The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing
Abstract
Ageing is associated with a variety of pathophysiological changes, including development of insulin resistance, progressive decline in β‐cell function and chronic inflammation, all of which affect metabolic homeostasis in response to nutritional and environmental stimuli. SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD)‐dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate‐limiting NAD biosynthetic enzyme, together comprise a novel systemic regulatory network, named the ‘NAD World’, that orchestrates physiological responses to internal and external perturbations and maintains the robustness of the physiological system in mammals. In the past decade, an accumulating body of evidence has demonstrated that SIRT1 and NAMPT, two essential components in the NAD World, play a critical role in regulating insulin sensitivity and insulin secretion throughout the body. In this article, we will summarize the physiological significance of SIRT1 and NAMPT‐mediated NAD biosynthesis in metabolic regulation and discuss the ideas of functional hierarchy and frailty in determining the robustness of the system. We will also discuss the potential of key NAD intermediates as effective nutriceuticals for the prevention and the treatment of age‐associated metabolic complications, such as type 2 diabetes.
Introduction
Ageing is one of the most serious risk factors for many metabolic complications, including obesity, atherosclerosis and type 2 diabetes. For example, among US residents aged 65 years and older, 10.9 million or 26.9% of all people in this age group suffered diabetes in 2010, based on the 2011 National Diabetes Fact Sheet from the Center for Disease Control and Prevention. Indeed, it has been well known that insulin resistance develops over time 1. It has also been shown that β‐cell function declines progressively during ageing 2, contributing to the pathogenesis of type 2 diabetes. Another important factor of ageing that affects metabolic homeostasis is chronic inflammation. It has been known that levels of inflammatory cytokines and markers, including interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and C‐reactive protein (CRP), elevate with age in healthy old individuals 3. The elevation of these inflammatory cytokines and markers is tightly associated with the development of insulin resistance and β‐cell dysfunction 4, 5. Therefore, one would speculate that factors that contribute to the regulation of systemic metabolic robustness and anti‐inflammatory responses could play a crucial role in the pathogenesis of these age‐associated metabolic complications, such as atherosclerosis and type 2 diabetes.
One such factor is the mammalian nicotinamide adenine dinucleotide (NAD)‐dependent protein deacetylase SIRT1, one of the seven family members of mammalian sirtuins 6, 7. In the past decade, an accumulating body of evidence suggests that SIRT1 plays an important role in the regulation of glucose and lipid metabolism, providing a hope that SIRT1 will be a promising therapeutic target for age‐associated metabolic complications, particularly type 2 diabetes 8. Because SIRT1 requires NAD for its enzymatic activity, understanding the regulation of mammalian NAD biosynthesis has also become a critical issue in the field of metabolism and ageing research. Particularly, nicotinamide phosphoribosyltransferase (NAMPT), a key NAD biosynthetic enzyme in mammals, has recently become a focus of intensive investigation 9. In this review, we will focus on the importance of a systemic regulatory network, named the ‘NAD World’, mediated by these two major players, SIRT1 and NAMPT. We will also discuss the translational aspect of the studies on SIRT1 and NAMPT for the treatment and prevention of type 2 diabetes.
SIRT1, a Key Mediator that Regulates Metabolic Responses to Nutritional Input
The biology of SIR2 family proteins, called ‘sirtuins’, has been evolving dramatically in the past decade since the discovery of their unique NAD‐dependent deacetylase activity 8. Through these tremendous amounts of studies on sirtuins, it has become clear that sirtuins function to maintain and/or enhance the robustness of the physiological system and secure the survival of individuals when organisms are exposed to internal and external perturbations 6, 7. Among these perturbations, energy limitation, such as fasting and diet restriction (DR), is one of the most important ones that are known to increase sirtuin dosages and/or enhance their activities. Sirtuins also respond to other types of stresses and damages, such as oxidative stresses and DNA damages. In this regard, it is likely that sirtuins have evolved primarily to prevent the physiological system from any destruction due to a wide variety of environmental perturbations, such as a famine. This particular evolutional trait of sirtuins might have likely put themselves to a universal position of mediating anti‐ageing effects in many different organisms.
Indeed, in yeast, worms and flies, sirtuins have been shown to play an important role in the regulation of ageing and longevity 10-12. However, some of those results, particularly the effects of SIR2 orthologs, Sir‐2.1 and dSir2, on longevity in worms and flies, respectively, have been called into a question 13, generating a serious controversy regarding the importance of sirtuins for ageing and longevity. Although this controversy still remains in the field, recent studies in yeast, flies and mice have provided further supportive evidence for the importance of sirtuins as key regulators of ageing and longevity 14-16. In mammals, it has been firmly established that sirtuins are critical metabolic mediators in multiple tissues 6, 7. In particular, SIRT1, the mammalian SIR2 ortholog, regulates a variety of metabolic responses to changes in nutritional input in multiple tissues, including the liver, skeletal muscle, adipose tissue, pancreatic islets and the brain (figure 1). SIRT1 also plays a critical role in the regulation of phenotypes induced by DR, a well‐known regimen that delays ageing and extends life span in a wide variety of organisms. Whereas the whole‐body and brain‐specific Sirt1 knockout mice fail to respond to DR 17-19, Sirt1‐overexpresing transgenic mice display phenotypes similar to DR mice 20 or prevention against metabolic complications caused by high‐fat diet (HFD) and ageing 21, 22. However, whole‐body Sirt1‐overexpressing mice have been reported to fail to show life span extension, although they show a lower incidence of spontaneous carcinomas and sarcomas and a reduced susceptibility to HFD/carcinogen‐induced liver tumours 23. Therefore, whether and how sirtuins, SIRT1 in particular, regulate ageing and longevity in mammals still remains a critical question, and intensive investigation is currently in progress in the field of sirtuin biology to address this long‐standing question.
Regulation of Insulin Sensitivity by SIRT1
Nonetheless, a number of genetic studies have so far strongly suggested that SIRT1 is important to maintain both insulin sensitivity and insulin secretion throughout the body. For example, in the liver, hepatic deletion of SIRT1 impairs peroxisome proliferator‐activated receptor (PPAR) α function and decreases fatty acid β‐oxidation, causing hepatic steatosis, inflammation and endoplasmic reticulum stress when exposed to a HFD 24. Another study has demonstrated that hepatic Sirt1 deficiency impairs the mammalian target of rapamycin complex 2 (mTORC2)/AKT signalling pathway, causing chronic hyperglycaemia, oxidative stress and systemic insulin resistance on a regular diet 25. In adipose tissue, adipose tissue‐specific Sirt1 deficiency causes increased adiposity and leads to insulin resistance under a HFD and during ageing 26. Interestingly, Sirt1 deficiency in adipose tissue causes changes in gene expression that largely overlap with those caused by a HFD 26. Most recently, it has been shown that SIRT1 promotes ‘browning’ of white adipose tissue by deacetylating PPARγ and recruiting Prdm16, a key co‐activator for the development and function of brown adipose tissue, to PPARγ, potentially contributing to the improvement of insulin sensitivity 27. In skeletal muscle, DR increases SIRT1 activity and enhances insulin‐stimulated phosphoinositide 3‐kinase (PI3K) signalling and glucose uptake through SIRT1‐mediated STAT3 deacetylation 28. These adaptive responses in skeletal muscle are completely abrogated by skeletal muscle‐specific Sirt1 deletion. These findings clearly demonstrate that SIRT1 plays a critical role in maintaining and improving insulin sensitivity in response to nutritional perturbations in major insulin sensitive tissues.
Regulation of Insulin Secretion by SIRT1
On the other hand, SIRT1 has also been demonstrated to positively regulate glucose‐stimulated insulin secretion (GSIS) in pancreatic β‐cells. Our group has previously demonstrated that an increased dosage of SIRT1 in β cells significantly enhances GSIS and improves glucose tolerance in pancreatic β‐cell specific SIRT1‐overexpressing (BESTO) transgenic mice 29. Given that DR enhances postprandial insulin secretion 30, the BESTO phenotype is an interesting phenocopy of this DR‐induced response of insulin secretion. Contrarily, Sirt1‐deficient mice and islets show blunted GSIS 31, further supporting the importance of SIRT1 in the regulation of GSIS in pancreatic β‐cells. SIRT1 is also important for β‐cell adaptation in response to increasing insulin resistance. Our group has shown that BESTO mice are able to maintain improved glucose tolerance with enhanced GSIS even under a long‐term (up to 30 weeks) HFD treatment 32. Consistent with our finding, other groups have also shown that SIRT1 protects pancreatic β‐cells from metabolic stress‐ and cytokine‐induced β‐cell death by deacetylating FOXO1 and the p65 subunit of NF‐κB, respectively 33, 34. Therefore, these findings indicate that SIRT1 is critical to protect pancreatic β‐cells from dysfunction caused by metabolic and age‐induced perturbations.
Regulation of Central Adaptive Response by SIRT1
In addition to regulating the balance between insulin sensitivity and insulin secretion in peripheral tissues and organs, SIRT1 is also required to regulate central adaptive responses to acute and chronic energy limitations. For example, DR significantly increases SIRT1 protein levels and induces neural activation in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively) 19. Brain‐specific SIRT1‐overexpressing (BRASTO) mice mimics DR‐induced neural activation in the DMH and LH, promotes physical activity and counteract the decrease in body temperature in response to different diet‐restricting paradigms 19. These adaptive responses are all abrogated in Sirt1−/− mice. In the DMH and LH, SIRT1 upregulates expression of the orexin type 2 receptor to mediate these adaptive responses. Furthermore, it has been reported that SIRT1 decreases the production of Aβ amyloid 35, prevents tau‐mediated neurodegeneration 36 and maintain memory and synaptic plasticity 37, contributing to the prevention of age‐associated cognitive disorders. These findings also provide strong support for the notion that SIRT1 functions to maintain physiological robustness against different kinds of perturbations, mediating beneficial effects against ageing.
Expanding Roles of Other Sirtuins in Metabolic Regulation
Recent studies have clearly proven the importance of other sirtuins in the regulation of insulin sensitivity and insulin secretion. For example, SIRT3, one of the mitochondrial sirtuin family members (SIRT3‐5), regulates insulin sensitivity in skeletal muscle 38, and Sirt3 deficiency is associated with the pathogenesis of metabolic syndrome including insulin resistance 39. SIRT4, another mitochondrial sirtuin, controls amino acid‐stimulated insulin secretion in pancreatic β‐cells 40. It has also been reported that SIRT6 promotes GSIS in β cells 41, whereas it suppresses gluconeogenesis in the liver 42. Currently, intensive investigation is being undertaken to understand the roles of mitochondrial sirtuins and SIRT6 in cancer metabolism 43, 44. It has now become apparent that sirtuins have extensively divergent, complex functions in the regulation of metabolism under many different pathophysiological conditions. Given that they all require NAD for their functions, sirtuins are likely the critical keys to connect between NAD availability and metabolic regulation.
NAMPT, a Key NAD Biosynthetic Enzyme That Functions as a Pacemaker and Fine‐Tunes SIRT1 Activity
The pathophysiological significance of SIRT1 and other sirtuins has fuelled more enthusiasm to investigate NAD biosynthetic pathways. NAD is a universal and essential co‐enzyme involved in many cellular redox reactions. To generate NAD, mammals utilize four different precursors, including tryptophan, nicotinamide and nicotinic acid (also known as two forms of vitamin B3) and nicotinamide riboside (NR) 45. It is known that the salvage pathway starting from nicotinamide is a predominant NAD biosynthetic pathway in mammals 46. In this pathway, NAMPT produces nicotinamide mononucleotide (NMN) from nicotinamide and 5′‐phosphoribosyl‐1‐pyrophosphate. NMN, together with ATP, is then converted into NAD by the second enzyme, nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT, figure 2). Studies have demonstrated that NAMPT is a dimeric type II phosphoribosyltransferase which functions as the rate‐limiting enzyme in mammalian NAD biosynthetic pathway and directly regulates SIRT1 activity 47, 48. Interestingly, mammals possess two different forms of NAMPT: intracellular and extracellular NAMPT (iNampt and eNampt, respectively, figure 2) 9, 49. In the past decade, the role of iNAMPT has been extensively studied in many biological processes. Particularly, iNAMPT plays an important role in regulating metabolic function by modulating SIRT1 activity. For example, FoxOs regulate Nampt transcription in the liver, and overexpression of iNAMPT reduces hepatic triglyceride levels 50. It has also been reported that the levels of hepatic iNAMPT protein decrease in the patients with non‐alcoholic fatty liver disease (NAFLD) 51. In skeletal muscle, both glucose restriction and exercise increase iNAMPT protein levels 52, 53, and iNAMPT levels correlate with mitochondrial contents in humans 52. iNAMPT also plays a protective role in the stress associated with ageing and high‐glucose in endothelial cells 54. Interestingly, we and other groups have reported that the Nampt gene is regulated by the core clock machinery and thereby iNAMPT and NAD levels display circadian oscillation patterns in peripheral metabolic tissues, such as the liver and adipose tissue 55-57. In turn, SIRT1 negatively regulates the transcriptional activation of clock genes. In other words, iNAMPT and SIRT1 together comprises a novel circadian‐regulatory feedback loop, connecting circadian rhythm regulation to metabolic regulation. These findings suggest that NAD functions as a ‘metabolic oscillator’ that dynamically influences rhythmic regulation of metabolic responses 55. We have recently found that both iNAMPT and NAD levels are reduced in multiple metabolic tissues and organs by HFD feeding and ageing, contributing to the pathogenesis of type 2 diabetes 58. It appears that inflammatory cytokines and oxidative stress cause the reduction in iNAMPT‐mediated NAD biosynthesis, implicating an interesting connection between chronic inflammation and NAMPT‐mediated NAD biosynthesis.
The physiological function of eNAMPT is still under debate. It has been reported that eNAMPT is positively secreted from fully differentiated adipocytes 49, mononuclear cells 59, hepatocytes 60 and cardiomyocytes 61. Our previous study has demonstrated that eNAMPT, secreted from adipocytes, has higher enzymatic activity compared with iNAMPT, and it might be involved in the extracellular synthesis of NMN, possibly in the blood circulation (figure 2) 49. However, one recent study shows the contradictory data that recombinant NAMPT is not capable of producing NMN in plasma in vitro 62. To further elucidate the function of eNAMPT in vivo, employing genetic approach, as well as biochemical approach, is important, and the detailed analysis of adipose tissue‐specific Nampt knockout mice is currently in progress.
The NAD World: a Systemic Regulatory Network Connecting Metabolism and Ageing
As summarized above, the functional interplay between SIRT1 and NAMPT‐mediated NAD biosynthesis plays a crucial role in the regulation of a variety of biological processes, particularly metabolic regulation. NAMPT‐mediated NAD biosynthesis functions as a ‘pacemaker’ that controls a novel transcriptional‐enzymatic arm of circadian regulation and fine‐tunes SIRT1 activity. In response to the alterations in NAMPT‐mediated NAD biosynthesis, SIRT1 functions as a key mediator that coordinates a number of metabolic responses throughout the body. Through this tight interplay, NAMPT‐mediated NAD biosynthesis and SIRT1 together comprise a novel systemic regulatory network, named the ‘NAD World’, that orchestrates physiological responses to internal and external perturbations and maintains the robustness of the physiological system in mammals 55, 63-65.
The significance of this concept is that it conveys the ideas of functional hierarchy and frailty in determining the robustness of the systemic regulation of metabolism and ageing. In this concept of the NAD World, critical frailty points are the tissues and organs that have very low levels of iNAMPT. Such tissues and organs likely rely on extracellular sources of NAD intermediates, such as NMN and NR, to maintain sufficient NAD levels for their functions (figure 3). In this regard, pancreatic β‐cells and neurons are likely the most critical frailty points in the mammalian physiological system because both cell types have very low levels of iNAMPT compared with other cell types. Our previous studies have clearly shown that pancreatic β‐cells are indeed an important frailty point in the NAD World that is susceptible to changes in NAMPT‐mediated NAD biosynthesis. Genetic, pharmacological and pathophysiological reductions in NAMPT‐mediated NAD biosynthesis all impairs β‐cell function, causing defects in GSIS and impaired glucose tolerance in vivo 32. Similarly, neurons are also likely another critical frailty point in the NAD World. It has been demonstrated that SIRT1 regulates memory and synaptic plasticity in the hippocampus 37 and neurobehavioral adaptation in the hypothalamus 19. Therefore, NAD supply for SIRT1 in these brain regions must be critical, and its reduction could cause neurological problems, including dementia and neurobehavioral complications.
As briefly described in the previous section, we have shown that tumour necrosis factor‐α (TNF‐α) and oxidative stress significantly reduce NAMPT and NAD levels in primary hepatocytes 58. Given that both inflammatory cytokines and oxidative stress contribute to age‐associated chronic inflammation 3, the development of chronic inflammation could be the reason why NAMPT‐mediated NAD biosynthesis is compromised during ageing, leading to reduction in SIRT1 activity and thereby a variety of metabolic complications in multiple tissues. Therefore, it will be of great interest to examine whether inflammatory cytokines, such as TNF‐α, and/or oxidative stress indeed affects NAD levels in pancreatic β‐cells and central neurons. If this is the case, serious dysfunction of these two cell types would be caused by chronic inflammation through defects in NAMPT‐mediated NAD biosynthesis. Such dysfunction of pancreatic β‐cells and central neurons would affect many other tissues and organs through insulin action and central metabolic regulation, resulting in the gradual deterioration of physiological robustness over time. We speculate that this cascade of robustness breakdown triggered by defects in NAMPT‐mediated NAD biosynthesis underlies in the induction of age‐associated pathophysiology. If so, is it possible to prevent this systemic robustness breakdown by enhancing NAD biosynthesis at a systemic level? We will discuss this interesting possibility in the next section.
Key NAD Intermediates: a Translational Perspective
Given the importance of SIRT1 in the regulation of metabolic responses in multiple tissues and organs, it has been speculated that modulating NAD levels may influence metabolic functions and provide an effective intervention to treat metabolic disorders such as type 2 diabetes, obesity and insulin resistance 66. Indeed, recent studies, including our own, show that enhancing NAD biosynthesis has beneficial effects on glucose and lipid metabolism by increasing SIRT1 activity. For example, genetically engineered mouse models demonstrate that inactivation of poly(ADP‐ribose) polymerase‐1 (NAD consuming enzyme) 67 or CD38 (NAD degrading enzyme) 68 significantly improves mitochondrial function in skeletal muscle and prevents diet‐induced obesity by enhancing energy expenditure. Slow Wallerian degeneration (WldS) mutant mice that contain a spontaneous mutation containing full‐length NMNAT1 enhance insulin secretion, and they are also protective against HFD‐induced glucose intolerance and streptozotocin‐induced hyperglycaemia in a SIRT1 dependent manner 69. Furthermore, administration of apigenin (a potent CD38 inhibitor) 70 and leucine 71 also increases tissue NAD levels and improves metabolic complications, such as glucose intolerance and insulin resistance, in HFD‐fed mice.
Our group has demonstrated that administration of a key NAD intermediate, NMN, treats the pathophysiology of metabolic disorders associated with haplodeficiency of Nampt, HFD‐feeding and ageing. NMN is a product of NAMPT enzymatic reaction and found in our daily food sources (our unpublished finding). NMN administration restores GSIS in Nampt heterozygous knockout mice 49 and old BESTO and wild‐type mice 32. Furthermore, NMN increases GSIS and insulin sensitivity in HFD‐fed type 2 diabetic model mice by restoring the defects in NAMPT‐mediated NAD biosynthesis 58. Interestingly, NMN appears to ameliorate inflammatory response, leading to the improvement in hepatic insulin sensitivity in HFD‐fed mice. Indeed, NMN administration enhances the deacetylation of the p65 subunit of NF‐κB through the activation of SIRT1 in the liver. Our bioinformatics analyses confirm that biological pathways associated with inflammatory response and NF‐κB target genes, such as IL‐1β and SA100 calcium binding proteins A8 and A9 (S100a8 and S100a9), are also reduced by NMN treatment. Consistent with our findings, NMN administration reduces the expression of IL‐1β and restores β‐cell function in fructose‐rich diet‐fed mice 72. Additionally, NMN restores insulin secretion in pro‐inflammatory cytokine‐treated islets 72, 73. These findings indicate that NMN treatment has anti‐inflammatory effects in pancreatic islets and the liver, improving insulin secretion and action in diabetic model mice. NR is another promising NAD intermediate to treat metabolic disorders. It has been reported that NR administration also improves mitochondrial function in skeletal muscle and brown adipose tissue, glucose tolerance, insulin secretion and action, plasma lipid panel and energy expenditure through activating SIRT1 and SIRT3 in HFD‐fed mice 74. Because SIRT1 functions to prevent a variety of age‐associated diseases 6, 8, it is likely that enhancing NAD levels through supplementation with NAD intermediates, such as NMN and NR, could prevent not only metabolic disorders but also other age‐associated diseases (figure 4). One recent study has shown that NR treatment significantly attenuates cognitive deterioration in the AD mouse model 75. Furthermore, it is also possible that NMN/NR supplementation directly affects NAD‐dependent redox metabolism such as β‐oxidation and glycolysis. Therefore, it will be of great importance to investigate the effect of NMN/NR supplementation on those biological processes. Given that both NMN and NR are natural compounds (unpublished data) and derivatives of vitamin B3, these compounds are expected to be translatable as effective anti‐ageing nutriceuticals into humans in the near future. To this end, it will be of great importance to carefully evaluate the effects of long‐term NMN/NR supplementation, as well as their potential side effects, on metabolism and other pathophysiological parameters in rodents and then possibly humans.
Conclusion
On the verge of historically unprecedented increases in elderly demographics through the globe, it is now of great importance to understand the spatial and temporal dynamics of the systemic regulatory network that integrates metabolic regulation to the ageing/longevity control in mammals. In this regard, the concept of the NAD World provides critical insight into how to dissect such system dynamics, focusing on two critical components, namely SIRT1 and NAMPT‐mediated NAD biosynthesis. Several important questions still remain unanswered. If chronic inflammation is a major cause for defects in NAMPT‐mediated biosynthesis at a systemic level, how and where does it happen during the process of ageing? Are ‘frailty’ cell types, such as pancreatic β‐cells and neurons, indeed sensitive to inflammation‐induced dysfunction of NAD biosynthesis? Can we reverse this destruction process by enhancing NAD biosynthesis with key NAD intermediates as nutriceuticals? Can we really improve the quality of life and eventually achieve longevity by administering these NAD intermediates in humans? Further investigation will be definitely required to address these questions. We hope that understanding the NAD World will guide us towards reasonable solutions for social and economic problems caused by heavily ageing societies.
Acknowledgements
We thank members of the Imai laboratory for their daily, stimulating discussions. This work was supported in part by grants from the National Institute on Ageing (AG024150, AG037457), the National Heart, Lung, and Blood Institute (HL097817), the Ellison Medical Foundation and the Longer Life Foundation to S. Imai and by institutional support from the Washington University Nutrition Obesity Research Center (P30DK056341) and the Washington University Diabetes Research Center (P60DK020579). J. Yoshino was supported by the Japan Research Foundation for Clinical Pharmacology, the Manpei Suzuki Diabetes Foundation, and the Kanae Foundation for the Promotion of Medical Science.
Conflict of Interest
S. I. serves as a scientific advisory board member for Sirtris, a GSK company, and has a Sponsored Research Agreement with Oriental Yeast Co., Tokyo, Japan. J. Y. has no conflict of interest.
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