aging research: a bird’s eye view - demystifying medicine · 2017-01-10 · endocytosis and...
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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