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The Times of Time

Timeissuchacomplexuniversethatitrequiresmuchmoreexplorationthantheseshortinsights.I/weshalltaketimetobreathe,reflect,discuss,inquire,searchselect,cherry-pickorexclude,andif-and-whentimeallows,presentafollow-uporanoveltakeontime.

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EarlyNovember2016JanW.Vasbinder,DirectoroftheParaLimesInstituteofNTUcametospendtwodaysatmyhome,andhementionedhisintentiontoorganizeamajorInternationalConferenceonTime–initsdifferentaspects-inMarch2018inSingapore.

Janisaphysicist,andhisprofessionalapproachtoTimeissomewhatdifferentfrommine.Buthe–again-sparkedinterestandthirstinme,andIdelvedintomyusualsourcesofknowledge,i.e.Google,Wikipedia,andthemyriadoftoolsavailableonline.Theharvestwasoverwhelming,andthetoughestorderwastheselectionofconcise,relevant,comprehensible(butnottotallycomprehensive),intelligibleinformation.

Thisfirstessayisadraftofanattempt.Iwascaughtbetweenbeingpontificalandsimplistic; this shows, and I failed to translate in accessible terms many highlytechnical jargons: I apologize. The list of referencesmay help some to findmoreusefulinformationandblamemyguillotine.

Eternity is long. Especially towards the end… Franz Kafka

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(Part 1)

“Time brings all things to pass” AeschylusTheLibationBearers

https://www.youtube.com/watch?v=wxMeu34o_jQ

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AsWikipedia introduces ‘Time is the indefinitecontinuedprogressofexistenceandevents that occur in apparently irreversible succession from the past through thepresenttothefuture.Timeisacomponentquantityofvariousmeasurementsusedtosequenceevents,tocomparethedurationofeventsortheintervalsbetweenthem,andto quantify rates of change of quantities in material reality or in the consciousexperience. Time is often referred to as the fourth dimension, alongwith the threespatialdimensions.’

Definingtimeinamannerapplicabletoallfieldswithoutcircularityhasconsistentlyeludedscholars.Nevertheless,diversefieldssuchasbusiness,industry,sports,thesciences, and the performing arts all incorporate some notion of time into theirrespectivemeasuringsystems.

Twocontrastingviewpointsontimedivideprominentphilosophers.Oneviewisthattimeispartofthefundamentalstructureoftheuniverse—adimensionindependentofevents,inwhicheventsoccurinsequence.IsaacNewtonsubscribedtothisrealistview,andhenceitissometimesreferredtoasNewtoniantime.

Theopposingviewisthattimedoesnotrefertoanykindof"container"thateventsandobjects"movethrough",nortoanyentitythat"flows",butthatitisinsteadpart

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of a fundamental intellectual structure (togetherwith space and number)withinwhichhumanssequenceandcompareevents.Thisview,e.g. forGottfriedLeibnizandImmanuelKant,holdsthattimeisneitheraneventnorathing,andisnotitselfmeasurablenorcanitbetravelled.

In Physics, time is unambiguously operationally defined as "what a clock reads".TimeisoneofthesevenfundamentalphysicalquantitiesinboththeInternationalSystemofUnits(SI)andInternationalSystemofQuantities(ISQ).Time isusedtodefine other quantities—such as velocity—so defining time in terms of suchquantitieswouldresultincircularityofdefinition.Anoperationaldefinitionoftime,whereinonesaysthatobservingacertainnumberofrepetitionsofoneoranotherstandard cyclical event (such as the passage of a free-swinging pendulum)constitutesonestandardunitsuchasthesecond,ishighlyusefulintheconductofbothadvancedexperimentsandeverydayaffairsoflife.

The operational definition leaves aside the questionwhether there is somethingcalledtime,apartfromthecountingactivityjustmentioned,thatflowsandcanbemeasured. Investigationsof a single continuumcalled space-timebringquestionsaboutspaceintoquestionsabouttime,questionsthathavetheirrootsintheworksofearlystudentsofnaturalphilosophy.

Furthermore, there is a subjective component to time, but is time "felt" as asensation,orisitajudgment,isstillamatterofdebate.

Measurementoftimewasaprimemotivationinnavigationandastronomy.Periodiceventsandperiodicmotionhavelongservedasstandardsforunitsoftime.Examplesincludetheapparentmotionofthesunacrossthesky,thephasesofthemoon,theswingofapendulum,andthebeatofaheart.Currently,theinternationalunitoftime,thesecond, isdefinedbymeasuring theelectronic transition frequencyofcesiumatoms.Timeisalsoofsignificantsocialimportance,havingeconomicvalue("timeismoney")aswellaspersonalvalue,duetoanawarenessofthelimitedtimeineachdayandinhumanlifespans.

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Measuring Time Chronometry takes two distinct forms: the calendar, a mathematical tool fororganizing intervals of time, and the clock, aphysicalmechanism that counts thepassageoftime.Ineveryday’slife,theclockisconsultedforperiodslessthanadaywhereasthecalendarisconsultedforperiodslongerthanaday.

Nowpersonalelectronicdevicesdisplaybothcalendarsandclockssimultaneously.

Thenumber(asonaclockdialorcalendar)thatmarkstheoccurrenceofaspecifiedeventas tohourordate isobtainedbycounting froma fiducialepoch—acentralreferencepoint.

Standards and Definitions Originallythesecondwasdefinedas1/86,400ofthemeansolarday,whichistheyear-averageofthesolarday,beingthetimeintervalbetweentwosuccessivenoons,

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i.e.thetimeintervalbetweentwosuccessivepassagesofthesunacrossthemeridian.In1832Carl-FriedrichGaussintroducedtheCGS(centimeter/gram/secondsystem)combining fundamental units of length, mass and time. This second is “elastic”,because tidal friction is slowing the earth’s rotation rate. For use in calculatingephemerides of celestial motion, therefore, in 1952 astronomers introduced the“ephemeris second”, currently defined as the fraction 1/31,556,925.9747 of thetropicalyearfor1900January0at12hoursephemeristime.

TheCGSsystemhasbeensupersededbytheSystèmeInternational(SI).TheSIbaseunitfortimeistheSIsecond.

TheInternationalSystemofQuantities,whichincorporatestheSI,alsodefineslargerunitsoftimeequaltofixedintegermultiplesofonesecond(1s),suchastheminute,hourandday.ThesearenotpartoftheSI,butmaybeusedalongsidetheSI.Otherunitsoftimesuchasthemonthandtheyeararenotequaltofixedmultiplesof1s,andinsteadexhibitsignificantvariationsinduration.

TheofficialSIdefinitionof thesecond isas follows: thesecond is thedurationof9,192,631,770periodsoftheradiationcorrespondingtothetransitionbetweenthetwohyperfinelevelsofthegroundstateofthecesium133atom.Atits1997meeting,theCIPM(ComitéInternationaldesPoidsetMesures)affirmedthatthisdefinitionrefers to a cesium atom in its ground state at a temperature of 0K. The currentdefinitionofthesecond,coupledwiththecurrentdefinitionofthemeter,isbasedonthe special theory of relativity, which affirms our space-time to be a Minkowskispace. The definition of the second in mean solar time, however, is unchanged.Atomicclocksdonotmeasurenucleardecayrates-acommonmisperception-butrathermeasureacertainnaturalvibrationalfrequencyofCesium133.

Theconceptofasingleworldwideuniversaltime-scalemighthavebeenconceivedmanycenturiesago,butinpracticalitythetechnicalabilitytocreateandmaintainsuchatime-scaledidnotbecomepossibleuntilthemid-19thcentury.ThetimescaleadoptedwasGreenwichMeanTime,createdin1847.AfewcountrieshavereplaceditwithCoordinatedUniversalTime,UTC.

TheGlobalPositioningSystemalsobroadcastsaveryprecisetimesignalworldwide,alongwithinstructionsforconvertingGPStimetoUTC.GPS-timeisbasedon,andregularlysynchronizedwithorfrom,UTC-time.

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Earthissplitupintoanumberoftimezones.Most(butnotall,e.g.India)timezonesareexactlyonehourapart,andbyconventioncomputetheirlocaltimeasanoffsetfromUTC.Inmanylocationstheseoffsetsvarytwice-yearlyduetodaylightsavingtimetransitions.WhileafewgovernmentsstilllegallydefinetheirnationaltimesasbeingbaseduponGMT,mostmajorgovernmentshavenowredefinedtheirnationaltimesasbeingbaseddirectlyuponUTC.

Siderealtimeisthemeasurementoftimerelativetoadistantstar(insteadofsolartimethatisrelativetothesun).Itisusedinastronomytopredictwhenastarwillbeoverhead.Due to the orbit of the earth around the sun a sidereal day is about 4minutes(1/366th)lessthanasolarday.

Theterm“time”isgenerallyusedformanyclose-butdifferent-concepts,including:instant;timeinterval;date;duration.

Chronology Wecanalsomeasuretimebystudyingthepast.Eventsinthepastcanbeorderedina sequence (creating a chronology), and can be put into chronological groups(periodization).Oneofthemostimportantsystemsofperiodizationisthegeologictimescale,whichisasystemofperiodizingtheeventsthatshapedtheEarthanditslife.Chronology,periodization,andinterpretationofthepastaretogetherknownasthestudyofhistory.

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Religion Many cultures ancient and recent- such as Inca, Mayan, Hopi, and other NativeAmerican Tribes -plus the Babylonians, Ancient Greeks, Hinduism, Buddhism,Jainism,andothers–haveaconceptofawheeloftime:theyregardtimeascyclicalandquantic,consistingofrepeatingagesthathappentoeverybeingoftheUniversebetweenbirthandextinction.

Conversely, the Islamicand Judeo-Christianworld-viewregardstimeas linearanddirectional,beginningwiththeactofcreationbyGod.ThetraditionalChristianviewseestimeending,teleologically,withtheeschatologicalendofthepresentorderofthings,the“endtime".

IntheOldTestamentbookEcclesiastes,traditionallyascribedtoSolomon(970–928BCE), time -as the Hebrew word עדן זמן, `iddan (time) zĕman (season) is oftentranslated-wastraditionallyregardedasamediumforthepassageofpredestinedevents.Whileanotherword, זמן"زمان "zamān,meanttimefitforanevent,andisusedasthemodernArabic,Persian,andHebrewequivalenttotheEnglishword“time”i.e.timing.

TheGreek languagedenotes twodistinctprinciples,Chronos(Χρόνος) andKairos(καιρός)Theformerreferstonumeric,orchronological,time.Thelatter,literally“therightoropportunemoment”,relatesspecificallytometaphysicalordivinetime.Intheology,Kairosisqualitative,asopposedtoquantitative.

InGreekmythology,ChronosisidentifiedasthePersonificationofTime.HisnameinGreekmeans“time”andisalternativelyspelledChronus(Latinspelling)orKhronos.Chronos isusuallyportrayedasanold,wisemanwitha long,graybeard,suchas“Father Time”. Some Englishwordswhose etymological root is khronos/chronosincludechronology,chronometer,chronic,anachronism,synchronizeandchronicle.

AccordingtoKabbalists,“time”isaparadoxandanIllusion.Boththefutureandthepastarerecognizedtobecombinedandsimultaneouslypresent.

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Philosophy of Time Abridged Philosophersalsowanttoknowwhichaspectsoftimewehavedirectexperienceof,andwhichwehaveonlyindirectexperienceof.Isourdirectexperienceonlyofthemomentary present, as Aristotle, ThomasReid, andAlexiusMeinong believed, orinstead do we have direct experience of what William James called a "speciouspresent," a short stretchofphysical time?Among thoseaccepting thenotionof aspecious present, there is continuing controversy about whether the individualspecious presents can overlap each other and about how the individual speciouspresentscombinetoformourstreamofconsciousness.AccordingtoRenéDescartes'dualisticphilosophyofmind,themindisnotinspace,butitisintime.

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Aristotleraisedtheissueofthemind-dependenceoftimewhenhesaid,“Whether,ifsoul(mind)didnotexist,timewouldexistornot,isaquestionthatmayfairlybeasked;foriftherecannotbesomeonetocounttherecannotbeanythingthatcanbecounted…”(Physics,chapter14).Hedoesnotanswerhisownquestionbecause,hesaysratherprofoundly,itdependsonwhethertimeistheconsciousnumberingofmovementorinsteadisjustthecapabilityofmovementstobenumberedwereconsciousnesstoexist.

St.Augustine,adoptingasubjectiveviewoftime,saidtimeisnothinginrealitybutexistsonlyinthemind’sapprehensionofthatreality.

The13thcenturyphilosophersHenryofGhentandGilesofRomesaidtimeexistsinrealityasamind-independentcontinuum,butisdistinguishedintoearlierandlaterpartsonlyby themind. In the13th century,DunsScotus clearly recognizedbothphysicalandpsychologicaltime.

In the20th century, thephilosopher of scienceBas vanFraassendescribed time,including physical time, by saying, “Therewould be no timewere there no beingscapableofreason” justas“therewouldbenofoodweretherenoorganisms,andnoteacupsiftherewerenoteadrinkers.”

Thecontroversyinmetaphysicsbetweenidealismandrealismisthat,fortheidealist,nothingexistsindependentlyofthemind.Ifthiscontroversyweresettledinfavorofidealism,thenphysicaltime,too,wouldhavethatsubjectivefeature.However,likevanFraassen,onecanbearealist ingeneralbutan idealistaboutcertainspecificentities.

When philosophers and scientists have said time is not real, they have meantdifferentthings:(1)thatbeingintimeisasubjectivequalitylikebeinggreenratherthan a primary quality like the frequency of lightwaves; (2) thatMcTaggart’s A-theoryisincorrectinsayingthereistemporalbecoming,andthattheB-theorywithitsblockuniverse istheproperwaytounderstandwhattimeis;(3)thatonlythepresentisreal;(4)thattheconceptoftimeisessentiallyinconsistentorincoherent;(5) that time is not fundamental but rather emerges from something morefundamental.This5thpositioncanbemeant inthesensethattimeemergesfromspacetime,orthatitemergesfromsomethingelseevenmorefundamental.The5thposition is the super-realist sense of “real” in which water and ice are not real

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becausetheyarecomposedofH20molecules,whicharemorefundamental.

ThephilosopherCraigCallenderoffersadifferentreasonforbelievingtimeisnotreal. Time is more like money, a feature of reality that exists only because ofconventions accepted by humans for their convenience. Although it would beinconvenient to do so, our society could eliminate money and return to bartertransactions.Analogously,Callenderasksus toconsider thequestion, “Whoneedstimeanyway”?

Most philosophers agree that time does exist, that it is objective rather thansubjective,andthatit isrealregardlessofwhetherit isfundamentaloremergent.Theyjustcannotagreeonwhattimeis.

Onestraightforwardanswertoourquestion,“Whatistime?”isthattimeiswhateverthetimevariabletisdenotinginthebest-confirmedandmostfundamentaltheoriesofcurrentscience(relativity,quantummechanics,andtheStandardModelofparticlephysics).Nearlyallphilosopherswouldagreethatwedolearnmuchaboutphysicaltimebylookingatthebehaviorofthetimevariableinthesefundamentalscientifictheories;buttheycomplainthatthefullnatureofphysicaltimecanberevealedonlywithaphilosophicaltheoryoftimethataddressesthemanyphilosophicalissuesthatscientistsdonotconcernthemselveswith.

Aristotleclaimedthat“timeisthemeasureofchange”(Physics,chapter12).Heneversaidspaceisameasureofanything.Aristotleemphasized“thattimeisnotchange[itself]”becauseachange“maybefasterorslower,butnottime…”(Physics,chapter10).Forexample,aleafcanfallfasterorslower,buttimeitselfcannotbefasterorslower.Indevelopinghisviewsabouttime,Aristotleadvocatedwhatisnowreferredto as the relational theorywhen he said, “there is no time apart from change….”(Physics,chapter11).Inaddition,Aristotlesaidtimeisnotdiscreteoratomisticbut“is continuous…. In respectof size there isnominimum; for every line isdividedadinfinitum.Henceitissowithtime”(Physics,chapter11).

René Descartes had a very different answer to “What is time?” He argued that amaterial body has the property of spatial extension but no inherent capacity fortemporalendurance,andthatGodbyhiscontinualactionsustains(orre-creates)thebodyateachsuccessiveinstant.Timeisakindofsustenanceorre-creation("ThirdMeditation"inMeditationsonFirstPhilosophy).

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Inthe17thcentury,theEnglishphysicistIsaacBarrowrejectedAristotle’slinkagebetweentimeandchange.BarrowsaidtimeissomethingthatexistsindependentlyofmotionorchangeandwhichexistedevenbeforeGodcreatedthematter intheuniverse.Barrow’s student, IsaacNewton,agreedwith this substantival theoryoftime.Newtonarguedveryspecificallythattimeandspacearelikeaninfinitelylargecontainerforallevents,andthatthecontainerexistswithorwithouttheevents.Headded that space and time are not material substances, but are like primarysubstancesinnotbeingdependentonanythingexceptGod.

Gottfried Leibniz objected. He argued that time is not an entity existingindependentlyofactualevents.HeinsistedthatNewtonhadunderemphasizedthefactthattimenecessarilyinvolvesanorderingofevents.Thisiswhytime“needs”events, so to speak. Leibniz added that this overall order is time. He accepted arelationaltheoryoftimeandrejectedasubstantivaltheory.

In the18thcentury, ImmanuelKant said timeandspaceare forms that themindprojectsupontheexternalthings-in-themselves.Hespokeofourmindstructuringourperceptionsso thatspacealwayshasaEuclideangeometry,and timehas thestructureofthemathematicalline.Kant’sideathattimeisaformofapprehendingphenomenaisprobablybesttakenassuggestingthatwehavenodirectperceptionoftimebutonlytheabilitytoexperienceindividualthingsandeventsintime.SomehistoriansdistinguishperceptualspacefromphysicalspaceandsaythatKantwasright about perceptual space. It is difficult, though, to get a clear concept ofperceptual space. Ifphysical spaceandperceptual spaceare thesame thing, thenKantisclaimingweknowapriorithatphysicalspaceisEuclidean.Withthediscoveryofnon-Euclideangeometriesinthe19thcentury,andwithincreaseddoubtaboutthereliabilityofKant’smethodoftranscendentalproof,theviewthattruthsaboutspaceandtimeareaprioritruthsbegantolosefavor.

Intheearly20thcentury,AlfredNorthWhiteheadsaidtimeisessentiallytheformofbecoming—acryptic,butinterestingphilosophicalclaim.

Bycontrast,aphysicsbookwillsay time is locallya linearcontinuumof instants.MichaelDummett’smodeloftimeimpliesinsteadthattimeisacompositionofnon-zeroperiodsratherthanofinstants.

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Hismodelalsoisconstructiveinthesensethatitimpliestheredonotexistanytimeswhicharenotdetectableinprinciplebyaphysicalprocess.

Is Time “Real”? Antiphon the Sophist (480-411 BCE) held that: “Time is not a reality (ὑπόστασις, hypostasis),butaconcept(νόηµα, noêma)orameasure(µέτρον, metron).”Parmenideswentfurther,maintainingthattime,motion,andchangewere illusions, leadingtotheparadoxesofhisfollowerZeno.

TimeasanillusionisalsoacommonthemeinBuddhistthought.

Theseargumentsoftencenteronwhatitmeansforsomethingtobeunreal.Modernphysicists generally believe that time is as real as space—though others, such asJulianBarbourinTheEndofTime,arguethatquantumequationsoftheuniversetaketheirtrueformwhenexpressedinthetimelessrealmcontainingeverypossiblenowormomentaryconfigurationoftheuniverse,called'platonia'byBarbour.

Thereisnoagreeduponanswertowhyouruniverseexistsinsteadofdoesn'texist,andwhyitcontainstimeinsteadofnotime,andwhyitcontainsphysicallawsinsteadof no physical laws, although there has been interesting speculation on all theserelatedissues.Assumingthattheexistenceoftimeisnotjustabrutefact,themostpopularreasonfromphysicistsforwhytimeexistsisthatatimelessandspacelessnothingisunstableandwilldecaynaturallyandinevitablytoalowerenergyinwhichthereisspacetimewithevents.Philosophersmayaskthecosmologistatthispointwhy thereare laws that imply theworldbehaves thisway,but there isa favoredanswer to this, too, which is that the laws just evolved at random without asupernaturalLawgiver.TheMultiverseTheorydescribesthisrandomevolutionaryprocess.

Giventhatspacetimeexists,whyisitnotempty—emptyofallparticlesandfields?Inother words, why isn't there pure nothingness? The leading answer from thephysicists' cosmological theories is that the philosophers' pure nothingness isunstableandthatthecosmologists'quantumvacuumismorestablebecauseitisata lowerenergythanpurenothingness.Thequantumvacuumnecessarilycontains

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particles and fields. As to the natural follow-up question of why there are lawsmaking the universe behave this way, there is an answer from the MultiverseTheory—theuniversehadtobethiswaybecauseanyspecific'way'isinevitable.Thislastpointisthatouruniversemighthavethelawsithasbyarandomprocess,byaprocess in which any possible universe inevitably arises as an actual universeaccordingtotheMultiverseTheory,inanalogytohowcontinualreshufflingadeckofcards inevitablyproducesanypossibleorderingof thecards.And to improve theanalogy,oneshouldsupposethatthereisnoSupernaturalShufflerinvolved.

Amodernphilosophicaltheorycalledpresentismviewsthepastandthefutureashuman-mind interpretations of movement instead of real parts of time (or“dimensions”)thatcoexistwiththepresent.Thistheoryrejectstheexistenceofalldirectinteractionwiththepastorthefuture,holdingonlythepresentastangible.Thisisoneofthephilosophicalargumentsagainsttimetravel.Thiscontrastswitheternalism(alltime:present,pastandfuture,isreal)andthegrowingblocktheory(thepresentandthepastarereal,butthefutureisnot).

From a biocentric point of view, time is the inner process that animatesconsciousnessandexperience.

Newexperimentsconfirmthisconcept. In2002,scientistscarriedoutanamazingexperiment,which showed that pairs of particles knew in advancewhat its twinwoulddointhefuture.Somehow,theparticlesknewwhattheresearcherwoulddobeforeithappened,asiftherewerenospaceortimebetweenthem.Morerecently(Science,2007),scientistsshotparticlesintoanapparatus,andshowedtheycouldretroactively change something that had already happened. The particles had todecide what to do when they passed a fork in the apparatus. Later on theexperimentercouldflipaswitch.Itturnsoutwhattheobserverdecidedatthatpoint,determinedwhattheparticledidattheforkinthepast.Theknowledgeinobserver'smindistheonlythingthatdetermineshowtheybehave.

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Time Travel Timetravelistheconceptofmovingbackwardsorforwardstodifferentpointsintime,inamanneranalogoustomovingthroughspace,anddifferentfromthenormal“flow”oftimetoanearthboundobserver.Inthisview,allpointsintime(includingfuturetimes)“persist”insomeway.Timetravelhasbeenaplotdeviceinfictionsincethe 19th century. Traveling backwards in time has never been verified, presentsmany theoretical problems, and may be impossible. Any technological device,whetherfictionalorhypothetical,thatisusedtoachievetimetravelisknownasatimemachine.

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Most scientists and philosophers of time agree that there is good evidence thathumantimetravelhasoccurred.Toexplain,let’sfirstclarifytheterm"timetravel."Wemeanphysicaltimetravel,notpsychologicaltimetravel,nortravelbydreamingofbeingatanothertime.HereisDavidLewis'well-accepteddefinition:

Inanycaseofphysicaltimetravel,thetraveler’sjourneyasjudgedbyacorrectclockattached to the traveler takes a different amount of time than the journey does asjudgedbyacorrectclockofsomeonewhodoesnottakethejourney.

DavidLewis'definitionoftimetravelhasnoimplicationsaboutwhether,ifyoutravelforwardtotheyear2276orbackwardto1776,youcansuddenlypopintoexistencethen,orinsteadmusthavetraveledcontinuouslythroughalltheinterveningyears.If Lewis' definition is acceptable, then any requirement that rules out suddenappearanceanddemandsspatiotemporalcontinuitywillhavetobesupportedbyanadditionalargument.Theargumentthatrelativitytheoryrequiresthiscontinuityissuchanargument.

Onepoint tokeep inmind is that even if a certainkindof time travel is logicallypossible,itdoesnotfollowthatitisphysicallypossible.Ourunderstandingofwhatis physically possible about time travel comes primarily from the implications ofEinstein’sgeneraltheoryofrelativity.Thistheoryhasneverfailedanyofitsmanyexperimentaltests,somostexpertstrustitsimplicationsfortimetravel.

Einstein’sgeneraltheoryofrelativitypermitstwokindsoffuturetimetravel—eitherby moving at high speed or by taking advantage of the presence of an intensegravitationalfield.Let'sfirstconsiderthetimetravelduetohighspeed.Actuallyanymotionproducestimetravel(relativetotheclocksofthosewhodonottravel).Thatmakes every bicycle be a timemachine. If youmove at a higher speed, then theforwardtimetravelismorenoticeable.Withextremelyhighspeed,youcanreturntoEarthtofindthattheyearis2276(asmeasuredbyclocksfixedtotheEarth)whileyourpersonalclockmeasuresthatmerelytenyearshaveelapsed.Bothclockscangivecorrectreadingsofthetime.

Youcanparticipateinthatfuture,notjustviewit.Buttimetravelthatchangesthefutureisimpossible.Andyoucannotusehighspeedinordertovisitthefutureoftheworldafteryourdeath.Norcanyoureverseyourvelocityandgobacktothetimebeforeyoubeganyourjourney.

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According to relativity theory, with time travel due to high speed, you do notsuddenly jumpdiscontinuously intothe future. InsteadyouhavecontinuallybeentravelingforwardinbothyourpersonaltimeandtheEarth’sexternaltime,andyoucouldhavebeencontinuouslyobservedfromEarth’stelescopesduringyourvoyage,althoughtheseEarthobserverswouldnoticethatyouareveryslowaboutturningthepagesinyourmonthlycalendar.

AsmeasuredbyanEarth-basedclock,ittakes100,000yearsforlighttotravelacrosstheMilkyWayGalaxy,butifyoutookthesametripinaspaceshiptravelingatverynearthespeedoflight,thetripmightlastonlytwenty-fiveyears,asjudgedbyyourownclock.Inprinciple,youhaveenoughtimetotravelanywherebeforeyoudie.

A second kind of future time travel is due to a difference in the strength of thegravitationalfieldbetweentwoplaces.IfyouleftEarthinaspaceshipthatflewclosetoablackholeandthenreturned,youmightreturnandfindthatyounowlookasyouthful as yourgrandchildrenalthoughyouwouldbemucholder than them, asjudgedbytheirclocks.Youwillnot,however,bemoreyouthfulthanthe‘you’whosteppedintothespaceship.

Howabouttraveltothepast,themoreinterestingkindoftimetravel?Thisisnotallowed by either Newton's physics or Einstein's special theory of relativity, butappearstobeallowedbythegeneraltheoryofrelativity,althoughthisclaimhasbeendisputed.In1949,KurtGödelconvincedAlbertEinsteinthatinsomeunusualworldsthatobeytheequationsofgeneralrelativity—butnotintheactualworld—youcancontinuallytravelforwardinyourpersonaltimebuteventuallyarriveintoyourownpast.

Whenwe speak of our time traveling to the future, we normallymean travel tosomeoneelse'sfuturebutnottoourownfuture.Whenwespeakofourtimetravelingtothepast,wenormallymeantraveltoourownpast.Unfortunately,saynearlyallphilosophersandscientists,evenifyoudotraveltoyourownpast,youwillnotdoanythingthathasnotalreadybeendone,orelsetherewouldbeacontradiction.Infact,ifyoudogoback,youwouldalreadyhavebeenbackthere.Forthisreason,ifyougobackintimeandtrytokillyourgrandfatherbeforeheconceivedachild,youwillfailnomatterhowhardyoutry.Youwillfailbecauseyouhavefailed.

ThemetaphysicianDavidLewisbelievesyoucaninonesensekillyourgrandfather

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butcannotinanothersense.Youcan,relativetoasetoffactsthatdoesnotincludethefactthatyourgrandfathersurvivedtohavechildren.Youcannot,relativetoasetoffactsthatdoesincludethisfact.ThemetaphysicianDonaldC.Williamsdisagrees,and argues that we always need tomake our “can” statement relative to all theavailablefacts.Lewisissayingyoucanandcan’t,andyoucanbutwon’t.

Williamsissayingsimplythatyoucan’t,soyouwon’t.

Acentralproblemwithtimetraveltothepastistheviolationofcausality;shouldaneffectprecedeitscause,itwouldgiverisetothepossibilityofatemporalparadox.

Someinterpretationsoftimetravelresolvethisbyacceptingthepossibilityoftravelbetweenbranchpoints,parallelrealities,oruniverses.

Anothersolutiontotheproblemofcausality-basedtemporalparadoxesisthatsuchparadoxes cannot arise simply because they have not arisen. As illustrated innumerousworksoffiction,freewilleitherceasestoexistinthepastortheoutcomesofsuchdecisionsarepredetermined.

Assuch, itwouldnotbepossibletoenact thegrandfatherparadoxbecause it isahistoricalfactthatyourgrandfatherwasnotkilledbeforehischild(yourparent)wasconceived.Thisviewdoesn'tsimplyholdthathistoryisanunchangeableconstant,butthatanychangemadebyahypotheticalfuturetimetravelerwouldalreadyhavehappenedinhisorherpast,resultingintherealitythatthetravelermovesfrom.

Hereareavarietyofphilosophicalargumentsagainstpast-directedtimetravel(intoone'sownpast,notmerelysomeoneelse'spast):

1. Youcouldgobackintimeandkillyourgrandfather,sothenyouwouldn’tbeborn and couldn’t goback in time andkill your grandfather. That’s acontradiction.

2. Ifpasttimetravelwerepossible,thenyoucouldbeintwodifferentbodiesatthesametime,whichismetaphysicallyimpossible.

3. Ifyouweretogobacktothepast,thenyouwouldhavebeenfatedtogobackbecauseyoualreadydid,andthisrulesoutfreewill.Yetwedohavefreewill,sotraveltothepastisimpossible.

4. Ifpasttimetravelwerepossible,thenyoucoulddiebeforeyouwereborn,whichismetaphysicallyimpossible.

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5. Ifyouwerepresentlytogobackintime,thenyourpresenteventswouldcausepastevents,whichviolatesourconceptofcausality.

6. Timetravelisimpossiblebecause,ifitwerepossible,weshouldhaveseenmany time travelers by now, but nobody has encountered any timetravelers.

7. Ifpasttimetravelwerepossible,criminalscouldavoidtheirfuturearrestbytravelingbackintime,butthatisabsurd,sotimetravelis,too.

8. Ifthereweretimetravel,thenwhentimetravelersgobackandattempttochangehistory,theymustalwaysbotchtheirattemptstochangeanything,and it will appear to anyone watching them at the time as if Nature isconspiring against them. Since observers have never witnessed thisapparentconspiracyofNature,thereisnotimetravel.

9. Traveltothepastisimpossiblebecauseitallowsthegainingofinformationforfree.Hereisapossiblescenario.BuyacopyofDarwin'sbookTheOriginofSpecies,whichwaspublishedin1859.Inthe21stcentury,enteratimemachinewithit,gobackto1855andgivethebooktoDarwinhimself.Hecouldhaveusedyourcopyinordertowritehismanuscriptthathesentoffto the publisher. If so, who first came up with the knowledge aboutevolution?NeitheryounorDarwin.Thisisfreeinformation.Becausethisscenariocontradictswhatweknowaboutwhereknowledgecomesfrom,past-directedtimetravelisn'treallypossible.

10. Thephilosopher JohnEarmandescribesarocketship thatcarriesa timemachinecapableoffiringaprobe(perhapsasmallerrocket)intoitsrecentpast.Theshipisprogrammedtofiretheprobeatacertaintimeunlessasafetyswitchisonatthattime.Supposethesafetyswitchisprogrammedto be turned on if and only if a sensing device on the ship detects the“return”or“impendingarrival”oftheprobe.Doestheprobegetlaunched?It seems to be launched if and only if it is not launched. However, theargumentofEarman’sParadoxdependsontheassumptionsthattherocketshipdoesworkas intended—thatpeopleareable tobuild thecomputerprogram, the probe, the safety switch, and an effective sensing device.Earmanhimselfsaysallthesepremisesareacceptableandsotheonlyweak

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pointinthereasoningtotheparadoxicalconclusionistheassumptionthattraveltothepastisphysicallypossible.ThereisanalternativesolutiontoEarman’sParadox.Natureconspirestopreventthedesignoftherocketshipjustasitconspirestopreventanyonefrombuildingagunthatshootsifandonlyifitdoesnotshoot.Wecannotsaywhatpartofthegunistheobstacle,andwecannotsaywhatpartofEarman’srocketshipistheobstacle.

These complaints about travel to the past are amixture of arguments that past-directedtimetravelisnotlogicallypossible,thatitisnotphysicallypossible,thatitisnottechnologicallypossiblewithcurrenttechnology,andthatitisunlikely,giventoday'sempiricalevidence.

Iftimeweretwo-dimensional,weprobablycouldtravelbackintimeanalogouslytohowwecangetbacktothestartingpointofourrunaroundanovalracetrack.Buttimeisnottwo-dimensional.

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Time as Space Althoughtimeisregardedasanabstractconcept,thereisincreasingevidencethattimeisconceptualizedinthemindintermsofspace.Thatis,insteadofthinkingabouttime in a general, abstract way, humans think about time in a spatial way andmentally organize it as such. Using space to think about time allows humans tomentallyorganizetemporaleventsinaspecificway.ThisspatialrepresentationoftimeisoftenrepresentedinthemindasaMentalTimeLine(MTL).Usingspacetothink about time allows humans to mentally organize temporal order. Manyenvironmentalfactorsshapetheseorigins–forexample,literacyappearstoplayalargeroleinthedifferenttypesofMTLs,asreading/writingdirectionprovidesaneveryday temporal orientation that differs from culture to culture. In Westerncultures,theMTLmayunfoldrightward(withthepastontheleftandthefutureonthe right) since people read andwrite from left to right.Western calendars alsocontinuethistrendbyplacingthepastontheleftwiththefutureprogressingtoward

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theright.Conversely,Israeli-Hebrewspeakersreadfromrighttoleft,andtheirMTLsunfold leftward (paston the rightwith futureon the left), andevidence suggeststhesespeakersorganizetimeeventsintheirmindslikethisaswell.

This linguistic evidence that abstract concepts are based in spatial concepts alsorevealsthatthewayhumansmentallyorganizetimeeventsvariesacrossculture–thatis,acertainspecificmentalorganizationsystemisnotuniversal.

So,althoughWesternculturestypicallyassociatepasteventswiththeleftandfutureeventswiththerightperacertainMTL,thiskindofhorizontal,egocentricMTLisnotthespatialorganizationofallcultures.

Althoughmostdevelopednationsuseanegocentricspatialsystem,thereisrecentevidence that some cultures use an allocentric spatialization, often based onenvironmentalfeatures.

ArecentstudyoftheindigenousYupnopeopleofPapuaNewGuineafocusedonthedirectionalgesturesusedwhenindividualsusedtime-relatedwords.Whenspeakingofthepast(suchas“lastyear”or“pasttimes”),individualsgestureddownhill,wherethe river of the valley flowed into the ocean.When speaking of the future, theygestureduphill,towardthesourceoftheriver.Thiswascommonregardlessofwhichdirectionthepersonfaced,revealingthattheYupnopeoplemayuseanallocentricMTL,inwhichtimeflowsuphill.

AsimilarstudyofthePormpuraawans,anaboriginalgroupinAustralia,revealedasimilardistinctioninwhichwhenaskedtoorganizephotosofamanaging“inorder,”individualsconsistentlyplacedtheyoungestphotostotheeastandtheoldestphotostothewest,regardlessofwhichdirectiontheyfaced.ThisdirectlyclashedwithanAmericangroupthatconsistentlyorganizedthephotosfromlefttoright.Therefore,this group also appears to have an allocentric MTL, but based on the cardinaldirectionsinsteadofgeographicalfeatures.

Thewidearrayofdistinctionsinthewaydifferentgroupsthinkabouttimeleadstothe broader question that different groups may also think about other abstractconceptsindifferentwaysaswell,suchascausalityandnumber.

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Time in Physics UntilEinstein’sreinterpretationofthephysicalconceptsassociatedwithtimeandspace, timewas considered to be the same everywhere in the universe, with allobserversmeasuringthesametimeintervalforanyevent.Non-relativisticclassicalmechanicsisbasedonthisNewtonianideaoftime.

Einstein,inhisspecialtheoryofrelativity,postulatedtheconstancyandfinitenessofthespeedoflightforallobservers.Heshowedthatthispostulate,togetherwithareasonabledefinitionforwhatitmeansfortwoeventstobesimultaneous,requiresthatdistancesappearcompressedandtimeintervalsappearlengthenedforeventsassociatedwithobjectsinmotionrelativetoaninertialobserver.

The theory of special relativity finds a convenient formulation in Minkowskispacetime,amathematicalstructurethatcombinesthreedimensionsofspacewithasingledimensionoftime.Inthisformalism,distancesinspacecanbemeasuredbyhowlonglighttakestotravelthatdistance,e.g.,alight-yearisameasureofdistance,andameterisnowdefinedintermsofhowfarlighttravelsinacertainamountoftime.TwoeventsinMinkowskispacetimeareseparatedbyaninvariantintervalthatcan be space-like, light-like, or time-like. Events that have a time-like separationcannot be simultaneous in any frame of reference, there must be a temporalcomponent(andpossiblyaspatialone)totheirseparation.

Events that have a space-like separation will be simultaneous in some frame ofreference, and there isno frameof reference inwhich theydonothavea spatialseparation.

Different observersmay calculate different distances and different time intervalsbetweentwoevents,buttheinvariantintervalbetweentheeventsisindependentoftheobserver(andhisvelocity).

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Spacetime Timehashistoricallybeencloselyrelatedwithspace,thetwotogethermergingintospacetimeinEinstein’sspecialrelativityandgeneralrelativity.Accordingtothesetheories,theconceptoftimedependsonthespatialreferenceframeoftheobserver,and the human perceptions aswell as themeasurement by instruments such asclocks are different for observers in relativemotion. For example, if a spaceshipcarryingaclockfliesthroughspaceat(verynearly)thespeedoflight,itscrewdoesnotnoticeachangeinthespeedoftimeonboardtheirvesselbecauseeverythingtravelingatthesamespeedslowsdownatthesamerate(includingtheclock,thecrew’sthoughtprocesses,andthefunctionsoftheirbodies).However,toastationaryobserver watching the spaceship fly by, the spaceship appears flattened in thedirectionitistravelingandtheclockonboardthespaceshipappearstomoveveryslowly.

Ontheotherhand,thecrewonboardthespaceshipalsoperceivestheobserverassloweddownandflattenedalongthespaceship’sdirectionoftravel,becausebotharemoving at very nearly the speed of light relative to each other. Because theoutsideuniverseappearsflattenedtothespaceship,thecrewperceivesthemselvesasquicklytravelingbetweenregionsofspacethat(tothestationaryobserver)aremanylightyearsapart.Thisisreconciledbythefactthatthecrew’sperceptionoftimeisdifferentfromthestationaryobserver’s;whatseemslikesecondstothecrewmight be hundreds of years to the stationary observer. In either case, however,causalityremainsunchanged:thepastisthesetofeventsthatcansendlightsignalstoanentityandthefutureisthesetofeventstowhichanentitycansendlightsignals.

Since1985,more thanhalfof theNobelprizes inphysicshavebeenawarded forworkdonemorethantwodecadespreviously.Thisyear’sprize,awardedonTuesday3October2017,wasdifferent.ItwenttoRainerWeiss,BarryBarishandKipThorne,allofwhomwereinvolvedinthefirst-everdetection,justtwoyearsago–anunusualfeat!-,ofgravitationalwaves.SuchwavesareoneofthemanypredictionsofAlbertEinstein’scentury-oldtheoryofrelativity.AsEinsteinrealized,gravityarisesfromthefactthatmassdistortsthespaceandtimearounditself.Thatdistortionmodifiesthe paths of objects moving nearby. Crunch the equations which describe theprocess,andtheysuggestthatmovingmassesshouldcreaterippleswhichradiate

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outintotheuniverse.

Severalyearsago,observationsofthebehaviorofpairsofdeadstarscalledpulsarsprovidedindirectevidencethatsuchwavesarereal.Butdetectingthemdirectlyhasprovedharder, forgravitationalwavesareephemeral things.Theonesspotted in2015camefromthecollisionofapairofblackholes,oneofthemostviolenteventsintheuniverse.BythetimetheripplesfromthatcatastrophehadreachedEarth,1.3billionyearsaftertheevent, theyhadfaded intothemerestbreath.Spottingsuchsusurrationsrequiressensitivemachines.AllthreelaureatesworkedonanAmericangravitational-wavedetectorcalledLIGO,whichwascompletedin2002.LIGOworksbysplittingalaserbeamintwoandsendingthedaughterbeamsupanddownapairoftunnels,eachfourkilometerslong,whicharesetatrightanglestoeachother.Anypassinggravitationalwaveshouldstretchandcompressthetwoarmsindifferentways,causinginfinitesimalchangesinthetimeittakesthelaserbeamstotraversethem.Inordertoconfirmthatitreallyisseeinggravitationalwavesthemachinehastwo such pairs of tunnels—one in Washington state and one in Louisiana. Agravitational wave, as opposed to some transient local disturbance, will be seenalmost(butnotquite)simultaneouslyatboth.Despiteitssensitivity,LIGO’sinitial

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runcameupempty-handed.Itwasonlyafteraseriesofupgrades,startingin2010,that it became sensitive enough to detect the waves finally and unambiguously.Spottingthemmeantrulingoutinterferencecreatedbythingslikelorriestravellingonnearbyroads,oroceanwavescrashingagainsttheshorehundredsofkilometersaway.

Since2015,morediscoverieshavebeenmade.AfewdaysbeforetheNobelaward,LIGOannouncedthedetectionofitsfourthgravitationalwave.Andmoredetectorsarecomingonline.ThemostrecentdetectionwasaidedbyaEuropeaninstrument,VIRGO,based in Italy.Otherdevicesareunderconstruction in Indiaand Japan.Aspace-basedsystemcalledLISA,with“arms”millionsofkilometerslong(and,thus,muchhighersensitivity)isscheduledforlaunchinthe2030s.Butthe2017PhysicsPrizehonorsmorethanjustanotherconfirmationofEinstein’scleverness.MachineslikeLIGOandVIRGOarenotmerelydetectors.Theycanbeusedastelescopes,too.Upuntilnow,astronomershavehadtorelyontheelectromagneticspectrum—fromradio waves, through visible light, to gamma radiation—to gaze at the universe.Gravitationalwavesofferanewwindowontheworld,andcouldhelpastronomersseethings,likeblack-holecollisionsorthestateoftheuniverse,shortlyaftertheBigBang,thatelectromagnetismcannot.

Timeappearstohaveadirection-thepastliesbehind,fixedandimmutable,whilethefutureliesaheadandisnotnecessarilyfixed.Yetforthemostpartthelawsofphysicsdonot specify anarrowof time, andallowanyprocess toproceedbothforwardandinreverse.Thisisgenerallyaconsequenceoftimebeingmodeledbyaparameter in the system being analyzed, where there is no “proper time": thedirectionofthearrowoftimeissometimesarbitrary.

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Examples of this include the Second law of thermodynamics, which states thatentropymustincreaseovertime;thecosmologicalarrowoftime,whichpointsawayfromtheBigBang,CPT(chargeparityandtimereversal)symmetry,andtheradiativearrowoftime,causedbylightonlytravelingforwardsintime.Inparticlephysics,theviolationofCP(chargeconjugationparity)symmetryimpliesthatthereshouldbeasmallcounterbalancingtimeasymmetrytopreserveCPTsymmetry.Thestandarddescriptionofmeasurementinquantummechanicsisalsotimeasymmetric.

Is the existence of change all that is required for there to be time, as Aristotlebelieved?Ifso,itisphysicallypossiblefortheretobeauniverseinwhichtimeexistsbuthasnoarrow.Ifthatuniversehadchanges,butthosechangeswereallrandominthesensethatanyprocessisnomorelikelytogoonewayratherthanthereverse,thentherewouldbetimebutnoarrowoftime.Therewouldbenoclockseither.

Somephilosophersrespondto thisreasoningbysaying it isdistasteful toallowauniverse to have time yet have no processes that could serve as clocks, so theyrecommendsayingtime'sexistencerequires,bydefinition,somesortofarrow.Theywouldsay that timemustbeacertainasymmetricorderingofeventsrather thanmightbe.Thedisputebetweenthesetwophilosophicalpositionsisstillunresolved.

Nowconsiderthedifferencebetweentime’sarrowandtime’sarrows.Thedirectionof entropy change is the thermodynamic arrow. Here are some suggestions for

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additionalarrows:

1. Causesprecedetheireffects.2. Werememberlastweek,notnextweek.3. Itiseasiertoknowthepastthantoknowthefuture.4. Thereisevidenceofthepastbutnotofthefuture.5. Ourpresentactionsaffectthefutureandnotthepast.6. Possibilitiesdecreaseastimegoeson.7. Radiowavesspreadoutfromtheantenna,butneverconvergeintoit.8. Ouruniverseexpandsinvolumeratherthanshrinks.9. Weseeblackholesbutneverwhiteholes;objects fall intobutneveroutofblackholes.

10. Bmesondecay,neutralkaondecay,andHiggsbosondecayareeachdifferentinatime-reversedworld.

11. Quantummechanicalmeasurementcollapsesthewavefunction.12. Weageandnevergetbiologicallyyounger.Mostphysicistssuspectmostofthesearrowsaresomehowlinkedsothatwecannothavesomearrowsreversingwhileothersdonot.Forexample, thecollapseofthewavefunctionisgenerallyconsideredtobeduetoanincreaseintheentropyofouruniverse.Regardingarrow12,agingisaprocessofdisorganizationaccumulatinginourcells.Itiswellacceptedthatentropyincreasecanaccountforthefactthatwerememberthepastbutnotthefuture(assumingmemoryisaformoforganization),andthateffectsfollowcausesratherthanprecedethem.However,thedetailsofthelinkageofthearrowsarestillanopenquestion.

Couldthecosmicarrowoftimehavegonetheotherway?Mostphysicistssuspectthattheanswerisyes,andtheysayitwouldhavegonetheotherwayiftheinitialconditionsofouruniverseatourBigBangeventhadbeendifferent.Thereareinitialconditionsthatmakescrambledeggsturneasilyintowholeeggsbutnotviceversa,andmakebellsun-ringbutneverring.

In1902inAppearanceandReality,theBritishidealistphilosopherF.H.Bradleysaid

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thatwhentimerunsbackwardscomparedtoourcurrentworld,"Deathwouldcomebefore birth, the blowwould follow thewound, and allmust seem irrational." TheAustralian philosopher J.J.C. Smart disagreed about the irrationality. He said allwould seem as it is now because memory would become precognition, so aninhabitantofatime-reversedworldwouldfeeltheblowandthenthewound.

G.J.WhitrowinTheNaturalPhilosophyofTime,defendedBradleyandarguedthatmemory would not become precognition; his justification was that memory, bydefinition,isofwhateverhappensfirst,so,"allmustseemirrational”.

Quantum Experiment and Time (as we think we know it)

“Wechoosetoexamineaphenomenonwhich is impossible,absolutely impossible, toexplaininanyclassicalway,andwhichhasinittheheartofquantummechanics.Inreality,itcontainstheonlymystery.”-RichardFeynman.

The concept of “time” is aweird one, and theworld of quantum physics is evenweirder.Thereisnoshortageofobservedphenomenathatdefyourunderstandingoflogic,bringingintoplaythoughts,feelings,emotions–consciousnessitself,andapost-materialistviewoftheuniverse.Thisfactisnobetterillustratedthanbytheclassicdoubleslitexperiment,whichhasbeenusedbyphysicists(repeatedly) toexplorethe role of consciousness and its role in shaping/affecting physical reality. Thedominantroleofaphysicalmaterial(Newtonian)universewasdroppedthesecondquantummechanicsenteredintotheequationandshookuptheveryfoundationofscience,asitcontinuestodotoday.

Thisquantumuncertainty is defined as the ability, “according to the quantummechaniclawsthatgovernsubatomicaffairs,ofaparticlelikeanelectrontoexistinamurkystateofpossibility—tobeanywhere,everywhereornowhereatall—untilclickedintosubstantialitybyalaboratorydetectororaneyeball.”

AccordingtophysicistAndrewTruscott,theexperimentsuggeststhat“realitydoesnotexistunlesswearelookingatit.”Itsuggeststhatwearelivinginaholographic-typeofuniverse.

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John Wheeler (1978)asksustoimagineastaremittingaphotonbillionsofyearsago,headinginthedirectionofplanetEarth.Inbetween,thereisagalaxy.Asaresultofwhat’sknownas“gravitationallensing,”thelightwillhavetobendaroundthegalaxyinordertoreachEarth,soithastotakeoneoftwopaths,goleftorgoright.Billionsof years later, if one decides to set up an apparatus to “catch” the photon, theresulting pattern would be an interference pattern. This demonstrates that thephotontookoneway,andittooktheotherway.

Onecouldalsochooseto“peek”attheincomingphoton,settingupatelescopeoneachsideofthegalaxytodeterminewhichsidethephotontooktoreachEarth.Theveryactofmeasuringor“watching”whichwaythephotoncomesinmeansitcanonlycomeinfromoneside.Thepatternwillnolongerbeaninterferencepatternrepresentingmultiplepossibilities,butasingleclumppatternshowing“one”way.

What does this mean? It means how we choose to measure “now” affects whatdirectionthephotontookbillionsofyearsago.Ourchoiceinthepresentmomentaffectedwhathadalreadyhappenedinthepast….

Thismakesabsolutelynosense,whichisacommonphenomenonwhenitcomestoquantumphysics.Regardlessofourabilitymakesenseofit,it’sreal.

Thisexperimentalsosuggeststhatquantumentanglementexistsregardlessoftime.Meaning twobits ofmatter can actuallybe entangled, again, in time.Timeaswemeasureitandknowit,doesn’treallyexist.

Quantum Gravity’s Time Problem Theoretical physicists striving tounify quantummechanics and general relativityintoanall-encompassingtheoryofquantumgravityfacewhat’scalledthe“problemoftime.”

Inquantummechanics, time isuniversalandabsolute; its steady ticksdictate theevolving entanglements between particles. But in general relativity (AlbertEinstein’s theory of gravity), time is relative and dynamical, a dimension that’sinextricably interwoven with directions x, y and z into a four-dimensional“spacetime”fabric.Thefabricwarpsundertheweightofmatter,causingnearbystufftofalltowardit(thisisgravity),andslowingthepassageoftimerelativetoclocksfar

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away.Orhopinarocketandusefuelratherthangravitytoacceleratethroughspace,andtimedilates;youagelessthansomeonewhostayedathome.

Inanewpaper(November2016),ErikVerlindeoftheUniversityofAmsterdamarguesthatdarkmatterisanillusioncausedbytheholographicemergenceofspacetimefromquantum

entanglement.

Unifying quantum mechanics and general relativity requires reconciling theirabsolute and relative notions of time. Recently, a promising burst of research onquantumgravityhasprovidedanoutlineofwhatthereconciliationmightlooklike—aswellasinsightsonthetruenatureoftime.

AsNatalieWolchoverdescribedinanarticlepublishedonDecember5th,2016inTheAtlantic on anew theoretical attempt to explain awaydarkmatter,many leadingphysicistsnowconsiderspacetimeandgravitytobe“emergent”phenomena:Bendy,curvyspacetimeandthematterwithinitareahologramthatarisesoutofanetworkofentangledqubits(quantumbitsofinformation),muchasthethree-dimensionalenvironmentofacomputergameisencodedintheclassicalbitsonasiliconchip.“Ithinkwenowunderstandthatspacetimereallyisjustageometricalrepresentationof

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the entanglement structure of these underlying quantum systems,” said Mark VanRaamsdonk,atheoreticalphysicistattheUniversityofBritishColumbia.

Researchers haveworked out themath showing how the hologram arises in toyuniversesthatpossessafisheyespacetimegeometryknownas“anti-deSitter”(AdS)space. In thesewarpedworlds, spatial incrementsget shorterandshorterasyoumoveoutfromthecenter.

Eventually, the spatial dimension extending from the center shrinks to nothing,hitting a boundary. The existence of this boundary -which has one fewer spatialdimension than the interiorspacetime,or “bulk” -aidscalculationsbyprovidingarigidstageonwhichtomodeltheentangledqubitsthatprojectthehologramwithin.“Insidethebulk,timestartsbendingandcurvingwiththespaceindramaticways,”saidBrianSwingleofHarvardandBrandeisuniversities.“Wehaveanunderstandingofhowtodescribethatintermsofthe‘sludge’ontheboundary,”headded,referringtotheentangledqubits.

Thestatesofthequbitsevolveaccordingtouniversaltimeasifexecutingstepsinacomputercode,givingrisetowarped,relativistictimeinthebulkoftheAdSspace.Theonlythingis,that’snotquitehowitworksinouruniverse.

Here,thespacetimefabrichasa“deSitter”geometry,stretchingasyoulookintothedistance.ThefabricstretchesuntiltheuniversehitsaverydifferentsortofboundaryfromtheoneinAdSspace:theendoftime.Atthatpoint,inaneventknownas“heatdeath,” spacetimewill have stretched somuch that everything in it will becomecausallydisconnectedfromeverythingelse,suchthatnosignalscaneveragaintravelbetween them. The familiar notion of time breaks down. From then on, nothinghappens.

On the timeless boundary of our spacetime bubble, the entanglements linkingtogetherqubits(andencodingtheuniverse’sdynamicalinterior)wouldpresumablyremainintact,sincethesequantumcorrelationsdonotrequirethatsignalsbesentbackandforth.Butthestateofthequbitsmustbestaticandtimeless.Thislineofreasoningsuggeststhatsomehow,justasthequbitsontheboundaryofAdSspacegive rise to an interior with one extra spatial dimension, qubits on the timelessboundaryofdeSitterspacemustgiverisetoauniversewithtime—dynamicaltime,inparticular.Researchershaven’tyetfiguredouthowtodothesecalculations.“Inde

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Sitter space,” Swingle said, “we don’t have a good idea for how to understand theemergenceoftime.”

One clue comes from theoretical insights arrived at by Don Page and WilliamWoottersinthe1980s.Page,nowattheUniversityofAlberta,andWootters,nowatWilliams,discoveredthatanentangledsystemthatisgloballystaticcouldcontainasubsystemthatappearstoevolve fromthepointofviewofanobserverwithin it.Calleda“historystate,”thesystemconsistsofasubsystementangledwithwhatyoumightcallaclock.Thestateofthesubsystemdiffersdependingonwhethertheclockisinastatewhereitshourhandpointstoone,two,threeandsoon.“Butthewholestateofsystem-plus-clockdoesn’tchangeintime,”Swingleexplained.“Thereisnotime.It’sjustthestate-itdoesn’teverchange.”Inotherwords,timedoesn’texistglobally,butaneffectivenotionoftimeemergesforthesubsystem.

A team of Italian researchers experimentally demonstrated this phenomenon in2013.Insummarizingtheirwork,thegroupwrote:“Weshowhowastatic,entangledstateoftwophotonscanbeseenasevolvingbyanobserverthatusesoneofthetwophotons as a clock to gauge the time-evolution of the other photon. However, anexternalobservercanshowthattheglobalentangledstatedoesnotevolve.”

Othertheoreticalworkhasledtosimilarconclusions.Geometricpatterns,suchastheamplituhedron,thatdescribetheoutcomesofparticleinteractionsalsosuggestthatrealityemergesfromsomethingtimelessandpurelymathematical.

It’sstillunclear,however,justhowtheamplituhedronandholographyrelatetoeachother.

Thebottom line, in Swingle’swords, is that “somehow, you can emerge time fromtimelessdegreesoffreedomusingentanglement.”

Timewilltell.

Next Step Life, human life, and the life of themyriadof livingorganisms isabsent from thisreview cum commentaries. It requires another essay, a complement or another

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vision.Breathe,rest,recoverandyouwillberewarded!Soon.

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(Part 2)

Life Clocks Time, Time Clocks Life

Every child fears getting old, really old and crippled. This fear obsesses humans,whethertheyadmititornot.Itisexclusivelyhumanandisnurturedbyallorganizedreligionsthatpromiseaparadisiaceternalafterlife–forfeesoralms.

We know that life follows a course, never strictly predictable, with bumps andelations,laughter,sorrow–andultimatelydeath.TheEndofOne’sTime,ofOne’sLife.

Life was not the prevalent, dominant issue in the time of Newtonian physics,measurement,travel,arrow(s)orevenphilosophy.

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Itwasonlywhenthebrain,hence themindwere involved that livingphenomenaemerged.Biologystudieslife,andisconfrontedtotimepermanently.ButlifeescapesNewtonian physics; it requires another system that is based on uncertainty,unpredictability,orevenchance.

My generation came to life with the lightning-speed development of quantummechanicsandphysics.ThesubatomicparticlesdidnotfitintotheNewtonianyoke;theirbehaviorwasuncertain(WernerHeisenberg)–justaslifeitself.AlbertEinsteinwas–foratime-reluctant,andunexpectedlyinvoked“God”,claimingthathe/shedidnotplaydice.Norroulette;butNewtonianphysicsdoNOTapplyverywelltoNature–i.e.life.

The prevalent, quite universal Western creed, since ancient Greece, tends torationality.RenéDescarteswas itschampion.Butthenmedicinewasamixtureofcrass ignorance,magicandreligiousblessings.Physicians (medicaldoctors)werekillingpatients,astheDiafoirusfather-and-sonofMolière.

TheteachingofQuantumMechanicsandPhysicswasabsentfromthemiddle-andhigh-schoolcurriculauntilthe1970s;Newtonian(andEuclidian!)physicsreigned,undisputed,untouchable.

The Enlightment started it all, with its rejection of blind faith, its exploration ofNature –hence Life to bring doubt, questioning, and ultimately universalexperimentalapproachthatcanbereplicated(withincertaintime limits).But thevictorywasnotwonwhenlifeisinvolved.Evenin2017–e.g.invastareasofEurope,theUnitedStatesandSouthAmerica-religiousinterdictionsrulewhenstudyinglifeisinvolved.Itgoeshand-in-glovewiththeworshipofwarandthedeathpenalty…

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Time and the Dao “Timeisacreatedthing.Tosay'Idon'thavetime,'islikesaying,'Idon'twantto.’”Laozi

TimeisimplicitintheDaodejing.ThetermDaomeansaroad,andisoftentranslatedas"theWay".Thisisbecausesometimesdaoisusedasanominative(thatis,"thedao")andothertimesasaverb(i.e.daoing).Dao is the process of reality itself, the way things come together, while stilltransforming.Allthisreflectsthedeep--seatedChinesebeliefthatchangeisthemostbasiccharacterofthings.IntheIChing易經 (ClassicofChanges,orBookofChanges)thepatternsofthischangearesymbolizedbyfigures(the“TenWings”)standingfor64relationsofcorrelativeforcesandknownasthehexagrams.Daoisthealterationoftheseforces,mostoftensimplystatedasyinandyang.TheXiciisacommentaryontheIChingformedinaboutthesameperiodastheDaodejing.It takes the Taiji太極 (Great Ultimate) as the source of correlative change andassociatesitwiththedao.The contrast is not between what things are or that something is or is not butbetweenChaos(Hundun混沌)andthewayrealityisordering(de).Yetrealityisnotorderingintooneunifiedwhole.Itisthe10,000things(Wanwu萬物).Thereisthe

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daobutnot"theWorld"or"thecosmos"inaWesternsense.

A central theme of the Daodejing is that correlatives are the expressions of themovementofdao.Correlatives inChinesephilosophyarenotopposites,mutuallyexcluding each other. They represent the ebb and flow of the forces of reality:yin/yang, male/female; excess/defect; leading/following; active/passive. As oneapproachesthefullnessofyin,yangbeginstohorizonandemerges.

JohnZerzanhasextensivelystudiedandcommentedtheDaodejing;forhimtimecanbeseenasthemasterandmeasureofasocialexistencethathasbecomeincreasinglyemptyand technicized.Time is expressedashistory -whichalso limitshumanity.History is eternal becoming and therefore eternal future. Nature is become andthereforeeternalpast.HencethecomplexityoftheYinYangsymbolanditsuniversalvalue.

Quantum Biology Takes Us Back To Laozi Thefieldofquantumbiologyappliesquantummechanicstobiologicalobjectsandproblems.Itcanbedefinedasthestudyofquantumphenomenawithinbiologicalsystems.

Many biological processes involve the conversion of energy into forms that areusable for chemical transformationsandarequantummechanical innature.Suchprocesses involve chemical reactions, light absorption, formation of excitedelectronic states, transfer of excitation energy, and the transfer of electrons andprotons(hydrogenions)inchemicalprocessessuchasphotosynthesisandcellularrespiration.

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Quantum biology uses computation tomodelbiologicalinteractionsinlightofquantummechanicaleffects.

Some examples of the biologicalphenomena that have been studied interms of quantum processes are theabsorbance of frequency-- specificradiation (i.e., photosynthesis andvision); the conversion of chemicalenergy into motion; magnetoreceptioninanimals;DNAmutationandBrownianmotorsinmanycellularprocesses.

Recentstudieshaveidentifiedquantumcoherence and entanglement betweentheexcitedstatesofdifferentpigmentsin the light-- harvesting stage ofphotosynthesis. The theory oforchestratedobjectivereductionarguesthatcoherentquantumprocesseswithinmicrotubules are the origin ofconsciousness.

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OneofthemostinfluentialpeopletolinkquantumphysicsandbiologywasErwinSchrödinger,whosebookWhatisLife?inspired,amongothers,DNApioneersJamesWatsonandFrancisCrick.

In fact, Schrödinger's viewwas based on biophysicistMaxDelbrück's theory, putforwardintheso--calledThreeManPaper,writtenwithgeneticistNikolayTimofeev--RessovskyandbiophysicistKarlZimmerin1935.

SchrödingerarguedthatifDelbrück'sviewofmutationwaswrong,then"weshouldhavetogiveupfurtherattempts",meaningwewouldhavetogiveuponusingphysicstoexplaingenes.

Delbrück'sapproachwascorrectonlyatthemostgenerallevel,andthediscoveryofthenatureofmutationsdidnotrefertohisideasatall.

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Experimentalstudiesattheinterfacebetweenquantumphysicsandthelifescienceshavesofarbeenfocusedontwodifferentquestions:

1. Cangenuinequantumphenomenaberealizedwithbiomolecules?Photon antibunching in proteins, the quantum delocalization of biodyes inmatter-waveinterferometryandtheimplementationofelementaryquantumalgorithmsinnucleotidesaresomerecentexamples.Theseexperimentsareoptimizedforrevealingfundamentalphysics,suchasquantumstatistics,delocalization,andentanglement.Buttheyallalsoshowthatquantumphenomenaarebestobservedinnear--perfectisolationfromtheenvironmentoratultralow temperatures, inorder toavoid thedetrimentalinfluenceofdecoherenceanddephasing.Theyarethusnotrepresentativeforlifeassuch.

2. Arenontrivialquantumphenomenarelevantforlife?Nontrivial quantum phenomena are here defined by the presence of long--ranged, long--lived, ormultiparticle quantum coherences, the explicit use ofquantum entanglement, the relevance of single photons, or single spinstriggeringmacroscopicphenomena.Photosynthesis, the process of vision, the sense of smell, or the magneticorientationofmigrantbirdsarecurrentlyhottopicsinthiscontext.Inmanyofthesecasesthediscussionstillcirclesaroundthebestinterpretationofrecentexperimentalandtheoreticalfindings.

a) The nuclear spins of amino acids have been used as qubits in quantum

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computingdemonstrations.b) Electron tunneling onnanometer scales has been established as a commonphenomenoninlife,forinstance,inreactionswithcytochrome.

c) Electron spin entanglement and coherent spin transport are part of anexplanationforthemagneticorientationofmigratorybirds.

d) Speculationsabouttheinfluenceofquantumphysicsonhumanconsciousnessareregardedasinspiring.

Fascinatingcombinationsofphysicsandbiologycanbeunderstoodalreadynow.Wehaveidentifiedalargenumberofinterconnectsbetweenquantumphysicsandthelifesciencesandthestatusofpresentexperimentalskillsisgreat.Butthecomplexityoflivingsystemsandhigh--dimensionalHilbertspacesisevengreater.

AsSchrödingerandothershavedemonstrated,oncewegetinsidetheatomsofthenuclei of our cells, quantum physics apply; this means that we move into animprecise,non-linearareawhereprevalence (notcertainty) reigns.Werejoin thephilosophyofLaozi.Thisaffectsusuniversally–aswellastheuniverse.

Neurosciences and Time Perception Thefieldofneurosciencesisexponentiallygrowingsincethe18thcenturyCE.It isnow using tools that are invented, created constantly, pushing back the limits ofknowledgeandopeningareasthatwereunthinkableafew…weeksago!Oneexample–thatattempts(soonsucceeds)tomimiclife-isArtificialIntelligence.Theskyisnotalimitanymore;itmightstillbethemultiverse.

Amongthemanyareassubjectedtointenseexplorationistimeperception,afieldofstudywithinpsychologyandneurosciencethatreferstothesubjectiveexperienceoflife:timeismeasuredbysomeone’sownperceptionofthedurationoftheindefiniteandunfoldingofevents.Theperceivedtimeintervalbetweentwosuccessiveeventsisreferredtoasperceivedduration.Anotherperson’sperceptionoftimecannotbedirectlyexperiencedorunderstood,but itcanbeobjectivelystudiedand inferredthroughanumberofscientificexperiments.

Timeperceptionisaconstructionofthebrainthat ismanipulableanddistortable

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undercertaincircumstances.Thesetemporalillusionshelptoexposetheunderlyingneuralmechanismsoftimeperception.

Although theperceptionof time is not associatedwith a specific sensory system,psychologistsandneuroscientistssuggestthathumansdohaveasystem,orseveralcomplementarysystems,governingtheperceptionoftime.

Timeperception ishandledby ahighlydistributed system involving the cerebralcortex,cerebellumandbasalganglia.Oneparticularcomponent,thesuprachiasmaticnucleus,isresponsibleforthecircadian(ordaily)rhythm,whileothercellclustersappear to be capable of shorter range (ultradian) timekeeping. There is someevidencethatveryshort(millisecond)durationsareprocessedbydedicatedneuronsinearlysensorypartsofthebrain

WarrenMeck found the representationof time tobegeneratedby theoscillatoryactivityofcellsintheuppercortex.Thefrequencyofthesecells’activityisdetectedbycellsinthedorsalstriatumatthebaseoftheforebrain.

Explicittimingisusedinestimatingthedurationofastimulus.Implicittimingisusedtogaugetheamountoftimeseparatingonefromanimpendingeventthatisexpectedtooccurinthenearfuture.

Implicittimingoccurstoachieveamotortask,involvingthecerebellum,leftparietalcortex,andleftpremotorcortex.

Explicit timing involves the supplementary motor area and the right prefrontalcortex.

In“TheBrain”,DavidEaglemanexplainsthatdifferenttypesofsensoryinformation(auditory,tactile,visual,etc.)areprocessedatdifferentspeedsbydifferentneuralarchitectures.Thebrainmustlearnhowtoovercomethesespeeddisparitiesifitisto create a temporally unified representation of the externalworld: “if the visualbrainwantstogeteventscorrecttimewise,itmayhaveonlyonechoice:waitfortheslowestinformationtoarrive.Toaccomplishthis,itmustwaitaboutatenthofasecond.Intheearlydaysoftelevisionbroadcasting,engineersworriedabouttheproblemofkeepingaudioandvideosignalssynchronized.Thentheyaccidentallydiscoveredthattheyhadaroundahundredmillisecondsofslop:Aslongasthesignalsarrivedwithinthiswindow,viewers’brainswouldautomaticallyresynchronizethesignals”.Hegoesontosaythat“Thisbriefwaitingperiodallowsthevisualsystemtodiscountthevarious

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delays imposed by the early stages; however, it has the disadvantage of pushingperceptionintothepast.

Thereisadistinctsurvivaladvantagetooperatingasclosetothepresentaspossible;ananimaldoesnotwanttolivetoofarinthepast.Therefore,thetenth-of-a-secondwindowmaybethesmallestdelaythatallowshigherareasofthebraintoaccountforthedelayscreatedinthefirststagesofthesystemwhilestilloperatingneartheborderofthepresent.Thiswindowofdelaymeansthatawarenessispostdictive,incorporatingdatafromawindowoftimeafteraneventanddeliveringaretrospectiveinterpretationofwhathappened.”

Experiments have shown that rats can successfully estimate a time interval ofapproximately 40 seconds, despite having their cortex entirely removed. Thissuggeststhattimeestimationmaybealowlevel(subcortical)process.

Changes with Age

Psychologistshavefoundthatthesubjectiveperceptionofthepassingoftimetendstospeedupwithincreasingageinhumans.Thisoftencausespeopletoincreasingly

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underestimateagivenintervaloftimeastheyage.Thisfactcanlikelybeattributedto a variety of age-related changes in the aging brain, such as the lowering indopaminergiclevelswitholderage.

B.Holmes,inNewScientist(Nov1996)reportsonanexperimentinvolvingagroupof subjects aged between 19 and 24, and a group between 60 and 80, whichcomparedtheparticipants’abilitiestoestimate3minutesoftime.Thestudyfoundthatanaverageof3minutesand3secondspassedwhenparticipantsintheyoungergroupestimatedthat3minuteshadpassed,whereastheoldergroup’sestimateforwhen3minuteshadpassedcameafteranaverageof3minutesand40seconds.

Veryyoungchildrenliterally“liveintime”beforegaininganawarenessofitspassing.A childwill first experience the passing of timewhen he or she can subjectivelyperceiveandreflectontheunfoldingofacollectionofevents.

Achild’sawarenessoftimedevelopsduringchildhoodwhenthechild’sattentionandshort-termmemorycapacities form—thisdevelopmentalprocess is thought tobedependentontheslowmaturationoftheprefrontalcortexandhippocampus.

Onedaytoan11-year-oldwouldbeapproximately1/4,000oftheirlife,whileoneday toa55-year-oldwouldbeapproximately1/20,000of their life.Thishelps toexplainwhyarandom,ordinarydaymaythereforeappearlongerforayoungchildthananadult.Theshort-termtimeappearstogofasterbysquarerootoftheirage.Soayearexperiencedbya55-year-oldwouldpassapproximately2¼timesmorequicklythanayearexperiencedbyan11-year-old.Iflong-termtimeperceptionisbasedsolelyontheproportionalityofaperson’sage,thenthefollowingfourperiodsinlifewouldappeartobequantitativelyequal:age5to10(1x),age10to20(2x),age20to40(4x),age40to80(8x).

Thecommonexplanationisthatmostexternalandinternalexperiencesarenewforyoungchildren,whilemostexperiencesarerepetitiveforadults.Childrenhavetobeextremelyengaged(i.e.dedicatemanyneuralresourcesorsignificantbrainpower)in the present moment because they must constantly reconfigure their mentalmodels of the world to assimilate it, and properly behave from within. On thecontrary,adultsmayrarelystepoutsideoftheirmentalhabitsandexternalroutines.Whenanadult frequentlyexperiences thesamestimuli, theirbrainrenders them“invisible”becausethebrainhasalreadysufficientlyandeffectivelymappedthose

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stimuli.

Thisphenomenonisknownasneuraladaptation.Thus,thebrainwillrecordfewerdensely richmemories during these frequent periods of disengagement from thepresentmoment.Consequently,thesubjectiveperceptionisoftenthattimepassesbyatafasterratewithage.

Effects of Drugs

Stimulants produce overestimates of time duration, whereas depressants andanestheticsproduceunderestimatesoftimeduration.

Psychoactivedrugscanalterthejudgmentoftime.

TheseincludetraditionalpsychedelicssuchasLSD,psilocybin,andmescalineaswellas the dissociative class of psychedelics such as PCP, ketamine anddextromethorphan. At higher doses timemay appear to slow down, speed up orseemoutofsequence.

Psilocybin significantly impairs the ability to reproduce interval durations longerthan 2.5 seconds, significantly impairs synchronizing motor actions (taps on acomputerkeyboard) to regularlyoccurring tones, and impairs the ability tokeeptempowhenaskedtotaponakeyataself-pacedbutconsistentinterval.

WithMescaline“timedoesnotseemtoend”.

Stimulants can lead both humans and rats to overestimate time intervals, whiledepressantscanhavetheoppositeeffect.

The level of activity in the brain of neurotransmitters such as dopamine andnorepinephrinemay be the reason for this. Dopamine has a particularly strongconnectionwithone’sperceptionoftime.

Drugsthatactivatedopaminereceptors(e.g.nicotine)speedupone’sperceptionoftime,whiledopamineantagonistscauseonetofeelthattimeispassingslowly(e.g.neuroleptics).

Effects of Clinical Conditions

Parkinson’s disease, schizophrenia, and attention deficit hyperactivity disorder

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(ADHD)havebeenlinkedtoabnormalitiesindopaminelevelsinthebrainaswellastonoticeableimpairmentsintimeperception.

Neuropharmacological research indicates that the internal clock, used to timedurations in the seconds-to-minutes range, is linked to dopamine function in thebasalganglia.StudiesinwhichchildrenwithADHDaregiventimeestimationtasksshowsthattimepassesveryslowlyforthem.ChildrenwithTourette’ssyndrome,forexample,whoneed touse thepre-frontal cortex justbehind the forehead tohelpthemcontroltheirtics,arebetteratestimatingintervalsoftimejustoverasecondthanotherchildren.

In his book “Awakenings”, Oliver Sacks discussed how patients with Parkinson’sdiseaseexperiencedeficitsintheirawarenessoftimeandtempo.Forexample,Mr.E,whenaskedtoclaphishandssteadilyandregularlydidsoforthefirstfewclapsbeforeclappingfasterandirregularly;culminatinginanapparentfreezingofmotion.Whenhefinished,Mr.Easkedifhisobserversweregladhediditcorrectlytowhichtheyreplied “no”.ThisoffendedMr.Ebecause tohim,his clapswereregularand

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steady. When given L-DOPA, these deficits are lessened or subside entirelydependingonthedose.ThiscasenotonlyshowsthatParkinson’sdiseaseisrelatedtotimeperceptiondeficitsbutitalsodemonstrateshowdopamineisinvolved.

Dopamine is also theorized to play a role in the attention deficits present withattentiondeficithyperactivitydisorder.

Specifically,dopaminergicsystemsareinvolvedinworkingmemoryandinhibitoryprocesses, both of which are believed central to ADHD pathology. Children withADHDhavealsobeenfoundtobesignificantlyimpairedontimediscriminationtasks(telling the difference between two stimuli of different temporal lengths) andrespondearlierontimereproductiontasks(duplicatingthedurationofapresentedstimulus)thancontrols.

Biological Rhythms and Chronobiology Disclosure: Since I have been personally involved in research on pharmaceuticals(mostlyofnaturalorigin)andtheircomplexmetaboliceffects (beforetheymanifestanypotentialusefulnessintherapeutics,chronopharmacologywasanintrinsic–albeitwidelyignoredorneglected-partofthatresearch.

Itstartedveryearly,sinceIcaredforasthmaticandallergicpatients. Inoticedthattiming was everything, but not by just multiplying doses over the 24 hours. Eachmedication,andeachpatienthasitsownscheduletooptimizetheeffect–orincreasedramaticallythe“side-effects”.

Alain Reinberg was my inspiration. Already when we met in 1944, as refugees inSwitzerland,heappearedasasolid,muscular,VERYsmart,witty,omniscient leader(he had fought brilliantly in theResistance duringWWII).He has acumen, flawlessjudgment,acornucopiaof ideasandaknackto identifyworthwhile trails to follow.With FranzHalberg andMichael Smolensky, he is one of the undisputed leaders inChronobiology, and possibly the inventor of chronopharmacology. At age 95 –andcounting-hestilltriumphsinsports,teaching,inspiringandtutoring,traveling,writing(includingsuccessfulnovels),andanunmatchedgenerosityandsenseofsocialjusticetoorarethesedays.Hisgroundbreakingworkopenedthegatesformyownrigorousevaluationofmanymedications,supplementsandfoodcomponents.

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Fromlefttoright:MichaelYoung,JeffreyHall,andMichaelRosbash

JeffreyHallandMichaelRosbashofBrandeisUniversityinWaltham,Massachusetts,andMichaelYoungofTheRockefellerUniversityinNewYorkCitysharedthe2017NobelPrizeinPhysiologyandMedicineequallyfortheirworkonhowseveralgenesworktogethertocontrolthebasiccircadianclock,encodingproteinsthatbuildupduringthenightandarebrokendownduringtheday.Theseclocksaretickinginsideplants,fungi,protozoa,andanimals.Inrecentyears,researchershavefoundthattheclockisrelatednotonlytooursleepcycle,butalsotometabolismandbrainfunction.

Circadian, or daily,rhythms are “just as fundamental as respiration,” saysCharalambosKyriacou,amoleculargeneticistat theUniversityofLeicester in theUnited Kingdom. “There isn’t any aspect of biology that circadian rhythms aren’timportantfor.Theyaretotallyfundamentalinawaythatwedidn’tanticipate”beforethediscoverieshonoredbythisNobelPrize.

Thepresenceofabiologicalclockwasalreadysurmisedinthe18thcentury.In1729,French astronomer Jean Jacquesd'OrtousdeMairan showed thatmimosa leaves,which open at dawn and close at dusk, continued this cycle even when kept indarkness.Butitwasn'tuntilthe20thcenturythattheideaofaninternalclock—asopposedonethatrespondstoexternalcueslikelight—wassettled.

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Thegeneticbasisforadailyphysiologicalcyclewasfirstdiscoveredinfruitfliesinthe 1970s. Seymour Benzer and Ronald Konopka at the California Institute ofTechnology inPasadenacreatedmutant flies thathadabnormalbiological clocks.One type had a broken clock—its patterns of activity became arhythmic—whereasthe others now had either a 19-hour ora 28-hour cycle. Benzer andKonopkashowedthemutationsallhadhitthesamegene,presumablyindifferentways.Theyandotherresearchershomedinonagenecalledperiod.

HallandRosbashfinallysequencedthegenein1984,asdidYoung.HallandRosbashshowed that itsprotein, calledPER, roseand fellover24hours,peakingatnight.They suspected the clock was driven by a feedback loop, with the protein PERinterferingwiththeperiodgene.(“Itmakesyouscratchyourheadandwonderifit’sevenpossible,”Youngsaidin1985.

Fortheclocktowork,PERhadtogetintothenucleus.Youngfiguredouthowthathappened.In1994,heandcolleaguesdiscoveredasecondclockgene,timeless,thatallowedPERtoenterthenucleusandstopperiodfrommakingmore.

Researchershavesincefoundhalfadozenmoregenesthatinfluencethecycle.Forexample,periodandtimelessare turnedonbyclock,discovered in1997by JosephTakahashi,nowatUTSouthwestern inDallas,Texas,andhiscolleagues.Withinayear,thisgroupdiscoveredanotherkeypartofthefeedbackloop:WhenPERandTIMgetintothenucleus,theyalsocurtailtheactivityoftheclock.

Clockgenesareextremely influential,affectingtheactivityofmostothergenes inthebodyinonewayoranother.Circadianmechanismsinfluencemetabolism—howourbodyusesandstoresenergy—bloodpressure,bodytemperature,inflammation,andbrainfunction.Timeofdaycaninfluencetheeffectivenessofdrugsandtheirsideeffects. And mismatches between the clock and the environment, for instancebecauseofjetlagorshiftwork,havebeenshowntoplayaroleinmooddisordersandevencancerrisk.

“Since the seminal discoveries by the three laureates,”the Nobel Assemblywrote,“circadianbiologyhasdevelopedintoavastandhighlydynamicresearchfield,withimplicationsforourhealthandwellbeing.”

Everylivingorganismdependsonrhythms,cycles,regularchangesthatoftenvaryovertime.

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We all know some: birth-infancy-childhood-adulthood-seniority and death; thecardiacbeats;ourbreathing;wakeandsleep;eating,digestion,excretion;etc.

Theterm Chronobiology comes from the ancient Greek χρόνος, already presented, and biology, that pertains to the study, or science, of life. The related terms chronomics and chronome have been used in some cases to describe either the molecular mechanisms involved in chronobiological phenomena, or the more quantitative aspects of chronobiology, particularly where comparison of cycles between organisms is required.

Chronobiological studies include but are not limited to comparative anatomy, physiology, genetics, molecular biology and behavior of organisms within biological rhythms mechanics. Other aspects include development, reproduction, ecology and evolution.

Thevariationsofthetiminganddurationofbiologicalactivityinlivingorganismsoccur formanyessential biologicalprocesses.Theseoccur (a) in animals (eating,sleeping,mating, hibernating,migration, cellular regeneration, etc.), (b) in plants(leafmovements,photosyntheticreactions,etc.),andinmicrobialorganismssuchasfungi andprotozoa.Theyhaveevenbeen found inbacteria, especiallyamong thecyanobacteria(akablue-greenalgae).

Physiologicalprocessesinalltheseorganismsthecircadianrhythm-aroughly24-hourcycleshowthemostimportantrhythminchronobiology.Thetermcircadiancomes from the Latin circa, meaning “around” and dies, “day”, meaning“approximatelyaday.”Circadianclocksregulateit.

Thecircadianrhythmcanfurtherbebrokendownintoroutinecyclesduringthe24-hourday:

- Diurnal,whichdescribesorganismsactiveduringdaytime

- Nocturnal,whichdescribesorganismsactiveinthenight

- Crepuscular,whichdescribesanimalsprimarilyactiveduring thedawnandduskhours(ex:white-taileddeer,somebats)

While circadian rhythms are defined as endogenously regulated, other biologicalcyclesmayberegulatedbyexogenoussignals.Insomecases,multi-trophicsystemsmayexhibitrhythmsdrivenbythecircadianclockofoneofthemembers(whichmayalsobeinfluencedorresetbyexternalfactors).

Manyotherimportantcyclesarealsostudied,including:

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- Infradian rhythms, which are cycles longer than a day, such as the annualmigrationorreproductioncyclesfoundincertainanimalsorthehumanfemalemenstrualcycle.

- Ultradian rhythms,whichare cycles shorter than24hours, suchas the90-minute REM cycle, the 4-hour nasal cycle, or the 3-hour cycle of growthhormoneproduction.

- Tidalrhythms,commonlyobservedinmarinelife,thatfollowtheroughly12.4-hourtransitionfromhightolowtideandback.

- Lunarrhythmsfollowthelunarmonth(29.5days).Theyarerelevante.g.formarinelife,asthelevelofthetidesismodulatedacrossthelunarcycle.

- Geneoscillations–somegenesareexpressedmoreduringcertainhoursofthedaythanduringotherhours.

More recently, light therapy and melatonin administration have been activelystudiedtoresetanimalandhumancircadianrhythms.Additionally,thepresenceoflow-levellightatnightacceleratescircadianre-entrainmentofhamstersofallagesby50%; this is thought tobe related to simulationofmoonlight.Humans canbemorning people (disclosure: I am one of these due to the FSAPS gene) or eveningpeople; these variations are called chronotypes for which there are variousassessmenttoolsandbiologicalmarkers.

As reported by Veronique Greenwood (New York Times, 8November 2017(https://nyti.ms/2hSZd3x) our sense of smellmay fluctuate insensitivityover thecourseof24hours,intunewithourcircadianclocks,withournosebestabletodoits jobduring thehoursbeforewego to sleep,according toastudy published 17 October 2017 in the journalChemical Senses(https://doi.org/10.1093/chemse/bjx067), and is part of alarger push to explorewhether adolescents’ senses of taste and smell influenceobesity.

Rachel S. Herz, a sensory researcher at Brown University, and her colleaguesdesigned thisstudy tosee if theremightbe timesofdaywhen thesenseofsmellwasmorepowerful—perhapsmakingfoodsmellparticularlyinviting.Fortheexperiment,37adolescentsranginginagefrom12to15cameintoalabforaverylongsleepoverparty.Forninedays,theyfollowedastrictscheduletoallow

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researcherstofocusonthecircadianclock,whichhelpscontrolwakeandsleep,butalsoinfluencesotherprocessesinthebody,includingmetabolism.Dr.Herzsaysthatasyougrowup,themakeupofthesmellreceptorsinsideyournosedoesn’tseemtochange,althoughthereisevidenceyourbodyclockmay.

The team kept track of where the teenagers were in their circadian cycle bymeasuringtheirsaliva’slevelsofmelatonin,ahormonethatrisesandfallsregularlyoverthecourseof24hours.Everyfewhours,thesubjectstookascenttest,sniffingdifferent concentrations of a chemical that smells like roses. The researchersrecordedthelowestconcentrationtheycoulddetectateachtimepoint.

Whentheresultsweretalliedup,theresearcherssawarangeofresponses.“Nobodyhasthesamenose,”Dr.Herzsaid.Someadolescentshadonlyverymildchangesinsensitivity,whilesensitivityaltereddramaticallyinothers.

Averagedtogether,however,theresultsshowedthatoverallthecircadianclockdoesaffectsmell,andthatthetimeswhenthesubjects’nosesweremostsensitivetendedtocorrespondtotheevening,withanaveragepeakof21:00.

“Theresultsmakesense—thecircadianclockaffectsvirtuallyeveryorgansysteminthe body,” writes Dr. Leslie Vosshall, a researcher at Rockefeller University whostudiessmellandwasnotinvolvedinthestudy.

Smellwasat its lowest ebb, intriguingly, fromabout02:00 to10:00. It is alreadyknownthatwhenweareasleep,astrongsmellwon’tdisturbusthewayaloudnoiseorabrightlightwill.Perhapsthebiologicalmachinerybehindsmellshutsitselfdownforthenight,atleastinsomepeople.ButDr.Herzspeculatesthathavingstrongerolfactory abilities as dusk fellmight have helped our ancestors survive. “It reallyunderscores the importanceofauditory firealarms,” shesaid.Still, theexperimentwasdesignedtotesttheeffectofthecircadianclock,andthatisnottheonlyfactorinvolvedinsmellsensitivity.Researchershavealreadyfoundthatanotherbigplayerishow long someonehasbeenawakeandwhatvarietyof smells theyhavebeenexposed to. It’s likely that all these have a role in determiningwhen, in real lifeoutsidethelab,oursenseofsmellworksbest.

There is also a food-entrainable biological clock that seems to be located in thedorsomedialhypothalamus.Duringrestrictedfeeding,ittakesovercontrolofsuchfunctions as activity timing, increasing the chances for successfully locating food

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resources–atleastinrodents.

Anewstudysuggeststhattimingalsomattersinskinhealing:skincellsthathelppatchupwoundsworkmorequicklyinthedaytimethantheydoatnight,thankstotheworkingsofourcircadianclock.Patientsmightrecoverfrominjurymorequicklyiftheyhavesurgeryduringtherighttimeofday.

Biologists andneuroscientists long thought thebody’s timekeeper, our circadianclock, resided only in the brain. In mammals, that place is a region of thehypothalamuscalledthesuprachiasmaticnucleus,whichreceivessignalsfromtheeyes.However,recentresearchdemonstratedthatcellsinotherpartsofthebody—includingthe lungsand liver—keeptheirowntime.Researchersaren’tquitesurehowtheymaintaintheirown24-hourschedule,whereasothercellsneedexternalreminders.

JohnO’Neill,abiologistattheMedicalResearchCouncil’sLaboratoryofMolecularBiology in Cambridge, U.K., and his team studied a type of skin cell known asfibroblaststhatareessentialforwoundhealing.Fibroblastsinvadethevoidleftbyascratchandlaythefoundationfornewskintogrow.

Thecellsarealsoknowntokeeptheirowntime.Forexample,culturedcellsexhibitrhythmicoscillations ingeneexpressionwhere there isno input fromthemasterclock.Giventhefibroblasts’time-keepingabilities,O’Neillandcolleaguessearchedforproteinswithinthecellsthatebbandflowwithdailyrhythms.Theycamebackwithanunexpectedresult:proteinsthatdirecttheconstructionofthecell’sactin-basedskeletonworkeddaytimeshifts.Thesecellularcontractorstellfibroblaststomoveintoaninjurytobeginthehealingprocess;thefindingsuggestedthatthetimeofdayawoundoccursmayaffecthowquicklyitheals.

TheresearchersthentestedthathypothesiswithcellsgrowninaflatlayerinaPetridish.Thefibroblasts filled inscratchesmorequicklyduringthedaythanatnight.“Youcanseebyeye,whenthecelliswoundedonly8hoursapartfromeachother,inadifferentcircadianphase,the[daytime]woundedonestakeoff,andthe[nighttime]onedrags,”O’Neillsaid.

Theresearchersthenshowedinmicethatskinwoundssufferedduringtheirwakinghours healed better than ones incurred during their resting hours.What’smore,thoseincreaseslinedupwiththecellculturedata.Abouttwiceasmanyfibroblasts

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migratedintothedaytimewoundsasnighttimeones.

“Wewerereallyastonished,”O’Neillsaid.Finally,O’Neillandcolleagues lookedforevidenceofsuchaneffectinhumans.TheteamexamineddatafromtheInternationalBurnInjuryDatabase,whichrecords,amongotherthings,thetimeofdayaninjuryoccurred. The analysis revealed that nighttimeburns took an average of 11dayslonger to heal than burns incurred during the day, the researchers reported inScienceTranslationalMedicineonNovember8,2017.

O’Neill emphasized theneed for further controlled clinical studies to confirm theeffect.Hespeculatesthatifreal,theeffectcouldhelppeoplerecovermorequicklybyscheduling surgeries in time with their personal circadian rhythms, earlier formorninglarksandlaterfornightowls.

Theresearcherssaythatfibroblasts’time-varyingresponsemaybeanevolutionaryadaptation.Aspeoplearemore likely tosustain injurieswhenprimedtorespondmorequicklyinthedaytime.

Chronobiologyisaninterdisciplinaryfieldofinvestigation.Itinteractswithmedicalandotherresearchfieldssuchassleepmedicine,endocrinology,geriatrics,sportsmedicine,spacemedicineandphotoperiodism.

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Chronopharmacology Most facetsofmammalianphysiologyandbehaviorvaryaccordingtotime-of-daythankstoanendogenous“circadian”clock.Therefore,itisnotsurprisingthatmanyaspectsofpharmacologyandtoxicologyalsooscillateaccordingtothesame24-hourclocks. Daily oscillations in abundance of proteins necessary for either drugabsorptionormetabolismresultincircadianpharmacokinetics;andoscillationsinthe physiological systems targeted by these drugs result in circadianpharmacodynamics.Theseclocksarepresentinmostcellsofthebody,butorganizedinhierarchicalfashion.Interestingly,someaspectsofphysiologyandbehaviorarecontrolled directly via a “master clock” in the suprachiasmatic nuclei of thehypothalamus,while “slave” oscillators in separate brain regions or body tissuescontrol others. Recent research shows that these clocks can respond to differentcues,andtherebyshowdifferentphaserelationships.

Therefore,fullpredictionofchronopharmacologyinpathologicalcontextswilllikelyrequire a systems biology approach considering “chrono-interactions” amongdifferentclock-regulatedsystems.

As a result of living on a planetwhose principal source of light and heat is onlyperiodicallypresent,organismsonEarthrapidlyadaptedphysiologicalsystemstoexploit thesevariations formaximumfitness.Collectively, theseclocksarenamed“circadian”(Latin:circadiem–aboutaday).Inmammals,circadianclocksinfluenceallmajororgansystems,andthisinfluencetranslatesdirectlyintodiseasepathologythatalsovarieswithtimeofday.

Historically,itwasearlyrecognizedthatrhythmicphysiologyresultedinrhythmicdiseasesymptoms.Hippocratesalreadynoticedca.400BCEthatdaytimesleepinessisindicativeofdisease,andnighttimesleeplessnesscanindicatepainandsuffering.Bymedievaltimes,reportsexistedofdailyvariationsindiseasessuchasbronchialasthma. For over thirty years, it has been known that drug absorption anddistributionissubjectedtodiurnalvariationinrodentsandhumans.Atwenty-four-hourchangeindrugbioavailabilityhasthereforebeenestablishedforhundredsofdrugs in rodents and humans. For example, acetaminophen/paracetamol ortheophylline(seeFig.)showdifferentpharmacokineticsinthemorningcomparedtoevening.Thesechangesaretheresultsofseveraltime-dependentmodificationsof

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physiologicalandmolecularaspectsthatinfluencedrugabsorptionanddistribution.

Considering thewide scope of circadian (patho-) physiology, it is logical that thepharmacodynamics and pharmacokinetics (PK/PD) of many drugs would becircadian,andthereforethatdrugefficacyandsafetyprofileswouldalsovarywithtimeofday.

Nevertheless, clinicians, drugdevelopers, or regulatorsonly seldomconsider thisvariation. Inpart, this apathymay stem froma lackof insight into themolecularmechanisms governing this control. However, two decades of intensive researchhave uncovered a wealth of information not only about basic mechanisms ofcircadianclocks,butalsoabouthowtheyinteractwithphysiologyanddisease.

Thebasicunitofcircadiantimekeepingisthecell:eveninverycomplexorganisms,most cells contain autonomous circuitry for circadian oscillations. Generallyspeaking,thismechanismiscomprisedofnegativefeedbackloopsoftranscriptionandtranslation:activationofarepressorgeneresultsinitslaterrepressionbyitsownproteinproduct,andtheinstabilityofthisrepressorinsuresthisrepressionisshort-lived,sothatanewcyclecanbegin.

Inmammals,theprincipalactivatorswithinthissystemaretheCLOCKandBMAL1proteinsandtheirhomologs,whichdimerizeandbindtocis-actingE-boxelements(withthesimpleconsensusDNAsequenceCAANTG)toactivate transcriptionofalargenumberofcircadiangenes.

Therearemanysteps,andateachofthesesteps,additionalprecisionandregulatoryfinesse is achieved through interaction with a wide range of auxiliary proteins:kinases that phosphorylate clock proteins to modify their stability or activity;chromatinmodifyingproteinsthatphosphorylate,acetylate,ordeacetylatehistonesandinsomecasesclockproteinstoregulatechromatinstructureandtranscriptionalactivation potential; and RNA-binding proteins that serve as scaffolds forcoactivatingandcorepressingactivities(seeFig.).

Aparallelandindependentcircadianmechanismindependentoftranscriptionalsoexists in parallel to the “canonical” transcription-translation-based clock inmammaliancells.Evidenceofthisoscillatorexistsintheformofdiurnalvariationinoxidationstatesofhemoglobinandantioxidantmolecules.Boththemechanismandthe physiological relevance of these posttranslational clocks remain unknown in

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mammals, though posttranslational clocks based on phosphorylation are wellstudiedinbacteria.

ThecanonicalmammaliancircadianoscillatorandoutputrelevantforxenobioticmetabolismTwo interlocked feedback loops composed of activators (green) and repressors (red) that drive gene expression of output genes such as those important for xenobiotic metabolism. Components of these loops make extensive use of auxiliary factors including histone methyltransferases (HMTs), histone deacetylases (HDACs), DHBS family RNA-binding proteins (beige), and kinases and proteasome machinery (grey). Important output genes, involved in transcriptional control of the detoxification metabolism (blue).

Thebasictimekeepingmechanismofcircadianoscillators iscell-autonomous,andself-sustained clocks exist in most cells of the body. However, under mostcircumstancestheseclocksareorganizedintoahierarchy:a“masterclock”tissuewithinthesuprachiasmaticnuclei(SCN)ofthehypothalamusreceiveslightinputviathe retina, and communicates timing signals to “slave” oscillators of similar

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molecularmechanismincells fromothertissues.Multipleredundantsignalshavebeen described. These include direct signals like innervation by the autonomousnervoussystemandhormoneslikeglucocorticoids,andindirectsignalsemanatingfrom SCN-controlled rhythmic behavior, such as timing of food intake and smallrhythmicchangesinbodytemperaturefromactivity.

Undermostcircumstances,entrainmentsignalsfromtheSCNtoclocksinperipheraltissues act in concerted fashion, resulting in somewhat coherent phase amongdifferentorgans.Theexactphaseofcircadianclocksvariessomewhatfromorgantoorgan, perhaps because of tissue-specific differences in clock gene expression, orperhaps due to local differences in accessibility to entrainment signals. Thesedifferences become particularly acute under certain perturbation. For example,duringanalteredlightingcyclecausedbytimezonetravelorshiftwork,theSCNwillshift its phase much more quickly (within a day or two) than peripheral clocks(whichcantakeaweekormore),creatingasituation inwhichclocks indifferentorgans exhibit gross differences in “internal clock time”. Similarly, systematicmanipulationofexternalcuessuchasfeedingtimetodifferentphasesofthelight-darkcycleresultinaphasechangeforperipheralclocks,butnotfortheSCN.

This hierarchical clock structure has two important implications forchronopharmacology.

First, if clocks in different tissues govern different aspects of drug activity andmetabolismthenthesedifferentphasesmustbeconsideredincalculatingthetimingfor optimal drug efficacy. The situation is further complicated because recentresearchsuggeststhatthesephaserelationshipsarealteredbyage:olderrodentsshowlaterSCNphasesbutearlierperipheralclockphases.

Secondly, increasingevidencesuggests thatchroniccircadiandysphasingby itselfhas significant negative consequences for health; either for rodents subjected tolaboratory conditions of chronic jetlag or shiftwork, or in humans subjected tosimilar stresses. Documented changes include cancer susceptibility, inflammation,and alteredmetabolism. Thus, increasing evidence suggests that basal physiologymaydifferinindividualswithclockdisruption.

Suchanobservationisparticularlyrelevanttopharmacologybecausemanydiseasesrangingfrompsychiatricandneurodegenerativedisorderstocancerarethemselves

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associatedwithmildtosevereclockdisruption.Thequestionofhowdiseasespecifictoaperipheralorganmightaffectclockworkwithinthistissuehasnotbeenstudiedyet,butcouldalsobehighlypertinenttopharmacology.

WhereasSCNclocksareentrainedbylight,andperipheralclocksareentrainedbyindirect and hormonal cues, individual aspects of cellular physiology are in turndirected by both local and central clocks through a variety of mechanisms. Onefundamental mechanism is via transcription: in total, about ten percent of alltranscripts in each tissue are regulated in circadian fashion. In large part, thisregulation occurs through the same cis–acting promoter elements that direct therhythmictranscriptionofclockgenesthemselves.

Nevertheless,thismechanismrepresentsonlyaportionofcircadiantranscriptioninlivinganimals.Experimentsinmicelackingfunctionalclocksinspecifictissuesshowthatonlyaportionofcircadiangeneexpressionisabolishedbysuchmanipulations,while anotherportionpersistsbecause it is systemicallydriven.Aportionof thistranscriptionlikelyarisesthroughrhythmicactivityofthehypothalamic-pituitary-adrenal axis, and another portion through circadian stimulation of action/SRFsignalingbyunknownligands.

Additional contributions likely arise from heat shock signaling and immunesignaling,alsoregulatedbytimeofday.Inallfourcases,specificexternally-activatedtranscription factorsbind to cis -acting elements todrive transcriptionof certaingenes. For example, rhythmic glucocorticoid production results in rhythmicactivation of glucocorticoid receptor. Likewise, circadian body temperaturevariationresultsinrhythmicoccupancyofheatshockelements(HSEs).Theresultiscircadian transcription of specific genes due to cell-extrinsic influences, andindependentofthecircadianclockworkpresentinthatcellortissue.

In addition to circadian transcription recent research has unearthed extensiveevidence of circadian posttranscriptional regulation in mammals – includingtranslationalcontrol,controloftranscriptionterminationand/orelongation,andtoalesserextentcircadiancontrolofsplicing.Thus,theactualnumberoftranscriptsshowing circadian abundance is significantly greater than the number of genestranscribedincircadianfashion,andthenumberofproteinsthatareexpressedincircadianfashionisgreaterthanthenumberoftranscriptswherethisquestionhasbeenaddressed.MajorsignalingmoleculeslikecAMPshowcircadianvariationsthat

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bothcontrolclockoutputandplayarolewithintheclock,andrecentlinksbetweenclocksandsirtuinssuggestasimilarinfluenceofredoxpotential.Altogether,throughamyriadofdifferentmechanisms,thecircadianclockregulatesasignificantamountofcellularphysiology.

OnecaseofsuchregulationmeritingspecialattentionisthecircadianregulationofthecellcycleandDNArepair.Giventhecentralimportanceofcellcyclederegulationto cancer, it is easy to understandwhy circadian control of cell division in adultanimals couldbeof central importance to clinicalpharmacology. In fact,multiplestudieshavedocumentedcircadianordiurnalregulationofcelldivision,bothinvivoduringrodentliverregeneration,andinvitroinculturedcells.Eveninhumans,skinblistertranscriptionalprofilingsuggestsasimilarlink.

Thiscircadianinteractionhasbeendemonstratedtobedirectlyimportantfortissueregeneration. Related to circadian cell cycle control, extensive regulation of DNAdamage repairby the circadianclockhasalsobeendocumented, and this controlwoulddirectlyinfluencesusceptibilitytocancer.

Todate, theprevailing viewof the circadian system is a hierarchical structure inwhichthelight--sensingmasterpacemakerandotherenvironmentalcuessynchronizenumerousperipheraloscillatorsviathe“input”pathwaysand,subsequently,driverhythmic physiologic “outputs.” Much effort is focused on the identification ofmolecularcomponentsoftheinputandoutputpathways.However,asexemplifiedby the interactions between the circadian clock and nuclear receptors, feedbackloopsarepervasivelypresentatthemolecular,cellular,tissue,andsystemslevels.The boundary between the input and output pathways is dissolving. Thus, it isprobablytimetorevisittheroleofthecircadiansysteminwhole--bodyphysiology.

In addition to keeping internal physiology synchronizedwith the environment—predominantlythelight/darkcycle—circadianclocksmayserveatleasttwootherancient purposes: (1) to temporally separate chemically incompatible metabolicprocesses, such as anabolism and catabolism; and (2) to coordinate distinctphysiological processes to maintain dynamic homeostasis. Evidence for thesescenariosisemerging.

Asillustratedinfigurebelow,itseemsthatconnectionsbetweenthecircadianclockand most (if not all) physiological processes are bidirectional. Therefore, the

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circadian system might provide a potential means of communications betweendifferent physiological domains. In view of the dissolving boundary betweendifferent physiological processes, the circadian clock is probably not merely atimekeeper,butalsoaguardianofphysiologicalhomeostasis.

From Physiology to Chronopharmacology

Asdemonstratedabove,atcellularlevellargeportionsofcellularphysiology–fromtranscription and translation to intracellular signaling cascades – can showdailyvariationsinactivity.Thiscellulardiurnalvariationtranslatesdirectlyintodiurnalphysiological variation in most organ systems, which in turn provides themechanisticrationaleforcircadianvariationinPK/PD.

Neurotransmitters and Circadian Behavior

Nearly all behaviors show diurnal patterns of activity. In most cases, theseoscillations have been shown to manifest themselves independently of external

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environment or the sleep-wake cycle. For example, long-term memory shows adirectdependenceuponthecircadianoscillator:notonlydorodentsandhumanslearnbetteratcertaintimesofdaythananother,butmicewithafunctionalcircadiansystem learn better than those without. Similarly, anxiety show a clear diurnalpatternthat ismodulatedbothbysleep-wakeandbythecircadianoscillator,andanxiety behaviors are elevated in mice lacking the Period clock genes. Evenperception ofmultiple different types of pain varies in circadian fashion in bothhumansandanimalmodels.

The likely basis for these circadian variations is that virtually all majorneurotransmitter systems show either marked circadian variations or clockinteractions.Forexample,circadianvariationsinopioidreceptorabundance,aswellasintheabundanceofnaturalopioidsthemselves,havebeenreportednumerouslyoverthepasttwodecades.

The serotonergic system shows clear ultradian variations corresponding to sleepstate,but these fasteroscillations interactmarkedlywith thecircadianclock, andserotonergicsignalsappearnecessaryforintegrationofcircadianinformationbythebasalforebrainincontrollingsleeptiming.

In the cholinergic system, numerous circadian variations have also beendocumented.Forexample,afterasustainedattentiontaskwithdailyrepetition,dailyincreaseinprefrontalcholinergicneurotransmissionisobservedevenintheabsenceofthetask.Ingeneral,thecholinergicsystemhasbeendocumentedtoplayacriticalroleinthistypeofcircadian“time–stamping”ofbehavior.Itissustainedbycircadianreleaseofacetylcholineduringtheactivephaseofmanymammals,accompaniedbyincreaseincholineacetyltransferaseanddecreaseinacetylcholinesteraseactivity.Globally,availabilityofmuscarinicacetylcholinereceptorsshowsaninversepatterntoacetylcholineavailability,withincreasedabundanceduringthequiescentphaseofthe24-hourday,irrespectiveofactivityperse.

Examinationofthedopaminergicsystemalsoshowsadiurnalpatternofdopamineabundance within the rodent forebrain. Interestingly, this circadian expressionappears necessary for oscillation of the circadian clock gene Per2 in forebrainneurons,suggestingarolefordopamineinmediatingcircadianinformationtothisbrainregion.

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Multipleotherneurotransmittersshowcircadianabundancethatstronglyinteractswiththesleep-wakecycle.Forexample,adenosineshowscircadianvariationswithinthebrain thatarebelievedtobesleep-wake-dependent.Morebroadly,purinergicsignaling shows a strong circadian component, and interacts directly with thecircadianmachinerythroughATP,cAMP,andAMP.

The hypocretin/orexin system also has circadian variation that regulates inparticular REM sleep. Circadian release of GABA and glutamate – the principalinhibitoryandexcitatoryneurotransmittersofthebrain,respectively–inturnnotonly control behavior, but also hypothalamic hormone release to regulate manyaspectsofphysiology.

Circadian clocks, hormones, and control of metabolism, digestion and cardiac function

Beyond the neurotransmitters whose circadian output is directly or indirectlyregulated by the SCN, numerous other hormones show diurnal regulation thatsignificantlyregulatesphysiologyandpharmacology.

Melatonin, a circadianhormoneof thepineal gland, influences various aspects ofretinalandcardiovascularfunction,aswellasaffectinglocalclocksindiversebrainregions.

Circadian regulation of the adrenal gland results in diurnal secretion ofglucocorticoidhormone,whichinturnstronglyinfluencesmetabolism,andinfactdirectlyregulates60%ofthelivertranscriptome.

Circadianregulationofgastrin,ghrelin,andsomatostatin,aswellasdirectregulationbyautonomousclockswithinthegastrointestinaltract,mediatecircadianinfluencesupondigestivefunction.

Moregenerally,autonomouscircadianclocksnotonlywithintheGItract,butalsoinnumerous other tissues, have considerable influences upon physiology andmetabolism.Forexample,ablationofclocksinpancreaticisletsresultsindiabetesbecause of defects in coupling of β-cell stimulus to insulin secretion, and localclockwork controls expressionofmultiple ion channels andkinases in heart thatinfluence cardiac function and triglyceride metabolism. Recent transcriptome

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studieshaveidentifiedwidespreadlocalcircadianregulationnotonlyinheart,butalsoinskeletalmuscleandfat,showingthatclocksinthesetissuesdirectlyregulatephysiology.

Circadian Immune Regulation

Asecondprominentpharmacologicaltargetwithstrongcircadianregulationistheimmunesystem.

Diurnalvariations inwhitebloodcell countandsusceptibility toendotoxic shockhavelongbeendocumented.However,recentresearchshowsthatcell-autonomousclocks within immune cells themselves direct variation in a large number ofcircadianimmuneparameters.Forexample,theresponseofT-cellstostimulationvariesincircadianfashion,andmacrophagesinturnstimulateimmuneresponsesinequallydiurnalfashionwiththeirownclocks.Bycontrast,farfewerreportsexistofcircadianB-cellactivity,andindeedtheoscillationsdocumentedincircadiangeneexpressioninperipheralbloodmononuclearcellsismuchlowerinamplitudethanthatobservedinothertissuessuchastheliver.

The consequences of pervasive circadian regulation of immune function arenumerous,andrangefarbeyondtheaforementioneddiurnalvariationininfectivesusceptibility.Forexample,apronouncedcircadianoscillationofbloodclottinghaslongbeenknown,and issupportedbycircadianvariation in factorsranging fromplateletaggregation(takeyour80/81mgAspirinatnight; itworksbetter&longer)andadhesiontoactualexpressionofclottingfactorslikePAI-1.

Circadian clocks also regulate circulation of many immune cells such ashematopoeticstemcells.

Finally,circadianimmuneregulationresultsindiurnalvariationsinrelatedimmuneparameters like inflammation,which plays a strong role in circadian variation inmanydiseases.

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Circadian Pharmacokinetics in Different Body Systems

Gastric & Intestinal Absorption DrugtransportanddiffusionishighlydependentongastricpHthatregulatesdrugionization and hydrophobicity. Inmost animal species includingman, gastric pHpresents a strong circadianpattern influencing drug solubility. At the same time,gastricemptyingafteramealandgastrointestinalmobilitypresentahigherspeedduring the day than at night, increasing in this way absorption during the day.Interestingly,atleastforthecolon,thisrhythmicmotilityseemstoberegulatedbythecircadianclock,asitisseverelyperturbedinmicewithoutaclock. Finally,theincreasedbloodflowtothegastrointestinaltractinthebeginningofthedayalsocontributedtoincreaseddrugdistributionindaytimeinhumans.

Modulationofdrugpharmacokineticbythecircadianclock

All rhythmic parameters influencing drug transport and metabolism are highlighted in red. Characteristic functions of the circadian clock on these processes are indicated in the respective organs.

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Rhythmic Liver Drug Metabolism

Xenobiotic detoxification is organized as a multistep system consisting of threegroupsofproteinsassumingdistinctandsuccessivefunctions.

ThephaseIproteinsfunctionalizedrugs(possiblyforinhibitionoractivation)bytheoxidase,reductase,andhydroxylaseactivitiesofthemicrosomalP450cytochrome(CYPP450)familyofenzymes.

ThephaseIIproteinsconjugatedrugstoahydrophilicmoleculeinordertoincreasesolubility.Theyhelptomakelipophiliccompoundshydrophilicenoughtofacilitatetheir excretion into urine, bile, and feces. Mainly sulfotransferases,UDPglucuronotransferases, glutathione S-transferases, and N-acetyltransferasesachievethesereactions.

Finally, phase III transporters –mainlyABC transporters – transport xenobioticsoutsidethecell.

Inversely, transporters of the solute carrier family (Slc) are involved in cellularimport.

Inadditiontothesethreeclassesofenzymes,otherproteinsgloballyregulatetheactivityofmostofthephaseIenzymesoftheP450oxydoreductasefamily.

Importantly for pharmacokinetics, expression of all of these proteins is carefullycoordinatedtofavorefficientliverdetoxification.Thiscontrolisachievedthroughthecomplextranscriptionalregulationofthesegenesinamannerthatiscell-typespecific, daytime dependent, and inducible by xenobiotics themselves.Transcriptional induction involves a heterogeneous class of transcription factorscollectivelynamed“xenobioticreceptors”.Thethreemainxenobioticreceptorsarethe nuclear receptors constitutive androstane receptor (CAR) and pregnane Xreceptor (PXR), and the PAS-domain helix-loop-helix transcription factor arylhydrocarbonreceptor(AhR).Mainlyexpressedintheliverandthesmallintestine,thesexenobioticreceptorsareassociatedwithchaperoneproteinsinthecytoplasm.In response to xenobiotics – either through direct binding or by way of signaltransduction – these proteins accumulate in the nucleus where they activatetranscriptionofphaseI,IIandIIIgenes.

Historical transcriptome analysis of mouse liver revealed that genes coding for

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enzymes involved in the three phases of xenobiotic detoxification represent animportantpartoftherhythmicallyexpressedgenes.Recentevidencesuggeststhatthese genes are not direct targets of BMAL1, but rather suggest regulation bycircadianclock-controlledtranscriptionfactors.

Acetaminophen/paracetamol time-dependent toxicity seems to be a result ofrhythmicexpressionoftheCYP2E1,dueitselftotherhythmicinhibitionoftheHNF1nuclearreceptorbyCRY1ontheCyp2e1promoter.

Whereas the relative importance of all these systems on global rhythmic drugdetoxificationinmouseliverisnotyetclearlydemonstrated,thereisnodoubtthatthecircadianclockisamajoractorinthisarena.

Elimination by the Hepatobiliary System

Althoughmostmetabolizeddrugsarefinallyexcretedintoplasmaandsubsequentlyurine,severalofthemarefirstexcretedthroughthehepatobiliarysystemintothegutandaresubjecttoasecondroundofhepaticmetabolismorfecalexcretion.Thehepatobiliary transport system is required not only for bile formation, but alsoeliminationofvariousendo-andxenobiotics includingcholesterol,phospholipids,anddrugs.

Depending on the nature of the molecule, a broad range of liver-specific exportsystemsareinvolved.Bileisformedbyexcretionofbilesalts(BS)andnon-bilesaltorganicanionsviaABC transporters.MonovalentBSareexcretedvia thebilesaltexportpump(BSEPorABCB11),whiledivalentBSandanionicconjugatesofendo-orxenobioticsareexcretedviatheconjugateexportpump(MRP2orABCC2).Thephospholipid export channel (MDR2 or ABCB4) allows the excretion ofphosphatidylcholine (PC), which forms micelles in bile together with BS andcholesterol. Cationic metabolized drugs are excreted by the multidrug exportchannel (MDR1orABCB1).Other export pumps include the two-half transporterABCG5/8forcholesterolandthebreastcancerresistanceprotein(BCRPorABCG2)foranionicconjugates.

Excretion of bile acids, lipids, and xenobiotics into the bile follows a stringentcircadianrhythm,atleastinrodents,andclockinvolvementhasbeendocumentedatmultipledifferentsteps.

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First, bile acid synthesis follows a stringent diurnal rhythm in both rodents andhumans. Conversion of cholesterol into bile acids involved the rate-limitingcholesterol-7α-hydroxylase (CYP7A1), whose rhythmic expression is directlyregulatedmainlythroughREV-ERBα.

Inaddition,mostofthegenesencodingtransportersinvolvedinbilesecretionareexpressedaccordingtoacircadianpatternintheliver.Asaconsequence,ithasbeenobserved that the biliary excretion of drugs, for example ampicillin or flomoxef,presents a diurnal pattern in rats and patients under percutaneous transhepaticbiliarydrainage.

Elimination by the Kidney

Mostwater-solubledrugsordrugmetabolitesareeliminatedbyurinethroughthekidney.

The rate of drug elimination in the urine depends on several intrinsic variablesrelatedtothekidneyfunctionincludingtherenalbloodflow(RBF),theglomerularfiltrationrate(GFR),thecapacityofthekidneytoreabsorbortosecretedrugsacrosstheepithelium,theurineflow,andtheurinepH,whichinfluencesthedegreeofurineacidification.

Interestingly, all these variables present a circadian behavior in differentmammalianmodels. Around20%of theRBF is converted into the urine throughglomerularfiltration.Intheproximaltubule,manyionizeddrugscanbesecretedintheurinefromtheremainingunfilteredbloodviavariousactivetransports.Finally,filteredandsecreteddrugscanbepassivelyoractivelyreabsorbedoutoftheurineintotheblood.Because, theRBFisakeydeterminantofglomerular filtrationandsecretion, it is intimately associated with the elimination of most ionized drugsthroughurine.TheRBFhasbeendemonstratedtofollowacircadianoscillationwithapeakduringtheactivephase.Althoughthisrhythmisprobablypartiallyentrainedbycircadianarterialbloodpressureandthecardiacoutput,therhythmicRBFcouldalso be generated by an intrinsic renal mechanism. For example, Cry1/Cry2knockoutexhibitdisruptedactivityoftherenin-angiotensin-aldosteronesystem,oneofthemajormechanismsregulatingRBF.

RhythmicoscillationsoftheGFRaresynchronizedwiththoseofRBF,buttheyare

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notfullydeterminedbyit,asGFRrhythmpersistsduringcontinuousbedrestandincondition of inverted blood pressure. Rhythmic GFR is also maintained intransplantedhumankidneys,indicatingthatsympatheticinnervationisnotrequiredfor this rhythm. These data indicate that GFR is generated by an intrinsic renalmechanismbutthemechanismresponsibleforthisfunctionalrhythmicityremainsunknown.

Renalreabsorptionandsecretionofwater-solubledrugsdependsontheexpressionofmembranetransportersoftheABCandSlcfamiliesthatfacilitatediffusionofpolarmoleculesthroughtheapicaland/orbasolateralmembranesoftubularcells.Mostofdrugreabsorption/secretiontakesplaceintheproximaltubuleofthekidneythatisenrichedinvarioustransporterswithapreferentialaffinityforsmallorganicanions.It has been shown that several of these transporters present a robust diurnalexpressioninthemoredistalnephronsegments,namelyinthedistalnephronandthecollectingduct.

Drugionization,whichismainlydeterminedbyurinepH,determinesdrugsolubilityandtherateofdrugreabsorptioninthenephron.HumanurinepHmayrangefrom4.5to8andiscontrolledbyacomplexsystemofreabsorption/secretion/productionof bicarbonate and secretion of protons. It usually exhibits lower values in themorning.Themostimportanttransporterinvolvedinrenalprotonsecretionisthesodium-proton exchanger 3 (NHE3 or Slc9A3) expressed in the proximal tubule.Expression of Nhe3 mRNA and protein in the kidney exhibit a robust circadianrhythminrodents,withthemaximalexpressioninthemiddleoftheactivephase(109).Interestingly,thiscircadianexpressionissignificantlybluntedinCry1/Cry2knockout mice, indicating that the circadian clock can influence the renal drugdisposalviathecontrolofurineacidification.

Chronobiology & Drug Treatment

To what extent has the knowledge presented above translated to effectivepharmaceutical interventions? The most obvious examples for successfulchronotherapyareoneswithobvioustime-of-day-dependentsymptoms.Treatmentofbronchialasthmahasbeentunedtoexhibitmaximumplasmalevelsatthetimeofhighestoccurrenceofdyspnea,andthereforealleviatesymptomsmosteffectively.Cetirizine, a non-sedative, very active anti-histamine is effective ~8 hours when

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absorbedinthemorning,whileitseffectsarerecodedupto20hoursafteranighttimeintake. Similarly, blood pressure shows a sharp peak in the early morning, importantlycoincidingwiththepeakforcardiovascularevents,andanextendedtroughduringthe night. Both healthy normotensive and patients suffering from essentialhypertension exhibit this variation (take your long-acting antihypertensivemedicationatnight).TheL-type calciumchannelblockerVerapamil, for example,usesextended-releaseformulationtohavetherapeuticallyeffectiveplasmalevelsinthe early morning after bedtime oral administration. In addition, such delayedrelease drugs have been beneficial for hypertensive patients that do not show anocturnaldipinbloodpressure,socalled“non-dippers”.Non-dippingisariskfactorforcongestiveheartfailureeveninclinicallynormotensivesubjects.

Asmentionedabove,notonlyPK/PDparametersaremodulatedbytime-of–day,butalso drug metabolism. For example, the over the counteracetaminophen/paracetamol(APAP)isaleadingcauseofdrug-inducedliverfailure.APAPisexclusivelymetabolizedbytheCYPP450systemoftheliver,andtoxicityisdependent on generation of N-acetyl-p-benzoquinone imine (NAPQI) by CYP2E1.APAPtoxicityistime-of-daydependent,butliverspecificablationoftheclockinmicebluntsthisrhythm.

Timeofdaydependentvariationinpharmacokinetics.Average 3-hourly steady state serum concentrations of theophylline from eight asthmatic children dosed with Theo24© before breakfast (06:00, red) or at bedtime (21:00, blue) as indicated by arrows. Shaded area represents the occurrence of dyspnea.

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Cancer

Whilethechronotherapeuticapproachoftheexamplesaboveisbasedonrelativelyfewwell-establishedvariables, inthecaseofchemotherapyandassociatedcancertreatmentsthepredictionsforoptimaltreatmentschedulesbecomehighlycomplex.

Ontheonehand,chemotherapeuticsshouldbedosedhighenoughtobetoxictothecancer, but on theotherhand thedose shouldbe lowenough toprevent seriousdamagetohealthytissueororgans.

Thatmeanspharmacokinetics anddynamicsoperate ina tight therapeutic range.Under thesepre-conditions, thevariations introducedby the circadian systemonmultiplelevelscanbecrucial.Thisisfurthercomplicatedbythepossibilitythatnotonlythehealthytissuehasaclockbutalsothetumor.Invivo,thishasbeenshownmeasuringtheincorporationofP32intumorsofterminallyillbreastcancer.TheseresultsareinlinewithnewerinvitrodatafromvarioushumanandmousecancercelllineslikethehumanU2osteosarcoma.

Thisisanimportantfactorbecausemostcancerdrugsaretoxiconlytodividingcellsorhaveamechanismofactionthatisparticularlyeffectiveinonephaseofthecellcycle, that is -at least inhealthytissues–gatedbytheclock.ThetopoisomeraseIinhibitoririnotecan,forexample,ismosteffectiveinS-phase,whilealkylatingagentscross-linkDNAatanyphaseofthecellcycle.Incaseofanarrhythmictumor,asisthecase in the mouse xenograft Glasgow osteosarcoma model, a further interestingcomplication emerged: seliciclib, a cyclin dependent kinase inhibitor, seemed toinducerhythmicgeneexpressionintumorsandmightslowdowntumorprogressionadditionallybythismodeofaction.

Given the known disturbance of circadian behavior in multiple human cancers,additional efficacy might be achieved harmlessly by this type of clockresynchronization.

Overall, in several different experimental rodent models it has been shown thatefficacy and side effects of anticancer therapies vary up to 10-fold depending ontime-of-day.However, theseparametersaremodel-and-drug-specific.Common tomost,efficacyisbasedonthemechanismofaction,metabolism,andtoxicity,andthebest treatment schedule has to take into account all those parameters. The

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therapeutic index of the alkylating agent cyclophosphamide, for example, issignificantlybetterifthecompoundisadministeredduringthefirstpartoftheactivedarkphase.

ThisrhythmhasbeensuggestedtobedependentonCLOCK:BMAL1binding inB-cells, changes in CYP P450 enzyme activity and even more importantly higherreducedglutathionelevelsatnightmightcontribute,ashasbeendescribedforotheralkylatingagentssuchascisplatin.Incontrast,5-fluorouracil’sfirstandratelimitedstep in metabolism is dependent on the availability of dihydropyrimidinedehydrogenase(DPD),andcertain5-FUmetabolitesthenblocktheactivityanddenovosynthesisofthymidilatesynthase(TS),whichisimportantforDNAsynthesis.DPDandTSexpressionarehighand low,respectively,duringthefirstpartof thelightphase.Therefore,5-FUexhibitsbesttolerabilityandefficacy180°outofphasewith cyclophosphamide and most other alkylating agents. Leucovorin (LV) is aninhibitorofTSandoftenco-administeredwith5-FU.Thisaddstotheeffectivenessof5-FUandchangestheDPDtoTSratio inthesamedirectionasobservedat theoptimaltimeofdayestablishedinanimalexperiments.

Interestingly, there are further common traits between irinotecan and 5-FU. Forboth, added value of chronotherapeutic treatment regimes is gender-specific inexperimental animalmodels. In the case of 5-FU this has even been observed inclinicalpopulations.Whilechronomodulateddeliveryof5-FUimprovessurvivalformalepatientscomparedtoconventionaltreatment,theoppositewastrueforfemalestudyparticipants.Theauthorsspeculatethatsincedisruptionoftherest/activityrhythm during chemotherapy has been shown to predict overall survival formetastaticcolorectalcancer,themencouldexhibitmorerobustcircadianrhythms.

Implications for Drug R&D

Classically,thedrugdiscoveryprocessisprecededbythevalidationofagiventarget.The mechanism of action is established and molecular targets defined. Takingdiurnalchangesofrelevantparametersintoaccountmightmeansignificantlyhighercostsbecausethesameexperimentsmighthavetobeconductedatmultipledifferenttimesofdayinordertoassessif,forexample,acertaintypeofreceptororproteinisonlyexpressedataspecifictimeofday.However,thereareonlineresourcesthatcanbemined for information about the circadian expression of a given transcript or

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metabolite. A special case presents in the quest for drugs against age-relateddiseases.Similarly tohumanbeings, rodent species typicallyused in theseassaysexhibitattenuatedcircadianrhythms.Thus,thePK/PDprofileandtargetavailabilityitselfcouldchangeduringthecourseofaging.

Once the target is confirmed, and the lead optimization process started, thepropertiesofthenovelchemicalentitiesareevaluatedandselected.Typically,CYPP450inductionandinhibitioninhumanandrodentprimaryhepatocytesistested.Thismightintroducebiastowardsonlyonephaseofthecircadiancycle,sincethecellsthatareusedtoevaluatethecompoundscontainafunctionalcellautonomousclock that can influence drug metabolism. The CACO-2 monolayer assay is anindustrystandardnotonlyusedtopredictabsorptionafteroralapplicationthroughthe intestinal barrier but also to assess interactionswith important transporterssuchasP-gp.Interestingly,liketheintestinalbarrieritself,thehumantumorderivedCACO-2 cells have a functioning clock that has been shown to directly controlexpressionlevelsofMdr1.

Two of the most common reasons for novel chemical entities to fail in drugdevelopmentorevenmarketeddrugstobewithdrawnarelivertoxicityandcardiacsafety. In fact,QTprolongationoftenassociatedwithblockadeof theK+ -channelencodedbyhumanether-à-go-gorelatedgene(hERG)andasurrogatemarkerfortorsadedepointeswasthesinglemostcommoncauseforwithdrawalofmarketeddrugsinrecentyears.

Therefore, an extensive battery of tests from in vitro channel function to in vivoelectrophysiologyinthefreelymovingdogormonkeyhasbeenestablishedandisperformedbeforeaso-called“thoroughQT/QTc”studyinPhaseIofdevelopment.Althoughnewmodelshavebeendevelopedthatadjustforcircadianvariabilityduetochangesinheartrateovertheday,thepossibilitythatdrugdependentQT-intervalprolongationisdirectlyinfluencedbytimeofdayinpatientshasnotyetbeenfullyexplored,but isnotunsupported.Moreover, there isaclearrationale forhowthecircadianclockwould influencecardiacrepolarization,namelykrüppel-like factor15.

Togetherthesefindingssuggestthatatime-of-daybiasintestingdruginducedQT–prolongationmight lead to a misjudgment of risk to patients. If, based on theseconsiderations,drugdeveloperswouldadopta circadian testingpolicy, there isa

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furthercomplication.Incontrasttomostpre-clinicalanimalmodels,thereisagreatdealof inter-individualvariability inthecircadianphenotypeofpeople:periodorphaseandamplitudeofclock-controlledrhythmsdescribedabovevariesgreatlyinhumanpopulations.Thesearenosmalldifferences,and the lay terms“larks”and“owls”forpeoplewithanearlyandlateactivityphase,respectively,illustratetheirmagnitude.

Moreover, diseases can even more severely alter rhythmic rest/activity andendocrine patterns. Some schizophrenic patients, for example, exhibit a nearlyarrhythmic behavioral pattern, and not only are the cortisol levels in depressedpatientselevatedbut theirdiurnalvariation isblunted.Twinstudies suggest thatgenetictraitsarepartiallydeterminingthechronotype.Infact,therearemultiplelocithat have been determined to contribute to differences in chronotype and sleep.Moreover, there are quite consistent age-dependent changes of chronotype, andrecentresultssuggestrelativelystablechangesdependentonpreviouslighthistory.

Inter-individual differences in clock phase are sizable and therefore probablyclinically relevant. Albeit significantmethodological advances have beenmade todeterminethepropertiesofanindividual’scircadianclockinasimpletest,thisgoalhas not been possible so far. The ability to use human skin biopsies that arelentivirallytransducedwithcircadianreporterstodetermineperiodisonecellularmethodinthisdirection,andhairfolliclessampleshavealsobenused.Alternatively,clock-controlled neuroendocrine signals such as the dim-light melatonin onset(DLMO)havebeenusedtoestimateclockphase.

Due to large inter-individual variation in the levels of these hormones betweenindividualsmultiplesamplingisnecessarytoestablishmeaningfulresults,whichisalso dependent on ambient light levels. To overcome these limitations,transcriptome and metabolome datasets have been used to establish timetablemethodsforinternaltimeinmiceandmen.Allofthesemethods,however,relyonatleasttwosamplingtimesthatareoptimally12hoursaparttocompensateforinter-individual difference in the absolute levels of gene ormetabolite expression, and“internal time”canbeapproximatedwith2hours’precision.Thus,a feasibleandaccuratecircadiantestremainstobeestablished.

Given aforementioned examples of arrythmicity in disease and inter-individualdifferencesinclockphase,thecircadianclockitselfmightbeaninterestingtargetfor

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drugdevelopment.

In fact, multiple pharmacological agents have been reported to phase-shiftbehavioralandbiochemicalrhythmsinexperimentalanimalmodelsandpeople,andfor example melatonin, melatonin agonists, or a combined melatonin agonist/5-HT2cantagonisthavealreadyreceivedmarketapproval,althoughnotnecessarilyasphase shiftingdrugs. In addition to themelatonin receptors, several independentmoleculartargetshavebeenidentifiedtoalterclockfunction.Amongstthefirstthatwasidentifiedwascaseinkinase1,andevensubform-specifictoolcompoundshavebeen described. As a target, however, kinase inhibitors are notwithout problem.Casein kinase 1 is, for example, involved in Wnt signaling and linked to cellproliferationandsurvival.

Furthermore,anumberofcompoundsthattargetcoremolecularclockcomponentsor arebelieved to be important linksbetween the clock andHPAaxis havebeenidentified and tested, including a Neuropeptide Y Y5-receptor, a tachykininantagonist,aninverseagonistofRORα,andacorticotrophinreleasingfactor(CRF)antagonist. Most recently, several unbiased small molecule screens have beenundertakeninaninvitromodelofthecircadianoscillator,andtheyhaveidentifiednewmolecularentitiesthattargetknownclockcomponentssuchasCRY,CK1,andREV-ERBα. WhethertheseinvitrodatafromU2OScellswillbeabletotranslateintheinvivosituationwillbeveryinteresting.

More generally, it remains to be proven if the clock does indeed present a“druggable” target, or if there are unsuspectedmechanistic problems in alteringcircadian rhythms.Should suchcompoundsexhibit safetyprofilesas favorableasmelatonin, for example, they could prove useful in a wide spectrum of possibleindications, ranging from sleep/wake problems in shift workers to amplitude-relatedproblemsinaging-relateddiseases.Ontheonehandsuchdrugscouldhelpto“boost”circadianrhythmicitybeyondwhatcanbeachievedthroughbehavioralmeasures, and on the other hand re-adjust specific rhythmic components to afavorable phase. This would be especially useful given the tendency of modernsocietytowardsa24/7lifestyle.

Inthisrespect,moreandmoreevidencehasaccumulatedshowingthesometimesdisastrouseffectsofsuchclockdisruptiononhealth.Unfortunately,thereseemstobeaviciouscyclebetweencauseandeffect.Clockdisruptionovertimecanleadto

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variousmajorpathologiesandtheseinturncanfeedbackontotheclockandfurtherabrogate rhythms. Interestingly, however, strengthening the clock by imposingstrong timing cues can alleviate symptoms. In a mouse model of Huntington’sdisease,forexample,eithertheuseofhypnoticsandscheduledmealscannormalizecircadian gene expression rhythms and improve disease symptoms. Similarly,melatoninandbrightlighttreatmenthavebeenshowntohaveapositiveeffectoninstitutionalizedAlzheimerpatients.

Tentative Directions Therecentfindingsthatwehavehighlightedallyieldinsightintothegrowingfieldofchronopharmacology,andintothemechanisticbasisforthevariationsinPK/PDthathavebeenobservedinavastnumberofinstances.However,manyimportantquestionsremainunanswered.Mostifnotallofthecircadianexpressiondataatthegenomiclevelonwhichtheseconclusionsarebasedareavailableonlyforrodents.Consideringthefactthatexpressionandfunctionalpropertiesofdrugmetabolizingenzymes anddrug transporters arehighly species-specific, extrapolationof theseresultstohumansisnotaforegoneconclusion.Inordertotranslateresearchdatainto clinical application, significant progress in the characterization of circadianvariationsinproteinexpressionandactivityinhumanisabsolutelynecessary.

Althoughtherehasbeenmuchmoreawarenessoftheimpactofthecircadianclockonhealth,disease,andtreatment inrecentyears, thesefindingsseemtonothavetranslated into clinics or regulatory agencies on a broad scale. Publicly availableclinicaltrialsdatabasessuchasclinicaltrials.govlistahistorictotalof205hitsforthesearchterm“circadian”.

Twelve of these are cancer-related but none try to establish chronotherapeutictreatmentregimens.Thesearchterm“chronotherapy”resultsin14hits.Incontrast,thesearchterm“cancer”produces38331results.SimilarresultswereobtainedfromtheEUclinical trialsregister.Given the fact thatabout20%of the transcriptome,proteomeandmetabolomeareunderclockcontrol,thisseemsdisproportionate.Inthecaseofregulatoryauthorities,noneofthechronobiologicaleffectsuponPK/PDoutlinedherearementionedinguidelinespublishedbytheInternationalConferenceonHarmonizationofTechnicalRequirementsforRegistrationofPharmaceuticalsfor

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Human Use (ICH). This is surprising, especially considering that unexpectedhepatoxicityandcardiacsideeffectsarethemostcommonreasonsforwithdrawalofmarketeddrugs.

Finally,thelargeproportionofphysiologyregulatedbythecircadianclocksuggeststhat the clock itself might present a possible pharmaceutical target to increaseefficacyandreducesideeffects.Inorderforsuchtreatmentstobeeffective,amoredetailedknowledgewillberequirednotonlyofhowclockscontrolphysiology,butalso of how clocks in different organ systems contribute to different processesrelevanttoPK/PD.

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Epilogue

Time,thesedays,isanobsession.Itisalso,possibly,oneoftherarenotionsthathasalwaysdrivenmeintoaformofobsessive(butnotcompulsive)neurosis.Beingontimeatschool;deliveringhomeworkontime;gettingto theexaminationroomontimeandnotstayingovertime;irritationwhenaflight(orapatient,orguests,oradate)waslate;cookingmealswell-timed,andservingthemontime;timingproperlymy200kmdailydrivetoandfromUCDavis,whiletakingaguessontraffic(beforetheGPSera);andyoucanaddyourownloooonglistoftimeobsessions,realorfancy.

Then there is chronobiology, and chronopharmacology. Practicing medicine anddevelopingnovelmodesoftreatmentwhileignoringtheseisunacceptable;youmustconsidertimeandtimingallthetime.

IamnowwaitingtolearnandunderstandmuchmorefromthefutureconferenceonTimetentativelyscheduledin2018attheParaLimesInstitute(NTU)inSingapore,andfromavidlyreadinganddiscussingtime,since–forme-timeisrunningout.

https://www.youtube.com/watch?v=ZH7dG0qyzyg

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Acknowledgements Iamindebtedtomanypersonsandsources,andIcannotmentionmanyof them.Obviously,JanandIritVasbindersparkedtheignitionforthisessay.ConversationswithTimurKouliev,BrianArthur, JonathanSim,DouglassCarmichael,AndrewLTSheng,RobinWang,Kei-onChan,YvesP.Huinbroughttherequiredbalancebetweenoverstuffingwithinformationandpalatablereading.TothoseIamnotmentioning,myapologies.

Without Yves P. Huin mastering the complexity of the website, this essay would be just lost time –and why not?

References • https://en.wikipedia.org/wiki/Time

• http://www.iep.utm.edu/time/

• http://www.iep.utm.edu/timetrav/

• http://www.collective-evolution.com/2015/07/20/quantum-experiment-shows-how-time-doesnt-exist-as-we-think-it-does-mind-altering/

• https://www.quantamagazine.org/20161201-quantum-gravitys-time-problem/

• https://www.theatlantic.com/science/archive/2016/12/is-the-search-for-dark-matter-a-wild-goose-chase/509441/?utm_source=atltw

• https://www.quantamagazine.org/20161129-verlinde-gravity-dark-matter/

• https://en.wikipedia.org/wiki/Time_perception

• http://medicine.yale.edu/compmed/icsnm/research/yang.aspx

• http://beyondthirtynine.com/complexity-and-interconnection-the-dao-sade-and-timequantum-biology-part-6/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885389/

• https://view.e.economist.com/?qs=cee969b76d950fd308e4375cd5db45fa09c02d499782d312fb2ad1e3ceade38dca3d9b6be96e23d9fbf692ca7c8876c6897103326481aac46ef64650b3298ac0c00016b411d2e1c0

• https://www.economist.com/news/science-and-technology/21729871-gene-and-protein-form-biological-pendulum-nobel-prize-medicine

• http://www.sciencemag.org/news/2017/11/daytime-wounds-heal-more-quickly-those-suffered-night

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Illustration Credits • http://www.pbs.org/wgbh/nova/physics/fabric-of-cosmos.html

• http://www.dalipaintings.com/melting-watch.jsp

• http://wallpapercave.com/2001-a-space-odyssey-wallpaper

• http://identity-mag.com/time-is-gold/

• https://www.goddessgift.net/chronos-god-statue-US-WU76248A4.html

• https://www.cartoonstock.com/directory/s/spiritual_teachers.asp

• http://lucidthoughts.com.au/wordpress/?attachment_id=1705

• https://www.pinterest.com/dakinepuaa/spaceships/

• https://dragallur.wordpress.com/2015/09/17/what-could-happen-to-our-universe-big-bounce/

• https://www.youtube.com/watch?v=04Grz77iEis

• https://en.wikipedia.org/wiki/Chronobiology

• http://www.jonathanlockwoodhuie.com/quote/time-like-life-itself-no-117/