In just the last 30 years, molecular biologists have discovered genes with the potential to extend longevity: SIR2 in yeast and its mammalian equivalent, SIRT1. In animal models, SIRT1, via the enzymes it encodes, has been shown to have healthspan extending regulatory effects on metabolism, stress resistance, cellular survival, cellular senescence, inflammation-immune function, endothelial function, and circadian rhythms. Clinically relevant findings first began to appear in the peer-reviewed medical literature a mere 10 years ago with the revelation that the keys that unlock and activate our longevity genes are naturally occurring dietary polyphenols.
Part I of this review highlights key historical high points of the research odyssey that cracked the longevity code and provides the reader with a backstage pass to meet the enzymes encoded by SIRT1—the seven nutrient-responsive NAD+-dependent histone deacetylase enzymes, dubbed the sirtuins. Part I’s interview with these intriguing enzymes provides answers to the following questions: What are the unique nutrient requirements of the sirtuins? How and why is their activation impacted not only by calorie restriction, but by certain phytonutrients such as resveratrol, and by the redox state of the cell, specifically its NAD+/NAD(H) ratio? What can be done to optimize this ratio via NAD+ salvage, and why will this—in conjunction with resveratrol and/or other SIRT1-activating compounds–optimize sirtuin activity? Why might a very recently discovered niacin-related compound, nicotinamide riboside, be a better sirtuin-activating partner for resveratrol than niacin (nicotinic acid) or its derivative, niacinamide?
Part II of this review details SIRT1’s anti-aging effects via an overview of the primary functions of key regulatory proteins deacetylated by Sirt1 and the mitochondrial sirtuins (sirtuins 3-5). Even the brief overview provided demonstrates why the sirtuins, nicknamed “the magnificent seven” have also been dubbed “the master switches of metabolism.” Although resveratrol’s beneficial effects are primarily mediated through its activation of SIRT1, resveratrol’s cellular targets also include a number of other important regulatory enzymes including cyclooxygenases, lipooxygenases, kinases, ribonucleotide reductase, adenylyl cyclase, aromatase and DNA polymerases. The potential impact on healthspan of resveratrol’s modulation of the activity of these extra-sirtuin targets is outlined. Lastly, a number of other naturally occurring dietary polyphenols have lately been recognized to be sirtuin activating compounds (STACs); these, and their common mechanism of action, are noted.
We have entered a new era in which the key genes and intracellular pathways responsible for aging and longevity have been identified. Our discovery of the sirtuins – and the fact that their activity is responsive to changes in cellular metabolism and a number of xenohormetic plant compounds –has proven that lifespan is tractable. Not only is the research progressing at an exponential rate, but, right now—today, we can safely utilize emerging knowledge to develop effective longevity-enhancing protocols.
Introduction: Cracking the Longevity Code
In his highly informative book, The Longevity Factor, Joseph Maroon, MD, delivers a most engaging summary of what he calls mankind’s very recent “ascent to the Himalayas of longevity.”1 It truly is mind-boggling to realize that, in just the last 30 years, molecular biologists have discovered human longevity genes with potent regulatory effects on metabolism, stress resistance, cellular survival, cellular senescence/aging, inflammation-immune function, endothelial function, and circadian rhythms. And it’s only been 10 years since they cracked the longevity code with the revelation that the keys that unlock and activate these longevity genes are naturally occurring dietary polyphenols.
A few historical high points of this odyssey to date:
In the 1930s, researchers at Cornell University discovered that rodents put on a diet providing comparable micronutrients to standard rat chow, but only 60% of normal calories, lived up to 50% longer than their peers, maintained youthful appearance and activity levels, and delayed the onset of age-related disease. Although this research was soon extended to other species from yeast to monkeys and its outcomes universally confirmed, few humans, researchers included, jumped on the “calorie restriction with adequate nutrition” (CRAN) bandwagon. CRAN has since been refined and defined as a 40% reduction versus ad libitum feeding without compromising adequate nutrition.2 Recognizing that for most people the level of calorie restriction required to receive CRAN’s healthspan and longevity extending benefits would be intolerable, over the next 60 years, scientists set about unraveling—at the molecular level—the mechanisms behind calorie restriction’s age-retarding magic.
In the late 1980s to mid-1990s, molecular biologists at the UC Irvine and San Francisco campuses, and at MIT, discovered that specific genes were activated by calorie restriction (CR), along with the enzymes that regulated them and were therefore responsible for CR’s longevity enhancing effects. When lecturing in Australia, one of the star researchers responsible for these discoveries, Dr. Leonard Guarente, met and recruited a young doctoral student named David Sinclair; together, their research shortly thereafter played a key role in cracking the longevity code.
Arriving at MIT in 1995, Sinclair teamed up with Guarente to discover that the principal cause of aging and death in yeast is not free radical wear and tear, but, more akin to the Hayflick limit (i.e., the theory that senescence is triggered by a cellular alarm clock after a preprogramed number of divisions), is due to the formation of extraneous “rings” of DNA that accumulate with each cell division, eventually resulting in DNA instability and cell death. Most importantly, Guarente and Sinclair discovered that cell death in yeast is a highly regulated, genetically-controlled process related to the function of one gene: silent information regulator 2 (a.k.a sirtuin 2 [SIR2]). When activated in yeast, the SIR2 gene encodes enzymes that stabilize DNA, preventing abnormal DNA formation and extending lifespan.
Further research soon confirmed all living organisms possess genes capable of producing SIR2-like enzymes, which were dubbed sirtuins. Once the mammalian counterpart to the SIR2 gene, christened SIRT1, was identified, the next question was “What, other than caloric restriction, turns on SIRT1?
Animal research conducted at Harvard by David Sinclair and Joseph Bauer that began to answer this question was published in 2006, in Nature, setting off a veritable firestorm of interest in the phytonutrient, resveratrol (3,5,4′-trihydroxystilbene).3 A constituent of red wine, resveratrol had long been suspected to have cardioprotective effects (à la French Paradox), had been identified as a chemopreventive agent versus skin cancer, and was shown by Bauer and Sinclair to activate the sirtuin gene, the same mechanism through which CR is now known to extend the lifespans of lower organisms.4
In lower organisms (e.g., Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster), lifespan extension is the result of the gene silencing activities of the deacetylase enzymes encoded by the SIR2 gene. In mammals, the corresponding gene is SIRT1, a principal modulator of pathways, also activated by CR, that improve control of glucose homeostasis, insulin sensitivity and vascular function; boost endurance; and inhibit tumor formation.5 SIRT1 modulates these processes via encoding the sirtuin enzymes: seven nutrient-responsive NAD+-dependent histone deacetylase enzymes, of which Sirt1 has been the most studied. (The histone deacetylases [HDACs] remove acetyl groups, which causes DNA to compact, and thus prevents transcription. For clarity, this review will use “SIRT1” to refer to the gene and “Sirt1-7” to refer to the enzymes it encodes.)
The sirtuin enzymes deacetylate not only histones within DNA, but also a number of post-translational proteins. This action results in modulation of a large number of transcriptional and post-transcriptional factors involved in cell growth, differentiation, stress resistance, glucose metabolism and redox capacity. (Key factors deacetylated by the sirtuins are discussed in Part II of this review in the section SIRT1: Longevity Extending Mechanisms of Action).67
|Sirtuin Enzyme||Primary location||Key Targets||Biological impact|
|Sirt 1||Nucleus (& cytosol)||FOXO, PGC-1α, NFκB, Ku70, LXR||Metabolism, lipid regulation, inflammation, stress response, cell cycle, autophagy|
|Sirt 2||Cytosol (& nucleus)||Histone 4, FOXO||Cell cycle|
|Sirt 3||Mitochondria (& nucleus)||Acetyl Co-A synthase, Glutamate dehydrogenase complex I||Thermogenesis, ATP production|
|Sirt 4||Mitochondria||Glutamate dehydrogenase, Insulin degrading enzyme||ATP production, insulin secretion|
|Sirt 5||Mitochondria||Carbamoyl phosphate synthetase||Urea cycle|
|Sirt 6||Nucleus||Histone 3, NFκB||Base excision repair, metabolism|
|Sirt 7||Nucleolus**||DNA polymerase 1||rDNA transcription|
* Adapted from Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95. PMID: 20078221
** Nucleolus: a non-membrane bound structure within the nucleus in which ribosomal RNA is transcribed and assembled.
Resveratrol, the most powerful natural SIRT1 activator
Resveratrol, the most powerful natural SIRT1 activator yet discovered, belongs to a subgroup of plant polyphenols called stillbenes and is classified as a phytoalexin: a stress-induced compound formed in plants in response to challenges such as fungal infestation, high UV radiation or drought.8
All plant phenols are characterized by having aromatic ring(s) with one or more hydroxyl groups of varying structural complexity. Resveratrol is composed of two phenolic rings connected by a double bond, and is found in two isoforms: trans-resveratrol and cis-resveratrol; the former is what has been used in the longevity research since it is more stable and exerts greater biological activity.9
Most highly concentrated in the skin of stressed red grapes, but also found in lesser amounts in Giant knotweed (Polygonum cuspidatum), peanuts, raspberries, blueberries, pomegranate, hops, pistachios, dark chocolate, and some pine trees,8,6 resveratrol activates the SIRT1 gene, thus producing the same effects as CR, for which reason it’s been called a “calorie restriction mimetic.
In Sinclair and Bauer’s landmark animal experiments, middle-aged mice put on a high-fat, high calorie diet—and also given resveratrol—experienced numerous physiological changes associated with longer lifespan, including:
- Increased insulin sensitivity
- insulin-like growth factor-1 (IGF-I) levels: Reduction is protective against cancer since the insulin-like growth factor pathway plays an important role in a number of human malignancies by contributing to unregulated cell proliferation.10
- Increased activity of AMP-activated protein kinase: AMPK activation stimulates hepatic fatty acid oxidation and muscle glucose uptake, and inhibits lipogenesis, decreasing synthesis of cholesterol, triglycerides, andadipocytes.
- Increased activity of peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha): activation results in mitochondrial biogenesis.
- Increased mitochondrial number
- Improved motor function
- Gene set analysis revealed that resveratrol opposed the deleterious effects of the high-calorie diet in these mice in 144 out of 153 significantly altered pathways.
The resveratrol-treated mice exhibited increased memory, as tested in mazes; reduced fat cell size despite their high calorie diet and sedentary lifestyle; transformation of ordinary muscle fibers into the “slow twitch” type found in highly trained athletes, boosted energy and endurance in muscle cells, enhanced muscle strength, decreased fatigue, and improved coordination and mobility—all despite no exercise training. In these animals, incidence of chronic age-related diseases, including cancer, vascular disease and brain degeneration, was reduced, and lifespan was prolonged ~25%.
Sinclair and Bauer declared, “These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.” Sinclair and others are now working on developing synthetic SIRT1 activators, (e.g., SRT1720, said to be both up to 1,000 times more potent than resveratrol) that will target only specific proteins, e.g., PGC-1α. Deacetylation of PGC-1α via SRT1720 has recently been shown to result in improved insulin sensitivity, glucose tolerance, weight loss and increased endurance in mice.51112
Xenohormesis: Plants’ Early Warning System Promotes Human Life Extension
How could small molecules, produced as secondary metabolites by stressed plants to increase their cellular defenses and repair mechanisms, promote longevity in humans?In one word: xenohormsis.1314
Certain secondary plant metabolites are xenohormetic: the root “xeno” implying foreign, and “hormesis,” a term first used in toxicology to describe a beneficial stress response invoked by exposure to very low doses of a toxin, but now also used to denote the beneficial signaling effects of stress-induced, non-toxic plant compounds. Xenohormetic compounds transmit signals to receptors on cells, which activate a complex web of enzymes including, not only the sirtuins, but post-translational kinases, thus altering cellular function.
Xenohormetic activation or inhibition of these enzymes alters genetic expression in the cell, which changes its function, and thus its phenotype, in response to the message. This discovery—that food is not merely calories but information, that it delivers substances that impact genetic expression—is the launch pad for the emerging field of nutrigenomics. And it is also the key to understanding our potential to extend healthspan in response to the messages sent by the xenohormetic substances we choose to ingest. Or to decrease lifespan—think about the full array of longevity-reducing physiological changes experienced by Morgan Spurlock in response to just a few weeks’ fast food diet in the movie “SuperSize Me.”
As Lamming, Wood and Sinclair propose in a paper published in Molecular Microbiology in 2004, entitled Small molecules that regulate lifespan: evidence for xenohormesis: “organisms have evolved to respond to stress signaling molecules produced by other species [italics added] in their environment. In this way, organisms can prepare in advance for a deteriorating environment and/or a loss of food supply.”15 Certain xenohoremetic substances in plants’ signal a high likelihood of impending calorie restriction. By doing so, they serve as an early warning system, readying human DNA, via their activation of the sirtuin gene and its enzymes, to go into life extension mode in the interests of the survival of the species. Resveratrol remains the most potent of these natural early warning system / sirtuin activators identified to date, and studies are just beginning to appear demonstrating its SIRT1-related longevity-promoting effects in humans at doses as low as 40 mg daily for just six weeks.16
How Sirtuin Deacetylation Impacts Genetic Expression
A brief review of the basics of genetic transcription may be helpful to set the stage:
Within the nucleus of eukaryotes, DNA—the genome—is densely compacted, first by being wrapped around histone protein spheres, like thread wrapped around a spool, and tightly coiled into nucleosomes, which then supercoil into chromatin, the stuff of chromosomes. Chromatin’s highly condensed nature efficiently packs DNA into the, literally, microscopic space available and protects it, but also renders the genome inaccessible to factors required for gene transcription, DNA replication and repair.
To cram two meters of DNA inside a 10 µm nucleus yet allow access, eukaryotes have developed distinct types of modifications on histones that allow them to interact with corresponding classes of enzymes and slightly uncoil or re-coil. These histone modifications are the keys to epigenetic regulation since they determine whether transcription factors can gain access to the promoter regions of a gene (its CPG islands). They include acetylation (uncoil/become accessible), methylation (compact/gene silencing), ubiquinatation (mixed read/don’t read messages) and phosphorylation (mixed messages [these are delivered by kinase enzymes]).
In relation to the sirtuin enzymes encoded by SIRT1, the histone modification involved is deacetylation, the ability to remove an acetyl group. Acetyl groups activate genes; deacetylation silences them. The sirtuin enzymes belong to a larger family of enzymes called histone deacteylases (HDACs), which play the counterpart role to the histone acetyltransferases (HATS), enzymes that add an acetyl group to an ε-N-acetyl lysine amino acid on a histone, causing DNA to unwind, thus allowing transcription. HDACs remove these acetyl groups, causing DNA to recompact, preventing transcription.
HDACs are also referred to as “lysine deacetylases” to more precisely describe their targets, which include numerous non-histone proteins. The sirtuin enzymes are Class III HDACs. HATS and HDACs (histone acetylators and deacetylators) play a key role in the regulation of gene expression since hyperacetylated chromatin is transcriptionally active; hypoacetylated chromatin (a result of SIRT1/sirtuin enzyme activity) is silent.
In addition to regulating gene transcription by modifying histones/chromatin structure, HDACs also affect the function, activity, and stability of proteins via post-translational modifications. The most widely studied post-translational modification has been protein phosphorylation, which involves phosphorylation of certain amino acid residues by protein kinases or their dephosphorylation by phosphotases. Very recently, however, the acetylation of lysine residues has emerged as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases, including the sirtuins.
In this context, Sirt1 is being found to interact with a variety of non-histone proteins whose functions significantly impact longevity. Just one example should make the point here: p53. Deacetylation of p53 suppresses its transcriptional activity and renders cells resistant to DNA damage and oxidative stress-induced apoptosis. However p53 deacetylation could potentially be a double-edged sword since suppression of p53, another of whose functions is to act as a tumor suppressor, could promote oncogenesis. Ramifications of Sirt1’s impact on p53 are discussed in Part II of this review in the section Primary Functions of Key Sirt1 Targets.)
NAD+/NAD(H) Ratio : Key to Sirtuin Enzyme Activity
The life-extending activities of the sirtuins are the result of their nicotinamide adenine dinucleotide (NAD+)-dependent deacetylation of acetylated lysine residues on histone and non-histone substrates. Via the activities of these NAD+-dependent deacetylating enzymes, SIRT1 modulates at least 34 distinct targets. (Key targets are discussed in Part II of this review in the sections Sirt1: Longevity Extending Mechanisms of Action and The Mitochondrial Sirtuins.)
NAD+ is a coenzyme found in all living cells whose primary function is to serve as an electron transfer agent in redox reactions. Thus, it is found in cells in two forms: NAD+, (or, if phosphorylated, NADP+), the oxidizing agent that accepts electrons and is reduced to NAD(H) [or NADP(H)], which can then be used as an electron donor.
The roles played by the NAD+:NAD(H) ratio are complex. It controls the activity of key enzymes in cellular respiration — glyceraldehyde 3-phosphate dehydrogenase, which catalyzes the sixth step in glycolysis, and pyruvate dehydrogenase, which decarboxylates acetyl-CoA for use in the Krebs cycle — thus linking glycolysis to oxidative phosphorylation. For this reason, the NAD+:NAD(H) ratio, the balance between the oxidized and reduced forms of NAD, is a key component of the redox state of a cell and a biomarker that reflects cellular health as well as metabolic activity.17 NAD+ is also used in other cellular processes, notably as a substrate for enzymes that add or remove chemical groups, including acetyl groups, from proteins. In this capacity, NAD+ serves as substrate for the deacetylating enzymes, including the sirtuin enzymes transcribed by SIRT1. All seven human sirtuins share the common action of deacetylation at modified lysine residues via a unique enzymatic mechanism that requires NAD+ cleavage with each reaction cycle.18
When the two primary aspects of NAD+ utilization—as redox monitor and enzyme substrate—are seen together, it’s obvious that oxidative stress, which depletes NAD+, not only compromises cellular energy production, but sirtuin activation. Since NAD+ is the substrate for the sirtuin enzymes, if NAD+ availability is compromised then, even if resveratrol is signaling the SIRT1 gene to increase output of these enzymes, their activity will be inhibited.
It has been determined that the most fundamental way in which calorie restriction extends yeast lifespan is by decreasing levels of NAD(H) (nicotinamide), which inhibits SIR2 in yeast and SIRT1 in humans.19 Excellent evidence also indicates that CR extends healthspan in mouse models via the same mechanism — increasing NAD+ availability, thus increasing sirtuin activity.
NAD+ Salvage: Key to CR’s Longevity-Enhancing Effects
Since CR renders increased exogenous supply of NAD+ precursors highly unlikely, the explanation for CR’s longevity-enhancing actions must lie in upregulation of the body’s NAD+ recycling or “salvage” pathways.20
To maintain adequate NAD+ (in addition to assembling NAD+ de novo from tryptophan), cells salvage and recycle compounds containing nicotinamide. Components of the de novo pathway reside evenly throughout the cell, but those of the salvage pathway are localized primarily in the nucleus, which is not surprising since many reactions that consume NAD+, including its use by of Sirt1, Sirt6, and Sirt7, take place within the nucleus.212218 (In addition to sirtuins, NAD+ is consumed by Poly ADP-ribose polymerase enzymes [PARPs], which are involved in DNA repair, so their activity is upregulated by DNA strand breaks. PARPs are thought to be the major source of intracellular NAD+ consumption, but NAD+ is also depleted by cADPribose synthases, a.k.a. CD38 and CD157, which are membrane-bound enzymes whose products play key roles in Ca2+ mobilization and signaling.)20
Three compounds contain the nicotinamide ring (see Figures 2 and 3 below) and are used in the salvage pathway: nicotinic acid, nicotinamide, and nicotinamide riboside. Niacin (vitamin B3), is found in the diet in a variety of foods, including tuna, salmon, halibut, sardines, chicken and turkey breast, crimini mushrooms, peanuts, lentils, and whole wheat bread and pasta.2324 The nicotinamide ring is also present in nicotinamide riboside, a cousin of niacin that is found in the diet within the whey fraction in milk, which is surely one reason for whey proteins’ beneficial anabolic, anti-hypertensive and antithrombotic, and hypocholesterolemic effects.2526 Along with nicotinamide, nicotinamide riboside is also produced within cells when the nicotinamide moiety is released from NAD+ in ADP-ribose transfer reactions.20
Nicotinamide adenine dinucleotide (NAD) consists of two nucleotides joined by a pair of bridging phosphate groups. The nucleotides consist of ribose rings, one with adenine attached to the first carbon atom (the 1′ position) and the other with nicotinamide at this position.
Despite the presence of these several salvage options, mammals (e.g., humans) require a constant supply of niacin from the diet or supplements because NAD+ is constantly consumed. As noted above, NAD+ plays numerous essential roles in metabolism, acting as a coenzyme in redox reactions; as a donor of ADP-ribose moieties in ADP-ribosylation reactions (post-translational modifications of proteins involved in cell signaling and control of many cell processes, including DNA repair and apoptosis); as a precursor of cyclic ADP-ribose (a second messenger in calcium signaling); and as a substrate for DNA ligases, (which repair discontinuities between DNA strands), and–of key relevance to our current topic–as substrate for the sirtuin enzymes (which use NAD+ to remove acetyl groups from proteins).27
Flowchart by John Morgenthaler
Three compounds contain the nicotinamide ring (see Figures 2 and 3 above) and are used to produce NAD+ via the salvage pathway: nicotinic acid, nicotinamide, and nicotinamide riboside.
Unique Aspects of Sirtuin Enzyme Deacetylation
As mentioned earlier, the sirtuins remodel chromatin to repress transcription by reversing acetyl modifications on histones and also deacetylate many non-histone regulatory proteins including p53, FOXO, Ku70, Rb, E2F1, NFkB, p73 and PGC-1α (ramifications related to Sirt1 activity are outlined in Part II of this review in Sirt1: Longevity Extending Mechanisms of Action). By virtue of acting on this wide array of important targets, Sirt1 activation impacts regulatory control of diverse normal and abnormal cellular processes related to longevity—from glucose metabolism to mitochondrial bioenergetics to cellular senescence, autophagy and cancer.28
Unlike the other known protein deacetylases (the Class I and Class II deacetylases), which simply hydrolyze acetyl-lysine residues and release acetate, the sirtuin (Class III deacetylase-) reaction couples lysine deacetylation to NAD hydrolysis, yielding nicotinamide plus a novel metabolite, the deacetylated substrate O-acetyl-ADP-ribose.
O-acetyl-ADP-ribose (AAR) is readily hydrolyzed to generate ADP-ribose in mammalian cells, and both AAR and ADP-ribose bind to a domain in an ion channel (specifically, an inactive Nudix hydrolase domain in transient receptor melastatin-related ion channel 2 [TRPM2]), potentiating its ability to induce cell death in response to oxidative stress and other insults—another highly protective effect of NAD+ metabolism.28
Nicotinamide, produced by sirtuin enzymes in their use of NAD+ in deacetylation, is a potent inhibitor of their activity—a seemingly instantaneous feedback loop. It has been estimated that physiological concentrations of nicotinamide are sufficient to reduce basal Sirt1 activity in mouse cells by up to 20-fold.5 (Nicotinamide [a.k.a. niacinamide] is the form of niacin sometimes used as a supplement because it does not cause flushing, but it also does not reduce cholesterol, most likely because it is an inhibitor of sirtuin activity. These issues are further discussed below in the section: Why is nicotinic acid, but not niacinamide. effective in improving dyslipidemia?27)
Nicotinamide inhibits sirtuin activity by re-entering the enzyme’s catalytic site immediately after its release. There, nicotinamide combines with a reaction intermediate (an ADP-ribose peptide-imidate complex), which—via the salvage pathway—is used in the regeneration of the original acetylated lysine and NAD+.
Flowchart by John Morgenthaler
The Sirtuin Deacetylation Reaction: Sirtuin deacetylases catalyze a two-step biological reaction, which consumes nicotinamide adenine dinucleotide (NAD+) and releases nicotinamide (NAM), O-acetyl-ADP-ribose (AADPR), and the deacetylated substrate. During this reaction, an intermediate compound, an ADP-ribose peptide-imidate complex, is formed that is present for just a few seconds, but this provides sufficient time to enable NAM to enter the sirtuin enzyme’s catalytic site, where it triggers a reverse reaction. Reactivation of the sirtuin is facilitated by the removal of NAM and its conversion to NAD+ via NAMPT, a gene upregulated in mammals by stress and nutrient limitation, which encodes nicotinamide phosphoribosyltransferase (Nampt), the enzyme for the rate-limiting step in this pathway.
Increasing NAD+ Salvage Increases Sirtuin Activation
Increasing flux through the NAD+ salvage pathway that generates NAD+ from nicotinamide is sufficient to cause sirtuin activation. Nicotinamide phosphoribosyltransferase (Nampt) is the enzyme that catalyzes the rate-limiting step in this pathway in mammals. Activation of the NAMPT gene (which is upregulated by stress and reduction in caloric intake) results in production of Nampt. Nampt converts nicotinamide to nicotinamide mononucleotide (NMN), which is then utilized to regenerate NAD+, thus increasing sirtuin activity.518
Of interest, the Nampt enzyme is found in human serum (where it is known as eNampt) along with NMN. NMN is proposed to be a signaling molecule that enables stressed or nutrient-deprived cells to communicate globally with the body—a concept called the “NAD world,” that investigators are avidly researching now in hopes of using NMN to treat diseases of aging, e.g., type 2 diabetes.18
Nicotinamide Riboside: a sirtuin-activating, non-flushing alternative to nicotinic acid?
Another potential route to increased NAD+ synthesis is through the administration of nicotinamide riboside, a recently discovered niacin-related compound in whey that, along with nicotinic acid and niacinamide, is one of the three precursors used in NAD+ salvage metabolism.520
Nicotinamide riboside may offer a better option for improving plasma lipid profiles than nicotinic acid. High dose (≥2 grams) nicotinic acid therapy has long been recognized as an effective means of improving lipid profiles. Treatment not only reduces levels of triglycerides and low-density lipoprotein cholesterol, but elevates HDL cholesterol—with one glitch—a painful flushing response that typically lasts for ~30 minutes and is so unpleasant that patient compliance becomes a real challenge. Niacinamide does not provoke flushing, but neither does it provide nicotinic acid’s lipid-profile benefits.27
Why does nicotinic acid cause flushing?
Nicotinic acid is an agonist of the G-protein-coupled receptor Gpr109A whose activation in epidermal Langerhans cells is directly responsible for its flushing effect. Fortunately, Gpr109A is not expressed in the liver, so its activation is not responsible for nicotinic acid’s beneficial effects on dyslipidemia. Nicotinic acid’s lipid altering benefits derive from its contribution to increased NAD+ biosynthesis in the liver.20
Why is nicotinic acid, but not niacinamide. effective in improving dyslipidemia?
Nicotinic acid activates Sirt1 in the liver. Sirt 1 deacetylates liver X receptor (LXR), a positive regulator of cholesterol and lipid homeostasis. Niacinamide, at the high doses required to impact dyslipidemia, inhibits sirtuin enzymes (via the mechanism shown above in The Sirtuin Deacetylation Reaction flowchart).
Belenky et al. have suggested that reverse cholesterol transport might be more effectively induced by high-dose niacin (i.e., nicotinic acid given in the range of 2-6 grams) and resveratrol, since both increase sirtuin activity, causing post-translational protein modifications that alter expression of apolipoproteins, transporters, receptors and enzymes involved in lipid metabolism.27 However, nicotinamide riboside might be an even better partner for resveratrol since it increases the availability of NAD+ (and therefore sirtuin activity) without causing flushing.
Activation of the SIRT1 gene has been revealed as the mechanism through which caloric restriction, and certain xenohormetic compounds, e.g., resveratrol, work their longevity-enhancing metabolic magic. Increasing the cellular NAD+ : NAD(H) ratio has emerged as the mechanism through which the activity of the seven sirtuin enzymes encoded by SIRT1, all of which are NAD+-dependent deacetylases, is upregulated. Calorie restriction extends healthspan by increasing NAD+ availability, thus increasing sirtuin activity.
Read Part II: Resveratrol, Niacin, Nicotinamide Riboside: Key Players in Activating Sirtuins to Mimic Calorie Restriction & Extend Lifespan
- Maroon J. The Longevity Factor. Atria Books: NY, 2009. p.41. ↑
- Masoro EJ. Overview of caloric restriction and ageing. Mech Ageing Dev. 2005 Sep;126(9):913-22. ↑
- Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. ↑
- Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006 Jun;5(6):493-506. ↑
- Baur JA. Biochemical effects of SIRT1 activators. Biochim Biophys Acta. 2010 Aug;1804(8):1626-1634. ↑
- Allard JS, Perez E, Zou S, et al. Dietary activators of Sirt1. Mol Cell Endocrinol. 2009 Feb 5;299(1):58-63. ↑
- Jiang WJ. Sirtuins: novel targets for metabolic disease in drug development. Biochem Biophys Res Commun. 2008 Aug 29;373(3):341-4. ↑
- Maroon J. op.cit., pp.48-9.. ↑
- Chung S, Yao H, Caito S, et al. Regulation of SIRT1 in cellular functions: Role of polyphenols. Arch Biochem Biophys. 2010 May 5. [Epub ahead of print] . ↑
- Velcheti V, Govindan R. Insulin-like growth factor and lung cancer. J Thorac Oncol. 2006 Sep;1(7):607-10. ↑
- Alcaín FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat. 2009 Apr;19(4):403-14. ↑
- Smith JJ, Kenney RD, Gagne DJ, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol. 2009 Mar 10;3:31. ↑
- Bland J. Breaking the thought barrier: What role has nutrition been playing in our health? The xenohormesis connection. IMCJ. Vol. 6, No. 3 June/July 2007, pp. 22-24. ↑
- Howitz K, Sinclair D. Xenohormesis: sensing the chemical cues of other species. Cell. 2008 May 2;133(3):387-91. ↑
- Lamming DW, Wood JG, Sinclair DA. Small molecules that regulate lifespan: evidence for xenohormesis. Mol Microbiol. 2004 Aug;53(4):1003-9. ↑
- Ghanim H, Sia CL, Abuaysheh S, et al. An Antiinflammatory and Reactive Oxygen Species Suppressive Effects of an Extract of Polygonum Cuspidatum Containing Resveratrol. J Clin Endocrinol Metab. 2010 Jun 9. [Epub ahead of print] . ↑
- Noctor G. Metabolic signalling in defence and stress: the central roles of soluble redox couples. Plant Cell Environ. 2006 Mar;29(3):409-25. ↑
- Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95. ↑
- Lin SJ, Ford E, Haigis M, et al. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev. 2004 Jan 1;18(1):12-6. ↑
- Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr. 2008;28:115-30. ↑
- Lin SJ, Guarente L. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol. 2003 Apr;15(2):241-6. ↑
- Yi J, Luo J. SIRT1 and p53, effect on cancer, senescence and beyond. Biochim Biophys Acta. 2010 Aug;1804(8):1684-1689. ↑
- The World’s Healthiest Foods. ↑
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