Hormesis And Exercise: Support For An Inverted-U

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ReosDHormesis and Exercise:Support for an Inverted-U Response toAcute and Chronic WorkenspoesBradley D. Hatfield, ProfessorDepartment of KinesiologyCenter on AgingSchool of Public HealthNeural and Cognitive Sciences ProgramCenter for the Advanced Study of LanguageUniversity of Maryland1020

A Report of the Surgeon General, 1996ReosDenspoes“Physical Activity Reduces Risk of PrematureMortality in General, and of Coronary HeartDisease, Hypertension, Colon Cancer, andDiabetes Mellitus in Particular.”-mental health and cognitive benefits (pp.135-141)20Institute of Medicine Report, 200710Bottom line: there is documentedevidence of significant health benefits of physical activity

DReosBut, can we get too muchphysical activity?esenspoWhat is the dose-response relationshipbetween the volume / intensity of worknegotiated over time and cell aging?1020Any evidence of hormesis?

To address this question -ReosDRelationship between Physical activity level,Telomere length, and Telomerase activityLudlow, Zimmerman, Witkowski, Hearn, Hatfield & RothMedicine & Science in Sports and Exercise, 2008esenspoTelomeres are DNA-protein complexes that cap chromosomalends and promote chromosomal stability - telomeresshorten with every replication of the cell1020Telomerase status and telomere length are well establishedindices of cellular health and longevity (PROLIFERATIVEVIABILITY - potential for further division)

Participants: 58 premenopausalmothers of healthy and chronicallyill children (age-controlled)BackgroundDReosEpel et al., PNAS 2004Accelerated telomere shortening in response to life stressenspoes1020Telomeres measured in PBMC

Highest vs lowest quartilesExercise is a stressorReosDenspoesEquivalent of 9 – 17 yrs aging1020Epel et al., PNAS 2004Mild – Moderate - Severe

Back to Ludlow et al.ReosD70 men and womenbetween the agesof 50 and 70enspoMedical screeningesYale Physical ActivitySurvey1020

Rae et al., EJAP (2010)ReosDSkeletal muscle telomere length in healthy,experienced, endurance runnersenspoes1020

Evidence forhormesis in cell agingStress reduction effect?ReosDCherkas et al., 2006Aging CellensRae et al., 2010poesLudlow et al., 20081020

Individual differences in Physical Activity and cognitive aging –an illustration of gene x environment interaction in dose-responseReosDThe NIH Cognitive and Emotional Health Project(CEHP)esenspoThe goal of CEHP is to identify thedemographic, biological, and psychosocialfactors that can help people maintain orenhance their cognitive and emotional health asthey grow older - a major public health goal for(Hendrie et al. 2006)the United States1020Alzheimer’s & Disease

ReosDWhat factors are protective?enspoesThe protective factors for cognitive health that weremost consistently reported in these large-scale highquality studies included (1) higher education levels, (2)higher SES, (3) emotional support, (4) mastery, (5) betterbaseline cognitive function, (6) better lung capacity, (7)more physical exercise, (8) moderate alcohol use, and(9) use of vitamin supplements.1020

Why might this be so?DReos1. The oxygenation hypothesis(cerebral circulation)Swain et al., 2003, Neuroscience; Rogers, 1990, J Cer Bloodflowesnspo2. The neurotransmitter hypothesis(catecholamines & serotonin)eSpirduso, 1983, RQES; Meeusen, 2001, Sports Medicine.10203. Attenuation of glucocorticoids4. The neurotrophic effect - (BDNF)Neeper, Gomez, Choi & Cotman, 1995, Nature

ReosDDoes exercise benefitthe animal brain?Answer- yes300*esC.D. 360BDNF (pg/ml)10024 0po012 060R2 0.77101000 2000 3000 4000 5000Distance (meters/night)eEX SEDGroup18 0nsCotman &Engessar-Cesar2002 - ESSRBDNF (pg/ml)3002002010This neurotrophic effect is most pronouncedin the areas of the brain devoted to memory (hippo).Such an effect in the human brain would holdmajor implications for the delay of dementia andAlzheimer’s Disease

Such a benefit may delay onset of symptoms of Alzheimer’s diseaseReosDenspoes1020Preclinical ADMild to Moderate ADSevere ADEtiology of Alzheimer’s Disease - Memory structures are destroyedAffects 10% over 65 and 50% of those over 85 years.

ReosDAerobic capacity is positively related to CNStissue density in middle age men & womenand appears to slow brain agingCould this be due to neurotrophic effects?Higher capacityenspoesLower capacity1020Voxel based morphometry to assess tissue densityColcombe et al., 2003J. Gerontology

ReosDSome are at greater riskfor this terrible diseaseesenspoA specific polymorphic variation in the APOEgene on chromosome 19, APOE e4 is present in 40% of late-onset AD patients while present inonly 17% of the US population. This suggeststhat the e4 allele interacts with other genes orlifestyle behaviors (exercise) in its contributionto decline.1020e4: Compromised removal of amyloid burdenand cholesterol transport

Exercise, APOE, and working memory:MEG and behavioral evidence for benefit of exercise in epsilon4 carriersReosDDeeny et al. (2008) Biological PsychologyPurposeesenspoTo determine if long-term Physical Activityattenuates APOE e4-related ‘deficits’ incortical activation in men and women (50 –70 years) during cognitive challenge1020

Sternberg Task(challenging the brain)ReosDenspoesC HLSP1020

Magnetoencephalography (MEG) measures magnetic fields160 channels of SQUID recordingReosDenspoes1020Excellent temporal resolutionPlus excellent spatial resolution forcerebral cortex

ReosDBlood samples were collectedto determine presence or absence ofAPOEe4 ( (BDNF) (COMT)nspoesCerebral cortical activity wasassessed in four groups ofintact middle-aged men and women (50 – 70):1. Active non-carriers2. Inactive non-carriers3. Active e4 carriers4. Inactive e4 carriersePrediction:Inactive carriers will show hypoactivation incritical brain regionsActive carriers will be similar to non-carriers1020Behavioral measures were also recordedfor Flankers, Stroop, Wisconsin, and WorkingMemory and related to physical activity

DesignReosD2 (Physical Activity) x 2(Genotype) x 12 (Time ms)poes551-600 ms501-550 ms451-500 ms401-450 ms201-150 ms151-200 msHighLowE4 10E4-0-600 ms20101-150 ms51-100 ms0-50 msens351-400 ms301-350 ms251-300 ms

ReosDenspoes1020Source reconstruction – fusiform gyrus

Low ReosDmsLeft Temporal M170 LatencyE4 Genotypens*230220210200190180170160150eThe study shows the needto consider genetic factors todetect links between physicalactivity and brain function1020mspoesRight Temporal M170 LatencyE4-E4 Genotype

ReospoesSternbergReactionTime latencye4 carriersDDose-responsedependent ongenotypee1020Carriers16nsNon-carriers38e4 carriers

Dose-response dependent on genotypeReosDe4 carriersenspoes1020

Threshold of cognitive declineD The threshold concept implies that aging is associated withdegenerative processes that do not result in clinical symptomatologyuntil they accumulate to a critical levelReosEXERCISERiskGenotypeenspoesε420NORMAL FUNCTIONINGNORMAL FUNCTIONINGDEMENTEDDEMENTED10

The Future:The effect of physical activity on the developing brain and cognitive reserve:DReosInvestment hypothesisenspoes1020Implications forPhysical education

Apolipoprotein E (ApoE) and Brain Structure andFunctionCortical thicknessGlucose metabolismespobrain structure and metabolism in late adolescenceensGlucose metabolismReosDCarrying e4 allele negatively influences1020Reiman et al. (2004)Scarmeas et al., (2005)Shaw et al., (2007)Young adult (20-39 years) College age (19-28 years) Children & adolescents( 21 years)

ReosDCardiovascular fitness modifies the relationship betweengenotype and neurocognitive function during executivechallenge in young menenspoes1020M. Woo, J. Polich, S. Roth & B. HatfieldU Maryland & Scripps Research Center

The purpose of the studyReosDnspoes To examine if cardiovascular fitness modifies therelationship between ApoE genotype and neurocognitive response during late adolescence.e To examine if the relationship between cardiovascularfitness and cortical response in e4 carriers is greaterduring a frontally-mediated executive challenge relativeto a non-executive challenge1020

MethodD ParticipantsReos– Healthy undergraduate male (18 – 23 years of age)– 30 non-carriers (4 of e2/e3 and 26 of e3/e3),– 29 e4 carriers (24 of e3/e4, 5 of e4/e4)esLow fitE4-carrierHigh fitNon-carrierLow fitNon-carrier14151520.67 (1.05)20.73 (1.71)poHigh fitE4- carrier15Age20.87 (1.30)20.29 (1.20)Weight181.87 (35.16)171.67 (31.03)Estimated VO2max52.72 (7.48)36.622 (5.94)K-BIT Composite108.93 (9.22)107.21 (8.63)ensNumber of subjects20176.73 (26.28)54.11 (3.91)40.73 (5.60)104.2 (9.20)106.53 (9.81)10175.33 (26.50)

Physical activity and executive function in the developing brain– a psychophysiological approachReosDP300(2) Peak latency (1) Base to peak: Amplitudepoes–Stimulus onset(2) P300 LatencyCognitiveprocessing speedP300 Amplitude1020Attentional resourceens(1) P300 AmplitudeP300 Latency

2 (Genotype) 2 (Physical fitness) 2 (Task) 3 itNogoE4 E4-

ReosDExpected findings: P300 amplitudeOddballGo-nogoP 3 0 0 a m p lit u d ensP 3 0 0 a m p litu d tral ParietalE4 FrontalCentral ParietalE4-Frontal Central ParietalE4 Frontal Central ParietalE4-

Genotype Physical fitness Region interactionon P300 amplitudeReosDenspoes1020carriersnon-carriers

P300 amplitudeDReos– ApoE e4 carriers may derive particular benefitfrom fitness– Cardiovascular fitness in e4 carriers may beprotective against the susceptibility to the liabilities(i.e., hypometabolism and cortical thinning)associated with this alleleenspoes P300 Latency2010– Both genotypes appear to benefit fromcardiovascular fitness in regard to the neuralprocesses indexed by P300 latency

So what?ReosDDavid Snowdon with participants in theReligious Orders studiesenspoes1020

ReosDenspoes1020During adolescence

Cognitive Functioning Associated with different levels ofCognitive ReserveDOnset of Deteriorationenspoes10High CRLow CR20Cognitive FunctionReosAnalogy of shrinkage allowanceTime (aging process)

ReosDConclusions and complexitiesre dose-responseAcute exercises and affective response – critical to “swallowing the medicine”poesModerate exercise benefits cell aging while higher levels of exerciseaccelerate aging - a point of diminishing returns (hormesis)ensLong-term benefits of moderate exercise on neurocognitive function in older– a case for genetic consideration in the dose-response relationshipBehavioral translation of neurobiological benefits of exercise may be morereadily detectable in those who are at a deficit re neural integrity1020The ‘investment hypothesis’ – benefit from PA in youth may not revealat the behavioral level until a later stage of development(complex temporal dynamic)

U Maryland:Steven RothDavid PoeppelJames HagbergJose Contreras-VidalMin Qi WangAmy HauflerMens Sana in Corpore SanoenspoGeorgetown U:John VanMeterChandan Vaidya1020NIA AG025505NIA AG022791U Cal-IrvineUMCPJohns Hopkins U:Jason BrandtDavid YoussemJay PillaiesStudentsSean DeenyMinjung WooJo ZimmermanMaureen KayesJeremy RietschelGhedem SolomonAndy LudlowSarah WitkowskiReosDA healthy mindin a healthy bodyScripps Research Inst:John PolichFrom Philosophy to ScienceGeorge Mason U:Craig MacDonald

Continued frontal lobe development after pubertyReosD Myelination– Prefrontal cortex continue to myelinate throughthe third decades of life or around 25 years ofPrefrontal cortex is a brainage.enspoesarea(Yakovlev & Lecours, 1967; Pfefferbaum et al.; 1994, Giedd et al., 1999;Sowell et al., 2003) to develop most and lastYoung adult teensin thecourse of individual development Synapticpruning1020– Synapses in prefrontal lobe are overproducedand subsequently pruned up to the age of 30.(Sowell, 2001; 2003)

Expected findings: P300 latencyReosDGo-nogoOddballP 3 0 0 l a te n c yHigh-fitnsP 300 laten cypoesHigh-fitLow-fiteLow-fit1020FrontalCentral ParietalE4 FrontalCentralE4-ParietalFrontalCentral ParietalE4 FrontalCentral ParietalE4-

Physical fitness Task Region interaction on the P300 latencyReosDenspoes1020