Amino acid modulation of lifespan and reproduction in Drosophila

Amino

acid

modulation

of

lifespan

and

reproduction

in

Drosophila

Katja

M

Hoedjes,

Marisa

A

Rodrigues

and

Thomas

Flatt

Manipulatingaminoacid(AA)intakeinDrosophilacan

profoundlyaffectlifespanandreproduction.Remarkably,AA

manipulationcanuncouplethecommonlyobservedtrade-off

betweenthesetraits.Thisfindingseemstochallengetheidea

thatthistrade-offisduetocompetitiveresourceallocation,but

herewearguethatthisviewmightbetoosimplistic.Wealso

discussthemechanismsoftheAAresponse,mediatedbythe

IIS/TORandGCN2pathways.Elucidatinghowthesepathways

respondtospecificAAwilllikelyyieldimportantinsightsinto

howAAmodulatethereproduction-lifespanrelationship.The

Drosophilamodelofferspowerfulgenetictools,combinedwith

optionsforprecisedietmanipulation,toaddressthese

fundamentalquestions.

Address

DepartmentofEcologyandEvolution,UniversityofLausanne,UNIL Sorge,Biophore,CH-1015Lausanne,Switzerland

Correspondingauthor:Flatt,Thomas(thomas.fl[email protected]) 1

Presentaddress:DepartmentofBiology,UniversityofFribourg, CheminduMuse´e10,CH-1700Fribourg,Switzerland.

Introduction:

dietary

effects

on

lifespan

and

reproduction

Nutritionplaysaprimaryroleinshapingthephysiology,

life history and behavior of organisms, and nutritional

interventions can have substantial health benefits [1].

Dietary restriction (DR),that is, the reduced intake of

nutrientswithoutmalnutrition,hasbeenthemostwidely

studiednutritionalinterventionsince the1930swhenit

wasfirstdemonstratedthatDRextendslifespaninrats.

Since then, a large body of research has established

positive effects of DR on longevity and age-related

pathology in numerous organisms, ranging from yeast

and worms to insects and mammals.At the same time,

DRtypicallyreducesreproductiveoutput[2,3].Thefact

thatreducedfoodintakeextendslifespanattheexpense

of reproduction makes thestudy of DR,and of dietary

effectsmoregenerally,ofkeysignificanceforour

under-standing of the commonly observed trade-off between

reproductionand longevity[4,5].

Originally,reduced intakeofcalorieswasthoughtto be

responsibleforthelifespan-extendingeffectsofDR,but

this view began to shift when studies in Drosophila

showed that lifespan extension under DR does not

dependoncaloricrestriction[5,6].Bytesting dietswith

different nutrient compositions (‘nutritional geometry

framework’) [7], it was found that the ratio of proteins

tocarbohydrates(P:Cratio),notoverallenergeticcontent,

affects lifespan and reproduction in Drosophila [8,9].

Today,thereisgrowingevidencethatespeciallydietary

proteinsplayamajorroleinmediatingtheeffectsofDR

[10,11](butsee[12]).Remarkably,beyondtheeffectsof

the proteins themselves, recent work suggests that the

buildingblocksof proteins, thatis,specificamino acids

(AA),canprofoundlyimpactlifespanandassociatedtraits.

Forexample,inbothfliesandmice,restrictionofdietary

methioninecanextendlifespantothesameextentasDR

[13–16].

Here,wegiveabriefreviewofhowAAmodulatelifespan

andreproduction,andthetrade-offbetweenthesetraits.

Wealsoprovideashortoverviewofthemolecular

mech-anisms bywhich AAmight control thesetwo traitsand

their relationship. We focus on recent research in the

Drosophilamodel,giventhatthissystemcombines

unri-valedgenetictools,asolidunderstandingoftheeffectsof

nutritional interventions, and the availability of holidic

diets that now allow researchers to precisely control

individualdietarycomponents[14,17–19].

Amino

acids

significantly

impact

lifespan

and

reproduction

The finding that protein restriction can mediate the

effects of DR opens up thepossibility thatspecific AA

might be responsible for the effects on lifespan and

reproduction. Consistent with this idea, restriction of

dietarymethioninehasbeenfoundtopromotelongevity

inratsandmice[13,20].Similarly,Troenetal.observed

thatreduceddietarylevelsof methionineoptimize

Dro-sophilalifespan,althoughtoolowlevelsweredetrimental

[14].

Inoneofthemostcomprehensivestudiestodate,

Grand-ison and colleagues fed flies a lifespan-extending

restricted diet (i.e. DR) and then added back specific

nutrientstodeterminewhichnutrientswouldrestorethe

http://doc.rero.ch

Published in "Current Opinion in Insect Science 23 (): 118–122, 2017"

which should be cited to refer to this work.

reducedlifespanandhighfecundityoffullyfedflies[15].

Whileaddingbackcarbohydrates,lipidsorvitaminshad

no effect, adding back all AA to the restricted diet

shortened lifespan and restored fecundity to the level

seeninfullyfedflies.Furtherexperimentsshowedthat

thislifespan-shorteningandfecundity-increasingeffectis

mainly due to essential AA (EAA, i.e. those AA that

cannotbesynthesizedbythebodyandmustbesupplied

bythediet)andnotduetonon-essentialAA.Next,the

authors investigated the role of individual AA. While

adding back all EAA (DR+EAA) shortened lifespan

and restored fecundity, adding back all EAA minus

methionine(DR+EAA M)failedtoshorten lifespan,

indicating that methionine restriction canpromote

lon-gevity.Remarkably,bymanipulatingeachEAA

individ-uallyGrandisonandcoauthorsfoundthatadding

methi-onine alone to the restricted diet (DR+M) restores

fecunditytonormallevelsbutwithoutreducingthelong

lifespanofDRflies(alsosee[21]).Thesefindingssuggest

thatmethionineis—atleastpartly—responsibleforthe

lifespan-shortening effect of full feeding, even though

methionine alone (DR+M) might be insufficient to

reducelongevity.Insupportofthisidea,Leeand

colla-boratorshaverecentlyfoundthatthelifespan-extending

effectof methionine restriction dependson the overall

concentration of otherAAand requires alowAA status

[16].Also, theeffects of AA onlifespan in Queensland

fruitfliesdependonothernutrients,includingvitamins,

mineralsandcholesterol[22].

Themostfascinatingimplicationof theworkof

Grand-isonetal.isthatfine-tuningthelevelsofspecificdietary

AAcanapparently increase lifespanwithoutany loss of

fecundityorfertility[15].Lifespanextensionmightthus

berealizedwithoutcostsbyprovidingan‘optimal’diet.

Toachievesuchadiet,Piperetal.[23]usedinformation

on the exome, that is, all protein-coding genes in the

genome,todeterminewhichproportionsofAAananimal

requires. The authors found that this exome-matched

diet extends lifespan without costs in terms of growth

or reproduction.Moreover, acomparison of the

exome-baseddiettoayeast-baseddietrevealedthatmethionine

isthemostlimitingAA,whichmightexplainwhy

fecun-dity is particularly sensitive to this specific AA [23].

However,in sterile workers of theArgentine ant

(Line-pithemahumile)ant,anexome-baseddietfailedtoincrease

lifespan[24].Whetherthisfailuremightsomehowhave

to do with the fact that the workers were sterile, thus

renderingnutrientallocationtoreproductionimpossible,

remainsanopenquestion.

Dietary

uncoupling

of

the

reproduction-lifespan

trade-off

Thereproduction-lifespan trade-offassociated withDR

isofteninterpreted intermsof differentialallocationof

resourcesbetweenthecompetingdemandsof

reproduc-tionversussomaticmaintenance(the‘resourceallocation’

model).SinceDRtypicallypromotesadultsurvivalatthe

costofdecreasedfecundityorfertility,DRmight

repre-sentanadaptiveplasticresponsethatallowsorganismsto

survive poor dietary conditions by reallocating energy

away from reproduction to somatic maintenance and

survival until optimal conditions have returned

[4,5,25,26]. Alternatively, the ‘direct constraints’ model

postulatesthatreproductiveprocessescausedirect

dam-ageor impairmaintenanceandsurvival [4,5].

The finding that a simple dietary intervention, that is,

adjustingthelevels ofa single AA,canextendlifespan

without apparent growth or reproductive costs clearly

challenges both models [4,15,16,23,27]. For example,

Grandison etal. concludedthat—since adding

methio-nine back to a restricted diet can increase fecundity

without reducing lifespan—the reduction of lifespan

underfullfeedingdoesnotresultfromnutrient

realloca-tion away from survival and somatic maintenance to

reproduction[15].Insupportofthisidea,DRcanextend

Drosophila lifespan even when flies are made sterile,

suggesting that DR does not extend lifespan because it

reducesreproduction[28](butseeconflictingevidencein

Caenorhabditiselegans[29]).

While the above work clearly demonstrates that both

lifespanandreproductioncanbemaximizedunder

spe-cificdietaryconditions[15,16,23],itmightbepremature

to dismiss trade-offsas a proximateexplanation for the

effectsofDRaltogether.ThefactthatDRwith

methio-nine supplementation can restore high fecundity while

lifespanremainsextendeddoesnotlogicallyimplythat

DR-induced lifespan extension is independent of

resourcereallocation.Itrather suggeststhatmethionine

is a major limiting factor for egg production. Since on

averagemethioninedoesnotconsistentlyaffectlifespan

acrossdietaryconditionsyetgenerallyincreasesfecundity

[16], allocation or reallocation of methionine seems to

mainlyinfluencereproduction,notlifespan.Methionine

mightthusnotbedirectlysubjecttocompetitiveresource

allocationorreallocationbetweenreproductionversus

life-spanwhenconditionschangefromfullfeedingtoDR,or

viceversa.Infact, whenmethionineisraised toalevel

thatdoesnotlimiteggproductionanymore,the

lifespan-reproductiontrade-offisonceagainobserved:increasing

EAA levels further enhance fecundity at the cost of

reduced lifespan [15,16]. Together, these findings

sug-gestthatonaverageprobablymostEAAtendtonegatively

affect lifespan, while positively influencing fecundity.

Reproductionandsurvivalthusseemtohavecompeting

demandswithregardtoAAlevels:reproductionrequires

highAAlevels,but suchhighlevelsshortenlifespan.

However,oneaspectofthereproduction-longevity

trade-off that has often been overlooked is sex-specificity.

Typically, effects of DR on this trade-off have been

studied predominantly in females [8,9], presumably

duetothehigherinvestmentoffemalesthanmalesinto

reproduction. Interestingly, females and males differ

substantiallyintheirresponsetoDR[30–32];moreover,

the two sexes exhibit a dramatically different genetic

architecture of lifespan[33]. It will thus beinteresting

to see studies that contrast the physiological

conse-quences of specific dietary AA manipulations between

femalesand males.

Another open questionis how manipulationof

methio-nine or other AA affectsfitness components other than

lifespan and fecundity, for example stress resistance or

immunity. At the level of fitness, trade-offs might be

multidimensional and involvemore than twotraits. For

example,previousevidencesuggeststhatmethionine is

importantforproperfunctionalityoftheimmunesystem

[34]—methioninemightthusimproveimmunityatthe

expenseof longevity.

Altogether, the observations that single dietary AA can

have a profound impact on lifespan and reproduction,

combined with the finding that DR is independent of

caloriccontentitself[5,6],indicatethatthefieldshould

revise simplisticnotionsof‘resource’or ‘energy’

alloca-tion trade-offs. Further in-depth studies of how single

dietarycomponentsaffectvariousfitnesstraits,including

reproduction and lifespan, would provide a more

com-prehensive understanding of commonly observed

life-historytrade-offs[15,16,23].

Amino

acids

affect

lifespan

and

reproduction

via

nutrient

sensing

How, mechanistically, do AA affect reproduction and

lifespan? A prime candidate is the insulin/insulin-like

growthfactor1(IIS)/targetofrapamycin(TOR)signaling

pathway, which is known to be a major regulator of

longevityinworms,fliesandrodents[35].For example,

the centrally important transcription factor foxo

down-streamofIISmodulatestheDRresponseinflies[36,37],

and the translational repressor 4E-BP downstream of

TORisfunctionallyrequiredforlifespanextensionupon

DR [38]. Moreover, given that insulin secretion in

response to leucineand isoleucine uptake iscontrolled

throughaTOR-dependentmechanism[39],itis

tempt-ingtospeculatethatAAmightactthroughTORtoaffect

lifespanandfecundity.TheresultsofGrandisonetal.and

of Leeet al.corroboratethisidea[15,16].

Grandisonet al.found thatadding backessentialAAto

restricted diet decreases lifespan, but only to a minor

extentinfliescarryingadominant-negative(DN)formof

theinsulin-likereceptorInR, showingthatthenegative

effects of AAonlongevityrequireafunctionalreceptor

[15].Furthermore, dietary methioninesupplementation

isunabletopromotefecundityinthesemutants,

suggest-ing that the fecundity-promoting effects of methionine

alsorelyonInRfunction.Similarly,Leeandcolleagues

foundthatunderconditionswheremethioninereduction

extendslifespanof wildtypeflies, restrictionof

methio-ninenolongerextendslifespaninInRDNmutantsorin

fliesthatoverexpresstheTORantagonisttuberous

scle-rosiscomplex2(TSC2)[16].Moreover,arecentstudyby

EmranandcolleagueshasreportedthatTORsignaling,

butapparentlynotIIS,isrequiredfortheeffectsofEAA

on fecundityand lifespan[40]. These findingsare also

interesting given the observation that

methionine-defi-cient mice exhibit lowered levels of serum IGF-1 and

insulin[13].

In addition to IIS/TOR, a number of other genes and

pathwayshavebeenshowntoplayaroleinAAsignaling.

For example, the general control nonderepressible 2

(GCN2)proteinprovidesaconservedAAsensing

mech-anism that is independent of AA identity [11,41]. In

Drosophila larvae, GCN2 signaling in a small subset of

dopaminergic neurons is required for the avoidance of

dietswithunbalancedAAlevels,aprocessthatseemsto

beindependentofTORsignaling[42].Itwillbeclearly

ofgreatinteresttolearnwhetherandhowthismechanism

contributes to the AA modulation of reproduction and

lifespan.

Finally,it will beinterestingto studyhow sensory

per-ceptionofAAmodulateslifespanandreproduction,given

thatolfactoryperceptionandtastecanaffectthelifespan

of flies independent of theiractual foodintake [43,44].

ThesefindingsraisethepossibilitythatperceptionofAA

alonemightimpactlifespan.Thefirstgustatoryreceptor

forAAinflieshasrecentlybeenidentified[45].Inlarvae,

thisreceptor,IR76B,respondstoasubsetofAA,

includ-ingmethionine,andisrequiredforthebehavioral

attrac-tion tocertain AA. Theseresults demonstratethat flies

can sense and respond to specific AA. Furthermore,

internal AA status and reproductive state influence

whether flies select or reject a particular diet [46,47].

Itisparticularlynoteworthyinthiscontextthatlifespan

andfecundityhavedistinctoptimaatdifferentdietaryP:

Cratiosandthatfliescanself-regulateP:Cintakeinaway

that maximizes lifetime fecundity at the expense of

longevity [8].An improvedfutureunderstanding of the

interplay of these mechanisms might explain how flies

can maintain tight nutritional homeostasis and balance

reproductionandlifespaninawaythatoptimizesfitness.

Concluding

remarks

We endwith a potentially important caveat for

experi-mentsdesignedtostudytheeffectsofAAonlifespanand

reproduction.DietaryAAdonotoccurinisolation:most

AAin naturaldietsare partofdietaryproteins.Asseen

above, the effects of methionine on reproduction and

lifespan depend critically on the background status of

otherAAandothernutrients.Moreover,recentresearch

in ants suggests that directly providing free AA in a

defined diet shortens lifespan considerably more than

supplying the equivalent amount of AA via whole

pro-teins,potentiallyduetoadifferenceintheuptakeofAA

versus proteins, or by bypassing protein digestion. In

addition, providing free AA affects the chosen intake

ratio of proteins to carbohydrates, suggesting that the

perception of free AA and whole proteins differ [24].

Thesefindingsthusindicatethatresultsbasedon

manip-ulatingspecificAAinchemicallydefineddietsneedtobe

interpretedwithsomecaution.Nonetheless,therecanbe

nodoubtthatthebodyofworkwehavereviewedhereis

greatly advancing our understanding of how diets and

their components impact organismal reproduction and

lifespan.

Acknowledgements

WethankCarlosRibeiroandMattPiperfortheirkindinvitationto contributethispaper,andFelixZajitschekforhelpfulcomments.This paperwaswrittenaspartoftheresearchcarriedoutbytheDFG CollaborativeResearchUnit(RU)‘SocialityandtheReversalofthe Fecundity-longevityTrade-off’(DFGFOR2281).Ourresearchis supportedbytheSwissNationalScienceFoundation(SNSFgrants# PP00P3_133641;PP00P3_165836;310030E-164207toTF)andaMarie SklodowskaCurieFellowship(#701949)fromtheEUH2020program(to KMH).

References

and

recommended

reading

Papersofparticularinterest,publishedwithintheperiodofreview, havebeenhighlightedas:

 ofspecialinterest ofoutstandinginterest

1. FontanaL,PartridgeL:Promotinghealthandlongevitythrough diet:frommodelorganismstohumans.Cell2015,161:106-118.

2. PartridgeL,GemsD,WithersDJ:Sexanddeath:whatisthe connection? Cell2005,120:461-472.

3. MairW,DillinA:Agingandsurvival:thegeneticsoflifespan extensionbydietaryrestriction.AnnuRevBiochem2008, 77:727-754.

4. FlattT:SurvivalcostsofreproductioninDrosophila.Exp Gerontol2011,46:369-375.

5. TatarM:Theplatehalf-full:statusofresearchonthe mechanismsofdietaryrestrictioninDrosophila melanogaster.ExpGerontol2011,46:363-368.

6. MinK-J,FlattT,KulaotsI,TatarM:Countingcaloriesin Drosophiladietrestriction.ExpGerontol2007,42:247-251.

7. SimpsonSJ,RaubenheimerD:TheNatureofNutrition:AUnifying FrameworkfromAnimalAdaptationtoHumanObesity.Princeton UniversityPress;2012.

8. LeeKP,SimpsonSJ,ClissoldFJ,BrooksR,BallardJWO, TaylorPW,SoranN,RaubenheimerD:Lifespanand reproductioninDrosophila:newinsightsfromnutritional geometry.ProcNatlAcadSciUSA2008,105:2498-2503.

9. SkorupaDA,DervisefendicA,ZwienerJ,PletcherSD:Dietary compositionspecifiesconsumption,obesity,andlifespanin Drosophilamelanogaster.AgingCell2008,7:478-490.

10. MinK-J,TatarM:Restrictionofaminoacidsextendslifespanin Drosophilamelanogaster.MechAgeingDev2006,127:643-646.

11. SoultoukisGA,PartridgeL:Dietaryprotein,metabolism,and aging.AnnuRevBiochem2016,85:5-34.

12. SpeakmanJR,MitchellSE,MazidiM:Caloriesorprotein?The effectofdietaryrestrictiononlifespaninrodentsisexplained bycaloriesalone.ExpGerontol2016,86:28-38.

13. MillerRA,BuehnerG,ChangY,HarperJM,SiglerR, Smith-WheelockM:Methionine-deficientdietextendsmouse lifespan,slowsimmuneandlensaging,altersglucose,T4, IGF-Iandinsulinlevels,andincreaseshepatocyteMIFlevels andstressresistance.AgingCell2005,4:119-125.

14. TroenAM,FrenchEE,RobertsJF,SelhubJ,OrdovasJM, ParnellLD,LaiCQ:Lifespanmodificationbyglucoseand methionineinDrosophilamelanogasterfedachemically defineddiet.Age2007,29:29-39.

15. GrandisonRC,PiperMDW,PartridgeL:Amino-acidimbalance explainsextensionoflifespanbydietaryrestrictionin Drosophila.Nature2009,462:1061-1064.

16. LeeBC,KayaA,MaS,KimG,GerashchenkoMV,YimSH,HuZ, HarshmanLG,GladyshevVN:Methioninerestrictionextends lifespanofDrosophilamelanogasterunderconditionsoflow amino-acidstatus.NatCommun2014,5:1-12.

17. TatarM:DietrestrictioninDrosophilamelanogaster.Interdiscip TopGerontol2007,35:115-136.

18. PiperMDW,BlancE,Leita˜o-Gonc¸alvesR,YangM,HeX, LinfordNJ,HoddinottMP,HopfenC,SoultoukisGA,NiemeyerC etal.:AholidicmediumforDrosophilamelanogaster.Nat Methods2014,11:100-105.

19. ReisT:Effectsofsyntheticdietsenrichedinspecificnutrients onDrosophiladevelopment,bodyfat,andlifespan.PLOSONE 2016,11:e0146758.

20. ZimmermanJA,MalloyV,KrajcikR,OrentreichN:Nutritional controlofaging.ExpGerontol2003,38:47-52.

21. DickKB,RossCR,YampolskyLY:Geneticvariationofdietary restrictionandtheeffectsofnutrient-freewaterandamino acidsupplementsonlifespanandfecundityofDrosophila. GenetRes2011,93:265-273.

22. FansonBG,TaylorPW:Additiveandinteractiveeffectsof nutrientclassesonlongevity,reproduction,anddiet consumptionintheQueenslandfruitfly(Bactroceratryoni).J InsectPhysiol2012,58:327-334.

23.

 PiperJuricicMD,P,HeSoultoukisX,AtanassovGA,BlancI,SalmonowiczE,MesarosH,A,YangHerbertMetSL,al.: Matchingdietaryaminoacidbalancetotheinsilico-translated exomeoptimizesgrowthandreproductionwithoutcostto lifespan.CellMetab2017,25:610-621.

Onthebasisofprotein-codinggenesintheD.melanogastergenomethe authorsdevelopedanexome-matcheddiet.Remarkably,thisdietcan increaselifespanwithoutanycoststogrowthandreproduction,similarto theearlierfindingsofGrandisonetal.[15].

24.

 ArgandaParsingtheSBS,lifeshorteningBazaziS,LeeffectsHesranofS,dietaryPugaC,protein:LatilGS,effectsDASJ:of individualaminoacids.ProcRSocB2017,284:2016-2052.

Theauthorscomparetheeffectsofawhole-proteindietversusafree-AA dietonlifespan,fatmetabolismandfeedingbehaviorinants.Thestudy showsthatfreeAAshortenlifespanmorethanproteins;andthat methio-nine,serine,threonineandphenylalanineseemtohavethemost detri-mentaleffectsonlifespan.

25. BoggsCL:Understandinginsectlifehistoriesandsenescence througharesourceallocationlens.FunctEcol2009,23:27-37.

26. FlattT:Plasticityoflifespan:areactionnormperspective.Proc NutrSoc2014,73:532-542.

27. FlattT:Ageing:dietandlongevityinthebalance.Nature2009, 462:989-990.

28. MairW,Sgro` CM,JohnsonAP,ChapmanT,PartridgeL:Lifespan extensionbydietaryrestrictioninfemaleDrosophila melanogasterisnotcausedbyareductioninvitellogenesisor ovarianactivity.ExpGerontol2004,39:1011-1019.

29. CrawfordD,LibinaN,KenyonC:Caenorhabditiselegans integratesfoodandreproductivesignalsinlifespan determination.AgingCell2007,6715–721.30.

30. MagwereT,ChapmanT,PartridgeL:Sexdifferencesinthe effectofdietaryrestrictiononlifespanandmortalityratesin femaleandmaleDrosophilamelanogaster.JGerontolABiolSci MedSci2004,59:3-9.

31. MaklakovAA,SimpsonSJ,ZajitschekF,HallMD,DessmannJ, ClissoldF,RaubenheimerD,BondurianskyR,BrooksRC: Sex-specificfitnesseffectsofnutrientintakeonreproductionand lifespan.CurrBiol2008,18:1062-1066.

32. ZajitschekF,ZajitschekSR,FribergU,MaklakovAA:Interactive effectsofsex,socialenvironment,dietaryrestriction,and methionineonsurvivalandreproductioninfruitflies.Age2013, 35:1193-1204.

33. LehtovaaraA,SchielzethH,FlisI,FribergU:Heritabilityoflife spanislargelysexlimitedinDrosophila.AmNat2013, 182:653-665.

34. LiP,YinYL,LiD,KimSW,WuG:Aminoacidsandimmune function.BrJNutr2007,98:237-252.

35. PartridgeL,AlicN,BjedovI,PiperMDW:AgeinginDrosophila: theroleoftheInsulin/IGFandTORsignallingnetwork.Exp Gerontol2011,46:376-381.

36. MinKJ,YamamotoR,BuchS,PankratzM,TatarM:Drosophila lifespancontrolbydietaryrestrictionindependentof insulin-likesignaling.AgingCell2008,7:199-206.

37. GiannakouME,GossM,PartridgeL:RoleofdFOXOinlifespan extensionbydietaryrestrictioninDrosophilamelanogaster: notrequired,butitsactivitymodulatestheresponse.Aging Cell2008,7:187-198.

38. ZidBM,RogersAN,KatewaSD,VargasMA,KolipinskiMC,LuTA, BenzerS,KapahiP:4E-BPextendslifespanupondietary restrictionbyenhancingmitochondrialactivityinDrosophila. Cell2009,139:149-160.

39. Ge´minardC,RulifsonEJ,Le´opoldP:Remotecontrolofinsulin secretionbyfatcellsinDrosophila.CellMetab2009, 10:199-207.

40. EmranS,YangM,HeX,ZandveldJ,PiperMDW:Targetof rapamycinsignallingmediatesthelifespan—extending

effectsofdietaryrestrictionbyessentialaminoacidalteration. Aging2014,6:390-398.

41. GallinettiJ,HarputlugilE,MitchellJR:Aminoacidsensingin dietary-restriction-mediatedlongevity:rolesof signal-transducingkinasesGCN2andTOR.BiochemJ2013,449:1-10.

42. BjordalM,ArquierN,KniazeffJ,PinJP,Le´opoldP:Sensingof aminoacidsinadopaminergiccircuitrypromotesrejectionof anincompletedietinDrosophila.Cell2014,156:510-521.

43. LibertS,ZwienerJ,ChuX,VanvoorhiesW,RomanG,PletcherSD: RegulationofDrosophilalifespanbyolfactionand food-derivedodors.Science2007,315:1133-1137.

44. OstojicI,BollW,WatersonMJ,ChanT,ChandraR,PletcherSD, AlcedoJ:Positiveandnegativegustatoryinputsaffect DrosophilalifespanpartlyinparalleltodFOXOsignaling.Proc NatlAcadSciUSA2014,111:8143-8148.

45.

 CrosetmolecularV,SchleyerandneuronalM,ArguellobasisJR,forGerberaminoB,acidBentonsensingR:Ainthe Drosophilalarva.SciRep2016,6:34871.

The authors describe a chemosensory receptor expressed in taste neurons of D. melanogaster larvae that is activated by specific AA, includingmethionine.Thesetasteneuronsmediatefeedingbehaviorin responsetodietaryAAimbalance.

46. ToshimaN,TanimuraT:Tastepreferenceforaminoacidsis dependentoninternalnutritionalstateinDrosophila melanogaster.JExpBiol2012,215:2827-2832.

47.

 Corrales-CarvajalnutrienthomeostasisVM,FaisalbymodulatingAA,Ribeiroexploration-exploitationC:Internalstatesdrive trade-off.eLife2016,5:e19920.

Theauthorsusevideo-trackingtoexaminehowinternalAAstatusaffects feedingbehavioranddietchoice.VirginDrosophilafemalesfedan AA-deficientdietconsumemoreyeastthansucrose,whilevirginfemalesthat arenotAA-deficientdotheopposite.Moreover,AA-deficientfliesspend mostoftheirtimenearknownyeastpatches.