SIRT1 and NAD as regulators of ageing Leopold Rehan, Krystyna Laszki-Szcząchor, Małgorzata Sobieszcza´nska, Dorota Polak-Jonkisz PII: DOI: Reference:
S0024-3205(14)00340-3 doi: 10.1016/j.lfs.2014.03.015 LFS 13967
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
31 October 2013 16 February 2014 10 March 2014
Please cite this article as: Rehan Leopold, Laszki-Szcz ąchor Krystyna, Sobieszcza´ nska Malgorzata, Polak-Jonkisz Dorota, SIRT1 and NAD as regulators of ageing, Life Sciences (2014), doi: 10.1016/j.lfs.2014.03.015
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ACCEPTED MANUSCRIPT Title: SIRT1 and NAD as regulators of ageing
Authors: a
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Rehan Leopold , Laszki-Szcząchor Krystyna , Sobieszczańska Małgorzata , Polak-Jonkisz Dorota Clinical Centre of Wroclaw Medical University, Wroclaw, Poland
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Department of Pathophysiology, Wroclaw Medical University, Poland
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Department of Paediatric Nephrology, Wroclaw Medical University, Poland
Contact author:
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Dr Dorota Polak-Jonkisz,
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Address: USK in Wroclaw, ul. Borowska 213, 50-556 Wrocław, Klinika Nefrologi Pediatrycznej (Department of Paediatric
Phone: +48 601 788 787
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e-mail: [email protected]
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Nephrology)
Abstract
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The recent research on ageing processes in mammals throws new light on the biochemistry of circadian clock. The already known regulatory pathways for biological rhythms and metabolism, combined with newly discovered
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functions of sirtuins, unveil a perspective for new hypotheses, regarding possible links between ageing and circadian rhythms. The NAD World hypothesis - postulated as a systemic regulatory network for the metabolism and ageing, linked
controlled
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with mammalian, NAD+ dependent Sirtuin 1 - conceptually involves two critical elements. One is the systemic, NamptNAD+
(Nicotinamide
phosphoribosyltransferase)
biosynthesis,
where
Nampt
(Nicotinamide
phosphoribosyltransferase) acts as “propulsion” for metabolism and the other is NAD+ dependent deacetylase (SIRT1) – a regulator responsible for various biological effects, depending on its localisation in organism. In this approach, the role of sirtuins, which are evolutionary conservative, NAD+ dependent histone deacetylases, may be very important for the mammalian metabolic clock. This paper is a review of current research on possible links among SIRT1 (Sirtuin 1), metabolism and ageing with particular consideration of the NAD World hypothesis.
Key words: NAD World, SIRT1, sirtuins, Nampt, NAD+, circadian rhythm, ageing, central metabolic clock.
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Abbreviations: SIRT 1 – Sirtuin 1, SCN - hypothalamic suprachiasmatic nucleus, PBEF - Nicotinamide phosphoribosyltransferase gene,
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CLOCK - Circadian Locomotor Output Cycles Kaput gene, CLOCK - Circadian Locomotor Output Cycles Kaput gene, PER2 - Period circadian protein homolog 2 gene, PER2 - Period circadian protein homolog 2, PGC-1α (Peroxisome proliferator-activated receptor γ coactivator 1- α, PPARγ - Peroxisome proliferator-activated receptor γ, Nampt Nicotinamide phosphoribosyltransferase, NMN - Nicotinamide mononucleotide, Nmnat - Nicotinamide mononucleotide
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adenylyltransferase, UCP2 – Uncoupling Protein 2 gene, UCP2 – Uncoupling Protein 2, CRH – Cortictropin Releasing
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Hormone, ACTH – Adrenocorticotropic Hormone, GSIS – Glucose Stimulated Insulin Secretion, CR – Calorie Restriction.
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Introduction
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Although numerous, evolutionary conservative regulators for metabolic cycles and their signalling pathways have already been described for lower organisms, like yeasts, worms or flies, the understanding of their role in mammals is still inadequate. Also the mutual correlations between ageing and circadian rhythms seem to be insufficiently represented in current research. Taking all this into consideration, we have attempted to throw more light on the role of SIRT1 (Sirtuin 1) in ageing, metabolism and circadian rhythmicity, with particular consideration of the NAD World hypothesis.
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The properties of sirtuins, evolutionary conservative, NAD(+)-dependent histone deacetylases (HDAC), are interesting and vividly debated. Sirtuins 1-7 (SIRT1-7) are the mammalian homologues of yeast Sir2 (silent information
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regulator 2), a protein, thought to be, at least partially, responsible for the life-prolonging effects of calorie restriction (CR) in yeasts. CR effects have also been observed in C. elegans, Drosophila Melanogaster and Mus Musculus (Raynes R et al. 2012) [1]. Although many studies suggest Sir2 to be the main factor in CR effects, it has recently been opposed for
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insufficient experimental verification and by some new, contradictory observations. According to Kaeberlein et al. 2004, the tests for CR effects in yeasts were, in general, conducted on different strains than tests for the link between Sir2 and
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longevity in yeasts. Furthermore, the authors have provided evidence that Sir2 is not independently responsible for the CR effects on ageing. In their experiments, the effects of CR and Sir2-overexpression on yeast lifespan proved to be
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complementary, what may indicate that Sir2-overexpression may not be the only lifespan extending mechanism of CR. In other experiments, they have demonstrated that, contrary to previous observations, Sir2 is not necessary for the lifespan
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prolonging effects of CR. Other controversies, indicated by Kaeberlein et al. 2004, include Sir2 activation by CR in vivo, as well as the exact mechanism of lifespan prolongation by CR in respiratory deficient mutants (that observation contradicts the previously identified links between NADH, NAD+ and Sir2 levels). Finally, they point to the rather uncertain role of Sir2 homologues in CR effects [2, 3]. Despite those controversies, a new research by Raynes R et al. 2012 has shown that Sir2 is specifically necessary for CR effects, as well as for the synergistic effects of CR and heat shock in C. elegans [1]. Whitaker R et al. 2013 have helped us understand the conflicting reports on Sir2 effects in Drosophila melanogaster. They have shown the effects of Sir2 overexpression to be dose-dependent, where medium levels of Sir2 act for lifespan extension, while its higher levels induce cellular toxicity [4]. All mammalian sirtuins (SIRT1-7) belong to Class III histone deacetylases and require NAD+ as cofactor. Since their substrates vary from histones to transcription regulators, sirtuins may play a fairly important role in a number of biological processes, like cell apoptosis, muscle and adipose cell differentiation, chromatin condensation, metabolism, etc. (Dali-Youcef N et al. 2007) [5]. Some recent reports have mentioned the issue of sirtuins functions in mammals (Haigis MC and Sinclair DA 2010; Imai S and Guarente L 2010; Chang HC and Guarente L 2013) [6, 7, 8].
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ACCEPTED MANUSCRIPT Possible associations between sirtuin enzymatic activity and ageing/longevity in mammals are still one of the open questions, which may only be answered via consequent research. The network of metabolic links in mammals is a very complex system. Imai has proposed clarification of the mechanisms in suitable answers to the following three basic questions: 1. Which tissues or organs play a dominant role in mammalian age-regulating network, assuming its
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hierarchical framework? 2. If such “age controlling centres” exist, certain hormones/humoral factors may communicate those centres with other tissues/organs. These centres may control the ageing rate on systemic level via factors, the identification of which may be of primary significance. 3. Are there any universal, molecular regulators, responsible for the production and secretion of the above-mentioned humoral factors? Imais’s hypothesis of NAD World is an attempt to resolve those questions in some plausible way (Imai S 2009a) [9].
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NAD World hypothesis
Shin-ichiro Imai, backed up by his research (the results of which were published in 2009 in a broad report),
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proposed a concept of systemic regulatory network for mammalian metabolism - NAD World (Imai S 2009a,b) [9,10]. In this theoretical model, NAD+ biosynthesis, controlled by Nampt availability (as a limiting enzyme), is a tissue metabolism-driving factor (by intra- and extracellular NMN biosynthesis) and SIRT1 plays the role of systemic mediator
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that initiates metabolic effects in various tissues (in response to changes in systemic NAD+ biosynthesis). According to NAD World hypothesis, the regulatory network controls metabolism on systemic level by synchronising the responses of
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various tissues to external stimuli (such as nutrition availability, environmental factors, etc.) [9]. In the proposed regulatory system of NAD World, Shin-ichiro Imai singles out tissues, which depend on
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external (systemic) synthesis of NMN as critical points. Shin-ichiro Imai, citing Revollo JR et al. 2007 [11], emphasises pancreatic β-cells and neurones to be such critical tissues in mammals, their significance being even higher, due to the
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regulatory role of these tissues in the organism. In case of decreased systemic NMN production (and thus, NAD+ biosynthesis), the critical tissues would react first with decreased SIRT1 activity and consequent metabolic modifications and, at later stages, would cause changes in other tissues/organs. According to the studies of Revollo JR et al. 2007 [11], a decrease in the systemic NAD+ biosynthesis results in reduced insulin secretion in pancreatic β-cells and impaired glucose tolerance. The authors also comment on the fact that one of vitamin B 3 deficiency symptoms is dementia, what may suggest that a decrease in the systemic NAD+ biosynthesis may cause functional changes in neurones. Imai answers the key (in his opinion) questions that illustrate the links between the systemic metabolic control and ageing processes in mammals. He postulates pancreatic β-cells and neurones as tissues essential for the systemic control of ageing, due to their dependency on systemic NMN supplies (and, consequently, on systemic NAD+ biosynthesis). A complex network of metabolic interactions between those tissues and other systemic organs in mammals makes it impossible to rule out a plausible role of other tissues in the control of ageing processes. NMN, being a product of circulatory eNampt, is considered to be a systemic humoral factor, synchronising the ageing clock in various
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ACCEPTED MANUSCRIPT tissues across the whole body. Due to the fact that adipose tissue seems to be the main source of circulatory eNampt, the existence of an adipose tissue-pancreatic β-cells-neurones feedback loop mechanism is possible. In the NAD World theory, the role of a universal, molecular regulator for the synthesis and secretion of the above-mentioned humoral
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factors is assigned to SIRT1 but a possible role of other mammalian sirtuins is not excluded, either (Imai S 2009a) [9]. Circadian oscillations of iNampt–dependent NAD+ biosynthesis - demonstrated by Ramsey KM et al. 2009 and Nakahata Y et al. in 2009, do not mean that NMN and eNampt levels exert same effects [12, 13]. Proving that circadian rhythmicity of the systemic NMN production depends on eNampt would be an essential argument, providing evidence for the hypothesis that links the circadian clock with ageing processes.
NMN levels, oscillating in the circadian manner and influencing NAD+ biosynthesis in critical tissues (and,
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consequently, affecting SIRT1 activity in those tissues) would be the final confirmation of the assumed correlations between the central clock mechanism and ageing process (because low levels of iNampt in these tissues may be
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insufficient for any effective control of SIRT1 activity, therefore iNampt circadian oscillation is not enough). If proven, eNampt and NMN oscillation would be the key elements of systemic synchronisation between NAD+ biosynthesis (with its circadian rhythmicity) and SIRT1 activity (Imai S 2010) [14].
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An important concern about the NAD World hypothesis is the lack of evidence for extracellular NMN synthesis and of studies which would show the effective function of Nampt as an extracellular catalyst of NMN biosynthesis in the
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absence of ATP, as mentioned later in the text. It would be beneficial to establish the sources of extracellular NMN, other than blood plasma biosynthesis, or prove sufficient efficiency of eNampt in blood plasma.
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A recent research of Ramsey et al. 2008 indicates the systemic NAD+ biosynthesis to be decreasing with age [15]. Its effects would first be perceived in critical tissues and the consequential functional changes in those tissues (as a
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result of dwindling SIRT1 activity) would result in deteriorating general efficiency at systemic level. This is why, according to Imai S., the tissues, primary to the NAD+ dependent regulatory networks of the circadian machinery, may be considered as “the ageing clock” [14]. Fig. 1 shows proposed connections between various elements of “NAD World”.
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Section C - SIRT1 functions
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Biological/circadian rhythms
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Fig. 1 (SIRT1, NAD+ and biological rhythms) Section A - central and peripheral biological clocks, Section B - NAD+ biosynthesis,
Biological rhythms (circadian - 24-hour, ultradian - > 24 h and infradian - < 24h) are observed in many organisms as oscillations in biological processes (the sleep/wake cycle, the cycles of hormonal activity, cyclic changes of
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body temperature, feeding behaviour, liver and kidney functions, etc.) (Sukumaran S et al. 2010) [16]. In 1973, Arthur Everitt was the first to have postulated the existence of a “metabolic clock”. He speculated that one or many such clocks might exist in the hypothalamus and also tried to integrate that idea with the hypothalamic/neuroendocrine theory of ageing, proposed by Vladimir Dilman in 1971 (ageing as “a process of disordered homeostatic stability of internal
environment”). The subsequent years of research and observations have proven that, in mammals, an internal clock controls biological rhythms, with its central component located in the hypothalamic suprachiasmatic nucleus (SCN) (Buijs RM et al. 1996; Van Esseveldt KE et al. 2000; Panda S et al. 2002) [17, 18, 19]. Light retinal stimuli activate the machinery of the central biological clock, synchronising it with the night/day rhythmicity (Griffett K and Burris TP 2013) [20]. The hypothalamic central clock synchronises energy balance, sympathetic outflow and the neuroendocrine system via the hypothalamus. For example, food anticipatory activity (increased activity even when food is provided in incorrect circadian phase) was linked with the dorsal medial hypothalamic area, proven to be the target for a large output from
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ACCEPTED MANUSCRIPT SCN. Another region with proven central clock association is the lateral hypothalamic area (with orexin expressing neurons – where orexin is responsible for the stimulation of arousal and energy expenditure) (Bass J 2012) [21]. The SCN additionally exerts its influence via peripheral clocks, located all over the body. These peripheral oscillators, responsible for various activities, have been investigated, as well as their links with the central clock. Since
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the discovery of clock genes, an ongoing research has proven that almost every tissue may demonstrate internal oscillation (when studied in isolation). These oscillations are subject to a central control, when studied in vivo. Although internal tissue oscillations result directly from the activity of peripheral clocks, the central control is necessary to maintain harmony at systemic level. Research results have shown various ways by which the central clock interacts with those peripheral oscillators via a complex network of feedback loops. This network comprises, at least, four levels: neural (by
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the autonomic nervous system), hormonal, body temperature and local signalling. Some control of peripheral clocks by the autonomic nervous system has, for example, been suggested in the liver (the rhythmicity of gluconeogenesis). Most of the research on hormonal interactions with circadian rhythmicity has been concentrated on glucocorticoids (the
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rhythmical secretion of glucocorticoids is thought to result from sympathetic control and as an effect of the corticotropin releasing hormone). Experiments have demonstrated that dexamethasone could influence the rhythms of peripheral
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tissues “in vivo”, thus suggesting that glucocorticoids may control signals for peripheral oscillators. Body temperature, controlled by the central clock, influences peripheral oscillators, providing an important synchronising mechanism. The
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central clock does not only control behaviour but it can also influence peripheral oscillators through local factors, such as feeding. The liver clock has been shown to be particularly sensitive to reset from changes in feeding rhythms (Mohawk
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JA et al. 2012) [22]. External factors may exert some influence over peripheral clocks, while leaving the central rhythmicity unaffected. For example, changing feeding hours to incorrect circadian hours alters the peripheral clock in the
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liver only, without any effect on the central clock, but findings about biochemical regulation of the clock in the liver (for example: glucocorticoid signalling, transcriptional control of heat-shock factor protein 1, ADP-ribosylation) suggest a multi-layer regulation, reinforcing the central clock regulation of the liver (SCN restrains the hormonal response to feeding) (Bass J. 2012) [21]. Fig. 1 section A presents interactions between central and peripheral clocks.
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Fig. 1 section A (Central and peripheral biological clocks) – the central clock, located in SCN, is synchronised with day-night rhythm through light stimuli of the retina. The central clock influences other parts of the hypothalamus (Lateral Hypothalamic Area, Dorsal Medial Hypothalamic Area) and the, so-called, peripheral clocks, located throughout the body (for example: liver, muscles, adipocytes,
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pancreas), while being also subject of their (reverse) control.
Both the amplitude and phase of circadian rhythms vary and are age-dependent. A relationship has then been
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proposed between age-related pathologies and disorders of metabolic oscillators (Imai S 2009a) [9]. SIRT1 as a circadian rhythm regulator at cellular level
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Research reports, published in 2000, showed SIRT1 activity as NAD(+)-dependent deacetylase (Imai S et al. 2000a; Landry J et al. 2000; Smith JS et al. 2000) [23, 24, 25]. This dependency of SIRT1 activity on cellular NAD+ levels (i.e. cellular energetic state) has made some authors proclaim SIRT1 to be a cellular energy detector, which links cellular energetic metabolism with epigenetic transcription control and, further, with ageing (Imai S 2009b; Imai S et al. 2000b) [10, 26]. While controlling energetic metabolism, SIRT1 can mediate the longevity-promoting effects of CR. Rodgers J. T. et al. 2005 established that CR effects on gluconeogenesis and glycolysis in the liver were exerted via SIRT1, which affected the function of peroxisome proliferator-activated receptor coactivator-1α (PGC-1α). SIRT1 deacetylates PGC-1α, thus inducing its function as a promoter of gluconeogenic and as an inhibitor of glycolytic genes in hepatic tissue (increasing glucose output in the liver) [27]. A similar process occurs in skeletal muscles, where, in states of nutrient deprivation, metabolism changes from glucose to fatty acid oxidation. Experiments have proven that SIRT1 deacetylates PGC-1α, which is required to activate genes responsible for fatty acid oxidation (Gerhart-Hines Z et al. 2007) [28]. CR mobilises fat in white adipocytes in mammals and Picard F et al. have proven an important role of SIRT1 in this process.
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ACCEPTED MANUSCRIPT In conditions of undernourishment, SIRT1 represses the Peroxisome proliferator-activated receptor γ (PPAR γ), binding with its cofactors, thus stimulating the mobilisation of fatty acids and impairing adipogenesis in white adipocytes [29]. Research on BESTO mice have proven that increased levels of SIRT1 in pancreatic β cells are linked with improved
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glucose tolerance and enhanced GSIS (glucose stimulated insulin secretion). It is thought that SIRT1 activity is enacted through the control of genes responsible for insulin secretion, such as UCP2 (Uncoupling protein-2). SIRT1 inhibits its translation and increases ATP levels in β cells. Consequently, BESTO pancreatic β cells show an increased insulin secretion in response to glucose and KCl (Moynihan KA et al. 2005) [30]. Fig. 1 section C presents various biological
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activities of SIRT1.
Fig. 1 section C (SIRT1 functions) - NAD+ is essential for SIRT1 deacetylase activity, SIRT1 influences tissues through its activity as deacetylase, exerting various effects (increase in fatty acids oxidation, GSIS, glucose tolerance, etc.), which in turn have influence over whole organism.
According to Cohen HY et al., chronic CR leads to increased cellular SIRT1 levels. They have stated that this SIRT1 increasing effect of CR is an evolutionary ancient mechanism of biological response to stress which delays ageing by improving the long-term functions and longevity of cells in critical tissues [31]. New observations may indicate that CR effects on SIRT1 levels are not as straightforward and might be species- or tissue-specific. For example, in studies by Chen D et al., CR proved to increase SIRT1 levels in muscle and white adipose tissue, while decreasing SIRT1 levels in murine livers. The authors suggested that the above-mentioned difference might be a direct result of a unique metabolic function of the liver - metabolism in the liver is accelerated after higher calorie intake [32].
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ACCEPTED MANUSCRIPT Although the majority of studies have focused on SIRT1 properties, new study projects emphasise the role of other sirtuins as well. A recent evaluation of the CR impact on longevity also suggests some role of SIRT3. SIRT3 was identified to be responsible for mitochondrial protein acetylation in response to CR (Hebert AS et al. 2013) [33]. Also other studies showed a reduced protective effect of CR on oxidative stress in genetically modified SIRT3-KO mice (Qiu X
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et al. 2010) [34]. Those findings suggest a probable role of other sirtuins in the beneficial effects of CR, thus demanding further investigations.
The functions of SIRT1 in circadian regulation and its integration with cellular metabolism have already been studied for many years. It is thought that SIRT1 is essential in the transcription of key genes, responsible for the mammalian circadian clock (as BMAL1 - Aryl hydrocarbon receptor nuclear translocator-like gene, PER2 - Period circadian protein homolog 2 gene, CRY1 -Cryptochrome 1 gene). SIRT1 relates the translation of their protein products
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(CLOCK - basic helix-loop-helix-PAS transcription factor, and BMAL1) to circadian rhythmicity and deacetylates the period circadian protein homolog 2 (PER2) (inducing its degradation). Asher G et al. and Nakahata Y et al. claim that,
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due to SIRT1 deacetylase activity dependence on NAD+, SIRT1 binds cellular metabolism with the central circadian clock machinery [35, 36]. Further studies by Chang HC and Guarente L proved an essential role of SIRT1 in the central circadian clock control, binding to the BMAL1 promoter (thus stimulating transcription) in murine brain. Their research
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showed that SIRT1 levels (also BMAL1 and PER2 levels) in SCN significantly decreased in aged mice (leading to abnormalities in activity patterns and impairing their adaptability to changes in light entrainment schedule). Furthermore,
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young mice with lacking SIRT1 expression in the brain present similar abnormalities, while aged mice with SIRT1 overexpression seem to be protected from ageing effects on circadian rhythmicity [8].
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Circadian oscillation of NAD+ and Nampt levels and its role as systemic regulators for SIRT1 Organisms synthesise NAD+ from three precursors: tryptophan, nicotinic acid and nicotinamide (Nam, one of
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the forms of vitamin B3) but, according Revollo JR et al. only the Nam pathway is significant in mammals. Nampt (Nicotinamide phosphoribosyltransferase) is the key element of NAD+ biosynthesis, which, in presence of ATP, catalyses the synthesis of NMN (Nicotinamide mononucleotide) from Nam. Next, Nmnat (Nicotinamide mononucleotide adenylyltransferase) converts NMN into NAD+. In mammals, two forms of Nampt exist: intracellular - iNampt and extracellular - eNampt. The only enzymatic function of iNampt seems to be NAD+ biosynthesis, while eNampt, being a more active catalyst of NAD+ biosynthesis, has also cytokine-like functions [37]. The cellular NAD+ levels and SIRT1 activity are controlled by iNampt availability. This correlation and its biological effects (given in brackets) were observed “in vitro” in mouse fibroblast cultures (changes in gene expression), human vascular smooth muscle cells (cell maturation and longevity) and rat cardiac myocytes (protection against cell death) (Revollo JR et al. 2004; Imai S 2009b) [37, 10]. It has been shown that iNampt expression is also induced by cellular stress and nutritional deficiency. It has been determined that, although induced iNampt does not prevent cellular NAD+ levels from decreasing, it does preserve its mitochondrial supplies, thus activating mitochondrial sirtuins (SIRT3 and 4) that protect from cell death (Yang H et al. 2007) [38].
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ACCEPTED MANUSCRIPT The importance of NAD+ biosynthesis for glucose-induced insulin secretion from pancreatic β-cells is a deeply studied issue. The pancreas has lower cellular levels of iNampt than other tissues, thus being dependent on extracellular NMN sources for NAD+ biosynthesis. This dependency explains why eNampt activity in blood serum (which should maintain high circulatory levels of NMN and its supplies appropriate to pancreatic needs) may be the key factor to
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preserve the normal functions of β-cells. The brain is another organ with low levels of iNampt (particularly neurones). The adipose tissue may play an important role in the metabolic regulation of tissues with scant iNampt supplies (mature adipocytes synthesise and secrete eNampt to bloodstream) (Imai S 2009a; Ramsey KM et al. 2009) [9, 12]. Fig. 1
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section B portrays NAD+ biosynthesis.
Fig. 1 section B (NAD+ biosynthesis) - NAD+ biosynthesis oscillates after the rhythmic changes in PBEF gene expression, regulated by central clock genes (CLOCK:BMAL1, PER2, etc.). Extracellular NMN biosynthesis provides the source of NMN in tissues with low levels of Nampt, therefore allowing for NAD+ biosynthesis.
Banerjee KK et al. have shown a fascinating mechanism in which Sir2, synthesised in Drosophila melanogaster fat tissue, exerted some effects in muscle cells, proving the the role of body fat in Drosophila as a central regulator of metabolic network and energy homeostasis [39]. Hara N et al. demonstrated possible flaws in the hypothesis of extracellular NMN synthesis. In collected murine blood serum, only small amounts of ATP were assayed and, consequently, no effective NMN biosynthesis was possible because Nampt requires ATP for its catalytic function. Further experiments with blood serum, incubated with various concentrations of Nampt, showed no biosynthesis of NMN; NMN production was observed only after ATP supplementation. Those results make it unlikely that effective NMM biosynthesis is possible in blood circulation [40].
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ACCEPTED MANUSCRIPT Other researchers claim that Nampt catalytic functions are not dependent on the presence of ATP (which, nevertheless, increases NMN biosynthesis rate 35 times). (Burgos ES and Schramm VL 2008) [41]. In 2009, Ramsey KM et al. and Nakahata Y et al. simultaneously published their results, proving circadian oscillation of NAD+ and Nampt levels, controlled by the central clock machinery (Ramsey KM et al. 2009; Nakahata Y et
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al. 2009) [12,13]. The circadian clock genes - CLOCK:BMAL1 – cause the circadian oscillation of PBEF (Nicotinamide phosphoribosyltransferase gene) expression (i. e. Nampt synthesis). Nampt, as a limiting enzyme in NAD+ biosynthesis, leads, in its turn, to a circadian rhythm of NAD+ oscillation. A biochemical network of feedback loops is formed, with NAD+ acting as a metabolic oscillator and reflective regulator of circadian clock. (Imai S 2010) [14]. Implications and future perspectives
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The latest research in association with the NAD World Hypothesis finally seems to provide convincing evidence for biochemical links among metabolism, biological rhythmicity and ageing in mammals. Further studies are
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necessary to confirm circadian oscillations of the systemic NAD+ biosynthesis and various biochemical effects of NAD+, SIRT1 in neurones and other tissues critical for NAD+ oscillation. Also the functions of sirtuins, other than SIRT1, require further investigation. The results, which may be obtained in the future, either in primary or in secondary research
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goals, may help answer questions, regarding the biochemistry of and genetic background behind ageing processes and degenerative changes at systemic, organ and tissue levels. One need not say that these answers, although obtained at
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from the clinical perspective.
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the level of pure science, may open a window into better understanding of human ageing and degenerative changes also
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de Cabo R, Sauve AA, Sinclair DA. Nutrient-sensitive mitochondrial NAD(+) levels dictate cell survival. Cell. 2007 Sep 21;130(6):1095-107. [39] Banerjee KK, Ayyub C, Sengupta S, Kolthur-Seetharam U. Fat body dSir2 regulates muscle mitochondrial physiology and energy homeostasis nonautonomously and mimics the autonomous functions of dSir2 in muscles. Mol Cell Biol. 2013 Jan;33(2):252-64. [40] Hara N, Yamada K, Shibata T, Osago H, Tsuchiya M. Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS One 2011; 6(8):e22781. doi: 10.1371/journal.pone.0022781. [41] Burgos ES and Schramm VL. Weak Coupling of ATP Hydrolysis to the Chemical Equilibrium of Human Nicotinamide Phosphoribosyltransferase. Biochemistry 2008; 47(42): 11086–11096
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Graphical Abstract
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S0024-3205(14)00340-3 doi: 10.1016/j.lfs.2014.03.015 LFS 13967
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
31 October 2013 16 February 2014 10 March 2014
Please cite this article as: Rehan Leopold, Laszki-Szcz ąchor Krystyna, Sobieszcza´ nska Malgorzata, Polak-Jonkisz Dorota, SIRT1 and NAD as regulators of ageing, Life Sciences (2014), doi: 10.1016/j.lfs.2014.03.015
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ACCEPTED MANUSCRIPT Title: SIRT1 and NAD as regulators of ageing
Authors: a
b
b
Rehan Leopold , Laszki-Szcząchor Krystyna , Sobieszczańska Małgorzata , Polak-Jonkisz Dorota Clinical Centre of Wroclaw Medical University, Wroclaw, Poland
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Department of Pathophysiology, Wroclaw Medical University, Poland
c
Department of Paediatric Nephrology, Wroclaw Medical University, Poland
Contact author:
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Dr Dorota Polak-Jonkisz,
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a
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Address: USK in Wroclaw, ul. Borowska 213, 50-556 Wrocław, Klinika Nefrologi Pediatrycznej (Department of Paediatric
Phone: +48 601 788 787
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e-mail: [email protected]
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Nephrology)
Abstract
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The recent research on ageing processes in mammals throws new light on the biochemistry of circadian clock. The already known regulatory pathways for biological rhythms and metabolism, combined with newly discovered
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functions of sirtuins, unveil a perspective for new hypotheses, regarding possible links between ageing and circadian rhythms. The NAD World hypothesis - postulated as a systemic regulatory network for the metabolism and ageing, linked
controlled
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with mammalian, NAD+ dependent Sirtuin 1 - conceptually involves two critical elements. One is the systemic, NamptNAD+
(Nicotinamide
phosphoribosyltransferase)
biosynthesis,
where
Nampt
(Nicotinamide
phosphoribosyltransferase) acts as “propulsion” for metabolism and the other is NAD+ dependent deacetylase (SIRT1) – a regulator responsible for various biological effects, depending on its localisation in organism. In this approach, the role of sirtuins, which are evolutionary conservative, NAD+ dependent histone deacetylases, may be very important for the mammalian metabolic clock. This paper is a review of current research on possible links among SIRT1 (Sirtuin 1), metabolism and ageing with particular consideration of the NAD World hypothesis.
Key words: NAD World, SIRT1, sirtuins, Nampt, NAD+, circadian rhythm, ageing, central metabolic clock.
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Abbreviations: SIRT 1 – Sirtuin 1, SCN - hypothalamic suprachiasmatic nucleus, PBEF - Nicotinamide phosphoribosyltransferase gene,
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CLOCK - Circadian Locomotor Output Cycles Kaput gene, CLOCK - Circadian Locomotor Output Cycles Kaput gene, PER2 - Period circadian protein homolog 2 gene, PER2 - Period circadian protein homolog 2, PGC-1α (Peroxisome proliferator-activated receptor γ coactivator 1- α, PPARγ - Peroxisome proliferator-activated receptor γ, Nampt Nicotinamide phosphoribosyltransferase, NMN - Nicotinamide mononucleotide, Nmnat - Nicotinamide mononucleotide
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adenylyltransferase, UCP2 – Uncoupling Protein 2 gene, UCP2 – Uncoupling Protein 2, CRH – Cortictropin Releasing
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Hormone, ACTH – Adrenocorticotropic Hormone, GSIS – Glucose Stimulated Insulin Secretion, CR – Calorie Restriction.
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Introduction
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Although numerous, evolutionary conservative regulators for metabolic cycles and their signalling pathways have already been described for lower organisms, like yeasts, worms or flies, the understanding of their role in mammals is still inadequate. Also the mutual correlations between ageing and circadian rhythms seem to be insufficiently represented in current research. Taking all this into consideration, we have attempted to throw more light on the role of SIRT1 (Sirtuin 1) in ageing, metabolism and circadian rhythmicity, with particular consideration of the NAD World hypothesis.
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The properties of sirtuins, evolutionary conservative, NAD(+)-dependent histone deacetylases (HDAC), are interesting and vividly debated. Sirtuins 1-7 (SIRT1-7) are the mammalian homologues of yeast Sir2 (silent information
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regulator 2), a protein, thought to be, at least partially, responsible for the life-prolonging effects of calorie restriction (CR) in yeasts. CR effects have also been observed in C. elegans, Drosophila Melanogaster and Mus Musculus (Raynes R et al. 2012) [1]. Although many studies suggest Sir2 to be the main factor in CR effects, it has recently been opposed for
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insufficient experimental verification and by some new, contradictory observations. According to Kaeberlein et al. 2004, the tests for CR effects in yeasts were, in general, conducted on different strains than tests for the link between Sir2 and
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longevity in yeasts. Furthermore, the authors have provided evidence that Sir2 is not independently responsible for the CR effects on ageing. In their experiments, the effects of CR and Sir2-overexpression on yeast lifespan proved to be
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complementary, what may indicate that Sir2-overexpression may not be the only lifespan extending mechanism of CR. In other experiments, they have demonstrated that, contrary to previous observations, Sir2 is not necessary for the lifespan
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prolonging effects of CR. Other controversies, indicated by Kaeberlein et al. 2004, include Sir2 activation by CR in vivo, as well as the exact mechanism of lifespan prolongation by CR in respiratory deficient mutants (that observation contradicts the previously identified links between NADH, NAD+ and Sir2 levels). Finally, they point to the rather uncertain role of Sir2 homologues in CR effects [2, 3]. Despite those controversies, a new research by Raynes R et al. 2012 has shown that Sir2 is specifically necessary for CR effects, as well as for the synergistic effects of CR and heat shock in C. elegans [1]. Whitaker R et al. 2013 have helped us understand the conflicting reports on Sir2 effects in Drosophila melanogaster. They have shown the effects of Sir2 overexpression to be dose-dependent, where medium levels of Sir2 act for lifespan extension, while its higher levels induce cellular toxicity [4]. All mammalian sirtuins (SIRT1-7) belong to Class III histone deacetylases and require NAD+ as cofactor. Since their substrates vary from histones to transcription regulators, sirtuins may play a fairly important role in a number of biological processes, like cell apoptosis, muscle and adipose cell differentiation, chromatin condensation, metabolism, etc. (Dali-Youcef N et al. 2007) [5]. Some recent reports have mentioned the issue of sirtuins functions in mammals (Haigis MC and Sinclair DA 2010; Imai S and Guarente L 2010; Chang HC and Guarente L 2013) [6, 7, 8].
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ACCEPTED MANUSCRIPT Possible associations between sirtuin enzymatic activity and ageing/longevity in mammals are still one of the open questions, which may only be answered via consequent research. The network of metabolic links in mammals is a very complex system. Imai has proposed clarification of the mechanisms in suitable answers to the following three basic questions: 1. Which tissues or organs play a dominant role in mammalian age-regulating network, assuming its
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hierarchical framework? 2. If such “age controlling centres” exist, certain hormones/humoral factors may communicate those centres with other tissues/organs. These centres may control the ageing rate on systemic level via factors, the identification of which may be of primary significance. 3. Are there any universal, molecular regulators, responsible for the production and secretion of the above-mentioned humoral factors? Imais’s hypothesis of NAD World is an attempt to resolve those questions in some plausible way (Imai S 2009a) [9].
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NAD World hypothesis
Shin-ichiro Imai, backed up by his research (the results of which were published in 2009 in a broad report),
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proposed a concept of systemic regulatory network for mammalian metabolism - NAD World (Imai S 2009a,b) [9,10]. In this theoretical model, NAD+ biosynthesis, controlled by Nampt availability (as a limiting enzyme), is a tissue metabolism-driving factor (by intra- and extracellular NMN biosynthesis) and SIRT1 plays the role of systemic mediator
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that initiates metabolic effects in various tissues (in response to changes in systemic NAD+ biosynthesis). According to NAD World hypothesis, the regulatory network controls metabolism on systemic level by synchronising the responses of
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various tissues to external stimuli (such as nutrition availability, environmental factors, etc.) [9]. In the proposed regulatory system of NAD World, Shin-ichiro Imai singles out tissues, which depend on
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external (systemic) synthesis of NMN as critical points. Shin-ichiro Imai, citing Revollo JR et al. 2007 [11], emphasises pancreatic β-cells and neurones to be such critical tissues in mammals, their significance being even higher, due to the
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regulatory role of these tissues in the organism. In case of decreased systemic NMN production (and thus, NAD+ biosynthesis), the critical tissues would react first with decreased SIRT1 activity and consequent metabolic modifications and, at later stages, would cause changes in other tissues/organs. According to the studies of Revollo JR et al. 2007 [11], a decrease in the systemic NAD+ biosynthesis results in reduced insulin secretion in pancreatic β-cells and impaired glucose tolerance. The authors also comment on the fact that one of vitamin B 3 deficiency symptoms is dementia, what may suggest that a decrease in the systemic NAD+ biosynthesis may cause functional changes in neurones. Imai answers the key (in his opinion) questions that illustrate the links between the systemic metabolic control and ageing processes in mammals. He postulates pancreatic β-cells and neurones as tissues essential for the systemic control of ageing, due to their dependency on systemic NMN supplies (and, consequently, on systemic NAD+ biosynthesis). A complex network of metabolic interactions between those tissues and other systemic organs in mammals makes it impossible to rule out a plausible role of other tissues in the control of ageing processes. NMN, being a product of circulatory eNampt, is considered to be a systemic humoral factor, synchronising the ageing clock in various
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ACCEPTED MANUSCRIPT tissues across the whole body. Due to the fact that adipose tissue seems to be the main source of circulatory eNampt, the existence of an adipose tissue-pancreatic β-cells-neurones feedback loop mechanism is possible. In the NAD World theory, the role of a universal, molecular regulator for the synthesis and secretion of the above-mentioned humoral
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factors is assigned to SIRT1 but a possible role of other mammalian sirtuins is not excluded, either (Imai S 2009a) [9]. Circadian oscillations of iNampt–dependent NAD+ biosynthesis - demonstrated by Ramsey KM et al. 2009 and Nakahata Y et al. in 2009, do not mean that NMN and eNampt levels exert same effects [12, 13]. Proving that circadian rhythmicity of the systemic NMN production depends on eNampt would be an essential argument, providing evidence for the hypothesis that links the circadian clock with ageing processes.
NMN levels, oscillating in the circadian manner and influencing NAD+ biosynthesis in critical tissues (and,
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consequently, affecting SIRT1 activity in those tissues) would be the final confirmation of the assumed correlations between the central clock mechanism and ageing process (because low levels of iNampt in these tissues may be
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insufficient for any effective control of SIRT1 activity, therefore iNampt circadian oscillation is not enough). If proven, eNampt and NMN oscillation would be the key elements of systemic synchronisation between NAD+ biosynthesis (with its circadian rhythmicity) and SIRT1 activity (Imai S 2010) [14].
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An important concern about the NAD World hypothesis is the lack of evidence for extracellular NMN synthesis and of studies which would show the effective function of Nampt as an extracellular catalyst of NMN biosynthesis in the
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absence of ATP, as mentioned later in the text. It would be beneficial to establish the sources of extracellular NMN, other than blood plasma biosynthesis, or prove sufficient efficiency of eNampt in blood plasma.
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A recent research of Ramsey et al. 2008 indicates the systemic NAD+ biosynthesis to be decreasing with age [15]. Its effects would first be perceived in critical tissues and the consequential functional changes in those tissues (as a
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result of dwindling SIRT1 activity) would result in deteriorating general efficiency at systemic level. This is why, according to Imai S., the tissues, primary to the NAD+ dependent regulatory networks of the circadian machinery, may be considered as “the ageing clock” [14]. Fig. 1 shows proposed connections between various elements of “NAD World”.
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Section C - SIRT1 functions
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Biological/circadian rhythms
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Fig. 1 (SIRT1, NAD+ and biological rhythms) Section A - central and peripheral biological clocks, Section B - NAD+ biosynthesis,
Biological rhythms (circadian - 24-hour, ultradian - > 24 h and infradian - < 24h) are observed in many organisms as oscillations in biological processes (the sleep/wake cycle, the cycles of hormonal activity, cyclic changes of
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body temperature, feeding behaviour, liver and kidney functions, etc.) (Sukumaran S et al. 2010) [16]. In 1973, Arthur Everitt was the first to have postulated the existence of a “metabolic clock”. He speculated that one or many such clocks might exist in the hypothalamus and also tried to integrate that idea with the hypothalamic/neuroendocrine theory of ageing, proposed by Vladimir Dilman in 1971 (ageing as “a process of disordered homeostatic stability of internal
environment”). The subsequent years of research and observations have proven that, in mammals, an internal clock controls biological rhythms, with its central component located in the hypothalamic suprachiasmatic nucleus (SCN) (Buijs RM et al. 1996; Van Esseveldt KE et al. 2000; Panda S et al. 2002) [17, 18, 19]. Light retinal stimuli activate the machinery of the central biological clock, synchronising it with the night/day rhythmicity (Griffett K and Burris TP 2013) [20]. The hypothalamic central clock synchronises energy balance, sympathetic outflow and the neuroendocrine system via the hypothalamus. For example, food anticipatory activity (increased activity even when food is provided in incorrect circadian phase) was linked with the dorsal medial hypothalamic area, proven to be the target for a large output from
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ACCEPTED MANUSCRIPT SCN. Another region with proven central clock association is the lateral hypothalamic area (with orexin expressing neurons – where orexin is responsible for the stimulation of arousal and energy expenditure) (Bass J 2012) [21]. The SCN additionally exerts its influence via peripheral clocks, located all over the body. These peripheral oscillators, responsible for various activities, have been investigated, as well as their links with the central clock. Since
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the discovery of clock genes, an ongoing research has proven that almost every tissue may demonstrate internal oscillation (when studied in isolation). These oscillations are subject to a central control, when studied in vivo. Although internal tissue oscillations result directly from the activity of peripheral clocks, the central control is necessary to maintain harmony at systemic level. Research results have shown various ways by which the central clock interacts with those peripheral oscillators via a complex network of feedback loops. This network comprises, at least, four levels: neural (by
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the autonomic nervous system), hormonal, body temperature and local signalling. Some control of peripheral clocks by the autonomic nervous system has, for example, been suggested in the liver (the rhythmicity of gluconeogenesis). Most of the research on hormonal interactions with circadian rhythmicity has been concentrated on glucocorticoids (the
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rhythmical secretion of glucocorticoids is thought to result from sympathetic control and as an effect of the corticotropin releasing hormone). Experiments have demonstrated that dexamethasone could influence the rhythms of peripheral
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tissues “in vivo”, thus suggesting that glucocorticoids may control signals for peripheral oscillators. Body temperature, controlled by the central clock, influences peripheral oscillators, providing an important synchronising mechanism. The
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central clock does not only control behaviour but it can also influence peripheral oscillators through local factors, such as feeding. The liver clock has been shown to be particularly sensitive to reset from changes in feeding rhythms (Mohawk
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JA et al. 2012) [22]. External factors may exert some influence over peripheral clocks, while leaving the central rhythmicity unaffected. For example, changing feeding hours to incorrect circadian hours alters the peripheral clock in the
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liver only, without any effect on the central clock, but findings about biochemical regulation of the clock in the liver (for example: glucocorticoid signalling, transcriptional control of heat-shock factor protein 1, ADP-ribosylation) suggest a multi-layer regulation, reinforcing the central clock regulation of the liver (SCN restrains the hormonal response to feeding) (Bass J. 2012) [21]. Fig. 1 section A presents interactions between central and peripheral clocks.
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Fig. 1 section A (Central and peripheral biological clocks) – the central clock, located in SCN, is synchronised with day-night rhythm through light stimuli of the retina. The central clock influences other parts of the hypothalamus (Lateral Hypothalamic Area, Dorsal Medial Hypothalamic Area) and the, so-called, peripheral clocks, located throughout the body (for example: liver, muscles, adipocytes,
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pancreas), while being also subject of their (reverse) control.
Both the amplitude and phase of circadian rhythms vary and are age-dependent. A relationship has then been
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proposed between age-related pathologies and disorders of metabolic oscillators (Imai S 2009a) [9]. SIRT1 as a circadian rhythm regulator at cellular level
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Research reports, published in 2000, showed SIRT1 activity as NAD(+)-dependent deacetylase (Imai S et al. 2000a; Landry J et al. 2000; Smith JS et al. 2000) [23, 24, 25]. This dependency of SIRT1 activity on cellular NAD+ levels (i.e. cellular energetic state) has made some authors proclaim SIRT1 to be a cellular energy detector, which links cellular energetic metabolism with epigenetic transcription control and, further, with ageing (Imai S 2009b; Imai S et al. 2000b) [10, 26]. While controlling energetic metabolism, SIRT1 can mediate the longevity-promoting effects of CR. Rodgers J. T. et al. 2005 established that CR effects on gluconeogenesis and glycolysis in the liver were exerted via SIRT1, which affected the function of peroxisome proliferator-activated receptor coactivator-1α (PGC-1α). SIRT1 deacetylates PGC-1α, thus inducing its function as a promoter of gluconeogenic and as an inhibitor of glycolytic genes in hepatic tissue (increasing glucose output in the liver) [27]. A similar process occurs in skeletal muscles, where, in states of nutrient deprivation, metabolism changes from glucose to fatty acid oxidation. Experiments have proven that SIRT1 deacetylates PGC-1α, which is required to activate genes responsible for fatty acid oxidation (Gerhart-Hines Z et al. 2007) [28]. CR mobilises fat in white adipocytes in mammals and Picard F et al. have proven an important role of SIRT1 in this process.
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ACCEPTED MANUSCRIPT In conditions of undernourishment, SIRT1 represses the Peroxisome proliferator-activated receptor γ (PPAR γ), binding with its cofactors, thus stimulating the mobilisation of fatty acids and impairing adipogenesis in white adipocytes [29]. Research on BESTO mice have proven that increased levels of SIRT1 in pancreatic β cells are linked with improved
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glucose tolerance and enhanced GSIS (glucose stimulated insulin secretion). It is thought that SIRT1 activity is enacted through the control of genes responsible for insulin secretion, such as UCP2 (Uncoupling protein-2). SIRT1 inhibits its translation and increases ATP levels in β cells. Consequently, BESTO pancreatic β cells show an increased insulin secretion in response to glucose and KCl (Moynihan KA et al. 2005) [30]. Fig. 1 section C presents various biological
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activities of SIRT1.
Fig. 1 section C (SIRT1 functions) - NAD+ is essential for SIRT1 deacetylase activity, SIRT1 influences tissues through its activity as deacetylase, exerting various effects (increase in fatty acids oxidation, GSIS, glucose tolerance, etc.), which in turn have influence over whole organism.
According to Cohen HY et al., chronic CR leads to increased cellular SIRT1 levels. They have stated that this SIRT1 increasing effect of CR is an evolutionary ancient mechanism of biological response to stress which delays ageing by improving the long-term functions and longevity of cells in critical tissues [31]. New observations may indicate that CR effects on SIRT1 levels are not as straightforward and might be species- or tissue-specific. For example, in studies by Chen D et al., CR proved to increase SIRT1 levels in muscle and white adipose tissue, while decreasing SIRT1 levels in murine livers. The authors suggested that the above-mentioned difference might be a direct result of a unique metabolic function of the liver - metabolism in the liver is accelerated after higher calorie intake [32].
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ACCEPTED MANUSCRIPT Although the majority of studies have focused on SIRT1 properties, new study projects emphasise the role of other sirtuins as well. A recent evaluation of the CR impact on longevity also suggests some role of SIRT3. SIRT3 was identified to be responsible for mitochondrial protein acetylation in response to CR (Hebert AS et al. 2013) [33]. Also other studies showed a reduced protective effect of CR on oxidative stress in genetically modified SIRT3-KO mice (Qiu X
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et al. 2010) [34]. Those findings suggest a probable role of other sirtuins in the beneficial effects of CR, thus demanding further investigations.
The functions of SIRT1 in circadian regulation and its integration with cellular metabolism have already been studied for many years. It is thought that SIRT1 is essential in the transcription of key genes, responsible for the mammalian circadian clock (as BMAL1 - Aryl hydrocarbon receptor nuclear translocator-like gene, PER2 - Period circadian protein homolog 2 gene, CRY1 -Cryptochrome 1 gene). SIRT1 relates the translation of their protein products
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(CLOCK - basic helix-loop-helix-PAS transcription factor, and BMAL1) to circadian rhythmicity and deacetylates the period circadian protein homolog 2 (PER2) (inducing its degradation). Asher G et al. and Nakahata Y et al. claim that,
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due to SIRT1 deacetylase activity dependence on NAD+, SIRT1 binds cellular metabolism with the central circadian clock machinery [35, 36]. Further studies by Chang HC and Guarente L proved an essential role of SIRT1 in the central circadian clock control, binding to the BMAL1 promoter (thus stimulating transcription) in murine brain. Their research
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showed that SIRT1 levels (also BMAL1 and PER2 levels) in SCN significantly decreased in aged mice (leading to abnormalities in activity patterns and impairing their adaptability to changes in light entrainment schedule). Furthermore,
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young mice with lacking SIRT1 expression in the brain present similar abnormalities, while aged mice with SIRT1 overexpression seem to be protected from ageing effects on circadian rhythmicity [8].
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Circadian oscillation of NAD+ and Nampt levels and its role as systemic regulators for SIRT1 Organisms synthesise NAD+ from three precursors: tryptophan, nicotinic acid and nicotinamide (Nam, one of
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the forms of vitamin B3) but, according Revollo JR et al. only the Nam pathway is significant in mammals. Nampt (Nicotinamide phosphoribosyltransferase) is the key element of NAD+ biosynthesis, which, in presence of ATP, catalyses the synthesis of NMN (Nicotinamide mononucleotide) from Nam. Next, Nmnat (Nicotinamide mononucleotide adenylyltransferase) converts NMN into NAD+. In mammals, two forms of Nampt exist: intracellular - iNampt and extracellular - eNampt. The only enzymatic function of iNampt seems to be NAD+ biosynthesis, while eNampt, being a more active catalyst of NAD+ biosynthesis, has also cytokine-like functions [37]. The cellular NAD+ levels and SIRT1 activity are controlled by iNampt availability. This correlation and its biological effects (given in brackets) were observed “in vitro” in mouse fibroblast cultures (changes in gene expression), human vascular smooth muscle cells (cell maturation and longevity) and rat cardiac myocytes (protection against cell death) (Revollo JR et al. 2004; Imai S 2009b) [37, 10]. It has been shown that iNampt expression is also induced by cellular stress and nutritional deficiency. It has been determined that, although induced iNampt does not prevent cellular NAD+ levels from decreasing, it does preserve its mitochondrial supplies, thus activating mitochondrial sirtuins (SIRT3 and 4) that protect from cell death (Yang H et al. 2007) [38].
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ACCEPTED MANUSCRIPT The importance of NAD+ biosynthesis for glucose-induced insulin secretion from pancreatic β-cells is a deeply studied issue. The pancreas has lower cellular levels of iNampt than other tissues, thus being dependent on extracellular NMN sources for NAD+ biosynthesis. This dependency explains why eNampt activity in blood serum (which should maintain high circulatory levels of NMN and its supplies appropriate to pancreatic needs) may be the key factor to
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preserve the normal functions of β-cells. The brain is another organ with low levels of iNampt (particularly neurones). The adipose tissue may play an important role in the metabolic regulation of tissues with scant iNampt supplies (mature adipocytes synthesise and secrete eNampt to bloodstream) (Imai S 2009a; Ramsey KM et al. 2009) [9, 12]. Fig. 1
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section B portrays NAD+ biosynthesis.
Fig. 1 section B (NAD+ biosynthesis) - NAD+ biosynthesis oscillates after the rhythmic changes in PBEF gene expression, regulated by central clock genes (CLOCK:BMAL1, PER2, etc.). Extracellular NMN biosynthesis provides the source of NMN in tissues with low levels of Nampt, therefore allowing for NAD+ biosynthesis.
Banerjee KK et al. have shown a fascinating mechanism in which Sir2, synthesised in Drosophila melanogaster fat tissue, exerted some effects in muscle cells, proving the the role of body fat in Drosophila as a central regulator of metabolic network and energy homeostasis [39]. Hara N et al. demonstrated possible flaws in the hypothesis of extracellular NMN synthesis. In collected murine blood serum, only small amounts of ATP were assayed and, consequently, no effective NMN biosynthesis was possible because Nampt requires ATP for its catalytic function. Further experiments with blood serum, incubated with various concentrations of Nampt, showed no biosynthesis of NMN; NMN production was observed only after ATP supplementation. Those results make it unlikely that effective NMM biosynthesis is possible in blood circulation [40].
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ACCEPTED MANUSCRIPT Other researchers claim that Nampt catalytic functions are not dependent on the presence of ATP (which, nevertheless, increases NMN biosynthesis rate 35 times). (Burgos ES and Schramm VL 2008) [41]. In 2009, Ramsey KM et al. and Nakahata Y et al. simultaneously published their results, proving circadian oscillation of NAD+ and Nampt levels, controlled by the central clock machinery (Ramsey KM et al. 2009; Nakahata Y et
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al. 2009) [12,13]. The circadian clock genes - CLOCK:BMAL1 – cause the circadian oscillation of PBEF (Nicotinamide phosphoribosyltransferase gene) expression (i. e. Nampt synthesis). Nampt, as a limiting enzyme in NAD+ biosynthesis, leads, in its turn, to a circadian rhythm of NAD+ oscillation. A biochemical network of feedback loops is formed, with NAD+ acting as a metabolic oscillator and reflective regulator of circadian clock. (Imai S 2010) [14]. Implications and future perspectives
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The latest research in association with the NAD World Hypothesis finally seems to provide convincing evidence for biochemical links among metabolism, biological rhythmicity and ageing in mammals. Further studies are
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necessary to confirm circadian oscillations of the systemic NAD+ biosynthesis and various biochemical effects of NAD+, SIRT1 in neurones and other tissues critical for NAD+ oscillation. Also the functions of sirtuins, other than SIRT1, require further investigation. The results, which may be obtained in the future, either in primary or in secondary research
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goals, may help answer questions, regarding the biochemistry of and genetic background behind ageing processes and degenerative changes at systemic, organ and tissue levels. One need not say that these answers, although obtained at
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from the clinical perspective.
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the level of pure science, may open a window into better understanding of human ageing and degenerative changes also
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Graphical Abstract
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