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Dietary restriction and Sirtuin 1 in metabolic health: connections and divergences

Published online by Cambridge University Press:  07 September 2015

Carles Cantó*
Affiliation:
Nestlé Institute of Health Sciences, Lausanne, CH-1015, Switzerland École Polytechnique Fédérale de Lausanne, Lausanne, CH-1015, Switzerland
*
Corresponding author: C. Cantó, email carlos.cantoalvarez@rd.nestle.com
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Abstract

Aging is the major risk factor for a constellation of multifactorial diseases, including insulin resistance, diabetes and cardiovascular complications. Dietary restriction has been shown to delay or prevent the manifestation of age-related health decline, extending lifespan in most species tested to date. Given the scarce willingness of human subjects to adhere to chronic dietary restriction exercises, there has been an interest in deciphering the molecular mechanisms triggering the adaptations to dietary restriction. In this context, Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase enzyme, has been proposed to act as a key mediator of the adaptations to nutrient deprivation in eukaryotes, and SIRT1 activating compounds have been often referred to as ‘dietary restriction mimetic’ molecules. Here, we will discuss the convergences and divergences between the effects of dietary restriction and SIRT1 activation, based on the recent advances in the field. As of now, most evidences indicate that SIRT1 is required, but not sufficient to trigger dietary-restriction induced adaptations.

Type
Conference on ‘Diet, gene regulation and metabolic disease’
Copyright
Copyright © The Author 2015 

Due to medical and pharmaceutical advances, developed societies are confronted with the fact that human subjects are living longer, leading to an increased prevalence of diverse age-related diseases, such as type 2 diabetes or cardiovascular complications. Therefore, there is an intense interest in developing strategies to allow people not only to live longer, but also to age healthily, a concept often referred to as healthspan.

To date, dietary restriction (DR) is the most well-known non-pharmacological intervention improving age-related health complications. In 1935, McCay et al. pioneered DR-related research when they tested how retarded growth, via dietary limitation, affected the ultimate size of the animal's body and their life span( Reference McCay, Crowell and Maynard 1 ). At the end of their studies, the authors concluded: ‘in retarded group individuals of both sexes attained extreme ages beyond those of either sex that grew normally’. The effect was especially dramatic in male rats. Hence, it was demonstrated for the first time that DR without malnutrition prolongs mean and maximal lifespan in rats compared with ad libitum feeding.

DR is now usually defined as a moderate (normally, 20–40 %) reduction in dietary intake as compared with an ad libitum diet, without compromising the maintenance of all essential nutrients( Reference Canto and Auwerx 2 , Reference Fontana, Partridge and Longo 3 ). Since the discovery of McCay et al. the effects of DR on health and lifespan extension have been shown to stretch all along the evolutionary scale, ranging from yeast to human subjects( Reference Fontana, Partridge and Longo 3 ). Up to a 50 % increase in maximum lifespan has been reported in dietary restricted yeast, rotifers, spiders, worms, flies, fish, mice and rats( Reference Canto and Auwerx 2 ). Two major studies have been performed in Rhesus monkeys( Reference Colman, Anderson and Johnson 4 , Reference Mattison, Roth and Beasley 5 ). While an impact of DR on maximal lifespan could only be observed in the first of them( Reference Colman, Anderson and Johnson 4 ), both studies have shown a delayed onset of age-associated pathologies in dietary-restricted monkeys( Reference Colman, Anderson and Johnson 4 , Reference Mattison, Roth and Beasley 5 ). In both rodent and primate animal models, DR promotes increased insulin sensitivity and prevents against age-related cardiovascular complications and cancer( Reference Baur 6 ). Importantly, DR is also protected against age-related mitochondrial dysfunction, a hallmark for multiple metabolic complications( Reference Baur 6 , Reference Martin-Montalvo and de Cabo 7 ).

Despite these potential benefits, there are a few aspects that need to be taken into account when considering the implementation of DR regimens. When performed from early stages in life, and in almost any specie tested to date, DR dramatically reduces fertility and promotes growth retardation( Reference Fontana, Partridge and Longo 3 ). In primates, DR has also been reported to lead to aggressiveness and stereotyped behaviours( Reference Weed, Lane and Roth 8 ). Further complicating the picture, the effects of DR might have a strong genetic component. Using one of the largest groups of recombinant inbred strains of mice presently available, the ILSXISS( Reference Williams, Bennett and Lu 9 ), Liao et al. tested the hypothesis that the lifespan response to DR would fluctuate depending on the genetic variations across these genotypes( Reference Liao, Rikke and Johnson 10 ). Contrary to the extensive contemporary literature, at least half of the strains showed lifespan shortening by DR, rather than lifespan lengthening( Reference Liao, Rikke and Johnson 10 , Reference Rikke, Liao and McQueen 11 ). Other points that are presently under debate include the degree of severity of the DR regime, the optimal age of onset of such regime and how the basal metabolic state of individuals might affect the effectiveness of the intervention( Reference Fontana, Partridge and Longo 3 ).

Most studies to date suggest that DR can positively impact on human longevity, especially by reducing the risk of developing age-associated complications( Reference Holloszy and Fontana 12 ). In several studies conducted in overweight human subjects, DR has been shown to improve a number of health outcomes, including a reduction in several cardiac risk factors( Reference Fontana, Meyer and Klein 13 Reference Lefevre, Redman and Heilbronn 15 ), an improvement in insulin-sensitivity( Reference Larson-Meyer, Heilbronn and Redman 16 ), and enhanced mitochondrial function( Reference Civitarese, Carling and Heilbronn 17 ). Additionally, prolonged DR has also been found to reduce oxidative damage( Reference Heilbronn and Ravussin 18 Reference Hofer, Fontana and Anton 20 ). This way, findings of initial human clinical trials appear to support the promise of DR raised by animal studies, at least in overweight adults. This said, one must take into account that human patients generally display a poor adherence to DR regimens. With this in mind, the scientific community has long pursued efforts to identify or generate DR-mimetic compounds/interventions. To do so, however, a precise understanding of the underlying mechanisms of the action of DR is needed. In this review, we will discuss how the activation of Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase enzyme, has been hypothesised to be key for DR-induced health benefits and the present standpoint on whether diverse SIRT1 activating strategies can truly be considered DR-mimetic.

Dietary restriction and silent information regulator 2/Sirtuin 1: connecting the dots

To understand the molecular mechanisms by which DR prevents age-related diseases, it could be important to first understand what triggers age-related physiological decline. Aging leads to a constellation of molecular alterations, including accumulative oxidative damage, inflammation, mitochondrial dysfunction, lack of protein turnover or increased covalent modification of proteins( Reference Canto and Auwerx 2 ). Given the multifactorial nature of aging, it was surprising to find that single-gene mutations markedly contribute to extend lifespan in diverse models including yeast, worms and flies( Reference Fontana, Partridge and Longo 3 ). Many of these longevity-extending mutations decrease the activity of molecular pathways activated by nutrients, such as the insulin signalling pathway, suggesting that they promote a physiological state similar to that experienced during DR( Reference Fontana, Partridge and Longo 3 ).

It was particularly exciting to find that a protein called silent information regulator 2 (SIR2) could modulate yeast replicative lifespan( Reference Kaeberlein, McVey and Guarente 21 ). SIR2 was initially identified as a gene that silenced the extra copies of the mating-type information in yeast( Reference Shore, Squire and Nasmyth 22 ). Simultaneous work by independent groups established that the SIR2 gene product was a protein, Sir2, containing a NAD+-dependent enzymatic histone deacetylase activity( Reference Imai, Armstrong and Kaeberlein 23 Reference Tanner, Landry and Sternglanz 26 ). The deacetylation reaction catalysed by Sir2 is coordinated with the cleavage of NAD+ into nicotinamide and 1-O-acetyl-ADP-ribose( Reference Tanner, Landry and Sternglanz 26 ). Given that multiple metabolic paths use NAD+, or its reduced form NADH, as a cofactor, it was proposed that Sir2 could act as a metabolic sensor, capable of modulating gene expression according to the metabolic state of the cell( Reference Imai, Johnson and Marciniak 27 ).

Increasing the dosage of SIR2 increased replicative lifespan in yeast by 30 %, while its deletion shortened lifespan by 50 %. Several studies indicated that Sir2 could be a critical mediator of the effects of DR on yeast lifespan( Reference Howitz, Bitterman and Cohen 28 , Reference Lin, Defossez and Guarente 29 ). For example, SIR2 overexpression was enough to increase replicative lifespan in a similar, non-additive, manner to DR( Reference Lin, Defossez and Guarente 29 ). In an opposite fashion, DR was unable to increase lifespan in yeast where the gene coding for SIR2 was deleted( Reference Lin, Defossez and Guarente 29 ).

Following these initial discoveries, similar observations were made in nematodes and flies. The Caenorhabditis elegans genome contains four sirtuin genes, among which Sir-2·1 is the most homologous to yeast SIR2. Sir-2·1 overexpression was enough extended nematode lifespan( Reference Tissenbaum and Guarente 30 Reference Viswanathan, Kim and Berdichevsky 32 ). The fly Drosophila melanogaster has five sirtuin homologues, and dSir2 also extends lifespan when overexpressed( Reference Rogina and Helfand 33 , Reference Wood, Rogina and Lavu 34 ). However, these findings were recently challenged and attributed to a poor control of the genetic background( Reference Burnett, Valentini and Cabreiro 35 ). Indeed, when the transgenic worms and flies were backcrossed to identical backgrounds, the lifespan extension was lost( Reference Burnett, Valentini and Cabreiro 35 ), although a small but significant effect has still been reported under similar conditions for Sir-2·1 overexpression in C. elegans ( Reference Viswanathan and Guarente 36 , Reference Mouchiroud, Houtkooper and Moullan 37 ).

Irrespective of the ultimate effects on maximal lifespan, Sir-2·1 and dSir2 have been identified as critical regulators of the response to nutritional stress induced by DR. Indeed, when dSir2 was deleted, DR failed to extend lifespan in flies( Reference Rogina and Helfand 33 , Reference Bauer, Morris and Chang 38 ). Similarly, worms lacking Sir-2·1 did not live longer upon DR, and displayed shorter lifespan when exposed to hydrogen peroxide, heat stress, or UV radiation( Reference Wang and Tissenbaum 39 ). These results suggest that Sir2 homologues are key regulators of the metabolic and transcriptional adaptations to DR.

SIRT1 is the closest mammalian homologue of the yeast Sir2. While initially described as a transcriptional silencing enzyme via histone deacetylation, the actions of SIRT1 have unfolded far beyond histone modifications( Reference Canto and Auwerx 40 ). In the past decade, a large number of non-histone deacetylation targets have been identified, including key orchestrators of mitochondrial and lipid oxidation gene expression as the peroxisome-proliferator activated receptor γ coactivator 1α( Reference Nemoto, Fergusson and Finkel 41 , Reference Rodgers, Lerin and Haas 42 ) and FOXO3a( Reference Brunet, Sweeney and Sturgill 43 , Reference Motta, Divecha and Lemieux 44 ). For an extended list of identified SIRT1 targets, the reader is referred to other recent reviews( Reference Canto and Auwerx 40 , Reference Chang and Guarente 45 ). The deacetylation of these targets by SIRT1 prompts their transcriptional activity on promoters encoding for genes aimed to extract energy through mitochondrial respiration( Reference Canto and Auwerx 40 ). Given the dual localisation of SIRT1, either in the cytoplasm and/or the nucleus, it is not surprising that SIRT1 targets have also been identified in both compartments( Reference Canto and Auwerx 40 ). This way, by sensing changes in NAD+ levels, SIRT1 is activated upon nutrient stress and triggers metabolic adaptations favouring energy production through non-carbohydrate energy sources and via oxidative processes. Recently, SIRT1 has been shown to trigger the mitochondrial unfolded protein response, which optimises mito-nuclear communication in order to ensure mitochondrial fitness through the efficient repair of damaged mitochondria( Reference Mouchiroud, Houtkooper and Moullan 37 ). Hence, SIRT1 activation could also contribute to alleviate mitochondrial function decay upon aging.

Dietary restriction and Sirtuin 1 in mammals (I): gain-of-function models

In addition to the prevention of age-related diseases, DR is known to promote a vast range of physiological and behavioural changes in mice. These effects include a reduction in body weight by a decrease in fat mass, enhanced insulin sensitivity and increased efficiency for energy production( Reference Fontana, Partridge and Longo 3 ). SIRT1 expression increases in many mammalian cells and tissues upon glucose deprivation or DR( Reference Canto and Auwerx 40 , Reference Chen, Bruno and Easlon 46 , Reference Fulco, Cen and Zhao 47 ). This, together with the data on lower eukaryotes, raised the hypothesis that forced SIRT1 activation could be used as a DR-mimetic strategy. In this section, we will discuss several approaches used to increase SIRT1 activity and whether they truly resemble the effects of DR.

The first SIRT1 gain-of-function model reported displayed several DR-like features: they were leaner and had improved glucose tolerance( Reference Bordone, Cohen and Robinson 48 ). One particularity of this model is that the overexpression of the SIRT1 protein occurred predominantly in the brain and in white- and brown-adipose tissues (BAT), but not in liver or muscle( Reference Bordone, Cohen and Robinson 48 ). Not much later, two mouse models for whole-body moderate SIRT1 overexpression were generated( Reference Pfluger, Herranz and Velasco-Miguel 49 , Reference Banks, Kon and Knight 50 ). In one of them, generated by the Serrano laboratory( Reference Pfluger, Herranz and Velasco-Miguel 49 ), the moderate overexpression of SIRT1 led to increased BAT function and thermogenic function, even on a low fat diet, which caused a modest increase in insulin sensitivity( Reference Boutant, Joffraud and Kulkarni 51 ). The involvement of SIRT1 on thermogenic functions was further strengthened by the second mouse model of moderate SIRT1 overexpression, generated by the Accili laboratory, where SIRT1 was shown to improve white adipose tissues ‘browning’ upon pharmacological or physiological adrenergic stimulation( Reference Qiang, Wang and Kon 52 ). In both models, however, no major effects on hepatic or muscle metabolism were observed under low-fat diets, despite a 2–4-fold increase in SIRT1 levels in both tissues( Reference Pfluger, Herranz and Velasco-Miguel 49 Reference Boutant, Joffraud and Kulkarni 51 ). Both mouse models, however, showed that a mild overexpression of SIRT1 prevented against high-fat diet induced hyperglycemia, insulin resistance and fatty liver, despite no significant differences in body weight( Reference Pfluger, Herranz and Velasco-Miguel 49 , Reference Banks, Kon and Knight 50 ). This was largely attributed to a protective effect of SIRT1 against high-fat diet-induced liver insulin resistance and inflammation( Reference Pfluger, Herranz and Velasco-Miguel 49 , Reference Banks, Kon and Knight 50 ). In line with this, liver-specific overexpression of SIRT1 is enough to effectively protect against insulin resistance in both dietary and genetic mouse models of obesity( Reference Li, Xu and Giles 53 ).

While initially surprising, the absence of effects of SIRT1 overexpression in muscle mitochondrial content and insulin sensitivity have been elegantly confirmed in mice with a selective overexpression of SIRT1 in muscle tissue( Reference White, Philp and Fridolfsson 54 ). However, it has recently been suggested that a 100-fold overexpression of SIRT1 in skeletal muscle can lead to decreased muscle mass, cross-sectional area and a shift towards a more oxidative, slow-twitch, muscle fibre types( Reference Chalkiadaki, Igarashi and Nasamu 55 ). Another recent report shows how a high, non-physiological, whole body SIRT1 overexpression prompts enhanced mitochondrial content in muscle, together with an improvement of whole-body glucose tolerance( Reference Price, Gomes and Ling 56 ). These observations suggest that endogenous SIRT1 is enough to account for the basal maintenance of mitochondrial content under physiological conditions in skeletal muscle, and that certain transcriptional programs might be forcedly enhanced under situations of massive SIRT1 overexpression.

Mice overexpressing SIRT1 in the β-cell display enhanced glucose-stimulated insulin secretion, even though whole-body moderate SIRT1 overexpression did not have any major effect on mice insulinemia on chow diet( Reference Chang and Guarente 45 , Reference Pfluger, Herranz and Velasco-Miguel 49 Reference Boutant, Joffraud and Kulkarni 51 ). These discrepancies could be attributed to differential SIRT1 overepression levels. However, whether SIRT1 overexpression at massive levels really mimics physiological SIRT1 activation upon DR is, unclear. Indeed, a caveat when comparing all these models is that higher SIRT1 levels do not necessarily have to correlate with SIRT1 activity, for example in situations where NAD+ might become rate-limiting, as can be the case during aging( Reference Mouchiroud, Houtkooper and Moullan 37 , Reference Braidy, Guillemin and Mansour 57 ). In this sense, it is interesting to note that the Serrano laboratory evaluated the impact of moderate SIRT1 overexpression on the aging process. While SIRT1 overexpression protected against diverse age-related pathologies including insulin resistance, osteoporosis, impaired wound healing and cancer, no effects on mouse lifespan were observed( Reference Herranz, Munoz-Martin and Canamero 58 ).

So, is SIRT1 overexpression comparable with DR? At a glance, one can clearly identify some overlaps (e.g. amelioration of glycemic profiles), but also some major discrepancies between both models. In most cases( Reference Pfluger, Herranz and Velasco-Miguel 49 Reference Boutant, Joffraud and Kulkarni 51 ), but not all( Reference Bordone, Cohen and Robinson 48 ), SIRT1 overexpression does not lead to reduced body weight. This is expected, as mice are not in a limited energy intake scenario. In some models, SIRT1 ovexpression enhanced insulin sensitivity under normal diet conditions( Reference Bordone, Cohen and Robinson 48 , Reference Boutant, Joffraud and Kulkarni 51 ), which would go in line with the expected DR-like effect. This increase in insulin sensitivity has been attributed to higher insulin-stimulated glucose uptake in BAT( Reference Boutant, Joffraud and Kulkarni 51 ). The positive influence of SIRT1 on BAT function and thermogenesis, however, is unlikely to be a feature of DR. Upon prolonged low food accessibility, organisms will tend to optimise ATP synthesis by decreasing mitochondrial proton leak (i.e. uncoupled respiration), which is the key feature of BAT through the expression of the Uncoupling Protein 1. This is a phenomenon observed even at the cellular level upon glucose deprivation( Reference Gomes, Di Benedetto and Scorrano 59 ). Some studies indeed indicate that DR in mice leads to reductions in BAT function( Reference Li, Cope and Johnson 60 ). Reduced BAT function generally manifested as lower energy expenditure, which is characteristic in rodents and human subjects upon DR regimes( Reference Heilbronn, de Jonge and Frisard 19 , Reference Martin, Heilbronn and de Jonge 61 ). This is opposite to the higher energy expenditure observed in some SIRT1 transgenic mouse lines( Reference Bordone, Cohen and Robinson 48 , Reference Boutant, Joffraud and Kulkarni 51 ). The impact of DR on behavioural traits is also not mimicked by SIRT1 overexpression, as DR promotes an increase in activity and foraging behaviour( Reference Chen, Steele and Lindquist 62 ), while daily activity was lower in some SIRT1 transgenic lines( Reference Banks, Kon and Knight 50 , Reference Boutant, Joffraud and Kulkarni 51 ).

SIRT1 biology has also been studied through the use of SIRT1 activating compounds (STAC), among which resveratrol and SRT1720 might be the most well-known. The ability of these compounds to specifically and directly activate SIRT1, however, is still a matter of debate( Reference Pacholec, Bleasdale and Chrunyk 63 Reference Lombard, Pletcher and Canto 65 ). Irrespectively of whether the action is direct or not, both compounds lead to SIRT1 activation and promote very overlapping effects in mice, including a large increase in mitochondrial biogenesis in skeletal muscle and BAT, enhanced energy expenditure and protection against high-fat diet-induced obesity( Reference Lagouge, Argmann and Gerhart-Hines 66 , Reference Feige, Lagouge and Cantó 67 ). In addition, STAC granted improved insulin sensitivity and a longer lifespan when mice were submitted to a high-fat diet( Reference Baur, Pearson and Price 68 , Reference Minor, Baur and Gomes 69 ). In the case of SRT1720, treated animals displayed enhanced lifespan even on chow diet conditions( Reference Mitchell, Martin-Montalvo and Mercken 70 ).

Other compounds used to activate SIRT1 are those aimed to elevate NAD+ bioavailability. This includes compounds that inhibit alternative NAD+ consuming activities, such as PARP-1( Reference Pirinen, Canto and Jo 71 , Reference Cerutti, Pirinen and Lamperti 72 ) or CD38( Reference Escande, Nin and Price 73 ), or that enhance NAD+ synthesis, such as nicotinamide mononucleotide( Reference Yoshino, Mills and Yoon 74 , Reference Gomes, Price and Ling 75 ) or nicotinamide riboside( Reference Cerutti, Pirinen and Lamperti 72 , Reference Canto, Houtkooper and Pirinen 76 , Reference Khan, Auranen and Paetau 77 ). In agreement with the ability of these strategies to increase NAD+ availability, all these compounds led to higher SIRT1 activity and ameliorations in glucose homeostasis. In the case of nicotinamide riboside or PARP inhibition, higher energy expenditure, decreased body weight gain upon high-fat feeding and enhanced mitochondrial biogenesis have also been reported( Reference Pirinen, Canto and Jo 71 , Reference Cerutti, Pirinen and Lamperti 72 , Reference Canto, Houtkooper and Pirinen 76 , Reference Khan, Auranen and Paetau 77 ).

It is interesting that NAD+ boosting strategies and STAC both converge at preventing high-fat diet-induced body weight gain, a phenomenon never observed in models of moderate SIRT1 overexpression( Reference Pfluger, Herranz and Velasco-Miguel 49 Reference Boutant, Joffraud and Kulkarni 51 ). Also, STAC promote dramatic increases in mitochondrial biogenesis, especially in skeletal muscle( Reference Lagouge, Argmann and Gerhart-Hines 66 , Reference Feige, Lagouge and Cantó 67 ), which, again, were not observed upon moderate SIRT1 overexpression( Reference Boutant, Joffraud and Kulkarni 51 ). Similarly, increases in skeletal muscle mitochondrial content are not generally seen upon DR, even though this is still a matter of debate( Reference Hancock, Han and Higashida 78 ). Therefore, all the earlier results indicate that, despite a significant overlap in the effects, there are remarkable differences between the different SIRT1 activating strategies. In some cases, such as the regulation of energy expenditure, the effect of SIRT1 activation might be even opposite to those of DR.

The earlier observations argue that forced SIRT1 activation and DR might lead to similar health benefits, yet not necessarily through similar means. This, however, does not rule out that SIRT1 participates in the adaptations to DR. This aspect can be tested through, at least, two strategies. For example, one could test the interaction between SIRT1 overexpression and the response to DR. In this sense, the overexpression of SIRT1 in skeletal muscle does not seem to alter the effects of DR on body weight, body composition or insulin sensitivity( Reference White, McCurdy and Philp 79 ). A possible explanation might be that endogenous SIRT1 levels could be enough to warrant full adaptability to DR in this tissue. A second, more conclusive, strategy is to evaluate the effects of DR in SIRT1 loss-of-function models, as discussed in the next section.

Dietary restriction and Sirtuin 1 in mammals (II): loss-of-function models

The whole-body deletion of SIRT1 leads to high prenatal lethality in inbred mice( Reference McBurney, Yang and Jardine 80 , Reference Cheng, Mostoslavsky and Saito 81 ). The very few pups that were born displayed marked cardiac and neurological problems, leading to death very early in the postnatal period( Reference McBurney, Yang and Jardine 80 , Reference Cheng, Mostoslavsky and Saito 81 ). In order to bypass this situation, SIRT1 deletion was performed in outbred mice( Reference McBurney, Yang and Jardine 80 ). These mice were viable and displayed a marked hypermetabolism due to decreased energy production efficiency, which, in turn, impeded the proper adaptation of metabolic rates to DR( Reference Boily, Seifert and Bevilacqua 82 ). DR is generally associated with behavioural changes at the level of food foraging activity. These changes, however, did not happen when DR was performed on SIRT1 deficient mice( Reference Chen, Steele and Lindquist 62 ). The role of SIRT1 in the influence of DR on mouse lifespan has been examined recently. For this purpose, SIRT1 knockout (KO), SIRT1 heterozygous and control wild-type mice, aged between 2 and 5 months old, were subjected to either 40 % DR or ad libitum diets. The results indicated that DR failed to increase lifespan in SIRT1 KO mice( Reference Mercken, Hu and Krzysik-Walker 83 ). Despite a trend for decreased maximum lifespan under DR conditions, DR extended the lifespan of both SIRT1 heterozygous or wild-type mice in a comparable manner( Reference Mercken, Hu and Krzysik-Walker 83 ). These results evoke two concepts: (1) SIRT1 is required in outbred mouse stocks for the lifespan extension caused by DR; and, (2) as suggested by the overexpression models, SIRT1 endogenous levels are largely enough to mediate DR-induced adaptations, since even a 50 % reduction in SIRT1 levels did not have a major impact on the lifespan extension promoted by DR.

One caveat of the earlier studies is that SIRT1 deficient mice display multiple defects on the basal state, including dwarfism, sterility, craniofacial abnormalities and several inflammatory conditions( Reference McBurney, Yang and Jardine 80 , Reference Mercken, Hu and Krzysik-Walker 83 ). Therefore, all these abnormalities could lead them to premature death irrespectively of feeding conditions. Given such detrimental effects on early development and global health, ensuring non-limiting SIRT1 levels in key central and peripheral tissues might have been naturally selected during evolutionary processes. Interestingly, an inducible model has been developed in order to genetically ablate SIRT1 exclusively in adulthood( Reference Price, Gomes and Ling 56 ). SIRT1 deletion in adult mice did not result in any overt phenotype or metabolic alteration( Reference Price, Gomes and Ling 56 ), making it a perfect model to precisely evaluate the impact of SIRT1 on DR-induced adaptations, even though efforts in this direction have not yet been reported.

While the requirement for SIRT1 in DR-induced adaptations in mice seems clear, there are still a number of open questions. For example: do all tissues require SIRT1 expression to allow DR-induced metabolic adaptations? Few efforts have been done in this direction, yet enough to conclude that this is the case in skeletal muscle. When submitted to a 60 % reduction in energy intake, mice display a marked increase in insulin sensitivity and insulin-induced glucose uptake in peripheral tissues( Reference Schenk, McCurdy and Philp 84 ). However, SIRT1 deletion specifically in skeletal muscle is enough to largely block the effects of DR on insulin-induced glucose disposal in skeletal muscle( Reference Schenk, McCurdy and Philp 84 ). In liver or adipocytes, where SIRT1 levels were similar between muscle-specific SIRT1 KO and control mice, DR-induced benefits on insulin signalling were comparable( Reference Schenk, McCurdy and Philp 84 ). This testifies that DR only failed to promote metabolic adaptations in skeletal muscle, where SIRT1 had been specifically deleted. Mechanistically, the authors proposed that DR improves the efficiency of insulin to trigger phosphoinositide 3-kinase signalling and that this is due to SIRT1-mediated deacetylation and inactivation of Stat3, a negative transcriptional regulator of the phosphoinositide 3-kinase regulatory subunits p55α and p50α( Reference Schenk, McCurdy and Philp 84 ). Hence, DR would enhance insulin signalling potency in skeletal muscle by increasing the expression of phosphoinositide 3-kinase regulatory subunits in a SIRT1-dependent manner.

The effects of DR have also been explored in liver-specific SIRT1 KO mice. In this case, liver-specific SIRT1 KO mice had similar body weight loss and fat reduction as control mice upon DR, and no major alterations were observed after the examination of different metabolic parameters, including fasting glycemia, insulinemia and glucose tolerance tests( Reference Chen, Bruno and Easlon 46 ). Hence, SIRT1 ablation in the liver does not seem to alter the physiological adaptation to DR. In part, this might be explained by the fact that, contrary to most tissues reported, SIRT1 expression is paradoxically decreased in livers upon DR( Reference Chen, Bruno and Easlon 46 ). As described earlier, SIRT1 has a key role in adipose tissue biology, where it enhances the action of ‘browning’ stimuli( Reference Boutant, Joffraud and Kulkarni 51 , Reference Qiang, Wang and Kon 52 ) and prevents high-fat diet induced metabolic complications, at least at early stages( Reference Chalkiadaki and Guarente 85 , Reference Mayoral, Osborn and McNelis 86 ). Hence, it will be interesting to evaluate how SIRT1 deficiency in adipose tissues impacts on DR-induced metabolic adaptations.

The adaptation of mice to DR also relies on changes at the level of the central nervous system. In order to evaluate the role of SIRT1 expression in the brain in the adaptations to DR, mice lacking SIRT1 specifically in neurons, astrocytes and glial cells were generated( Reference Cohen, Supinski and Bonkowski 87 ). Wild-type and brain-specific SIRT1 KO mice lost weight similarly after a 7-month 40 % reduction in energetic intake. DR dramatically increased the insulin sensitivity of wild-type animals( Reference Cohen, Supinski and Bonkowski 87 ). However, DR induced only a modest improvement in insulin sensitivity in brain-specific SIRT1 KO mice( Reference Cohen, Supinski and Bonkowski 87 ), suggesting that SIRT1 expression in the brain is required to achieve the full benefits on insulin sensitivity conferred by DR. When placed on monitored running wheels, wild-type animals dramatically up-regulated their activity in response to DR. In contrast, while brain-specific SIRT1 KO mice were slightly more active than control mice when fed ad libitum, their activity markedly decreased upon DR( Reference Cohen, Supinski and Bonkowski 87 ). Therefore, SIRT1 activity in the brain is required to modulate several metabolic and behavioural adaptations to DR. A caveat of this model is that brain-specific SIRT1 KO mice, as whole-body SIRT1 deficient mice, display numerous abnormalities at the basal state, including dwarfism and a reduced somatotropic signalling (i.e. lower circulating growth hormone and insulin-like growth factor-1 levels)( Reference Cohen, Supinski and Bonkowski 87 ), which call for caution when interpreting the effects of DR in this model.

Conclusions and perspectives

Overall, most studies in genetically engineered mouse models indicate that SIRT1 is necessary to trigger many of the metabolic and behavioural adaptations to DR, even though the role of SIRT1 mediating these effects might differ from tissue to tissue. This fits nicely with the hypothesis that SIRT1 acts as an evolutionary conserved sensor of nutrient stress, promoting adaptations aimed to improve energy production efficiency. In line with this, SIRT1 activity directly impinges on many molecular pathways linked to longevity and that critically regulate metabolic adaptation to energy stress, including the FOXO family of transcription factors( Reference Fontana, Partridge and Longo 3 , Reference Calnan and Brunet 88 ) and AMP-activated protein kinase signalling( Reference Canto and Auwerx 89 ).

Most results to date, however, also indicate that SIRT1 activation does not act per se a DR-mimetic. Several features of DR are not mimicked, or even opposed, by diverse SIRT1 gain-of-function models. Nonetheless, one should take into account the limitations of these models. For example, moderate SIRT1 overexpression might be aligned with the increases in SIRT1 observed in white adipose tissues or BAT upon DR, but, in fact, tissues such as brain or liver do not show increases in SIRT1 content on dietary restricted mice( Reference Chen, Bruno and Easlon 46 , Reference Cohen, Supinski and Bonkowski 87 ). STAC might push SIRT1 activity beyond physiological limits and might activate additional paths, such as the AMP-activated protein kinase, which could explain the strong effects on skeletal muscle mitochondrial biogenesis( Reference Canto and Auwerx 89 ). Therefore, two aspects will be worthy of our attention in the years to come: (1) the key elements influencing endogenous SIRT1 activity upon DR in diverse tissues and (2) a global landscape of the cooperation between SIRT1 and other pathways upon DR. While referring to SIRT1 activating strategies as ‘DR-mimetic’ might be misleading, the data in mouse models highlight that they bear an undeniable therapeutic potential for the amelioration of metabolic and age-related diseases. Novel approaches, such as enhancing NAD+ synthesis via nicotinamide mononucleotide or nicotinamide riboside supplementation are providing spectacular effects in the management of glucose homeostasis( Reference Yoshino, Mills and Yoon 74 , Reference Canto, Houtkooper and Pirinen 76 ), and their true potential in human subjects still needs to be unveiled.

Acknowledgements

I would like to thank the members of the Canto lab and Professor Johan Auwerx for fruitful continuous discussions on SIRT1 biology and the metabolic impact of DR.

Financial Support

Nestlé Institute of Health Sciences S.A.

Conflicts of Interest

C. C. is an employee of the Nestlé Institute of Health Sciences S.A.

Authorship

C. C. is the sole author of the paper.

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