Biomarkers of Aging in Epidemiological Research Biomarkers of Aging Workshop University of...

Biomarkers of Aging in Biomarkers of Aging in Epidemiological Research Epidemiological Research

Biomarkers of Aging WorkshopBiomarkers of Aging WorkshopUniversity of Pittsburgh Mind Body CenterUniversity of Pittsburgh Mind Body Center

Anne B. Newman, MD, MPHAnne B. Newman, MD, MPHProfessor of Epidemiology and MedicineProfessor of Epidemiology and Medicine

11/07/0611/07/06

11/7/0/711/7/0/7 Biomarkers of Aging - Pittsburgh Mind Body centerBiomarkers of Aging - Pittsburgh Mind Body center

OverviewOverview

IntroductionIntroduction– Definitions of biomarkers of agingDefinitions of biomarkers of aging– Models for determining markers in human studiesModels for determining markers in human studies

Example of biomarkers at basic and system levelExample of biomarkers at basic and system level– Serum markers that change with ageSerum markers that change with age– Muscle strength as a physiologic markerMuscle strength as a physiologic marker– Relationship of serum markers to physiologic markers – DHEAS Relationship of serum markers to physiologic markers – DHEAS

and muscle strengthand muscle strength

Physiologic markers of age related diseasePhysiologic markers of age related disease– Cardiovascular agingCardiovascular aging– Multisystem physiologic indexMultisystem physiologic index– FrailtyFrailty


DefinitionsDefinitions

What is a biomarker?What is a biomarker?– Surrogate measure to track a physiologic Surrogate measure to track a physiologic

processprocess

Biomarker of agingBiomarker of aging– Marker of physiologic rather than chronologic Marker of physiologic rather than chronologic

ageage


How would a biomarker of aging How would a biomarker of aging useful?useful?

Risk stratificationRisk stratification– Complement or substitute for chronological Complement or substitute for chronological

age.age.

Intervention targetsIntervention targets– that could delay age-related loss of physical that could delay age-related loss of physical

or cognitive functioning (loss of strength, or cognitive functioning (loss of strength, speed)speed)

– That could delay age-related chronic disease.That could delay age-related chronic disease.


Some commonly, but loosely used Some commonly, but loosely used definitions of biomarkers of agingdefinitions of biomarkers of aging

Anything that is correlated with age.Anything that is correlated with age.

Anything that predicts mortality in older Anything that predicts mortality in older adults.adults.

Correlated with age and predictive of Correlated with age and predictive of mortality.mortality.


More specific criteria proposed for More specific criteria proposed for defining aging biomarkersdefining aging biomarkers

An aspect of the fundamental process of aging*An aspect of the fundamental process of aging*

Demonstrated cross-sectional and longitudinal Demonstrated cross-sectional and longitudinal change agingchange aging

Consistently ranks a person across the life span Consistently ranks a person across the life span (not just in old age)(not just in old age)

Consistently ranks one species relative to Consistently ranks one species relative to anotheranother

Changes with interventions that modify the rate Changes with interventions that modify the rate of agingof aging

* Need to define aging* Need to define aging


What is Aging?What is Aging?

The The processprocess that converts healthy adults that converts healthy adults into frail onesinto frail ones– With diminished physiologic reservesWith diminished physiologic reserves– With decreased homeostatic control With decreased homeostatic control – With exponentially increased vulnerability to With exponentially increased vulnerability to

diseases and death.diseases and death.– Usually referring to processes that are Usually referring to processes that are

universal, deleterious, and irreversible.universal, deleterious, and irreversible.

But these are aspects of risk that imply need to stress an individual to determine vulnerability


Are there external standards for Are there external standards for definition of aging ?definition of aging ?

Increasing risk of mortality Increasing risk of mortality – After the fact standard – useful for fruit flies, worms After the fact standard – useful for fruit flies, worms

and miceand mice

Increasing high risk of age-related chronic Increasing high risk of age-related chronic diseasesdiseases– DementiaDementia– Cardiovascular diseaseCardiovascular disease– CancerCancer– OsteoporosisOsteoporosis– DiabetesDiabetes

Increasing risk of age-related disabilityIncreasing risk of age-related disability


Caloric restriction model for Caloric restriction model for identifying biomarkersidentifying biomarkers

Examine the change in potential Examine the change in potential biomarkers in long lived animal modelsbiomarkers in long lived animal models

Evaluate the parameters that change as Evaluate the parameters that change as predictors of mortality in humanspredictors of mortality in humans

11/7/0/711/7/0/7 Biomarkers of Aging - Pittsburgh Mind Body centerBiomarkers of Aging - Pittsburgh Mind Body centerPublished by AAAS

Biomarkers of Caloric Restriction May Predict Longevity in Humans

Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD, Muller D, Metter EJ. Science. 2002;297(5582):811.


Successful aging model of Successful aging model of identifying biomarkersidentifying biomarkers

Examine the change in biomarkers in an Examine the change in biomarkers in an elite subgroup of humans with minimal elite subgroup of humans with minimal diseasedisease

Define aging biomarkers as the changes Define aging biomarkers as the changes seen in this subgroup that by the selection, seen in this subgroup that by the selection, are related to aging and not disease. are related to aging and not disease.

11/7/0/711/7/0/7 Biomarkers of Aging - Pittsburgh Mind Body centerBiomarkers of Aging - Pittsburgh Mind Body centerCopyright ©2005 American Heart Association

Fleg, J. L. et al. Circulation 2005;112:674-682

Longitudinal and cross-sectional changes in peak VO2 per kg FFM by quartile of age-adjusted high-intensity LTPA


Biomarkers of agingBiomarkers of agingLevels of assessmentLevels of assessment

Molecular Cellular Organ System Organism

age, disease, ionizing radiation, injury, behavior, toxins


Some candidate biomarkers of Some candidate biomarkers of aging in humansaging in humans

DHEASDHEAS

GH/IGF-1GH/IGF-1

Interleukin-6Interleukin-6

Telomere lengthTelomere length

Oxidative damage markersOxidative damage markers

Mitochondrial DNA mutationsMitochondrial DNA mutations

Less evidence but under study in epidemiologic studies

Have been demonstrated as important in epidemiologic studies of aging


DHEAS – DHEAS – Dihydroepiandrostendione sulfateDihydroepiandrostendione sulfate

Major component of adrenal androgen Major component of adrenal androgen productionproduction

No known disease stateNo known disease state

Strongly declines with ageStrongly declines with age

Predicts mortality more so in menPredicts mortality more so in men

Modified by caloric restriction in animalsModified by caloric restriction in animals

Rate of decline correlates with life span Rate of decline correlates with life span across speciesacross species


DHEAS - Adrenal Androgens and DHEAS - Adrenal Androgens and AgingAging

Nafziger AN, Bowlin SJ, Jenkins PL, Pearson TA. Longitudinal changes in dehydroepinadrosterone concentrations in men and women. J Clin Lab Med. 1998;131:316-323.

11/7/0/711/7/0/7 Biomarkers of Aging - Pittsburgh Mind Body centerBiomarkers of Aging - Pittsburgh Mind Body centerCopyright ©2001 The Endocrine Society

Trivedi DP,Khaw KT. Dehydroepiandrsterone sulfate and mortality in elderly men and women. J Clin Endocrinol Metab 2001;86:4171-4177.

DHEAS predicts mortalityDHEAS predicts mortality

Survival curve according to quartile of DHEAS in men (age adjusted).

Survival curve according to quartile of DHEAS in women (age adjusted).


Growth Hormone and IGF-1Growth Hormone and IGF-1

Essential for growth in development but not lifeEssential for growth in development but not lifeStrong decline with ageStrong decline with ageLower levels of GH and IGF-1 have been studied as Lower levels of GH and IGF-1 have been studied as predictors of loss of lean mass, increased body fat,– predictors of loss of lean mass, increased body fat,– inconsistent, generally negative findings inconsistent, generally negative findings May be related to low strength and low physical May be related to low strength and low physical functioning , also diabetes.functioning , also diabetes.Higher levels of GH/IGF may predict cancerHigher levels of GH/IGF may predict cancerManipulations that reduce IGF Manipulations that reduce IGF increaseincrease lifespan in lifespan in animal modelsanimal modelsGrowth hormone supplements widely advertised as anti-Growth hormone supplements widely advertised as anti-aging supplementaging supplement


From O’Connor et al, J Geron Med Sci, 1998

Decline in IGF-1 with ageDecline in IGF-1 with age


IGF-1 may be related to disability IGF-1 may be related to disability outcomesoutcomes

Women’s Health and Aging StudyWomen’s Health and Aging Study

617 women aged 70-79617 women aged 70-79

Low IGF-1 was related to Low IGF-1 was related to – Lower extremity strengthLower extremity strength– Walking speedWalking speed– Self reported difficulty in walking tasksSelf reported difficulty in walking tasks

Cappola AR, et al Journal of Clinical Endocrinology and Metabolism 86; 4136-4146, 2001


Interleukin 6 (IL-6)Interleukin 6 (IL-6)

Cytokine that modulates the immune Cytokine that modulates the immune responseresponse

Goes up with ageGoes up with age

More closely related to disease status in More closely related to disease status in that it may not change until later in lifethat it may not change until later in life

Predicts all cause mortality and disability Predicts all cause mortality and disability in older adultsin older adults


IL-6 goes up with ageIL-6 goes up with age

0.50.55

0.60.65

0.70.75

0.80.85

0.90.95

1

71-72(reference)

73-74 75-76 77-80 >=80

Lo

g p

g/m

l

Age (years)

Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R. Associations of elevated interleukin-6 and c-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506-512.


Il-6 is a robust predictor of all- cause mortalityIl-6 is a robust predictor of all- cause mortality

Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R. Associations of elevated interleukin-6 and c-reactive protein levels with mortality in the elderly. Am J Med. 1999;106:506-512.


Inflammatory markers are related to Inflammatory markers are related to Incident Mobility LimitationIncident Mobility Limitation

*Based on chi-square statistics for categorical variables and t test or nonparametric Mann-Whitney statistics for continuous variables. IL=interleukin; TNF=tumor necrosis factor; IQR=interquartile range.

Penninx BWJH, Kritchevsky SB, Newman AB, Nicklas BJ, Simonsick EM, Rubin S, Nevitt M, Penninx BWJH, Kritchevsky SB, Newman AB, Nicklas BJ, Simonsick EM, Rubin S, Nevitt M, Visser M, Harris T, Pahor M. Inflammatory Markers and Incident Mobility Limitation in the Visser M, Harris T, Pahor M. Inflammatory Markers and Incident Mobility Limitation in the Elderly. Elderly. J Am Geriatr Soc.J Am Geriatr Soc. 2004;52: 1105-1113. 2004;52: 1105-1113.

00.5

11.5

22.5

33.5

44.5

5

C-reactive protein,mg/L, median (IQR)

IL-6, pg/ml, median(IQR)

TNF-alpha, pg/ml,median (IQR)

No incident mobility limitation n=2,081

Incident mobility limitation n=898

p=<.001*



Molecular Cellular Organ System Organism

age, disease, ionizing radiation, injury, behavior, toxins

Oxidative damage

Mitochondrial function

Muscle strength

Functional ability


Muscle strength might be a good Muscle strength might be a good biomarker of agingbiomarker of aging

Declines across the age span Declines across the age span

Predicts mortalityPredicts mortality

Predicts from middle agePredicts from middle age

Loss of strength and other metabolic Loss of strength and other metabolic functions seems to be a fundamental functions seems to be a fundamental aging process – few age-related muscle aging process – few age-related muscle diseasesdiseases

11/7/0/711/7/0/7 Biomarkers of Aging - Pittsburgh Mind Body centerBiomarkers of Aging - Pittsburgh Mind Body centerLarsson et al. J. Appl. Physiol.,1978

Muscle strength across the lifespanMuscle strength across the lifespan


Lower quadriceps muscle strength Lower quadriceps muscle strength predicts mortality in Health ABCpredicts mortality in Health ABC

Men Women

Newman AB, Kupelian V, Visser M, Simonsick EM, Goodpaster BH, Kritchevsky SB, Tylavsky Newman AB, Kupelian V, Visser M, Simonsick EM, Goodpaster BH, Kritchevsky SB, Tylavsky FA, Rubin SM, Harris TB, The Health, Aging and Body Composition Investigators.FA, Rubin SM, Harris TB, The Health, Aging and Body Composition Investigators.Strength, but not muscle mass is associated with mortality in the Health, Aging and Body Strength, but not muscle mass is associated with mortality in the Health, Aging and Body Composition Study Cohort. J Gerontol A Biol Sci Med Sci. 2006;61A:M72-M77.Composition Study Cohort. J Gerontol A Biol Sci Med Sci. 2006;61A:M72-M77.

Su

rviv

al

months

0 6 12 18 24 30 36 42 48 54 60 66 72

.65

.7

.75

.8

.85

.9

.95

1

<90

90-130 130-170

>170

Su

rviv

al

months

0 6 12 18 24 30 36 42 48 54 60 66 72

.85

.9

.95

1

<60

60-80

80-100

>100


Grip strength in middle age predicts Grip strength in middle age predicts mortality in the Honolulu Heart Studymortality in the Honolulu Heart Study

Rantanen T, Harris T, Leveille SG, Visser M, Foley D, Masaki K, Guralnik JM. Muscle Rantanen T, Harris T, Leveille SG, Visser M, Foley D, Masaki K, Guralnik JM. Muscle strength and body mass index as long-term predictors of mortality in initially healthy men. J strength and body mass index as long-term predictors of mortality in initially healthy men. J Gerontol A Biol Sci Med Sci. 2000;55A:M168-M173.Gerontol A Biol Sci Med Sci. 2000;55A:M168-M173.


-15

-10

-5

0

% l

oss

of

stre

ng

th

Percent loss of leg strength

White Black White BlackMen Men Women Women

-15

-10

-5

0

-3.4% -4.1% -2.7% -3.0% *

% l

oss

of

l ean

ma s

s

and leg lean mass

* Annualized rates for strength declineGoodpaster B, J Gerontol 2006


Skeletal Muscle fat

Less More Most

CT Scans of the mid thigh from actual Health ABC participants showing muscle area, subcutaneous fat and intermuscular fat (highlighted in pink) variability in thighs of similar cross-sectional area

Scatter plots of log[DHEAS] and lower Scatter plots of log[DHEAS] and lower extremity muscle strength according to ageextremity muscle strength according to age

Valenti G, Denti L, Maggio M, Ceda GP, Volpato S, Bandinelli S, Ceresini G, Cappola A, Valenti G, Denti L, Maggio M, Ceda GP, Volpato S, Bandinelli S, Ceresini G, Cappola A, Guralnik JM, Ferrucci. Effect of DHEAS on skeletal muscle over the life span: the InCHIANTI Guralnik JM, Ferrucci. Effect of DHEAS on skeletal muscle over the life span: the InCHIANTI Study. J Gerontol A Biol Sci Med Sci. 2004;59A:M466-M72.Study. J Gerontol A Biol Sci Med Sci. 2004;59A:M466-M72.


Physiologic functions that decline Physiologic functions that decline with agewith age

EyesEyes– Lens accommodationLens accommodation

EarsEars– High frequency hearingHigh frequency hearing

SkinSkin– ElasticityElasticity

Nervous systemNervous system– Central nervous system Central nervous system

processing speedprocessing speed– Peripheral nerve functionPeripheral nerve function

HormonesHormones– Sex steroids, growth hormone, Sex steroids, growth hormone,

insulin sensitivity, cortisol insulin sensitivity, cortisol regulationregulation

Immune functionImmune function– depletion of naive memory depletion of naive memory

cells,cells,– increase in markers of increase in markers of

inflammationinflammation

BoneBone– Loss of mass and dilation of Loss of mass and dilation of

cross-sectional areacross-sectional area

JointsJoints– Cartilage stiffeningCartilage stiffening

Muscle functionMuscle function– loss of strength and oxidative loss of strength and oxidative

capacitycapacity

LungsLungs– loss of forced vital capacity and loss of forced vital capacity and

lung elasticitylung elasticity

Heart and blood vesselsHeart and blood vessels– vascular stiffening, dilation and vascular stiffening, dilation and

loss of recoilloss of recoil

Physiologic measures can Physiologic measures can capture very early chronic capture very early chronic disease and age related disease and age related

changeschanges


Age DiseaseAge Disease

AgeAge Grey ZoneGrey Zone DiseaseDisease

Vascular StiffnessVascular Stiffness High BPHigh BP AtherosclerosisAtherosclerosis

Bone lossBone loss OsteopeniaOsteopenia OsteoporosisOsteoporosis

Decline in glucose Decline in glucose tolerancetolerance

Pre-diabetesPre-diabetes DiabetesDiabetes

Loss of neuronsLoss of neurons MCIMCI Alzheimer’s and other Alzheimer’s and other neurodegenerative neurodegenerative

diseasesdiseases

Loss of visual Loss of visual accommodation (lens accommodation (lens

stiffening)stiffening)

PresbyopiaPresbyopia CataractCataract


Age vs. disease - Grey zone issuesAge vs. disease - Grey zone issues

Age-related biological changes are risk Age-related biological changes are risk factors for chronic disease factors for chronic disease (example - stiffening (example - stiffening of vasculature increases risk of plaque deposition) of vasculature increases risk of plaque deposition)

Similar biologic changes lead to both age-Similar biologic changes lead to both age-related physiologic declines and to age-related physiologic declines and to age-related chronic disease – related chronic disease – (example - oxidative (example - oxidative stress hypothesized in almost every chronic disease and stress hypothesized in almost every chronic disease and in the aging process) in the aging process)

It may be the same biology underlying It may be the same biology underlying physiologic decline and diseasephysiologic decline and disease . .


Which comes first?Which comes first?The vicious cycleThe vicious cycle

Age change

Age-related chronic disease change



Molecular Cellular Organism

InflammationMuscle hypertrophy and fibrosis

Atherosclerosis

Function – heart attack or stroke

Vascular stiffening

Organ System

Aging vs. Age-Related Chronic Disease

Are you as old as your arteries?Are you as old as your arteries?


Initiation, Progression and Complication Initiation, Progression and Complication of Atherosclerotic Plaqueof Atherosclerotic Plaque

Libby P, et al. Current Concepts 2001;104:365-372


CCA Progression - Participant 2CCA Progression - Participant 2

Baseline Follow-up


Prevalence of CVD by Race and Prevalence of CVD by Race and Gender,Gender,CHS N=5843CHS N=5843

25

35.4

26.2

41.3

32.5

39.737.2

41.9

20.8

37.2

43.7

19.2

05

101520253035404550

None Subclinical Clinical

Per

cen

tage

(%

)

White Women n=2791 Black Women n=577White Men n=2136 Black Men n=339

Kuller L et al; Arterioscler Thromb Vasc Biol 1998;18:283-293


Coronary Artery Calcification Scoring

HounsfieldHounsfield(Agatston Scoring)(Agatston Scoring)

130-199 1130-199 1

200-299 2200-299 2

300-399 3300-399 3

>400 4>400 4

Area = 15 mmArea = 15 mm22

Peak CT = 450Peak CT = 450

Score = 15 x 4 = 60Score = 15 x 4 = 60

Area = 8 mmArea = 8 mm22

Peak CT = 290Peak CT = 290

Score = 8 x 2 = 16Score = 8 x 2 = 16

Total Score = Total Score = all areas thisall areas thisSubject >400Subject >400

LAD RCA

Rumberger, Mayo Clinic Proc 1999;74:243-252


00 0 0 4118

24

539

1064

0 00 3 16 41

151167

126120

725

328

542

0

200

400

600

800

1000

1200

Women, n=367 Men, n=247

Med

ian

Cor

onar

y ar

tery

cal

cific

atio

n sc

ore

Raggi 35-39 40-44 45-49 50-54 55-59

60-64 65-70 CHS 67-74 80-84 85-100

Median CAC Scores for two populations: EBT Nashville* and ACE-CHS by age in men and women

*Raggi, et al, Circulation 2000;101:850-855.


Total Mortality by CVD and CAC Score Quartile – Total Mortality by CVD and CAC Score Quartile – ACE-CHS ACE-CHS (N=614, 40% men, 23% black, Mean age 80 yrs.)(N=614, 40% men, 23% black, Mean age 80 yrs.)

p=.0086

CAC CAC ScoreScore

Events Events

NN

Rate/100 Rate/100 p-yrp-yr

Age-CVD Age-CVD Adjusted HRAdjusted HR

(95% CI)(95% CI)

0-560-56 1111 2.142.14 1.0 (ref)1.0 (ref)

57-33257-332 1616 3.063.06 1.41 (0.65-1.41 (0.65-3.03)3.03)

333-333-917917

2222 4.474.47 1.91 (0.92-1.91 (0.92-3.96)3.96)

918-918-54595459

3434 7.597.59 2.78 (1.37-2.78 (1.37-5.64)5.64)

Newman AB, AHA 2004


Incident CVD by level of coronary artery calcium in Incident CVD by level of coronary artery calcium in men and women age 80-100 in the Cardiovascular men and women age 80-100 in the Cardiovascular

Health Study, N= 559Health Study, N= 559

Quartiles of CAC Quartiles of CAC (Agatson Units)(Agatson Units)

Events per 100 p-yEvents per 100 p-y Adjusted HR* (95% CI)Adjusted HR* (95% CI)

Q1 (0-56)Q1 (0-56) 1.91.9 ReferentReferent

Q2 (57-332)Q2 (57-332) 5.45.4 3.0 (1.2, 7.3)3.0 (1.2, 7.3)

Q3 (333-917)Q3 (333-917) 6.36.3 4.1 (1.7, 10.2)4.1 (1.7, 10.2)

Q4 (>917)Q4 (>917) 6.96.9 4.6 (1.7, 12.3)4.6 (1.7, 12.3)

* Adjusted for age, sex, race, hypertension, diabetes, SBP, smoking status, cholesterol and LDL cholesterol Newman AB, AHA Epi Council 2005


Newman AB, Arnold AM, Naydeck BL, et al. Successful aging: effect of subclinical cardiovascular disease. Arch Intern Med. 2003;163:2315-2322 .

Years of successful lifeYears of successful lifeby age, sex and CVD riskby age, sex and CVD risk

0

2

4

6

8

10

12

14

16

18

Women Men

Succ

essf

ul Y

ears

Women All High Risk Median All Low RiskMen All High Risk Median All Low Risk

16.4

9.0

2.6

14.0

8.1

2.2

10.8

6.3

1.7

7.8

4.31.3

4.51.90.7

14.7

8.9

2.4

12.5

7.4

2

9.7

4.8

1.5

7.03.8

1.1

4.02.30.6

Average effect of subclinical CVD –

Women - 6.5 years

Men - 5.6 years

Women Men


Epidemiologic model for defining Epidemiologic model for defining “biomarkers” that explain chronologic aging“biomarkers” that explain chronologic aging

Marker or measures should be strongly related Marker or measures should be strongly related to age-related outcomes – such as disease, to age-related outcomes – such as disease, injury and death.injury and death.

Should explain a large component of the effect Should explain a large component of the effect of chronologic age on these outcomes.of chronologic age on these outcomes.

Holy Grail – factor (s) that have stronger Holy Grail – factor (s) that have stronger relationship to outcomes than age itself and relationship to outcomes than age itself and even explain away the effect of age altogether.even explain away the effect of age altogether.


Risk Factors for 5 Year Mortality in CHSRisk Factors for 5 Year Mortality in CHS

Fried LP. Kronmal RA. Newman AB. Bild DE. Mittelmark MB. Polak JF. Robbins JA. Gardin JM. Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JAMA. 279(8):585-92, 1998

Substantial age attenuation achieved - 27 risk factors explained 40% of age effect


Construction of aConstruction of a“Physiologic Index”“Physiologic Index”

Index of “physiologic integrity” (0-10) from 5 non-Index of “physiologic integrity” (0-10) from 5 non-invasive tests including invasive tests including – internal carotid artery wall thickness (vascular internal carotid artery wall thickness (vascular

disease), disease), – fasting glucose (diabetes), fasting glucose (diabetes), – cystatin C (kidney disease), cystatin C (kidney disease), – white matter grade on brain magnetic resonance white matter grade on brain magnetic resonance

imaging (cerebrovascular disease), and imaging (cerebrovascular disease), and – forced vital capacity (lung disease). forced vital capacity (lung disease).

Best tertile for all measures =10Best tertile for all measures =10

Newman AB. AGS Annual Meeting, 2006


Physiologic Index - Frequency DistributionPhysiologic Index - Frequency DistributionThe Cardiovascular Health Study 1992-1993, n=2928The Cardiovascular Health Study 1992-1993, n=2928

0

5

10

15

20

0 1 2 3 4 5 6 7 8 9 10

Physiologic Index

%

Worst Best



155.5

80.5

33.826.5

20.1 16.8

50.7

109.4

69.1

9.1 70

20406080

100120140160180

0 1 2 3 4 5 6 7 8 9 10

Physiologic index

Mo

rtal

ity

rate

per

100

0 p

erso

n y

ears

Number of deaths

10 52 87 152 162 119 105 72 43 13 3

Worst Best

Total mortality rates by physiologic Total mortality rates by physiologic indexindex



Survival by physiologic indexSurvival by physiologic index

Physiologic IndexPhysiologic Index Mortality Rate per 1000 P-YMortality Rate per 1000 P-Y HR *HR *

0 - 30 - 3

4 - 54 - 5

6 – 76 – 7

8 - 108 - 10

72.172.1

37.237.2

21.021.0

12.612.6

6.316.31

3.063.06

1.701.70

(ref)(ref)



Predictive Models for MortalityPredictive Models for MortalityPhysiologic Index vs. Continuous VariablesPhysiologic Index vs. Continuous Variables

Age onlyAge only Index Index onlyonly

IndexIndex

AdjustedAdjusted**

Continuous Continuous VariablesVariables††

Continuous Continuous variables plus variables plus Interactions Interactions

between between systemssystems††

AUCAUC .673.673 0.7060.706 0.7580.758 0.7750.775 0.7780.778

Model FitModel Fit

(SBC)(SBC)

1249412494 1241212412 1220712207 12194*12194* 1221612216

* Adjusted for age, sex, race, physical activity, smoking, BMI, clinical comorbidity index† Continuous variables for ICA, FVC, white matter grade, fasting glucose, cystatin C



Mortality - Attenuation of the hazards ratios Mortality - Attenuation of the hazards ratios for age with adjustment for physiologic index for age with adjustment for physiologic index

7.7

4.4

2.51.0 1.6

4.7

2.8

2.01.0 1.5

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

65-69 70-74 75-79 80-84 85+

Haz

ard

rat

io Sex, Race Adj.

Multivariate

11.04



FrailtyFrailty

Summarizes deficits at the organism levelSummarizes deficits at the organism levelOperational definition:Operational definition:– Multiple (3-5/5) criteria present:Multiple (3-5/5) criteria present:

Weight loss Weight loss WeaknessWeaknessExhaustionExhaustionSlowed walking speedSlowed walking speedLow activityLow activity

Fried et al. J. Gerontol: Medical Science, 2001Fried et al. J. Gerontol: Medical Science, 2001


Fried et al. J. Gerontol: Medical Science, 2001Fried et al. J. Gerontol: Medical Science, 2001



Molecular Cellular Organism

Inflammation, Hormones, Genes

Sarcopenia, Anemia

Frailty

Decreased physiologic reserve in multiple systems

Organ System

disease, ionizing radiation, injury, behavior, toxins

Age


Frailty vs. Robust AgingFrailty vs. Robust Aging

N

Frail Robust

<10%3/5

Frail

45% 0/545%

1-2/5


SummarySummary

No one marker of age or disease appears No one marker of age or disease appears to adequately describe aging. to adequately describe aging.

Some important systems include brain, Some important systems include brain, vascular, muscle strength, lung function, vascular, muscle strength, lung function, metabolismmetabolism

Challenges remain to put these togetherChallenges remain to put these together– Across the life span longitudinallyAcross the life span longitudinally– Across systemsAcross systems

Physiologic Changes Related to AgingOperational Definitions for Studies on Aging

35 100

• The aging process described decline of physiological parameters(The Nathan Shock Model)

Few examplesCognitive StatusNerve Conduction VelocityMuscle StrengthVisual AcuityVascular stiffeningInsulin SensitivityTestosteroneEstrogensIGF-1CytokinesROS / Antioxidants

Age

Ph

ys

iolo

gic

al

Pa

ram

ete

r

35 100

• Information on patterns of functional decline in multiple physiological systems with age is scant

Age

Ph

ys

iolo

gic

al

Pa

ram

ete

rPhysiologic Changes Related to Aging

Operational Definitions for Studies on Aging

35 100

• Aging manifest as decline in anatomical integrity and function across multiple physiological systems.

• Relationship between systems across the lifespan not fully understood.

Age

Ph

ys

iolo

gic

al

Pa

ram

ete

rPhysiologic Changes Related to Aging

Operational Definitions for Studies on Aging


For discussionFor discussion

What are the best criteria for defining a What are the best criteria for defining a biomarker of aging?biomarker of aging?– Do we have an adequate framework?Do we have an adequate framework?

Biomarkers of aging vs. biomarker of age Biomarkers of aging vs. biomarker of age related diseaserelated disease– Is glucose sensitivity an aging biomarker?Is glucose sensitivity an aging biomarker?

How will biomarkers lead to improving our How will biomarkers lead to improving our understanding of aging and age related understanding of aging and age related chronic disease?chronic disease?

Biomarkers of Aging in Epidemiological Research Biomarkers of Aging Workshop University of...

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