle daily dose of NR (1000 mg). Another study showed that NMN (32) is metabolized extracellularly to pro- duce NR, which is then converted into NAD+ intracellular [138]. In metabolically impaired mice, the addition of NR was related to increased SIRT1 expression, reduced oxidative stress level and enhanced mito- chondrial function [139]. In a fly model of Parkinson’s disease, NR supplementation reduces the loss of dopa- minergic neurons and improves motor skills [140]. NR supplementation reduces tau phosphorylation and enhances cognitive function in a mouse model of Alzheimer’s disease with DNA repair defects [141].

Another study showed that NMN (32) supplementation was sufficient to promote mitogenesis in nematode neurons and improve cognitive decline caused by Alzheimer’s disease [142, 143]. In a rat model of Alzheimer’s disease, NMN reduced Aβ aggregation, enhanced spatial memory, and increased neuronal survival, in part by reducing ROS [144].⫷[11]

◉ This intimate connection between NAD+ and sirtuins has an ancient origin and provides a mechanistic foundation that translates the regulation of energy metabolism into aging and longevity control in diverse organisms. Evidence has shown that sirtuins are essential factors that delay cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes.

◉ 600 Milligrams of NMN daily, has been show to be the optimal does in individuals older than 45. This daily does was safe and produced increases in levels of NAD in the blood and increases in activities of daily living and age associated reduction in laboratory blood markers. [6]

▶︎ ◉ Sirtuins may counteract at least six hallmarks of organismal aging: neurodegeneration, chronic but ineffective inflammatory response, metabolic syndrome, DNA damage, genome instability, and cancer incidence.

◉ NAMPT and NAD+ levels decline with age in multiple organs, such as pancreas, adipose tissue, skeletal muscle, liver, and brain.

◉ The communication between the nucleus and mitochondria seems to be compromised when NAD+ availability declines and thereby sirtuin activity decreases over age (Figure 5a).

◉ Decreased SIRT1 activity also reducesthe functions of PGC-1α and FOXO1, resulting in the reduction inmitochondrial biogenesis, oxidative metabolism, and anti-oxidant defense pathways

◉ It has recently been demonstrated that SIRT1 and SIRT3 activities are involved in the mitochondrial unfolded protein response (UPRmt) pathway and mitophagy. (Figure 5a)

◉ Decreased SIRT1 activity also reducesthe functions of PGC-1α and FOXO1, resulting in the reduction inmitochondrial biogenesis, oxidative metabolism, and anti-oxidant defense pathways

◉ It has recently been demonstrated that SIRT1 and SIRT3 activities are involved in the mitochondrial unfolded protein response (UPRmt) pathway and mitophagy (Figure 5a).25,76.◉ At a systemic level, the communication between the control center of aging (the hypothalamus) and its modulator (adipose tissue) might be compromised when systemic NAD+ biosynthesis decreases. (Figure 5b)

◉ The breakdown of this intimate interplay between NAD+ and sirtuins, particularly SIRT1, in each tissue likely leads to the breakdown of the inter-tissue communication between the hypothalamus and adipose tissue, resulting in systemic functional decline over age and eventually limiting lifespan in mammals.◀︎[3]

◉ SIRT1, an NAD+-dependent proteindeacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Rorg, Per2, and Cry1. SIRT1 bindsCLOCK-BMAL1 in a circadian manner and promotesthe deacetylation and degradation of PER2. Giventhe NAD+ dependence of SIRT1 deacetylase activity,it is likely that SIRT1 connects cellular metabolism tothe circadian core clockwork circuitry. [5]

▶︎ Function by SIRT

SIRT1 Glucose metabolism, fatty-acid and cholesterol metabolism, differentiation, insulin secretion, and neuroprotection, stress responses, DNA repair, vascular protection and other cellular processes.

SIRT2 Cell-cycle control, carbohydrate and lipid metabolism, tubulin and transcription factors deacetylation and antiinflammatory.

SIRT3. Regulation of mitochondrial enzymes deacetylation, ATP production, reactive oxygen species (ROS) management, boxidation, ketogenesis, cell death, and carbohydrate and lipid metabolism

SIRT4 Insulin secretion, glutamine and fatty acid metabolism and regulate the ATP homeostasis

SIRT5 Urea cycle, regulation of ATP synthesis, metabolism, apoptosis and intracellular signaling, regulation of ammonia detoxification, fatty acid oxidation.

SIRT6 Telomeres and telomeric functions, DNA repair, metabolic homeostasis, inflammation, stress responses, and genomic stability.

SIRT7 Regulates the transcription of rDNA and mediate histone desuccinylation. ◀︎ [4]

⫸ NAD, nicotinamide adenine dinucleotide, is one of the most abundant molecules in human body that involves in

over 500 important biological reactions, and its decline of intracellular concentration with age is reviewed as one of

the most important factors that causes age-related health issues.[12] It plays critical roles in all the aforementioned

“nine hallmarks of aging”.[13–15] The biological mechanism of NAD on aging is mainly through its functions of

energy metabolization and activations of PARP and Sirtuin proteins in mammalian cells.[12] NMN has been drawn

tremendous attention during recent years as a potential nutritional supplementation for restoring NAD levels.[16] Huge

amount of research papers on NMN have been published from laboratories around the world on its roles of lifespan

and healthspan, as well as its underlying biological mechanisms.16–17⫷[6]

Precursers to the production of NAD+:

• Tryptophan (L-Trp)

• (NA) • Nicotinic Acid [Vitamin B3]

• (NAM) • Nicotinamide [No flush Niacin]

• (NR) • Nicotinamide Riboside

• (NMN) • Nicotinamide Mononucleotide

◉ 600 Milligrams of NMN daily, has been show to be the optimal does in individuals older than 45. This daily does was safe and produced increases in levels of NAD in the blood and increases in activities of daily living and age associated reduction in laboratory blood markers. [6]

It is important to store NMN in your refrigerator as the compound degrades into

SIRTUINS / NAD+

Source: Biochemistry and Cell Biology of Aging: Part II 2019

▶︎ Silent Information Regulators or sirtuins are well recognized as anti-ageing molecules that regulate lifespan. Sirtuins are highly conserved NAD+-dependent enzymes that play a role in resistance to stress, genomic stability and energy metabolism (Finkel et al. 2009; Watroba et al. 2017). Of the 7 sirtuins found in mammals most attention has centered on sirtuin-1 and sirtuin-6, as both are associated with prolongation of lifespan in many species, including mammals (Guarente 2011). Sirtuin-1 deacetylates many key regulatory proteins and transcription factors that are known to be involved in DNA repair, infammation, antioxidant gene expression and cellular senescence, including the PI3K-AKT-mTOR pathway and autophagy (Fig. 3.3). Sirtuin-1 deacetylates the transcription factor FOXO3a, which enhances antioxidant responses (particularly superoxide dismutases) and inhibits p53-induced cellular senescence, inhibits NF-κB leading to suppression of infammation and activates PGC-1α, which maintains mitochondrial function. Sirtuin-1 is markedly reduced in peripheral lung and circulating PBMC of patients with COPD (Nakamaru et al. 2009; Rajendrasozhan et al. 2008; Baker et al. 2016b). Sirtuin-1 is reduced by oxidative stress via reduction in PTEN and activation of the PI3K-mTOR pathway and in turn sirtuin-1 inhibits mTOR signaling. Sirtuin-1 also activates autophagy by inhibiting mTOR (Lee et al. 2008). The polyphenol resveratrol, found in the skin of red fruits and in red wine, activates sirtuin-1, but is poorly bioavailable, so this has led to the development of more potent sirtuin-1 activating compounds (STACs), which are now in clinical development for the treatment of age-related diseases (Hubbard and Sinclair 2014; Bonkowski and Sinclair 2016). Sirtuin-6 is an ADP ribosylase as well as protein deacetylase and plays a key role in regulating DNA repair, telomere maintenance, inflammation and metabolic homeostasis and, like sirtuin-1, is linked to extension of lifespan (Kugel and Mostoslavsky 2014). Sirtuin-6 expression is reduced in the lungs of patients with COPD (Nakamaru et al. 2009; Takasaka et al. 2014). Reduced sirtuin-6 is found in airway epithelial cells of COPD patients and is reduced by cigarette smoke exposure, resulting in cellular senescence and impaired autophagy (Takasaka et al. 2014). As discussed above, oxidative stress activates PI3K-mTOR signaling, which increases the expression of miR-34a that directly inhibits sirtuin-1 and sirtuin-6 mRNA and protein expression without any effects on the other sirtuins (Baker et al. 2016b). Circulating sirtuin-1 concentrations are also reduced in patients with COPD (Yanagisawa et al. 2017b).The role of sirtuins in other lung diseases is less well defined. Reduced sirtuin-1 is found in PBMC from elderly patients with severe asthma and appears to increase IL-4 secretion though increased acetylation of the transcription factor GATA-3 (Colley et al. 2016). Sirtuin-1 knockout in mice enhances lung fibrosis, and sirtuin-1. ◀︎[1]

► Since the first discovery of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity of the silent information regulator 2 (Sir2) family (‘sirtuins’),1 the field of sirtuin biology has been evolving rapidly over the past 16 years. Many researchers from different fields have encountered sirtuins in their own research, enriching our knowledge of this fascinating family of enzymes. It is now clear that sirtuins are involved in the regulation of many fundamental biological processes throughout the body.2,3 Furthermore, it has been revealed that sirtuins possess much broader enzymatic activities, namely, deacylases, including deacetylase, desuccinylase, demaloynylase, deglutarylase, long-chain deacylase, lipoamidase, and ADP-ribosyltransferase.4,5. All these enzymatic activities specifically require NAD+, and the co-substrate, NAD+.

Even in mammals, the brain-specific SIRT1-overexpressing (BRASTO) transgenic mice have been demonstrated to exhibit significant delay in aging and lifespan extension in both male and female mice.27 Given that the whole-body SIRT1-overexpressing transgenic mice fail to show lifespan extension,22 this study strongly suggests that SIRT1 in the brain, more specifically in the hypothalamus, is a key to control aging and longevity in mammals.31 In addition, whole-body SIRT6 transgenic mice have been reported to show lifespan extension, although only males exhibit the phenotype.24 These recent studies have established a firm foundation for the significance of sirtuins as an evolutionarily conserved aging/longevity regulator.32–34

Nicotinamide riboside (NR), a key NAD+ intermediate, is produced and secreted by yeast cells,37,38 and exogenous NR increases NAD+ biosynthesis and promotes lifespan through two independent pathways, the one mediated by NR kinase Nrk1 and the other mediated by uridine hydrolase Urh1 and purine nucleoside phosphorylase Pnp1.39

Different from yeast, worms, and flies, mammals do not have Pnc1 homologs but utilize NAMPT instead, converting nicotinamide, an amide form of vitamin B3, and 5′-phosphoribo- syl-pyrophosphate to nicotinamide mononucleotide (NMN), another key NAD+ intermediate (Figure 1).41,42 NMN is adenylated to NAD+ by three NMN adenylyltransferases, NMNAT1-3. It has been well established that the NAMPT-mediated NAD+ biosynthetic pathway regulates sirtuin activity in the nucleus and mitochondria.43–47

An unique feature of this particular NAD+ biosynthetic pathway is that transcription of the Nampt gene is mediated by the key circadian transcription factors CLOCK/BMAL, rendering NAD+ biosynthesis and the activity of sirtuins circadian. In addition, SIRT1 and SIRT6 feedback on the circadian oscillator in peripheral tissues and likely in the suprachiasmatic nucleus of the hypothalamus.43,45,52 The circadian oscillation of NAD+ drives at least SIRT1, SIRT3, and SIRT6 activities, impacting a variety of metabolic functions, including glucose, cholesterol, and fatty acid metabolism (Figure 3).44,53

Given that the hypothalamus functions as a high-order ‘control center of aging’ in mammals,27,54 it is conceivable that adipose tissue functions as a ‘modulator’ of this control center (see Figure 5). Indeed, knock-in mice in which iNAMPT is overexpressed specifically in adipose tissue (ANKI mice) show significant increases in circulating eNAMPT levels, hypotha- lamic NAD+ and SIRT1 target gene expression, and physical activity, particularly in response to fasting.8 Therefore, it will be of great interest to examine whether these ANKI mice show a significant slowing in aging and lifespan extension.◀︎[2]

[12] [2020] Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men

The study linked above conducted in Japanese men found no safety concerns following a single, oral administration of NMN at up to 500mg daily. There were no changes in heart rate, blood pressure, oxygen saturation, or body temperature. As the authors of the study state, “The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects.”