NAD + metabolism: A therapeutic target for age-related metabolic disease

“Since then resveratrol has been shown to be effective in preventing and delaying the progression of various diseases such as cancer (Jang et al., 1997), cardiovascular disease and glucose intolerance (Timmers et al.”

“…several hallmarks of aging, such as reduced inflammatory and apoptotic events in vascular endothelium, limiting the formation of cataracts, preservation of bone density and conservation of motor activity with age (Barger et al., 2008; Baur et al., 2006; Lagouge et al., 2006; Pearson et al., 2008).”

“In chow fed mice, resveratrol significantly attenuated several hallmarks of aging, such as reduced inflammatory and apoptotic events in vascular endothelium, limiting the formation of cataracts, preservation of bone density and conservation of motor activity with age (Barger et al., 2008; Baur et al., 2006; Lagouge et…”

“A few decades later, in 1963, resveratrol was extracted from the roots of another plant, Japanese knotweed (Reynoutria japonica), commonly used in traditional Chinese and Japanese medicine (reviewed in Baur & Sinclair, 2006).”

“The nuclear sirtuin SIRT1 is the best-known member of the family especially after it was described as the target of the polyphenol, resveratrol (Howitz et al., 2003), which is found in low quantities in red wine (see section ‘‘Pharmacological control of NAD+ levels’’).”

“, 1986; Rine & Herskowitz, 1987), which was originally described as a NAD-dependent class III histone deacetylases (Imai et al., 2000).”

“During fasting and exercise, the level of NAD+ increases (Canto et al., 2009, 2010).”

“SIRT1 deacetylates histones, but its key activity involves the regulation of mitochondrial biogenesis and stress response through the deacetylation of PGC-1a (Rodgers et al., 2005) and FOXO1 (Brunet et al., 2004; van der Horst et al., 2004).”

“These observations could explain the conflicting results obtained with CR in non-human primates, where two independent studies – both of which using a different control diet and feeding regimen – showed a different extent of CR health benefits (Colman et al., 2009; Mattison et al., 2012).”

“It was already known for ages that moderation and composition of diet can influence the aging process (Schafer, 2005), but the modern day founder was Clive McCay, who put its benefits in the scientific spotlight in 1935 (McCay et al., 1989).”

“Thus, the increased dosage of SIR2 in yeast prevents the formation of extrachromosomal ribosomal DNA circles and prolongs lifespan, whereas its inhibition has the opposite effect, reducing the replicative lifespan by 50% (Kaeberlein et al., 1999).”

“Sirtuins are a class of metabolic regulators, of which seven orthologs exist in mammals (Blander & Guarente, 2004; Chalkiadaki & Guarente, 2012; Haigis & Sinclair, 2010; Houtkooper et al., 2012).”

“Sirtuins are a class of metabolic regulators, of which seven orthologs exist in mammals (Blander & Guarente, 2004; Chalkiadaki & Guarente, 2012; Haigis & Sinclair, 2010; Houtkooper et al., 2012).”

“The nuclear PARP1 accounts for most of the PARP activity in vivo and is the best-studied family member, but critical functions for other PARPs are emerging (Luo & Kraus, 2012; Schreiber et al., 2006).”

“1 or Sir2p, respectively)dependent manner (Howitz et al., 2003; Wood et al., 2004), although this is controversial (Bass et al.”

“…concentration of the growth medium from 2% to 0.5% is sufficient to extend lifespan to a similar level as by overexpressing Sir2, and these effects were dependent on the Sir2 gene or the nicotinate phosphoribosyltransferase-1 gene, which is involved in the biosynthesis of NAD (Lin et al., 2000).”

“Since then resveratrol has been shown to be effective in preventing and delaying the progression of various diseases such as cancer (Jang et al., 1997), cardiovascular disease and glucose intolerance (Timmers et al., 2011) and ischemic stroke (Sinha et al., 2002; Wang et al., 2002).”

“metabolic abnormalities in mice models (Feige et al., 2008; Milne et al., 2007).”

“Additionally, Sirt6 / mice have reduced insulinlike growth factor 1 levels and are severely hypoglycemic (Mostoslavsky et al., 2006), possibly mediated by the hypoxia-inducible factors-1a-dependent activation of glycolysis and subsequent decreases in glucose levels (Zhong et al.”

“Initial work reported that increased expression of the yeast protein Sir2 and of related sirtuin proteins in Caenorhabditis elegans and D. melanogaster extends lifespan (Rogina & Helfand, 2004; Tissenbaum & Guarente, 2001).”

“The cytosolic SIRT2 was shown to deacetylate tubulin (North et al., 2003), as well as the sterol regulatory element-binding protein-2 (LuthiCarter et al., 2010), although genetic evidence for this latter association is so far lacking.”

“Sirtuins are a class of metabolic regulators, of which seven orthologs exist in mammals (Blander & Guarente, 2004; Chalkiadaki & Guarente, 2012; Haigis & Sinclair, 2010; Houtkooper et al., 2012).”

“In addition, some of the sirtuins were reported to ADP-ribosylate proteins rather than deacetylate (Haigis et al., 2006), and SIRT5 was shown to act as a demalonylase and desuccinylase (Du et al., 2011; Peng et al., 2011; Wang et al., 2011).”

“1 being the closest homolog of Sir2 (Frye, 2000), and sir-2.”

“In the fruitfly Drosophila melanogaster, which expresses five homologs of Sir2 (Frye, 2000), CR extends lifespan and increases dSir2 mRNA expression, but was unable to mediate lifespan extension in flies where dSir2 had been deleted (Rogina & Helfand, 2004).”

“Conversely, caloric excess by means of an HFD (Kim et al., 2011), but also aging (Braidy et al., 2011; Yoshino et al., 2011), lead to reduced NAD+ levels.”

“Importantly and reassuring from a clinical point of view, resveratrol supplementation in obese humans reached beneficial effects at a far lower dose (150 mg/day) (Timmers et al., 2011).”

“The mitochondrial sirtuins – SIRT3, SIRT4 and SIRT5 – deacetylate protein targets involved in oxidative phosphorylation (Ahn et al., 2008), fatty acid oxidation (Hirschey et al., 2010), ketogenesis (Shimazu et al., 2010), oxidative stress (Someya et al., 2010), glutamate metabolism (Haigis et al.,…”

“Indeed, supplementation of NR to cells or mice increases the levels of NAD+ and results in the activation of its downstream signaling cascades (Canto et al., 2012), as will be discussed in more detail below.”

“…do not develop an overt metabolic DOI: 10.3109/10409238.2013.789479 NAD+ in metabolic disease 399 phenotype under basal non-challenged conditions (FernandezMarcos et al., 2012; Haigis et al., 2006; Haigis & Sinclair, 2010; Hirschey et al., 2010; Lombard et al., 2007; Nakagawa et al., 2009).”

“…studies in worms added a new layer of complexity in this dynamic mechanism, by showing that an early burst of reactive oxygen species (ROS) is required for the induction of the ROS defense pathway and for the lifespan extension under CR conditions (Mouchiroud et al., 2011; Schulz et al., 2007).”

“than deacetylate (Haigis et al., 2006), and SIRT5 was shown to act as a demalonylase and desuccinylase (Du et al.”

“…several hallmarks of aging, such as reduced inflammatory and apoptotic events in vascular endothelium, limiting the formation of cataracts, preservation of bone density and conservation of motor activity with age (Barger et al., 2008; Baur et al., 2006; Lagouge et al., 2006; Pearson et al., 2008).”

“…in oxidative phosphorylation (Ahn et al., 2008), fatty acid oxidation (Hirschey et al., 2010), ketogenesis (Shimazu et al., 2010), oxidative stress (Someya et al., 2010), glutamate metabolism (Haigis et al., 2006), urea cycle (Nakagawa et al., 2009), as well as several other mitochondrial…”

“These observations could explain the conflicting results obtained with CR in non-human primates, where two independent studies – both of which using a different control diet and feeding regimen – showed a different extent of CR health benefits (Colman et al., 2009; Mattison et al., 2012).”

“While PARP inhibitors have not yet been tested for metabolic effects, their clinical development for cancer therapy could provide interesting opportunities in this direction (Audeh et al., 2010; Gelmon et al., 2011).”

“…new evidence suggest that other pro-longevity pathways, induced by CR and/or stress conditions, could also potentially involve SIRT1, such as mitophagy, mitochondrial dynamics (fission/fusion) and mitochondrial unfolded response (Durieux et al., 2011; Egan et al., 2011; Yang et al., 2011).”

“Additionally, Sirt6 / mice have reduced insulinlike growth factor 1 levels and are severely hypoglycemic (Mostoslavsky et al., 2006), possibly mediated by the hypoxia-inducible factors-1a-dependent activation of glycolysis and subsequent decreases in glucose levels (Zhong et al., 2010).”

“…the ATP synthase complex in the oxidative phosphorylation (Zheng & Ramirez, 2000), it was hypothesized that the effects of resveratrol could be mediated by activation of the AMPK, rather than direct SIRT1 activation (Beher et al., 2009; Canto et al., 2010; Pacholec et al., 2010; Um et al., 2010).”

“…the ATP synthase complex in the oxidative phosphorylation (Zheng & Ramirez, 2000), it was hypothesized that the effects of resveratrol could be mediated by activation of the AMPK, rather than direct SIRT1 activation (Beher et al., 2009; Canto et al., 2010; Pacholec et al., 2010; Um et al., 2010).”

“levels in brown adipose tissue, at least in female mice, was shown to impair glucose-stimulated insulin secretion (Revollo et al., 2007).”

“Resveratrol has attracted the attention of the scientific community when it was demonstrated that this molecule could be the origin cardioprotective effects specific to red wine which is commonly referred to as ‘‘the French paradox’’ (Kopp, 1998; Pace-Asciak et al., 1995).”

“It is also present in red wine at concentration ranging from 0.1 to 14.3 mg/l (Soleas et al., 1997).”

“Following AMPK activation, expression of NAMPT increased, leading to increased NAD levels and activation of SIRT1 (Canto et al., 2009, 2010; Fulco et al., 2008).”

“The effects of Parp1 deletion were due to elevation of NAD+ levels and subsequent SIRT1-dependent activation of mitochondrial metabolism in brown adipose tissue and muscle (Bai et al., 2011b).”

“…the Sirt1 gene, exhibit a range of features that are reminiscent of the phenotypes seen in CR mice, as they are lighter and metabolically more active, show improved glucose homeostasis and develop less cancer (Banks et al., 2008; Bordone et al., 2007; Herranz et al., 2010; Pfluger et al., 2008).”

“Indeed, CR permits to maintain neuronal plasticity with age (Adams et al., 2008; Halagappa et al., 2007; Patel et al., 2005) and reduces cancer risk (Kalaany & Sabatini, 2009), suggesting that increasing NAD+ levels could also be interesting within this context (Speakman & Mitchell, 2011).”

“…effects mediated by SIRT1 under CR conditions have been proposed to be due to an improvement of the mitochondrial function and biogenesis (Guarente & Picard, 2005), but also to a global increase in stress resistance and maintenance of the cellular and mitochondrial homeostasis (Figure 3).”

“…do not develop an overt metabolic DOI: 10.3109/10409238.2013.789479 NAD+ in metabolic disease 399 phenotype under basal non-challenged conditions (FernandezMarcos et al., 2012; Haigis et al., 2006; Haigis & Sinclair, 2010; Hirschey et al., 2010; Lombard et al., 2007; Nakagawa et al., 2009).”

“The nuclear PARP1 accounts for most of the PARP activity in vivo and is the best-studied family member, but critical functions for other PARPs are emerging (Luo & Kraus, 2012; Schreiber et al., 2006).”

“It is interesting to note, however, that a recent study demonstrated a role for CD157 in the response of intestinal Paneth cells to caloric restriction (CR) (Yilmaz et al., 2012).”

“In addition, some of the sirtuins were reported to ADP-ribosylate proteins rather than deacetylate (Haigis et al., 2006), and SIRT5 was shown to act as a demalonylase and desuccinylase (Du et al., 2011; Peng et al., 2011; Wang et al., 2011).”

“Even though this pathway for NAD biosynthesis was already known in bacteria, it was only recently demonstrated that NR – which is found in milk and yeast – could also be used to synthesize NAD+ in eukaryotes (Bieganowski & Brenner, 2004).”

“, 2004), although this is controversial (Bass et al., 2007; Kaeberlein et al., 2005).”

“…the Sirt1 gene, exhibit a range of features that are reminiscent of the phenotypes seen in CR mice, as they are lighter and metabolically more active, show improved glucose homeostasis and develop less cancer (Banks et al., 2008; Bordone et al., 2007; Herranz et al., 2010; Pfluger et al., 2008).”

“metabolic abnormalities in mice models (Feige et al., 2008; Milne et al., 2007).”

“After a period of relative anonymity, NAD+ became again in the spotlight because it was identified as a substrate for a major class of deacetylase proteins, the sirtuins, named after the founding member of the family yeast Sir2p (Ivy et al., 1986; Rine & Herskowitz, 1987).”

“…metabolism (Haigis et al., 2006), urea cycle (Nakagawa et al., 2009), as well as several other mitochondrial pathways (Hebert et al., 2013), and thereby regulate multiple facets of mitochondrial metabolism (reviewed in Houtkooper et al., 2012; Pirinen et al., 2012 and Verdin et al., 2010).”

“…the Sirt1 gene, exhibit a range of features that are reminiscent of the phenotypes seen in CR mice, as they are lighter and metabolically more active, show improved glucose homeostasis and develop less cancer (Banks et al., 2008; Bordone et al., 2007; Herranz et al., 2010; Pfluger et al., 2008).”

“Resveratrol promotes mitochondrial biogenesis and functions through indirect AMPK and SIRT1 activation.”

“A thorough characterization of Sirt7 / mice has not been performed but mice deficient for SIRT7 display hyperacetylation of p53, develop cardiomyopathy and die young (Vakhrusheva et al., 2008).”

“…(Someya et al., 2010), glutamate metabolism (Haigis et al., 2006), urea cycle (Nakagawa et al., 2009), as well as several other mitochondrial pathways (Hebert et al., 2013), and thereby regulate multiple facets of mitochondrial metabolism (reviewed in Houtkooper et al., 2012; Pirinen et al., 2012…”

“No in vivo molecular deacetylation targets have been described for the nucleolar SIRT7, but knockdown or overexpression of SIRT7 resulted in decreased or increased RNA polymerase I-mediated transcription, respectively (Ford et al., 2006).”

“1 and fly SIR2 on lifespan is, at best, limited or even absent (Burnett et al., 2011; Viswanathan & Guarente, 2011).”

“In line with these beneficial effects of CR on age-associated pathologies, transgenic mice with SIRT1 overexpression are not only protected against HFD-induced metabolic pathology, but also show protection against tumor development (Herranz et al., 2010) and progression of neurodegenerative disease (Donmez et al.”

“Indeed, CR permits to maintain neuronal plasticity with age (Adams et al., 2008; Halagappa et al., 2007; Patel et al., 2005) and reduces cancer risk (Kalaany & Sabatini, 2009), suggesting that increasing NAD+ levels could also be interesting within this context (Speakman & Mitchell, 2011).”

“…several hallmarks of aging, such as reduced inflammatory and apoptotic events in vascular endothelium, limiting the formation of cataracts, preservation of bone density and conservation of motor activity with age (Barger et al., 2008; Baur et al., 2006; Lagouge et al., 2006; Pearson et al., 2008).”

“In a similar way, CR in mouse models leads to an increase in the level of NAD in different tissues, such as muscle, liver and white adipose tissue (Canto et al., 2010; Chen et al., 2008).”

“, 2010), although recent evidence suggests that this may be dictated by specific hydrophobic residues in SIRT1 substrates (Hubbard et al., 2013).”

“SIRT1 deacetylates histones, but its key activity involves the regulation of mitochondrial biogenesis and stress response through the deacetylation of PGC-1a (Rodgers et al., 2005) and FOXO1 (Brunet et al., 2004; van der Horst et al., 2004).”

“Since then resveratrol has been shown to be effective in preventing and delaying the progression of various diseases such as cancer (Jang et al., 1997), cardiovascular disease and glucose intolerance (Timmers et al., 2011) and ischemic stroke (Sinha et al., 2002; Wang et al., 2002).”

“Its function as a cofactor for a multitude of enzymatic reactions has been appreciated since the early 1900s, when NAD+ was described as a ‘‘cozymase’’ in fermentation and its characteristics were elucidated, not in the last place by several Nobel prize winners (Berger et al., 2004).”

“…SIRT5 – deacetylate protein targets involved in oxidative phosphorylation (Ahn et al., 2008), fatty acid oxidation (Hirschey et al., 2010), ketogenesis (Shimazu et al., 2010), oxidative stress (Someya et al., 2010), glutamate metabolism (Haigis et al., 2006), urea cycle (Nakagawa et al., 2009), as…”

“Indeed, CR permits to maintain neuronal plasticity with age (Adams et al., 2008; Halagappa et al., 2007; Patel et al., 2005) and reduces cancer risk (Kalaany & Sabatini, 2009), suggesting that increasing NAD+ levels could also be interesting within this context (Speakman & Mitchell, 2011).”

“CR remains the most effective and reproducible intervention to extend lifespan and delay the development of ageassociated diseases in divergent species, from yeast to monkeys (Houtkooper et al., 2010b; Koubova & Guarente, 2003).”

“Since it was known that resveratrol acts as an inhibitor of the ATP synthase complex in the oxidative phosphorylation (Zheng & Ramirez, 2000), it was hypothesized that the effects of resveratrol could be mediated by activation of the AMPK, rather than direct SIRT1 activation (Beher et al., 2009;…”

“1 or Sir2p, respectively)dependent manner (Howitz et al., 2003; Wood et al., 2004), although this is controversial (Bass et al., 2007; Kaeberlein et al., 2005).”

“In fact, in Sirt1 / mice the beneficial effects on metabolism and longevity induced by a CR diet are attenuated, although it should be noted that these mice are very sick to start with (Boily et al., 2008; Chen et al., 2005).”

“For example, when protein translation is stalled, PARP13 localizes to cytosolic stress granules and regulates microRNA expression and activity, alleviating the protein stress (Leung et al., 2011).”

“Its role in stress response is further confirmed by the identification of p53, hypoxiainducible factor-1a, and NF- B as SIRT1 targets (reviewed in Canto & Auwerx, 2012; Houtkooper et al., 2012).”

“…the ATP synthase complex in the oxidative phosphorylation (Zheng & Ramirez, 2000), it was hypothesized that the effects of resveratrol could be mediated by activation of the AMPK, rather than direct SIRT1 activation (Beher et al., 2009; Canto et al., 2010; Pacholec et al., 2010; Um et al., 2010).”

“phosphoenolpyruvate carboxykinase to control gluconeogenesis (Jiang et al., 2011) and was recently shown to deacetylate the receptor-interacting protein-1, and thereby serve as a critical component of the tumor necrosis factor a-mediated programmed necrosis pathway (Narayan et al.”

“In fact, in Sirt1 / mice the beneficial effects on metabolism and longevity induced by a CR diet are attenuated, although it should be noted that these mice are very sick to start with (Boily et al., 2008; Chen et al., 2005).”

“Resveratrol has attracted the attention of the scientific community when it was demonstrated that this molecule could be the origin cardioprotective effects specific to red wine which is commonly referred to as ‘‘the French paradox’’ (Kopp, 1998; Pace-Asciak et al., 1995).”

“It should be noted, however, that resveratrol failed to exert beneficial effects in non-obese female subjects (Yoshino et al., 2012), in line with mouse data where resveratrol is particularly effective in HFD fed mice (Baur et al., 2006; Lagouge et al., 2006).”

“, 2010) and progression of neurodegenerative disease (Donmez et al., 2010; Jeong et al., 2012; Wareski et al., 2009).”

“This effect on longevity is, however, only observed when mice are fed with an HFD.”

“…questioned whether the beneficial effects observed under CR were not due to a simple ‘‘rescue’’ of the deleterious effects brought by the state of overnutrition specific of the artificial diets prepared in laboratories (Harper et al., 2006; Longo & Finch, 2003; Martin et al., 2010; Prentice, 2005).”

“Sirtuins are a class of metabolic regulators, of which seven orthologs exist in mammals (Blander & Guarente, 2004; Chalkiadaki & Guarente, 2012; Haigis & Sinclair, 2010; Houtkooper et al., 2012).”

“Indeed, CR permits to maintain neuronal plasticity with age (Adams et al., 2008; Halagappa et al., 2007; Patel et al., 2005) and reduces cancer risk (Kalaany & Sabatini, 2009), suggesting that increasing NAD+ levels could also be interesting within this context (Speakman & Mitchell, 2011).”

“Still, even if most CD38 activity occurs outside the cell, the resultant metabolites can be transported inside, most likely in the form of NR (Nikiforov et al., 2011).”

“NA, also called niacin, has been used to treat dietary tryptophan deficits (pellagra) and hyperlipidemia (Elvehjem et al., 1937; Karpe & Frayn, 2004; Sauve, 2008).”

“The concept that enhanced mitochondrial function upon CR contributes to its beneficial effects on lifespan was extended to humans, in which a general improvement in metabolic health occurs during CR (Civitarese et al., 2007 and reviewed in Holloszy & Fontana, 2007).”

“After a period of relative anonymity, NAD+ became again in the spotlight because it was identified as a substrate for a major class of deacetylase proteins, the sirtuins, named after the founding member of the family yeast Sir2p (Ivy et al., 1986; Rine & Herskowitz, 1987).”

“1 is required for the lifespan extension in response to the CR-mutation eat-2 (Wang & Tissenbaum, 2006).”

“The effects of Parp1 deletion were due to elevation of NAD+ levels and subsequent SIRT1-dependent activation of mitochondrial metabolism in brown adipose tissue and muscle (Bai et al., 2011b).”

“While PARPs are stress response proteins, the NAD+-consuming CD38 is an ubiquitous, but still quite enigmatic enzyme, involved in maintaining calcium homeostasis (Lee, 2012).”

“Pellagra, in dogs prevalent as black tongue disease, is caused by deficiency of NAD+ (precursors) and can be easily treated by providing the vitamin in the diet (Elvehjem et al., 1937).”

“De novo biosynthesis, which starts from the amino acid tryptophan, occurs primarily in the liver and kidney but is considered a minor contributor to the total pool of NAD+ (reviewed in detail in Houtkooper et al., 2010a).”

“…questioned whether the beneficial effects observed under CR were not due to a simple ‘‘rescue’’ of the deleterious effects brought by the state of overnutrition specific of the artificial diets prepared in laboratories (Harper et al., 2006; Longo & Finch, 2003; Martin et al., 2010; Prentice, 2005).”

“While PARPs are stress response proteins, the NAD+-consuming CD38 is an ubiquitous, but still quite enigmatic enzyme, involved in maintaining calcium homeostasis (Lee, 2012).”

“NA, also called niacin, has been used to treat dietary tryptophan deficits (pellagra) and hyperlipidemia (Elvehjem et al., 1937; Karpe & Frayn, 2004; Sauve, 2008).”

“Indeed, CR permits to maintain neuronal plasticity with age (Adams et al., 2008; Halagappa et al., 2007; Patel et al., 2005) and reduces cancer risk (Kalaany & Sabatini, 2009), suggesting that increasing NAD+ levels could also be interesting within this context (Speakman & Mitchell, 2011).”

“Finally, SIRT2 controls myelin formation in vivo through the atypical protein kinase C regulator PAR3 (Beirowski et al., 2011).”

“1 and fly SIR2 on lifespan is, at best, limited or even absent (Burnett et al., 2011; Viswanathan & Guarente, 2011).”

“Small molecule CD38 inhibitors (or CD157 inhibitors if identified) may circumvent this problem, but further insights in the NAD+ accumulation and trafficking are required (Sauve et al., 1998; Sauve & Schramm, 2002).”

“…development, it has become apparent that pathways involved in synthesis or consumption of NAD+ are attractive targets for the management of conditions with dysfunctional metabolism, including not only obesity and diabetes, but also cancer and neurodegenerative diseases (Houtkooper & Auwerx, 2012).”

“More recently, however, the role of the different PARPs in metabolism has become more apparent, as Parp1 and Parp2 knockout mice are protected against high-fat diet (HFD)induced obesity (Bai et al., 2007, 2011a,b).”

“In addition, some of the sirtuins were reported to ADP-ribosylate proteins rather than deacetylate (Haigis et al., 2006), and SIRT5 was shown to act as a demalonylase and desuccinylase (Du et al., 2011; Peng et al., 2011; Wang et al., 2011).”

“…questioned whether the beneficial effects observed under CR were not due to a simple ‘‘rescue’’ of the deleterious effects brought by the state of overnutrition specific of the artificial diets prepared in laboratories (Harper et al., 2006; Longo & Finch, 2003; Martin et al., 2010; Prentice, 2005).”

“…studies in worms added a new layer of complexity in this dynamic mechanism, by showing that an early burst of reactive oxygen species (ROS) is required for the induction of the ROS defense pathway and for the lifespan extension under CR conditions (Mouchiroud et al., 2011; Schulz et al., 2007).”

“…new evidence suggest that other pro-longevity pathways, induced by CR and/or stress conditions, could also potentially involve SIRT1, such as mitophagy, mitochondrial dynamics (fission/fusion) and mitochondrial unfolded response (Durieux et al., 2011; Egan et al., 2011; Yang et al., 2011).”

“SIRT1, SIRT6 and SIRT7 are mainly found in the nucleus, SIRT2 is predominantly in the cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in mitochondria (Pirinen et al., 2012).”

“While PARPs are stress response proteins, the NAD+-consuming CD38 is an ubiquitous, but still quite enigmatic enzyme, involved in maintaining calcium homeostasis (Lee, 2012).”

“Small molecule CD38 inhibitors (or CD157 inhibitors if identified) may circumvent this problem, but further insights in the NAD+ accumulation and trafficking are required (Sauve et al., 1998; Sauve & Schramm, 2002).”

“2014), TOR (Kapahi et al., 2010; Johnson et al., 2013), AMPK (Geer et al., 2007; Burkewitz et al. 2014), sirtuins (Mouchiroud et al., 2013; Guarente.”

“The NAD system is increasingly recognized as an attractive target for intervention in age-associated disorders (72).”