GGuest Speaker: Dr. Christiaan Leeuwenburgh

TTopic: Sarcopenia, Prevention and Rehabilitation of Disability

IInstitute oon AAgingDepartment of Aging and GeriatricsDivision of Biology of Aging UF Century Tower

“Aging of America”“Aging of America”

6.8 7.1 7.5 8.5 9.7 11 12

29.2 32.2 37.444

51.658.3

27.3

0

10

20

30

40

50

60

70

80

2000 2005 2010 2015 2020 2025 2030

Mill

ion

Disabled Non disabled

Year

according to Instrumental and basic Activities of Daily Living (IADL+ADL) assuming a decline in disability rate of 0.1% per year

Projected US population aged >65 yearsProjected US population aged >65 years

Hence the Study of Geriatrics and Gerontology is ESSENTIAL for future generations

Hence the Study of Geriatrics and Gerontology is ESSENTIAL for future generations

Key features that identify Geriatrics and Gerontology as a distinct discipline:

• The study and management of the outcome of physical disability

• The study and management of the effects of coexisting multiple diseases or co-morbidity

Challenge to expand active life expectancy

Age (years)

%

Survival

0

50

0 10050

Active life

Active life freeof disability

100

Co-morbid factorsCVD, COPD

cognitive disordersdiabetes, osteoporosis

DisabilityDisability

Impairment Functional limitation

Impairment Functional limitation

SarcopeniaObesity

SarcopeniaObesity

Behavioral factorsPhysical exercise - diet

GenesGenesBiological factorsinflammation, hormones,

oxidative damage, anemia, renin-angiotensin system

Causal model of disabilityCausal model of disability

Social, economic &

environmental factors

Social, economic &

environmental factors

Institute on Aging overarching themeInstitute on Aging overarching theme

The etiology, prevention and rehabilitation of

cognitive and physical disability

Institute on Aging Mission StatementInstitute on Aging Mission Statement

The Institute on Aging serves as the major catalyst for developing models and synergisms in the areas of research, education and health care across all Colleges and Departments at the University of Florida and its affiliates to provide regional and national models of health care, which will improve the health and quality of life of older adults

National Institute on HealthRoadmap Strategy

National Institute on HealthRoadmap Strategy

Bench Bedside PracticeBuilding Blocks PathwaysMolecular LibrariesBioinformatics and

Computational Biology

Structural BiologyNanomedicine

TranslationalResearchInitiatives

Clinical ResearchInformatics

Integrated ResearchNetworksClinical outcomes

TrainingNational Clinical Research Associates

Interdisciplinary ResearchPioneer Award Nanomedicine

Public PrivatePartnerships

Medicine

Genetics

Cancer

VA

PHHP

CLAS

HHP

Brain

Pharmacy

Nursing

Dentistry

Engineering

JAX

Institute on Aging CoresInstitute on Aging Cores• Leadership and administration• Pilot and Exploratory Studies• Career Development• Recruitment, Adherence, Retention & Ethics• Clinical Research• Epidemiology, Health Services, & Demography• Body Composition and Imaging• Pre-clinical and Translational Research• Human Performance Laboratory• Genomics, Metabolism and Biomarkers• Biology of Aging• Biostatistics, Data Analysis, Management and

Quality Control (DMAQC)

Co-morbid factorsCVD, COPD

cognitive disordersdiabetes, osteoporosis

DisabilityDisability

Impairment Functional limitation

Impairment Functional limitation

SarcopeniaObesity

SarcopeniaObesity

Behavioral factorsPhysical exercise - diet

GenesGenesBiological factorsinflammation, hormones,

oxidative damage, anemia, renin-angiotensin system

Causal model of disabilityCausal model of disability

Social, economic &

environmental factors

Social, economic &

environmental factors

Sarcopenia and frailty in older adultsSarcopenia and frailty in older adults

Lexell J, et al. J Neurol Sci 1988

Time course of muscle lossTime course of muscle loss700

500

300

100

3^ 5^ 7^ 9^

Fibe

r num

ber /

mm

2

Age (decades)

Hypothetical Sarcopenic Obesity Curve

Normative Aging

Prevalence of sarcopenia in older adultsPrevalence of sarcopenia in older adults

0

10

20

30

40

≤70 ≥80Age (years)

Prev

alen

ce (%

)

Baumgartner RN, et al. Am J Epidemiol 1998

29 years

77 years

Even Roy Hilligenn Experiences “Sarcopenia”

Even Roy Hilligenn Experiences “Sarcopenia” 54 years

0

50

100

150

200

250

300

350

400

450

29 years 54 years 77 years

Full SquatBench PressSeated Press

Average decrease ~ 30%

Roy HilligennRoy Hilligenn

Short Performance Physical Battery Tests helps to identify level of Sarcopenia

Short Performance Physical Battery Tests helps to identify level of Sarcopenia

The SPPB is composed of tests for walking speed, standing balance and ability to rise from a chair.

Walking speed will be defined as the best performance (in meter/second) of two 4-meter walks along a corridor.

Standing balance, participants will be asked to stand in three progressively more difficult positions for 10 seconds each: a side-by-side feet standing position, a semi-tandem position and a full tandem position.

Chair stand test, the participant will be asked to perform 5 repetitions of standing up and sitting down from a chair without using hands and the performance will be timed.

The hand grip strength will be assessed using a hand-held dynamometer (hydraulic hand “JAMAR” dynamometer, Sammons Preston Rolyan, Bolingbrook, IL).

Strength TestingStrength Testing

Biodex to measure the maximal concentric isokinetic strength of the knee extensors.

Impact of sarcopenia in older adultsImpact of sarcopenia in older adults

All-cause mortality according to grip-strength tertiles and BMI over a 30 years follow-up in initially healthy men.

Rantanen T, et al. J Gerontol A Biol Sci Med Sci 2000

0

5

10

15

20

25

30

≥25 20-24.99 <20

HighestMiddleLowest

Dea

ths/

1,00

0 pe

rson

-yea

r BMI categories

Pre-Clinical Studies Translational Grip strength meter

Pre-Clinical Studies Translational Grip strength meter

Carter et al., Journal of Gerontology: Biological Sciences, 2002.

Physical Performance Declines with AgePhysical Performance Declines with Age

Carter et al., Journal of Gerontology: Biological Sciences, 2002.

p= 0.001

p= 0.002

24 25 26 27 28 29 30

Spe

ed in

cm

/sec

0

222426283032

Age (in months)

24 25 26 27 28 29 30

Late

ncy

to fa

ll in

sec

/g

0.04

0.08

0.12

0.16

0.20

0.24

Sarcopenia and frailty in older adultsWhat are the causes?

Sarcopenia and frailty in older adultsWhat are the causes?

Mitochondria -- Powerhouse of Cell, Mitochondria -- Powerhouse of Cell,

Encodes:13 OXPHOS polypeptides22 tRNAs2 rRNAs

but mitochondrial DNA may be susceptible to mutationsbut mitochondrial DNA may be susceptible to mutations

Podrez et al (Hazen) (2002) J. Biol. Chem. 277:38503-16Podrez et al (Hazen) (2002) J. Biol. Chem. 277:38517-23 Leeuwenburgh et al (1997) J. Biol. Chem. 272:1433-1436 Leeuwenburgh et al (1997) J. Biol. Chem. 272:3520-3526

Inflammation is the Hallmark of Diseases;Risks factors, such as IL-6, CRP are predictors for

MI, heart disease, and frailty and disability

Inflammation is the Hallmark of Diseases;Inflammation is the Hallmark of Diseases;Risks factors, such as ILRisks factors, such as IL--6, CRP are predictors for 6, CRP are predictors for

MI, heart disease, and frailty and disabilityMI, heart disease, and frailty and disability

CRP

TNF-α , CRP, IL-6

Dirks, A.J., and Leeuwenburgh, C. 2004. Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of apoptosis, caspase-3, and caspase-12. Free Radic Biol Med 36:27-39. Dirks, A., and Leeuwenburgh, C. 2002. Apoptosis in skeletal muscle with aging. Am J Physiol Regul Integr Comp Physiol 282:R519-527.Wanagat et al. 2001. Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. Faseb J. 15:322-32

Programmed Cell Death or ApoptosisProgrammed Cell Death or Apoptosis

Interventions/BehavioralInterventions/Behavioral

Life-Long Exercise HabitsLife-Long Moderate Calorie Restriction

Voluntary Wheel Running and Calorie RestrictionVoluntary Wheel Running and Calorie Restriction

Holloszy et al., J Appl Physiol 82, 1997Sedentary and Runners were 8% restrictedCaloric Restriction was 30%

Weindruch and Prolla

What is CR: Reduction in caloric intake without malnutrition

CR increases mean and maximum life-span improves neuronal and muscle function as well as reduces cardiomyopathy

What is CR: Reduction in caloric intake without malnutritionWhat is CR: Reduction in caloric intake without malnutrition

CR increases mean and maximum lifeCR increases mean and maximum life--span improves neuronal and muscle span improves neuronal and muscle function as well as reduces cardiomyopathyfunction as well as reduces cardiomyopathy

Weindruch and Prolla

Laboratories of *Neurosciences and Experimental Gerontology, National Institute on Aging Intramural Research Program

Calorie Restriction Calorie Restriction IS THE ONLY NATURAL INTERVENTION TOIS THE ONLY NATURAL INTERVENTION TOincrease mean and maximum lifeincrease mean and maximum life--span by 30span by 30--40% compared to ad 40% compared to ad libitumlibitum (as much as animal wants to eat) fed controls(as much as animal wants to eat) fed controls

In 2002, life expectancy in the United States reached a new high of 77.4 years, up from 77.2 in 2001……BUT

In 2002, life expectancy in the United States reached a new high of 77.4 years, up from 77.2 in 2001……BUT

Leading Causes of Death

1900; 2003;

1) pneumonia, tuberculosis 1) heart disease

2) GI infections, diarrhea 2) cancer

3) heart disease 3) neurodegenerative diseases

Healthy Centenarians in Okinawa (Japan)Healthy Centenarians in Okinawa (Japan)

Humans (~45-85 years) Maximum 122y?

Moreover most centenarians are females

World Thirst and Hunger

World Obesity Epidemic

Healthy Okinawa Life Style

Caloric Restriction and Human HealthCaloric Restriction and Human Health

Okinawans eat about 40% fewer calories as others in the western world and 8% less then Japan and have the highest proportion of centenarians

Higher caloric intakes are associated with the development of cancers of the prostate, breast and gastrointestinal tract

Recent findings link lower caloric intakes with reduced risk of Alzheimer and Parkinson’s diseases

Prevents neuron and muscle fiber losses?

Compared to Americans, Okinawan elders

Compared to Americans, Okinawan elders

are 75% more likely to retain cognitive ability

get 80% fewer breast and prostate cancers

get 50% fewer ovarian and colon cancers

have 50% fewer hip fractures

have 80% fewer heart attacks

Biological Mechanisms of how Calorie Restriction and Exercise Maintains

Healthy Cellular Function

Biological Mechanisms of how Calorie Restriction and Exercise Maintains

Healthy Cellular Function

Reduces oxidant production

Improves Energy Levels

Reduces DNA damage

Improves Cell “Cleansing” and Prevents Cell Death

Reduces inflammation

Oxidative Stress and Aging: A critical Role for Mitochondria

Oxidative Stress and Aging: A critical Role for Mitochondria

Weindruch

Lysosomal theory of agingLysosomal theory of agingDecrease in lysosomal activity increases the accumulation of defective organelles (i.e. mitochondria) . “Decreased visits from the garbage man”

AP

EarlyAutophagosome

Late Autophagosome

AutolysosomeLysosome

Membrane of unknown origin,maybe rER

AP

APAP

Rapamycin3MA

WortmanninLY294002

PI3 KinaseBeclin (ATG6)

mTorP70 S6 Kinase

REGULATION OF MACROAUTOPHAGY

Phosphatase 2AOkadaic AcidCalyculin AMicrocystin-LR

hATG7(GSA7)hATG9 (GSA14)hATG8 (MAP-LC-3)

hATG13

Ceramide2,3-Butanedione

monoxime

Phagophore

LAMP-1 (LGP120)

W. A. Dunn, Jr.

AP

EarlyAutophagosome

Late Autophagosome

AutolysosomeLysosome

Membrane of unknown origin,maybe rER

AP

APAP

Rapamycin3MA

WortmanninLY294002

PI3 KinaseBeclin (ATG6)

mTorP70 S6 Kinase

REGULATION OF MACROAUTOPHAGY

Phosphatase 2AOkadaic AcidCalyculin AMicrocystin-LR

hATG7(GSA7)hATG9 (GSA14)hATG8 (MAP-LC-3)

hATG13

Ceramide2,3-Butanedione

monoxime

Phagophore

LAMP-1 (LGP120)

W. A. Dunn, Jr.

6 AD 6 CR

26 AD 26 CR

M

M

M

M

6 AD 6 CR

26 AD 26 CR

M

M

M

M

Slight CR and voluntary exercise counteract muscle increases in extracellular space, reduces inflammation

and decrease in CSA with age

Slight CR and voluntary exercise counteract muscle increases in extracellular space, reduces inflammation

and decrease in CSA with age6 AL 24 AL

24 CR 24 CR+EX

Plantaris muscle cross-sections. Increase of extracellular space and decrease of fiber CSA with age. These changes are attenuated by CR and by CR+EX.

Lawler et al. Submitted.

HumansCalorie Restriction Society

HumansCalorie Restriction Society

The Calorie Restriction Societyfor people trying to live longer by eating fewer calories

http://www.calorierestriction.org/Home

Studies in Collaboration with John Holloszy and Luigi Fontana

Clinical Characteristics of Study ParticipantsCR Exercisers Control

n (35) (28) (35)Age, yr 53±12 55±12 55±6Sex, F/M 4/31 4/24 4/31Body Weight, kg 59.3±6.6 67.1±8.0 78.1±11.8Height, m 1.7±0.1 1.7±0.1 1.7±0.1BMI 19.6±1.7 22±1.9 26.7±2.6Body Fat % 8.4±6.9 12.4±6.0 32.1±9.1Mean, Body Fat % 6.9±4.6 10.4±4.4 24.4±5.8Trunk Fat % 4.6±5.5 8.7±5.9 32.5±8.9Mean, Trunk Fat % 3.7±4.5 7.5±5.7 26.6±7.8

Values are means ± SD

Clinical Characteristics of Study ParticipantsCR Exercisers Control

n (35) (28) (35)Age, yr 53±12 55±12 55±6Sex, F/M 4/31 4/24 4/31Body Weight, kg 59.3±6.6 67.1±8.0 78.1±11.8Height, m 1.7±0.1 1.7±0.1 1.7±0.1BMI 19.6±1.7 22±1.9 26.7±2.6Body Fat % 8.4±6.9 12.4±6.0 32.1±9.1Mean, Body Fat % 6.9±4.6 10.4±4.4 24.4±5.8Trunk Fat % 4.6±5.5 8.7±5.9 32.5±8.9Mean, Trunk Fat % 3.7±4.5 7.5±5.7 26.6±7.8

Values are means ± SD

Risk Factors for Atherosclerosis/CAD

CR Exercisers Control

Total Cholesterol (mg/dl) 160±35 171±31 207±36LDL Cholesterol (mg/dl) 84±24 93±25 125±32HDL Cholesterol (mg/dl) 64±18 64±18 53±12Total Chol/HDL Chol. (mg/dl) 2.6±0.5 2.8±0.7 4.1±1.1Triglycerides (mg/dl) 57±18 66±23 147±90CRP (mg/L) 0.22±0.27 0.98±1.21 2.48±3.00Systolic BP 102±12 125±17 132±14Diastolic BP 62±7 72±9 82±9

Values are means ± SD

Glucose Tolerance and Insulin Action

CR Exercisers Control

Fasting Glucose (mg/dl) 84±8 90±8 96±92hr Glucose (mg/dl) 126±42 106±29 140±44Glucose AUC 16029±3195 15005±2670 18037±3276 Fasting Insulin (µU/ml) 1.5±1.0 1.8±1.2 7.4±52hr Insulin (µU/ml) 37±23 17±11 66±58Insulin AUC 4174±3836 2454±956 7285±4323ISI 17.9±7.1 20.9±8.7 6.2±3.9

Values are means ± SD

Healthy lifestyle ALSO helps fiscal $ fitnessHealthy lifestyle ALSO helps fiscal $ fitness

It is estimated that a couple retiring today will need $200,000 to cover health costs over a 15 year period. Prescription drugs represent 1/3 of this amount.

Moderate exercise -30 minutes/day most days of the week and a low caloric diet- can substantially reduce the risk of developing some of the most costly and debilitating conditions: heart disease, some cancers, diabetes, depression, obesity and stroke.

Walk 30 minutes a day - put off or avoid diabetes and save $13,000 a year; control blood pressure and cholesterol and save $50-$100 a month; 15-30 minutes three times a week and reduce chance of developing dementia and save $70,000 a year on nursinghome costs.

Supervised Aerobic Exercise StudiesSupervised Aerobic Exercise Studies

Endurance training:65-70% VO2peak for 15-30 min2-4 x week

Recommendations for Resistance TrainingRecommendations for Resistance Training

Resistance training: 6 exercisesBegan at 2 sets of 6-8 repetitions at 65% 1-RMProgressed to 3 sets of 8-12 reps at 85% 1-RM

For more information on how you can help Americans to live stronger longer contact:UF Institute on Aging Development OfficePhone: (352) 265-7228Toll free: (888) 374-2867E-mail: tmunn@aging.ufl.edutmunn@aging.ufl.eduInstitute on Aging• http://www.aging.ufl.edu/

The End

Age-Related Declines in VO2max in Sedentary and Physically Active Individuals

Age-Related Declines in VO2max in Sedentary and Physically Active Individuals

Age (years)

VO

2M

AX

(ml/k

g/m

in)

40 50 60 70 80 9010

50

60

70 Sedentary

40 yr Longitudinal50 yr Longitudinal60 yr Longitudinal70 yr Longitudinal

20

30

40

menwomen

((WiswellWiswell et al., J Gerontol 56:M618, 2001)et al., J Gerontol 56:M618, 2001)

~ Lowest valuecompatible with life

IoA Major Funding Goals to Study Frailty and Disabilitiesas well as the Biology of Aging

IoA Major Funding Goals to Study Frailty and Disabilitiesas well as the Biology of Aging

Claude Pepper Center Fall 05

The LIFE Study Summer 06

NIH Roadmap Consortium Winter 07

Program Project Fall 07

Nathan Shock Center Summer 08

Donation

Fiber loss with ageLexell et al., 1988

Fiber loss with ageFiber loss with ageLexellLexell et al., 1988et al., 1988

Apoptosis In Human Skeletal MuscleApoptosis In Human Skeletal Muscle

NIH RoadmapResearch Teams of the Future

Scale and complexity of 21st C research requirenew organizational models for scientific teams

NIH RoadmapResearch Teams of the Future

Scale and complexity of 21st C research requirenew organizational models for scientific teams

Multi-disciplinary and Inter-disciplinary Teams

Larger, coordinated, resource sharing Teams

Preserve the investigator(s)-initiated strategy

Challenges in research on disability

Lack of definitive Phase 3 trials

Limited number of Phase 2 trials

Extremely limited knowledge of the mechanisms and risk factors

Lack of pre-clinical models

Dearth of translation between HSR, clinical research and basic sciences

Muscle Strength--Inclined PlaneMuscle Strength--Inclined Plane

Myocardial Aging, Sarcopenia and Neurodegeneration

Myocardial Aging, Sarcopenia and Neurodegeneration

• Oxidative Stress, Inflammation and Apoptosis may be one major factor

Critical Targets in Aging are Non-Dividing Cells

Critical Targets in Aging are Non-Dividing Cells

Dramatic increases in ageDramatic increases in age--related mortality related mortality involves involves diseases of the heart, muscle and diseases of the heart, muscle and nervous systemnervous system: : CardiomyocytesCardiomyocytes, skeletal muscle , skeletal muscle fiber and Neuron # decreases.fiber and Neuron # decreases.

Cellular dysfunctionCellular dysfunction, loss of cells and subsequent , loss of cells and subsequent tissue dysfunction may contribute to heart failure, tissue dysfunction may contribute to heart failure, AlzheimerAlzheimer’’s and muscle wasting (Sarcopenia).s and muscle wasting (Sarcopenia).