topic: sarcopenia, prevention and institute i on o agingahelps to identify level of sarcopenia short...
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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
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“Aging of America”“Aging of America”
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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
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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
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Challenge to expand active life expectancy
Age (years)
%
Survival
0
50
0 10050
Active life
Active life freeof disability
100
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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
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Institute on Aging overarching themeInstitute on Aging overarching theme
The etiology, prevention and rehabilitation of
cognitive and physical disability
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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
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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
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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)
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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
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Sarcopenia and frailty in older adultsSarcopenia and frailty in older adults
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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
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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
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29 years
77 years
Even Roy Hilligenn Experiences “Sarcopenia”
Even Roy Hilligenn Experiences “Sarcopenia” 54 years
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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
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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.
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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.
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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
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Pre-Clinical Studies Translational Grip strength meter
Pre-Clinical Studies Translational Grip strength meter
Carter et al., Journal of Gerontology: Biological Sciences, 2002.
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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
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Sarcopenia and frailty in older adultsWhat are the causes?
Sarcopenia and frailty in older adultsWhat are the causes?
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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
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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
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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
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Interventions/BehavioralInterventions/Behavioral
Life-Long Exercise HabitsLife-Long Moderate Calorie Restriction
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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%
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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
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Weindruch and Prolla
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Laboratories of *Neurosciences and Experimental Gerontology, National Institute on Aging Intramural Research Program
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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
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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
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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
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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?
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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
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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
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Oxidative Stress and Aging: A critical Role for Mitochondria
Oxidative Stress and Aging: A critical Role for Mitochondria
Weindruch
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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
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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.
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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
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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
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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
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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
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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.
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Supervised Aerobic Exercise StudiesSupervised Aerobic Exercise Studies
Endurance training:65-70% VO2peak for 15-30 min2-4 x week
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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
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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: [email protected]@aging.ufl.eduInstitute on Aging• http://www.aging.ufl.edu/
The End
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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
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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
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Fiber loss with ageLexell et al., 1988
Fiber loss with ageFiber loss with ageLexellLexell et al., 1988et al., 1988
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Apoptosis In Human Skeletal MuscleApoptosis In Human Skeletal Muscle
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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
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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
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Muscle Strength--Inclined PlaneMuscle Strength--Inclined Plane
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Myocardial Aging, Sarcopenia and Neurodegeneration
Myocardial Aging, Sarcopenia and Neurodegeneration
• Oxidative Stress, Inflammation and Apoptosis may be one major factor
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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).