AgingResearch:ABird’sEyeView

DemystifyingMedicine

RichardJ.Hodes,M.D.January10,2017

World’sOlderPopulationisGrowing

Heetal.U.S.CensusBureau,InternationalPopulationReports,P95/16-1,AnAgingWorld:2015

• America’s65-and-overpopulationisprojectedtonearlydouble,from48millto88millby2050

• Globallifeexpectancyisprojectedtoincreasebyalmosteightyears,from68.6yearsin2015to76.2yearsin2050

• Theglobalpopulationofpeopleaged80andolderisexpectedtomorethantriple,growingfrom126.5millto446.6millby2050

Epigenetics

MetabolismInflammation

Damage(Repair)

Stress(Adaptation)

Genetics

StemCells

Immunity

Proteostasis

Biologyof

Aging

AgingistheMajorRiskFactorforMostChronicDiseases

St.Sauver,JLetal.(2015)BMJOpenFeb3;5(2):e006413.

ChronicKidneyDisease

Stroke OsteoporosisCong.HeartFailure

COPD

Hyperlipid. HTN Depression Diabetes

Arthritis Cancer CardiacArrhythmias

CAD

DiseasePrevalenceasaFunctionofAge

Schizophrenia

Lifeexpectancyfallingforthepoor,risingfortherich

FromNIAHealthandRetirementStudydata

U.S.ranks34th inlifeexpectancyatbirth

Source:America’sHealthRankings,APHA,2014

Totallifeexpectancyatbirthinyears,1980-2011

LeadingCausesofDeath,Adults65+Years,2014

Rank Cause of Death

1 Heart disease

2 Cancer

3 Chronic lower respiratory diseases

4 Stroke

5 Alzheimer’s disease

6 Diabetes

7 Accidents (unintentional injuries)

8 Influenza and pneumonia

9 Kidney disease

10 Septicemia

SOURCE:CDC/NCHS,.Public-use2014MortalityFile.Deaths:Finaldatafor2014.Nationalvitalstatisticsreports.Availablefrom:http://www.cdc.gov/nchs/data/dvs/lcwk3_2014.pdf

ClinicalResearchatNIH

• Advancesourunderstandingofmanyconditionsthatcontributetothesecausesofdeath

•Diverseclinicaltrialsinclude:Ø SPRINTstudyØ SmokingCessationProgramsØ UFOVTrainingØ DiabetesInterventionØ ADTrials

SystolicBloodPressureInterventionTrialPrimaryOutcome

TheSPRINTResearchGroup(2015)NEJM 373(22):2103-16.

SPRINTStudy

SPRINTFollow-upinAdults75yearsorOlder

Williamson,JeffD.,etal.(2016)JAMAEpub aheadofprint

• Cumulativehazardwasreducedinparticipants,eventhoselessfitandfrail

• Incidentcardiovasculardiseasewasreducedby33%andmortality(fromanycause)wasreducedby32%

• Therateofseriousadverseeventswasnotstaticallydifferentacrosstreatmentgroups,includingamongthemostfrailparticipants

RandomizedTrialofFinancial-IncentiveProgramsforSmokingCessation

Halpern,SDetal.(2015)NEJM372(22):2108-17.

“Reward”and“Commitment”participantsquitmoreoftenthantreatmentasusual

UsefulFieldofViewAreafromwhichonecanextractvisualinformationataglancewithoutheadoreyemovements.Visualimpairment,difficultiesindividingattentionorignoringdistractinginformation,andslowerprocessingspeedcouldallcontributetoreductionsinUFOV.

KarleneBall(NIAgrantee)wastheco-developerofUFOVandhasalsoshownthatbytraining UFOVyoucanprospectivelyreducecrashrates(e.g.,Ball,Edwards,andRoss,2007)

MD,CA,andFLMotorVehicleDepartmentsareusingandtestingUFOVandStateFarmandAllStateareofferingdiscountswiththistraining.

UFOVTrainingReducesAutomobileCrashes• Olderadultsrandomizedtotrainingexperiencedhalfthenumberofat-faultcrashes(resultsfromACTIVE)

AdjustedOddsRatioforAt-FaultCrashes(5-yearCrashData)

*significantassociationsBall,K.etal.(2010)JAmGeriatrSoc58(11):2107-13.

LifestyleInfluenceonDiabetesIncidence

0

3

6

9

12

15

25-44(n=1000)

45-59(n=1586)

>60(n=648)

Cases/10

0pe

rson

-yr

Lifestyle Metformin Placebo

Source: Diabetes Prevention Program, 2001

BrainimagescourtesyofGeorgeGrossberg M.D.;St.LouisUniversity.

Normal AD

NeuropathologicChangesCharacteristicofAlzheimer’sDisease

NeurofibrillaryTangles

SenilePlaques

Tau(T807)

Ab(PiB)

CN

AmyloidandTauPETImaging

Sperling,R,Mormino,EC,andJohnson,K(2014)Neuron 84(3):608-22.

Tau(T807)

Ab(PiB)

ADDementia

CN

Sperling,R,Mormino,EC,andJohnson,K(2014)Neuron 84(3):608-22.

AmyloidandTauPETImaging

Tau(T807)

Ab(PiB)

ADDementia

CNCN

Sperling,R,Mormino,EC,andJohnson,K(2014)Neuron 84(3):608-22.

AmyloidandTauPETImaging

ProductionofAmyloidPlaques

BetaSecretase

Outsidethecell

Amyloidprecursorprotein(APP)

Betaamyloidplaqueformed

Cellmembrane

Beta

loid

Amy

Beta

loid

Amy

GammaSecretasePS1/PS2

CourtesyofTammieBenzinger;Bateman,Retal.(2012)NEngl JMed 367(9):795-804.

AβDepositioninAutosomalDominantAlzheimer'sDiseaseYearsbeforeExpectedClinicalSymptoms.

Alzheimer’sdisease:Biomarkerprogression

Jack,Cetal.(2013)LancetNeurol 12(2):207-16.

Alzheimer’sdisease:Treatingsymptomaticdisease

Jack,Cetal.(2013)LancetNeurol 12(2):207-16.

Alzheimer’sdisease:Interveningearly

Jack,Cetal.(2013)LancetNeurol 12(2):207-16.

AfamilyinColombiathatdevelopsADearlyisgenerouslyworkingwithresearchers

Non-Carriers, late 30’s

EarlyInterventionsareinTrialsNow

Fleisher, AS et al. (2012) Lancet Neurology 11(12):1057-65.

Gene Carriers, late 30’sBeta-amyloid, late 20’s

Dementia onset is in late 40’s

● APP

● APOE

●●●●●●

Early-onset genes

Innate immune/brain inflammatory response genesEndocytosis and cellular protein trafficking, including APP trafficking and Aβ processing

Lipid transport/metabolism

Synaptic transmissionCytoskeletal function, including tau

No assigned mechanism of action

● PS1

● PS2●● CR1

●● CLU● PICALM

● BIN1

● CD33

● TREM2

●● ABCA7

● HLA-RB5 ● TRIP4

● MAPT

KEY

● SORL1

● CD2AP

● MS4A4/MS4A6E

● EPHA1

GeneticRegions of InterestinAlzheimer’s Disease

By year of discoveryNOTE: Color indicates mechanism of action in the body. See key below.

● MEF2cC

● PTK2B

● FERM T2

● CASS4

● NME8

● CELF1

SLC24A4/RIN5

IMPP5D

Relationshipbetweensleepandamyloidload

MeanPETPiBimagesshowincreasedamyloidburdeninthosesubjectswhoreportsleepinglessthan6hoursnightly

Spira,Aetal.(2013)JAMANeurology70(12):1537-1543.

≤6h>6hto≤7h>7h

Epigenetics

MetabolismInflammation

Damage(Repair)

Stress(Adaptation)

Genetics

StemCells

Immunity

Proteostasis

Arthritis

Sarcopenia CKD

COPD Heart Disease

Immunity

VascularDiseaseNeurological

Disease

Cancer

MacularDegeneration HearingBiology

ofDisease

Biologyof

Aging

Proteostasis

Epigenetics

MacromolecularDamage

Inflammation

OtherBiology

Metabolism

StemCells

StressResponse

Sierra&KohanskiJGerontol June2014

Kennedyetal.CellNov2014

TheEmergenceofGeroscience

Heterochronicparabiosis

AgingInterventionAffectsMultipleHealthParameters

Villeda etal.Nature477:90(2011);Villeda etal.NatMed20:659 (2014);Sinhaetal.Science 344:649(2014);Katsimpardi etal.Science 344:630(2014)

SynapticplasticityNeuro-

vasculature

OLFACTIONMUSCLES

Cognitivefunction

CardiacHypertrophy

Smell

Post-injuryrepair

Strength&Endurance

GDF-11

Loffredo etal.Cell 153:828(2013)

Conboy etal.Nature 433:760(2005)

CCL11

StemCells&Niches

LEARNING&MEMORY

DNAMethylationPredictsAll-causeMortality

• HighcorrelationbetweentwopapersaddressingDNAMethylation(Hannum andHorvath)

• Methylationstatuscorrelateswithallcausemortality

Marioni etal.– GenomeBio16:25(2015)

BakerDJetal.Nature479:232(2011)Coppe etal.PLoS Biol 6:e301(2008)

SenescentCellsarePhysiologicallyActive

Deletesenescentcells

DeMariaetal.(Campisi)– DevCell2014

SenescentCellshaveBeneficialFunctions

FOXO3 genotypeandageatdeath

Willcox,B.J.,etal.(2016)AgingCell15(4):617-24.

Carrierstatusfortheprotective G alleleincreasedwithageforindividualsintheir70sto≥ 90 yearsold,consistentwithprotectionagainstmortalityforcarriersinthethreepopulations

Summary

• Theworldisgrowingolder;butlifeexpectancyisdecreasingforseveralgroups

• Ageisariskfactorformanyserioushealthconditions

• Researchhascontributedtoadvancesinunderstandingmanyofthesespecificconditionsandhowtotreatorpreventthem

• Geroscience isanemergingfieldthathelpsusunderstandwhyagingisariskfactor– inthehopethatwecanextendhealthspan aswellaslifespan