A longer and healthier life with TOR down-regulation: genetics and drugs

460 Biochemical Society Transactions (2011) Volume 39, part 2

A longer and healthier life with TORdown-regulation: genetics and drugsIvana Bjedov*1 and Linda Partridge*†1

*Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London

WC1E 6BT, U.K. and †Max Planck Institute for Biology of Ageing, Gleueler Strasse 50a, 50931 Koln, Germany

AbstractGenetic down-regulation of a major nutrient-sensing pathway, TOR (target of rapamycin) signalling, canimprove health and extend lifespan in evolutionarily distant organisms such as yeast and mammals.Recently, it has been demonstrated that treatment with a pharmacological inhibitor of the TOR pathway,rapamycin, can replicate those findings and improve aging in a variety of model organisms. Theproposed underlying anti-aging mechanisms are down-regulated translation, increased autophagy, alteredmetabolism and increased stress resistance.

IntroductionDespite the complexity of the aging process, single genemutations suffice to delay the onset of age-related phenotypesin a variety of model organisms, from yeast to mammals.Importantly, these long-lived mutants are healthier andprotected from a broad spectrum of aging-related diseases.Remarkably, the processes mediating lifespan extension areevolutionary conserved, suggesting that discoveries frommodel organisms could be applied to ameliorate aging andprevent diseases in humans.

The most robust and well-studied improvements in agingare caused by dietary restriction, a reduction of nutrientswithout malnutrition, and also by genetic down-regulationof nutrient-sensing pathways, namely TOR (target-of-rapamycin) and IIS (insulin/insulin-like growth factorsignalling) [1,2]. However, since both dietary restriction andgenetic inhibition of IIS and TOR signalling are difficultto translate directly into human studies, aging research hasrecently focused on pharmacological approaches to targetthese pathways.

The present review focuses on the TOR pathway andits pharmacological inhibitor rapamycin, with the aim ofoutlining downstream processes implicated in aging.

The TOR pathwayThe TOR pathway is an evolutionarily conserved nutrient-sensing pathway that adjusts metabolism and growth toamino acid availability, growth factors, energy status andstress [3,4]. The central component of the TOR pathway,

Key words: aging, autophagy, metabolism, stress, target of rapamycin (TOR), translation.

Abbreviations used: AMPK, AMP-activated protein kinase; daf-2, abnormal dauer formation

2; 4E-BP, eukaryotic initiation factor 4E-binding protein; FOXO, forkhead box O; HIF-1, hypoxia-

inducible factor 1; IIS, insulin/insulin-like growth factor signalling; ROS, reactive oxygen species;

S6K, S6 kinase; TOR, target of rapamycin; raptor, regulatory associated protein of TOR; TORC1,

TOR complex 1; TORC2, TOR complex 2; TSC, tuberous sclerosis complex.1Correspondence may be addressed to either authors (email [email protected] or

[email protected])

the TOR kinase, forms two functionally different complexes:TORC (TOR complex) 1 and TORC2. When activated,TORC1 promotes growth by positively regulating S6K (S6kinase) [5] and favours cap-dependent translation throughinhibitory phosphorylation of 4E-BP (eukaryotic initiationfactor 4E-binding protein) [6]. Under starvation conditions,TORC1 is responsible for up-regulating autophagy, a processthat generates energy by degrading portions of the cytoplasm[7,8]. Less is known about TORC2, whose principal outputsare to regulate the actin cytoskeleton and to phosphorylateand activate the pro-survival Akt kinase of the IIS pathway[9,10]. Once activated, Akt phosphorylates and inhibitsPRAS40 (proline-rich Akt substrate of 40 kDa) and TSC2(tuberous sclerosis protein 2), the latter leading to activationof the GTPase Rheb, thus causing TOR signalling up-regulation. In contrast with TORC2, TORC1 acts as aninhibitor of IIS through negative feedback of S6K on IRS(insulin receptor substrate) [3]. Owing to the intricate wiringbetween IIS and TOR signalling, these pathways should beregarded as a network (summarized in Figure 1).

Genetic and pharmacologicaldown-regulation of the TOR pathway

Genes in the TOR pathway that are implicated inlongevityGenetic down-regulation of TOR signalling delays aging inevolutionarily distant organisms from yeast to mammals [11].For example, both chronological and replicative lifespansare extended in the yeast tor1� mutant (reviewed in [12]).Nematode worms mutated in TOR (let-363) or S6K (rsks-1) [13] are long-lived, as are fruitflies overexpressing eithera dominant-negative form of S6K or negative regulators ofthe TOR pathway, TSC1 (tuberous sclerosis complex 1) orTSC2 [14]. Importantly, mice carrying a deletion in S6K1have lifespan extension and amelioration of health, including

C©The Authors Journal compilation C©2011 Biochemical Society Biochem. Soc. Trans. (2011) 39, 460–465; doi:10.1042/BST0390460Bio

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mTOR Signalling in Health and Disease 461

Figure 1 TOR pathway and its biochemical interactions

TOR signalling interacts with the IIS pathway and incorporates signals from amino acid status and various stresses, in order to

modulate growth and metabolism accordingly. Bar-ended lines indicate inhibitory interaction, and arrows indicate activation.

Details of the Figure are described in the text. IGF, insulin-like growth factor; IR, insulin receptor; rictor, rapamycin-insensitive

companion of mTOR.

improved glucose homoeostasis, immune cell profile andmotor activities [15]. Overall, TOR signalling plays animportant and robust role in modulating aging.

Pharmacological inhibition of the TOR pathwayby rapamycinAs an alternative to genetic interventions, the TORC1branch of the TOR pathway can be successfully inhibitedpharmacologically by rapamycin [16]. As the name suggests,it was the search for the target of this anti-fungal andimmunosuppressant agent that led to the discovery of theTOR pathway [17]. Rapamycin and its analogues are alreadyapproved for human use as immunosuppressants and foradvanced renal carcinoma [16,17].

Importantly, rapamycin treatment reproduces the longev-ity effects of the genetic TOR pathway mutants, extendinglifespan in yeast [17] and in fruitflies [18]. Excitingly,600-day-old mice treated with rapamycin also had lifespanextension [19]. Therefore pharmacological interventionsinitiated even in middle age can be beneficial for aging.However, despite its anti-cancer properties, no decrease intumour incidence was observed for the rapamycin-treatedmice in this study, although exposure to rapamycin at anearlier age or a different dosage might possibly have shown amore pronounced anti-cancer outcome.

In addition, rapamycin is effective in the preventionof various neurodegenerative diseases, showing protectionand reducing pathology in fruitfly and mouse models ofParkinson’s, Huntington’s and Alzheimer’s disease (reviewed

C©The Authors Journal compilation C©2011 Biochemical Society


in [20]). There is also evidence that rapamycin can restorehaemopoietic stem cell function [21] and rescue cellularsenescence caused by the DNA-damaging agent doxorubicin[22]. Overall, this suggests that rapamycin could potentiallybe envisaged as a treatment to improve human health, themain drawback being its side effects such as hyperlipidaemia,although this is reversible, treatable and dose-dependent [23].

An additional cautionary note is rapamycin’s effect on theimmune system. Despite being frequently considered a potentimmunosuppressant used in organ transplant patients, recentreports describe rapamycin as a modulator of the immunesystem. This is due to its opposing roles on different immunecells: rapamycin inhibits T-cell proliferation, but promotespro-inflammatory responses in monocytes, macrophages andperipheral myeloid dendritic cells, the latter shown to protectagainst bacterial infections [24,25]. On the other hand, thesusceptibility to viral infection increases upon rapamycintreatment, because of its negative effect on genes encodinginterferons [26]. A further complex effect of rapamycin onimmunity is its enhancement of immune memory [27].

The immune response is clearly implicated in aging[28], and rapamycin modulates the immune system byaffecting both innate and adaptive immune response inmammals. However, in Drosophila at least, the main anti-aging mechanism of rapamycin seems to be independent ofimmunity, requiring alterations in autophagy and translation[18]. It should be noted that studies with laboratory mice areperformed in a pathogen-free environment, and most mousestrains are devoid of severe cardiovascular problems, whichmay be caused by hyperlipidaemia in humans. Therefore itremains to be established whether the side effects of rapa-mycin represent a valid obstacle for its usage in human agingstudies, where long-term administration would be needed. Itmay be that very low rapamycin doses could be effectivein ameliorating health and preventing age-related disease,while minimizing side effects. Alternatively, other drugs, forinstance targeting either both TORC1 and TORC2, or aspecific downstream effector of the TOR pathway, mightprove more effective for health improvement [16].

TOR signalling processes that slow agingAlteration of TOR signalling results in changes to manycellular processes, such as translation, ribosomal biogenesis,autophagy, mitochondrial activity, lipid biosynthesis andglycolysis [3,29]. Because of these numerous outputs, themechanisms responsible for TOR-mediated lifespan exten-sion await elucidation. Separating the anti-aging processesfrom the negative side effects of TOR down-regulationmay provide valuable drug targets for more robust healthimprovements compared with inhibition of the entire TORpathway. Some of the potential anti-aging processes linked tothe TOR pathway are described below.

Down-regulation of translationRegulation of translation is among the best describedfunctions of the TOR pathway, exerted mainly by TORC1

through activating phosphorylation of S6K and inhibitoryphosphorylation of 4E-BP [3]. Lowering protein synthesisin yeast, nematode worms and fruitflies promotes longevity:mutants having decreased expression of translation initiationfactors and ribosomal proteins, as well as S6K mutants,are all long-lived [11–13,30]. Lowering global translationmay be beneficial, by creating less burden for the proteinrepair and degradation machinery, leading to improvedprotein quality and fewer protein aberrations. Alternativelyor additionally, TOR inhibition may result in the preferentialtranslation of a specific set of proteins compared withtranslation under favourable growth conditions, and theseproteins may be responsible for longevity. For instance, 4E-BP activation favours translation of mRNAs that do notpossess complex secondary structures in their 5′-UTRs (5′-untranslated regions) [6,31]. In Drosophila under dietaryrestriction when 4E-BP is derepressed, there is enrichmentin mRNAs of nuclear-encoded mitochondrial genes, such asthose for the electron transport chain complexes, which areimplicated in longevity [31]. Furthermore, in yeast, depletionof the 60S ribosomal subunit leads to the reduction inprotein synthesis and extension of lifespan by specificallypromoting translation of the mRNA encoding the nutrient-responsive transcription factor Gcn4 (general control non-derepressible 4), via a mechanism of short upstream ORFs(open reading frames) [30]. Overall, complete understandingof how decreased translation governs lifespan extension andimproved health will be crucial for the unravelling the agingprocess.

Up-regulation of autophagyAutophagy is up-regulated when nutrients are low andsignalling through the TOR pathway diminishes. Autophagyconstitutes a major cellular mechanism that enables sur-vival under starvation, accomplished by lysosome-mediateddegradation of a portion of the cytoplasm captured within theautophagosome. Thereby the cell is replenished with buildingblocks such as amino acids and sources of energy to produceATP. In addition, autophagy removes damaged cellularcomponents and is the only known mechanism for degradingdamaged mitochondria. Entire bacteria can also be engulfed,thus contributing to cellular immunity [8]. Autophagy isnecessary for the lifespan-extension of daf-2 (abnormal dauerformation 2) insulin-receptor mutant nematode worms [32],of TOR pathway mutants and by dietary restriction [33]as well as for rapamycin-treated fruitflies [18]. Althoughup-regulation of autophagy is important for longevity,presumably through the removal of damage and generationof energy, increased autophagy in nematode worms doesnot seem to be sufficient for lifespan extension, becausea mutation in the forkhead transcription factor daf-16[abnormal dauer formation 16; FOXO (forkhead box O)],the main downstream effector of the IIS pathway, blocksdaf-2 longevity, but does not reduce autophagy levels [33].In contrast, in fruitflies, up-regulation of autophagy byoverexpression of the autophagy protein Atg8 is beneficialfor lifespan and it also decreases levels of protein damage [34].



Lack of more extensive genetic evidence that an increase inautophagy alone has anti-aging properties might be becauseautophagy is also a degradative process associated with celldeath. Hence, although small increases could be beneficial,extensive enhancement of autophagy may be detrimental. Itshould be mentioned that drugs that increase autophagy, suchas rapamycin and spermidine, promote longevity [35].

Importantly, autophagy is proposed as a potential targetin treatments of neurodegeneration and cancer [8]. Increasedautophagy is protective against neurodegenerative diseasesby the removal of toxic aggregates. However, the situationwith cancer is complex, and whether autophagy should beenhanced or inhibited depends on the tumour stage and type[8]. In addition, autophagy has been implicated in a varietyof cellular processes, such as lipid metabolism genomic DNAstability, degradation of ribosomes, presentation of antigensto T-lymphocytes and programmed cell death (reviewed in[8]). Thus autophagy plays a critical, but complex, role amonganti-aging processes downstream of TORC1.

Effects of the TOR pathway on metabolismThe TORC1 branch of the pathway positively regulatesglycolysis, the pentose phosphate pathway and lipidmetabolism by acting on HIF-1 (hypoxia-inducible factor1) and SREBP (sterol-regulatory-element-binding protein)[29,36]. Interestingly, lipid metabolism is important forlongevity in Caenorhabditis elegans, where germline stemcells promote lifespan extension by up-regulating a specificlipase in the intestine, which then leads to lipid hydrolysisand longevity [37]. In contrast, cancer cells depend on lipidbiosynthesis, and its inhibition by down-regulation of fattyacid synthase reduces their tumorigenic phenotype in vitroand in vivo [38].

Whole-body knockout mice for any component ofTORC1 or TORC2 are embryonic lethal. Therefore mostprogress in understanding the role of TOR signalling inmetabolism has been made with tissue-specific knockoutmice, for instance targeting raptor (regulatory associatedprotein of TOR), which is a specific and essential componentof TORC1. Interestingly, raptor knockout can either improveor damage glucose homoeostasis and mitochondrial function,depending on whether it is deleted in adipose tissue ormuscles respectively (reviewed in [39]). Presumably, thistissue specificity is partly a consequence of differences inraptor-interacting proteins present in those tissues. Whole-body knockouts of TORC1 downstream targets are alsoinformative, such as mice carrying deletions in the TORC1negative effectors 4E-BP1 and 4E-BP2, causing insulinresistance and augmented diet-induced obesity [40]. On theother hand, S6K1-null mice are long-lived, lean, resistant todiet-induced obesity, and have improved glucose toleranceand insulin sensitivity in old age [15,39,41].

Mitochondria have long been considered one of theimportant determinants of the aging process, because theygenerate energy but can also induce damage via ROS (reactiveoxygen species) production [42]. As the TOR pathwayregulates both mitochondrial activity [39] and removal of

damaged mitochondria via autophagy [8], this may underliesome of its anti-aging mechanisms.

Collectively, which energy store is used and how thisenergy is extracted seem to contribute towards health andlongevity, with low TOR signalling providing the healthiestbalance.

Stress resistanceLong-lived mutants are commonly resistant to variousstresses, such as starvation, oxidative stress and xenobiotics,and this is believed to contribute to their health and longevity[43,44]. The TOR pathway integrates various stresses, such ashypoxia signals from the transcription factors HIF-1, REDD(regulated in development and DNA damage responses) 1and 2, and cellular energy levels from AMPK (AMP-activatedprotein kinase) [4]. The output of the TOR pathway upon agiven stress depends on the cell type, the amount of stress andcell environment (reviewed in [4,45]).

Concerning aging, in C. elegans, both down-regulationand up-regulation of HIF-1 are implicated in longevity(reviewed in [11]) and overexpression of the catalytic subunitof the AMPK extends lifespan [46]. Furthermore, recentlydiscovered stress-responsive proteins, sestrins, keep TORsignalling in check by down-regulating it when it is inexcess [47]. Interestingly, sestrin-mediated inhibition of theTOR pathway, upon the presence of ROS and genotoxicstress, results in the delayed onset of various pathologies inDrosophila [47]. In general, low TOR signalling facilitatesdamage repair, promotes stress resistance and extends lifespan[4].

TOR pathway and related anti-aginginterventions, IIS and dietary restrictionBecause of its role in regulating gene expression under low-nutrient conditions, the TOR pathway has emerged as theprime candidate to mediate extension of lifespan by dietaryrestriction. Supporting this hypothesis, the lifespan of TORmutants in nematode worms [13] and fruitflies [14] cannotbe extended further by dietary restriction. It should be notedthat, rather than a cut in caloric intake, it has been suggestedthat lifespan extension by dietary restriction is mediatedby a reduction in amino acids [48,49]. Recent compellingevidence reveals that amino acid levels are communicatedto TORC1 by Rag GTPases [50], making them a potentialdruggable target that might mimic the benefits of dietaryrestriction without the difficulties of reduced food intake. Inaddition, the liver transcription profiles of long-lived S6K-null mice and mice under dietary restriction are strikinglysimilar [15]. In this respect, it has been suggested that theTORC1 inhibitor rapamycin might act as a dietary restrictionmimetic.

Besides dietary restriction and TOR signalling, IIS isanother well-established evolutionarily conserved processthat is implicated in aging from C. elegans to mice [1].Importantly, all these interventions are interconnected and,



as mentioned above, IIS and TOR signalling cross-talk atseveral levels [3]. Interestingly, the FOXO transcriptionfactor is responsible for the longevity of the mutants withdown-regulated IIS, but it is not required for the lifespanextension of TOR mutants [13]. This argues that the TOR andIIS pathways have different anti-aging downstream targets.Nevertheless, double mutants affected in both TOR and IISdo not have additive effects on lifespan [13,18]. Perhaps care-fully combining anti-aging downstream targets, thus avoidingnegative outputs of these two nutrient-sensing pathways, mayresult in additive beneficial effects on health and longevity.

ConclusionsRemarkable progress has been made in aging research overthe past decade, firmly demonstrating that the main factorsresponsible for modulating lifespan are the evolutionarilyconserved nutrient-sensing TOR and IIS network. Recentpharmacological approaches to translate these findings andtreat age-related diseases in humans have proven successful,and rapamycin is the first drug that improves longevityfrom yeast to mice. Anti-aging outputs of the TORpathway include autophagy, translation, stress responses,mitochondrial regulation and metabolism. Since the TORpathway plays an essential role in numerous key cellularprocesses, its deregulation is implicated in various diseasessuch as cancer, diabetes and neurodegeneration. Althoughthese diseases have diverse aetiologies and current treatmentstrategies, lessening TOR signalling may ameliorate healthin all instances by improving stress resistance and bycarefully adjusting metabolism. Thus drugs targeting theTOR pathway may have broad-spectrum preventive effectsfor the different diseases of old age.

Acknowledgements

We thank Helena Cocheme, Matthew Piper and Jorge Ivan Castillo

Quan for a critical reading of the paper. We are grateful to Helena

Cocheme for improving the Figure.

Funding

This work was supported by Age UK, The Wellcome Trust and The

Max Planck Society.

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Received 30 November 2010doi:10.1042/BST0390460


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A longer and healthier life with TOR down-regulation: genetics and drugs