Cover Page

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

CHAPTER 1

GENERALINTRODUCTION

1

1

12

Chap

ter 1

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.

1

General introduction

13

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.

1

14

Chap

ter 1

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.

1

General introduction

15

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.

1

16

Chap

ter 1

FIG

URE

1.4

| StudyprotocolfollowedbybothgroupsofSwitchboxphaseIparticipants.

1

General introduction

17

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.

1

18

Chap

ter 1

FIG

URE

1.5

| StudyprotocolfollowedbySwitchboxphaseIIparticipants.

1

General introduction

19

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.

1

20

Chap

ter 1

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

1

21

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.