Chapter 1 Gener ... ion aim and aims of thesis
Transcript of Chapter 1 Gener ... ion aim and aims of thesis
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The handle http://hdl.handle.net/1887/44266 holds various files of this Leiden University dissertation Author: Akintola, Abimbola Title: Human longevity : crosstalk between the brain and periphery Issue Date: 2016-11-16
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GENERAL INTRODUCTION
Even thoughmortality inoldagehas significantlydecreasedover the lastfiftyyears in
the developedworld (1), there still remains a large inter- individual variability in ageing
trajectories,morbidityandmortality (2).Theageingprocess isassociatedwithnumerous
physiologicalalterationsacrossmultipleorgansystems,includingthebrain.Thus,theneed
tobetterunderstandthephysiologicalmechanismsandprocessesthatunderlietheageing
processisvital.
Longevitypotential isdeterminedbygeneticandenvironmental factors (2,3).Various
attempts have been made to delineate the regulatory pathways that underlie human
longevity. Studiesinmodelorganismssuggestthatlongevityispromotedbyconserved
geneticmechanismsthatorchestratetheorganism’sresponsestoitschangingenvironment,
suchasinsulin/insulin-likegrowthfactor-1(IGF-1)signaling(4,5). Also in humans, the ability
tomaintainthestabilityofthebody’sinternalenvironmentwhiledynamicallyadaptingto
changesinexternalconditions,knownashomeostasis,hasbeenidentifiedasbeingakey
to healthy longevity (6).Thismaintenance is brought aboutby an intact communication
between the brain and the peripheral bodily functions. Loss of homeostatic control is
hypothesizedtocontributetobothbodilyandcognitivedecline.
Crosstalk between brain and peripheryHomeostasis is essential for health throughout lifetime, since age- related changes to
physiologyaccumulatefromearly life (7,8).Homeostaticcontrol isacomplexmechanism
requiringreciprocalprojectionsfromthebraintotheperiphery,andhaveat leastthree
interdependentcomponents:receptor/sensor,controlcenterandeffector(9).Homeostasis
requires the integrationofnumerousperipheralcues (sensor)bythehypothalamusand
nearbybrainstructures (controlcenter), tomountacoordinatedresponsetoadaptand
maintaintheinternalenvironmentwithinnarrowlimits.Tightregulationofthesesystems
is key to healthy ageing.
Amongthekeymodifiersoftheageingprocessidentifiedareinsulin/IGF-1signaling
(IIS),thehypothalamic/pituitary/thyroid(HPT)axis,thehypothalamic/pituitary/adrenal
(HPA)axisandtheautonomicnervoussystem.Whileahealthyinteractionbetweenthese
systemsiscrucialformaintenanceofhomeostasisofvitalparameters(figure1),alackof
communicationortheirdysregulationisimplicatedinacceleratedandunhealthyageing.
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FIGURE 1.1 | Schematicfiguredepictingthebrain-peripherydialogue.TakenwithpermissionfromtheSwitchboxprojectproposal.
Inthis thesis,emphasiswillbeplacedonthreekeymodifiersof theageingprocess,
namelythecommunicationbetweenthebrainandglucoseandinsulinmetabolism,HPT
axisandtheautonomicnervoussystem,usingdatafromtheLeidenLongevityStudyand
theSwitchboxstudy.
Data Sources- the Leiden Longevity StudyTheLeidenLongevitystudy(LLS)wasdesignedtoidentifydeterminantsofhumanlongevity
bystudyingoffspringoflong-livedsiblingsandtheirpartners.Between2002and2006,
some421DutchCaucasianfamilieswererecruitedofwhichatleasttwolong-livedsiblings
werealiveandaged89yearsorolderformenand91yearsorolderforwomen,without
selectiononhealthordemographiccharacteristics.Furthermore, theoffspringof these
long-livednonagenariansandtheirpartners,werealsoenrolled(figure2).Theseoffspring
carry50%ofthegeneticadvantageoftheirlong-livedparentandwereshowntohavea
35%lowermortalityratecomparedtotheirbirthcohort(10).Theirpartnerswithwhommost
havehadarelationshipandsharedenvironmentfordecades,wereincludedaspopulation-
based,environment-matchedcontrols.
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FIGURE 1.2 | StudydesignoftheLeidenLongevityStudy.
Brain MRI data from offspring and partners in the LLS were used to study the relation between parameters of glucose metabolism and brain function.
Data Sources- the Switchbox StudyTheSwitchboxstudyisasatellitestudyfromtheLLS.Thestudyisentitled‘Maintaining
healthinoldagethroughhomeostasis’,andhastheacronym‘Switchbox’.ItisanEuropean
project comprising partners from Paris,Munich, Budapest, Braga and Leiden,with the
collectiveaimof improvinghealthy longevityby studying thebrain-peripherydialogue
withaviewto re-settingthecriticalhypothalamicset-points. InLeiden,Switchboxwas
conductedintwophases-PhasesI&II,overaperiodof4.5years(figure3).Thefirstphase
(phaseI)wasanobservationalstudyofoffspringoflong-livedsiblingsandtheirpartners,
whilephaseIIwasarandomisedcontrolledclinicaltrialinvolvinghealthyvolunteersfrom
thegeneralpopulation.
FIGURE 1.3 | Switchboxtimelinecoveringtheperiodof4.5yearsduringwhichtheSwitchboxstudywasconducted.
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Switchbox Phase IThehypothesisoftheSwitchboxphaseIstudy isthatcontrolofhomeostasiswouldbe
better preserved in the offspring of long-lived sibling,who growolder in better health
comparedtotheirpartnerswhoshow‘regular’ageing.Thiswashypothesizedtobereflected
indifferencesinbrainfunction,neuro-endocrineoutputandperipheralmetabolism.Thus,
weexaminedthelinksbetweenthethreemainsignalingaxes-Hypothalamo-adrenalaxis
(HPA),Hypothalamo- thyroid axis (HPT)& Insulin- IGF-1 signaling axis (IIS) and critical
measuresthatdeteriorateduringtheageingprocess,suchasmetabolism,brainstructure
andfunction,andheartrateandheartratevariability.
BetweenMarch2012andJuly2013,135offspringandpartnersfromtheLLSwere
includedforSwitchboxphase I. Inclusioncriteriawerebeingmiddle-aged (55-77years)
andhavinga stablebodymass index (BMI)between19kg/m2<BMI<33kg/m2.All
women in the studywere postmenopausal. Participantswere excluded if their fasting
plasmaglucosewasabove7mmol/L, if theyhadany significant chronic, renal, hepatic
orendocrinedisease,oriftheyusedanymedicationknowntoinfluencelipolysis,thyroid
function, glucose metabolism, GH/IGF-1 secretion or any other hormonal axis. Other
exclusioncriteriaweredifficultiestoinsertandmaintainanintravenouscatheter,anaemia
(Hemoglobin < 7.1mmol/L), blood donationwithin the last twomonths, smoking and
alcoholaddiction,severeclaustrophobiaandextremediettherapies.Dataforcomparison
ofmeasuresofbrainfunction(structuralandfunctionalbrainMRI,cognitivetests),neuro-
endocrine output (24-hour hormone rhythms), and peripheral metabolism (continuous
glucose monitoring, indirect calorimetry, diaries), cardiac parameters (continuous
ambulatoryECGmonitoring)toestimatesympathetic/parasympathetictoneandmotion
(continuoustri-axialaccelerometry)werecollectedoverfivedays(figure4)fromoffspring
andtheirpartners,toidentifyparametersmostrelevantforaslowerpaceofageing.
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Switchbox Phase IIInsulin is an important modulator of brain functions, including central regulation of
energyhomeostasis,cognitivefunctions,neuronalactivityandotherbehavioral,cellular,
biochemical,andmolecularfunctions(11,12).Duetothepresenceofdirectpathwaysfrom
thenasalcavitytotheCNS,insulincanbedelivered,non-invasivelyandrapidlytotheCNS
throughtheintranasalroutewithoutbeingabsorbedintothebloodstreamorhavingdirect
systemiceffects(13).
PhaseIIinvolvedtestingwhetherandtowhatextentparametersidentifiedinPhase
Icouldbemodulatedby intranasal insulinapplication.Tothisend intranasal insulinand
placebowere administered to 19 adults (8 young and 11 elderly) volunteers from the
general population in a blinded, cross- over designed randomized clinical trial inwhich
eachparticipantservedashisowncontrol.Participantswererandomizedintotwogroups
fortheorderofintranasalapplicationofinsulinandplacebo(insulinfirstorplacebofirst
groups), Inaddition, theyoungerparticipantsadditionally receivedeither75grglucose
solutionorwaterduringtheMRIprotocol.Thus,theyoungerparticipantswererandomized
tofourstudydays(insulinandglucose,insulinandwater,placeboandglucose,placeboand
water)(figure5)whereastheolderhadtwovisits(insulinandwaterandplaceboandwater).
In this thesis, we report on the neuro-endocrine, metabolic and autonomic
characteristicsthatappeartobepertinentforslowerpaceofageing.
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REFERENCES:
1. OeppenJ,VaupelJW.Demography.Brokenlimitstolifeexpectancy.Science.2002;237:1029
2. WestendorpRG.Whatishealthyageinginthe21stcentury?AmJClinNutr.2006;83:404S-9S
3. Zwaan BJ. The evolutionary genetics of ageing and longevity. Heredity (Edinb). 1999;82
(Pt6):589-97
4. Holzenberger M,Dupont J,Ducos B, Leneuve P, Geloen A, Even PC, et al. IGF-1 receptor
regulateslifespanandresistancetooxidativestressinmice.Nature.(2003)421(6919):182–7.
doi:10.1038/nature01298
5. BartkeA,ChandrashekarV,DominiciF,TurynD,KinneyB,StegerR,etal. Insulin-likegrowth
factor 1 (IGF-1) and E: controversies and new insights. Biogerontology. (2003) 4(1):1–8.
doi:10.1023/A:1022448532248
6. Marieb,ElaineN.,Hoehn,KatjaN.(2009).EssentialsofHumanAnatomy&Physiology(9thed.).
SanFrancisco,CA:Pearson/BenjaminCummings.ISBN0321513428.
7. Gavrilov LA, Gavrilova NS. Early-life programming of aging and longevity: the idea of high
initial damage load (the HIDL hypothesis). Annals of the New York Academy of Sciences.
2004;1019:496-501.
8. GillmanMW.Developmentaloriginsofhealthanddisease.TheNewEnglandjournalofmedicine.
2005;353(17):1848-50.
9. Source:Boundless.“HomeostaticControl.”BoundlessAnatomyandPhysiology.Boundless,21
Jul. 2015. Retrieved 09 Oct. 2015 from https://www.boundless.com/physiology/textbooks/
boundless-anatomy-and-physiology-textbook/introduction-to-human-anatomy-and-
physiology-1/homeostasis-32/homeostatic-control-284-3141/
10. SchoenmakerM,deCraenAJ,deMeijerPH,BeekmanM,BlauwGJ,SlagboomPE,Westendorp
RG(2006)Evidenceofgeneticenrichmentforexceptionalsurvivalusingafamilyapproach:the
LeidenLongevityStudy.EurJHumGenet.14:79–84.doi:10.1038/sj.ejhg.5201508
11. DuarteAI,MoreiraPI,OliveiraCR.Insulinincentralnervoussystem:morethanjustaperipheral
hormone.JAgingRes.2012;2012:384017.
12. SchwartzMW,SeeleyRJ,TschopMH,WoodsSC,MortonGJ,MyersMG,etal.Cooperation
betweenbrainandisletinglucosehomeostasisanddiabetes.Nature.2013;503(7474):59-66.
13. HallschmidM,BenedictC,SchultesB,PerrasB,FehmHL,KernW,etal.Towardsthetherapeutic
useofintranasalneuropeptideadministrationinmetabolicandcognitivedisorders.Regulatory
peptides.2008;149(1-3):79-83.
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Chap
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OUTLINE OF THIS THESIS
Themainobjectiveof this thesis is toprovidenew insights into thecrosstalkbetween
thebrainandtheperiphery,withafocusonglucoseandinsulinmetabolism,thethyroid
axis and the autonomic nervous system. Each section beginswith the validation of a
measurementdeviceforuseforakeyparameterinthiscrosstalk.
Part Iofthisthesisdiscussestheroleofthebraininglucoseandinsulinmetabolism,in
bothoffspringoffamiliesenrichedforfamiliallongevityandtheirpartners.Sinceglucose
metabolismwaspreviouslyshowntoassociatewithlongevitypotential,weexploredways
tomeasureglucoselevelsnon-invasively.Thus,westartedinchapter 2withthevalidation
ofacontinuousglucosemonitorfornon-invasiveglucosemeasurementinolderpersons.
Basedon thehypothesis thatmaintenanceofglucosemetabolism is importantnot just
formetabolichealthbutalsoforthebrain,weassessedtherelationbetweenglucoseand
insulinmetabolism on brainmacro- andmicrostructure in chapter 3. Then,we further
testedtheeffectofageandbeingadescendantoffamiliesenrichedforfamiliallongevity
on the relation between parameters of glucose metabolism and the brain integrity in
chapter 4.Togainmechanisticinsightsintotheroleofthebraininglucosemetabolism,
we examined the effect of intranasal administration of insulin on the brain, as it was
foundpreviouslytoimprovecognitioninhumans.Inchapter 5,weexaminedtheeffectof
intranasallyadministeredinsulinoncerebralbloodflowandperfusioninyoungandolder
adults.PartIconcludeswithchapter 6,wherewereviewedthecrosstalkbetweenglucose
andinsulinmetabolism,ageingandthebrain.
In Part IIof this thesis,we investigatedanothersystemthat is implicated inhuman
longevity; i.e. the thyroid axis.Thus,we set out to characterize the thyroid axis. First,
wedevisedaversatilemethodforfrequentbloodcollectioninolderparticipants.Thisis
presentedaschapter 7.Then,inchapter 8,fromfrequentlysampledblood,weinvestigated
the thyroid stimulating hormone (TSH) secretion pattern on the one hand, andwhole
bodyenergymetabolismon theotherhand in relation to longevity. In chapter 9, via a
systematicreviewandmeta-analysisofexistingliterature,wefurtherlookedattheeffect
ofsubclinicallyraisedTSHlevelsoncognition.
Summarily,ourstudyofthethyroidaxisshowedthathumanlongevityischaracterized
byhigherTSHlevels,butwithoutdifferencesinbasalmetabolism.Sincethethyroidgland
isinnervatedbytheautonomicnervoussystem,anditsactivitymightbeaffectedbythe
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Thesisoutline
sympathetic/para-sympathetictone,wetestedtheinfluenceoftheautonomicnervous
system,usingheart rateandheart ratevariability as aproxy,onhuman longevity.This
formsthebasis for thethird part (Part III)of this thesis. In thispart, inchapter 10, we
firstvalidatedadevice-theEquivital(EQ02)lifemonitor-fornon-invasivemeasurementof
ambulatoryECG,heartrateandheartratevariabilityinolderadults.Then,inchapter 11,
weexaminedtheroleofheartraterhythmsandheartratevariabilityinfamiliallongevity.
Finally,inchapter 12,thekeyfindingsofthisthesisaresummarized.Thesearethen
discussedincontextofcurrentknowledgeofhumanlongevity.