Frailty from Bedside to Bench:
Recommendations for a Research
Agenda on Frailty
Findings from the AGS/NIA- sponsored
national conference on Frailty
January, 2004
Background: Bedside to Bench
Conference on Frailty
• AGS- sponsored conference series: Bedside to
Bench
• Funded by NIA
• Major clinical issues that would benefit from
enhanced research to improve patient care
– 2004: Frailty
– 2005: Comorbidity
– 2006: Cognitive Activity
Organizing Committee,
Conference on Frailty
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•
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Linda Fried, M.D., M.P.H., PI
William Ershler, M.D.
Luigi Ferrucci, M.D., Ph.D.
Jack Guralnik, M.D., Ph.D.
Evan Hadley, M.D.
Tamara Harris, M.D., M.H.S.
Anne Newman, M.D., M.P.H.
Stephanie Studenski, M.D., M.P.H.
Jeremy Walston, M.D.
Goal for Frailty Conference
• Define the state of knowledge of causes of
frailty
• Define the research needed to determine the
causes of frailty
Premises of Frailty Conference
• Frailty is a biologic and physiologic syndrome
associated with aging
• Frailty is a result of multisystem dysregulation
• The hallmark of frailty is enhanced vulnerability
to stressors
• The clinical presentation of frailty is definable and
may appear subsequent to the development of
physiologic vulnerability.
Symposium: Research Agenda for
Frailty in Aging
• Rationale and Goals; Preliminary
Phenotype
• Research in Organ System Pathophysiology
• Research into Molecular Basis of Frailty
and Potential for Animal Models
• Opportunities for Intervention
• Recommendations and next steps
Clinical Presentation of Frailty
3 case histories
The patient’s illness:
• Contributors to health outcomes:
– The disease
– The underlying health status and vulnerability
Two patients: 75 y/o men
#1
• H/o ischemic
cardiomyopathy; stable
CHF; knee OA
• Lifts weights; exercises
regularly
• Hospitalized for surgery
for BPH;
• ambulated with IV;
sedative for sleep.
• D/c home after uneventful
hospital course
#2
• CHF, knee OA
• Hospitalized for surgery
for BPH.
• Fell walking to bathroom
with IV. Pain meds,
resulting confusion. Bed
rest led to progressive
weakness; became
incontinent. Little PO
intake.
• D/c to NH for rehab
#3: 85 y/o man
• Presented to ER after stumbling, nonsyncopal fall;
unable to get up from floor for 5 hours; neighbor
called 911
• PMHx: 1999 fall with femoral head fx; OA in hip
and hands; 15 lb weight loss in last year, fair
appetite, increasing weakness, fatigue, not
depressed but grieving.
• Social Hx: widowed (1999); lives alone; family &
friends bring him food, check on him.
Physical Exam in ER
– Cachectic;
– Musculoskeletal: muscle wasting, DIP changes
c/w OA
– Neuro: diffuse weakness, cognition intact.
– Unable to walk or transfer
• Admission to Medicine Service for falls;
• 3 days on acute service; workup negative
• transferred to Inpatient Rehabilitation Unit for PT
and OT; very slow course.
• After 2 weeks, ambulate 40 feet with walker
• Unable to care for self; concerns re: safety
• Transferred to assisted living facility, hoping to
eventually return home.
Frailty: clinical & subclinical
• Patient #3: sarcopenia, wasting, weight loss,
low activity, falls prior to admission; loss of
independence identified at admission
• Patient #2: in hospital: onset of
manifestations of frailty: progressive
weakness, falls, loss of independence
Ho: Spectrum of resilience and
frailty in older adults
A:
• Resilient;
• Not frail
•
•
•
•
B:
Vulnerable;
Poor recovery
Decompensates
with minor
external stress.
Onset of frailty
C:
• Frailty
Syndrome;
• Outcomes:
• Loss of
independence
• D: Endstage
frailty/ predeath
Clinical observations
• Endstage frailty:
– associated with death;
– not remediable;
– presentation:
• malnutrition/undernutrition
• severe weakness, sarcopenia
• low albumin, cholesterol
Verdery 1996
Clinical Manifestations of Frailty
- Consensus of Working Groups •
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•
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•
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Sarcopenia: loss of muscle mass
Weight loss/undernutrition
Decreased strength, exercise tolerance
Slowed motor processing, performance
Decreased balance
Low physical activity
Cognitive vulnerability?
Increased vulnerability to stressors
(Fried and Walston, 1998)
Preliminary Clinical Criteria for
Frailty Adopted by AGS Conference
Formalized phenotype: definition
and validation of the clinical
syndrome of frailty
Multiple (3-5/5) criteria present:
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Weight loss
Weakness
Exhaustion
Slowed walking speed
Low activity
Fried, Tangen, Walston, Newman, Tracy, et al, J
Ger Med Sci, 2001
Baseline Frailty Status Predicting Adverse
Outcomes Clinically Associated with
Frailty
Incident Fall
Worsening Mobility
Worsening ADL Disability
First Hospitalizations
Death
Hazard Ratios*
Estimated Over 3 Years
Frail
1.29
1.50
1.98
1.29
2.24
* Covariate Adjusted, p  .05
(Fried et al, 2001)
Preliminary Clinical Criteria for
Frailty Adopted by AGS Conference
• Rationale for adopting standardized criteria:
– Essential for next generation of research
– Supports clinical practice and education
– Basis for improvement: subsequent criteria
should demonstrate advantages and biologic
rationale relative to preliminary criteria.
Weight Loss
•
>
•
Clinical Presentation
 physical activity •
•
 Motor performance
•
Sarcopenia
 Strength
Exhaustion/  exercise tolerance
Weight Loss
•
>
•
Clinical Presentation
 physical activity •
•
 Motor performance
Physiologic Vulnerability
•
Sarcopenia
 Strength
Exhaustion/  exercise tolerance
Weight Loss
•
>
•
Clinical Presentation
 physical activity •
•
•
 Motor performance
Physiologic Vulnerability
Physiologic
Dysregulation
Cellular
Function,
Molecular and
Genetic
Characteristics
Sarcopenia
 Strength
Exhaustion/  exercise tolerance
Frailty from bedside to bench. Findings from the NIA R13 Conference Grant
Major Developments Based on Research in
Organs System Pathophysiology
Luigi Ferrucci, MD, PhD
Longitudinal Studies Section
Clinical Research Branch
National Institute on Aging
NIH
Baltimore, MD, USA
Aging, Homeostatic Mechanisms and Frailty
Operational Definitions for Studies on Aging
Physiological Parameter
1. The aging process described decline of physiological parameters
(The Nathan Shock Model)
Few examples
Reaction Time (longer)
Cognitive Status
Nerve Conduction Velocity
Muscle Strength
Visual Acuity
Macro and Micronutrients intake
Insulin Sensitivity
Testosterone
Estrogens
IGF-1
Cytokines and APR (higher(
ROS / Antioxidants
Complexity of CV reflexes
65
Age
100
Aging, Homeostatic Mechanisms and Frailty
Operational Definitions for Studies on Aging
Physiological Parameter
2. . . .but . . the rate of decline in cross-sectional studies is influenced
by secular trends and the effect of diseases
Few examples
Reaction Time (longer)
Cognitive Status
Nerve Conduction Velocity
Muscle Strength
Visual Acuity
Macro and Micronutrients intake
Insulin Sensitivity
Testosterone
Estrogens
IGF-1
Cytokines and APR (higher(
ROS / Antioxidants
Complexity of CV reflexes
65
Age
100
Aging, Homeostatic Mechanisms and Frailty
Operational Definitions for Studies on Aging
Physiological Parameter
3. Additionally, information on patterns of functional decline in multiple
physiological systems with age is scant
65
Age
100
Aging, Homeostatic Mechanisms and Frailty
Operational Definitions for Studies on Aging
Physiological Parameter
4. The “replacement therapy” approach postulates the disease model,
but results are mostly disappointing
65
Age
100
Aging, Homeostatic Mechanisms and Frailty
Operational Definitions for Studies on Aging
Physiological Parameter
5. Frailty as accelerated decline in anatomical integrity and function
across multiple physiological systems. The “replacement therapy”
approach is unlikely to be effective.
65
Age
100
Aging, Homeostatic Mechanisms and Frailty
FACING THE COMPLEXITY OF FRAILTY
Multiple Levels of Measure and Interaction
Hormones
Insulin, Ghrelin,
Leptin, IGF-1,
Testosterone,
Estradiol, DHEAs,
TSH, FT4, PTH,
Inflammation
PCR, IL-6, sIL-6R,
TNF-alfa
Autonomic
HRV, Complexity
Of CV reflexes
Ox Stress
?
Nutrition
Phys Activity
Food Intake, VitD,
VitB12, Folate,
B6, VitE, Album.
Self-Report
CNS
Cognition, Motivation
Motor Control,
Plasticity, Adaptation
PNS
NCV and Neuromusc.
Interaction
MUSCLES
Strength, Power,
Structure, Motor Units,
Intramuscular Fat,
Muscle Density
BONE, JOINTS
ENERGY
FEEDBACK
Pain, ROM, Struct.
Changes Bone Quantity,
Quality, 3D Structure
Balance
Gait
Endurance
Body
Shape
Cardiac Structure and
Function, Arterial Compl,
And IMT, Exercise Toller,
VO2 max, Resp. Function,
Nutritional Status, Anemia
Dexterity
Visual Acuity, Contrast,
3-D, Proprioc, Pallestesic,
Thermal, Sensation, Space
Perception, Body Image
Vitality
Complexity and
Noise
Gait Variability,
Dynamic Posture,
Mental Loading
Exhaustion, and
Tiredness vs.
Dyspnea
Weight, BMI,
Waist Circ.,
Kiphosis etc.
Upper Extremity
ADLs and IADLs
Emotional
Homeostasis
Aging, Homeostatic Mechanisms and Frailty
FACING THE COMPLEXITY OF FRAILTY
Compensations and Vicious Cycles
Reduced
Physical
Activity
Reduced
Muscle
Strength/Mass
Poor
Walking
Performance
Impaired
Executive
Function
Neurological
Dysfunction
Impaired
Motor
Control
IGF-1
Inflammation
Insulin
Resistance
Aging, Homeostatic Mechanisms and Frailty
Frailty is parallel, accelerated decline in multiple systems
CONCLUSIONS
1. The next generation of studies on aging should study patterns of
changes in multiple physiological parameters over the aging process in
the attempt to understand how specific patterns affect change in
functional status, the development of the frailty syndrome and survival.
2. Information on multiple physiological parameters may be required to
identify persons that may benefit from specific ‘Replacement Therapy’
3. Frailty is characterized by accelerated decline of multiple physiological
parameters
4. The identification of “compensatory mechanisms” and “vicious cycles”
is central to translational research
Research into the Molecular
Basis of Frailty and
Potential for Animal Models
Jeremy D. Walston, M.D
Associate Professor of Medicine
John Hopkins University
Frailty: Potential Causal
Pathway(s)
Primary
Causes of Frailty:
Age-related
molecular changes
Genetic variation
Immune
Dysfunction
IL-6
Sarcopenia
 Hemoglobin
Secondary Causes
of Frailty:
Depression
Cancer
Chronic Infection
CHF
Neuroendocrine
Dysregulation
IGF-1
DHEA-S
Clinical
Syndrome
of Frailty
Molecular Alterations May Underlie
Multisystem Change
 SNS activity
Altered hormones
PHYSIOLOGIC
Glucose intolerance
Inflammation
 Hematopoiesis
Mitochondrial Dysfunction
Altered hormones,
Environmental factors
Altered cellular metabolism
MOLECULAR
& GENETIC
 Free radicals
Cellular senescence
 DNA damage
Altered telomeres
Genetic Variation
Biology of Aging Meets
Frailty:
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•
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Oxidative stress & free radicals
Dysfunctional telomeres
DNA damage & repair
Cellular senescence & antagonistic
pleiotropy
Free Radicals:
• Oxidize proteins, impair protein
synthesis, and damage DNA
• Alter redox dependent signaling and
gene expression
• Activate NFkB signal transduction
and inflammation
Induction of Cell
Senescence
Oxidative Stress
Chromatin Instability
Irreversible
arrest of cell
proliferation
DNA Damage
Oncogenes
Dysfunctional Telomeres
The Senescent Cell
Phenotype:
Irreversible
Growth
Arrest
Resistance
to
Apoptosis
Altered
Differentiated
Function
Do Senescent Fibroblasts
Promote Frailty?
• Disruption in growth & differentiation
of several cells
• Secretion of inflammatory cytokines
• Promotion of disease states
Hypothesized Molecular
Pathway to Frailty
Mitochondrial Dysfunction
Altered Hormones,
Environmental
Factors
Altered
Cellular
Metabolism
 Free Radicals
 DNA Damage
Cellular Senescence
Altered Telomeres
Genetic Variation
Molecular Alterations May Underlie
Multisystem Change
 SNS activity
Altered hormones
PHYSIOLOGIC
Glucose intolerance
Inflammation
 Hematopoiesis
Mitochondrial Dysfunction
Altered hormones,
Environmental factors
Altered cellular metabolism
MOLECULAR
& GENETIC
 Free radicals
Cellular senescence
 DNA damage
Altered telomeres
Genetic Variation
Development of Animal & Cell
Models
• Critical need for molecular and
physiological studies
• Necessary first steps in
development of intervention and
prevention studies
Ideal Criteria for Frail Mouse
or Rat Model
• Live near normal lifespan without
phenotypic alterations in youth
• Display increasing vulnerability to
stressors with increasing age
• Development of accelerated loss of
physiologic reserves in multiple
systems later in life
Recommendations for
Animal Model Development
• Further refinement of phenotypic
measurements
• Improved measurement of body
composition
• Phenotype candidate strains from
already existing transgenics and
knockouts.
Specific Candidates
• Superoxide Dismutase (SOD) altered mice
– Test oxidative stress hypotheses
• Suppressor of cytokine signaling (SOCS)
altered mice
– Test accelerated inflammatory change
hypotheses
• Klotho, Dwarf, & GH/IGF-1 variants
– May develop phenotype components, but known
endocrine deficiencies may be responsible
• Old wildtype rats and mice
Caloric Restriction Models
• May provide clues for physiologic and
metabolic systems to study in frailty
– Decreased SNS activity
– Improved immune function
– Improved DNA repair
– Decreased visceral fat
Research Agenda for Frailty in Older Adults
Towards a Better Understanding of Physiology and
Etiology
Opportunities for Intervention
Anne B. Newman, MD, MPH
University of Pittsburgh
Types of Intervention Studies
that can inform about frailty
• Studies that targeted frail older adults with
interventions to prevent poor health outcomes
– such as falls, disability, mortality
• Studies intervening to prevent frailty or aspects of
frailty
– such as loss of strength, loss of muscle mass
• Other interventions that included older adults
– That might include a frail subset
– Or might have frailty outcomes as secondary outcomes
Types of interventions
• Non-pharmacologic:
– Physical activity/Exercise – endurance/strength training
– “Prehabilitation” (targeted multi-factorial intervention)
• Pharmacologic:
– Hormonal agents
• GH Secretagogues
• Testosterone, DHEAs
– Other agents with potential beneficial effects for frailty
• Angiotensin converting enzyme (ACE) inhibitors,
• HMG-CoA reductase inhibitors (Statins)
• Other novel agents
Physical activity/Exercise
• Resistance exercise – increases muscle strength
and functional capacity in frail and non-frail older
adults
• Interventions that combine drug with exercise no
more effective than exercise alone
• Dietary Protein requirements with exercise
– Current RDA may be inadequate for older adults
Prehabilitation
• Physically frail
• Home-based, targeted PT and OT
– including resistance exercise 3 x per week
• Reduced or prevented disability
• Less beneficial in frail or cognitively
impaired
– Suggests “window of opportunity”
Growth hormone secretagogues
• Acute deconditioning model (post-hip
fracture)
• IGF levels clearly increased
• Treatment was limited by decrements in
glucose tolerance and fluid retention
• Did not improve functional outcomes.
Testosterone and DHEA
• Target population?
• Beneficial effects: lean mass, strength, bone
density, QOL
• Adverse effects: BPH, Prostate cancer,
Polycythemia
• DHEA appears to be safe but ineffective
• Newer “designer androgens”
ACE Inhibitors
• Benefits in diabetes and post-stroke
– beyond blood pressure lowering effects.
• Frail older adults treated with ACE inhibitors have
higher strength and muscle mass.
• This effect has also been found in experimental
rodent models.
• Frailty outcomes included in ongoing trial of ACE
inhibitors.
Statins
• Statin trials have included older adults to age 80
• Major benefit demonstrated for reducing
cardiovascular disease events – should reduce
frailty
• Anti-inflammatory effects well documented
• Secondary outcomes related to frailty – no
significant differences noted
– Cognition
– Fracture
Summary
• Exercise-based inventions clearly beneficial
– In frail older adults to prevent disability
– For treating aspects of frailty such as low strength and
function
• “Hormone replacement” studies disappointing
• Other types of drugs may have effects via other
pathways such as inflammation, body composition
Opportunities
• Intervention studies, even if disease specific,
should define level of frailty in study participants
• Aspects of frailty should be included as study
outcomes
– including a global index and continuous measures of
performance
• Interventions can proceed without understanding
mechanisms, but assessment of mechanisms
should be incorporated into study
Frailty from bedside to bench. Findings from the NIA R13 Conference Grant
Frailty:
Recommendations and Research Questions
Stephanie A. Studenski, MD, MPH
Test and Revise Phenotypes
• Ways to improve CHS definition
• ? Add vulnerability, other elements
• Evaluate alternative definitions relative to a
standard
• Criteria for evaluation? Degree of clustering
of elements, ability to identify pathologic
processes, clinical relevance
• Consider multiple phenotypes
Vulnerability
•
•
•
•
Define- predictors, measures
Provocative tests?
? critical risk periods
Factors that precipitate frailty
Etiology, Physiology and System
Interconnections
• Relationship to fundamental mechanisms of
aging
• Interactions of multiple systems (brain,
hormones, cytokines, muscle, fat, nerve,
etc)
• Ways to define physiological reserves
• Ways to connect basic biology to pathology
and physiology
• Pathophysiology of individual components
Resources and Methods
What do basic and clinical scientists need from each
other?
• Animal models
• Explore methods that could be standardized across
studies
• Innovative analytic techniques
• Collaborative networks
• Develop/use large case controlled populations for
genetic and biologic research
Clinical Trials
• We may not need to know the etiology or have a clear
definition of frailty to develop interventions.
• Interventions may help us understand mechanisms:
underlying pathophysiology or molecular etiology.
• Exercise interventions are ready for major trials as a
treatment for frailty but we need to work more on
adherence and include behavioral and social elements.
• Many pharmacologic agents have potential based on
preliminary evidence, but trials in frail populations against
clinical endpoints are needed.
• Combined interventions with exercise, pharmacologic and
psychosocial elements should be tested.
www.frail-fragile.ca
Canadian Initiative on
Frailty and Aging
Howard Bergman MD
Christina Wolfson PhD
David Hogan MD
François Béland PhD
Sathya Karunananthan MSc (cand)
for the Investigator Group
Funding :
Max Bell Foundation
Institute on Aging, CIHR
Quebec Research Network on Aging (FRSQ)
Gustav Levinschi Foundation
In partnership with Canadian, European, Israeli
Research Groups
Ver 21.02.04
Version April 30 04 HB
The Canadian Initiative on Frailty and Aging
Objectives 2002-2006
Investigators and collaborators from Canada, Europe, USA, Japan
1.
Through a systematic review, collate, critically review and
synthesize the evidence in the literature and identify the gaps
in order to lay down a working framework;
2.
Identify research priorities and develop a research program;
3.
Propose to clinicians evidence based recommendations on
interventions which may prevent or delay onset or slow
progression of frailty;
4.
Propose recommendations to policy makers and the
population
Approach
• Integrative
– Start from a broad and flexible perspective, integrating
physiological, psychological and cognitive components;
• Life Course approach
– An integrative approach that includes the genetic,
biological, social, cognitive, psychological and
environmental determinants and mediators which interact
across a person’s lifespan and which may promote healthy
aging and either delay or promote the emergence of frailty
» Adapted from Ben-Shlomo, Kuh. International Journal of
Epidemiology 2002;31:285-293
• Societal
– A population approach; health promotion and policy;
• Develop a working framework through the process
Why conduct a systematic review
of Frailty?
Hogan DB, MacKnight C, Bergman H. June 2003. Models, definitions, and
criteria of frailty. Aging Clin Exp Research. Vol 15, suppl. to No. 3: 3-29
Systematic Review:
The Questions and the Investigators
Questions
History, concept, current definitions
Biological basis
Social basis
Prevalence
Risk factors
Impact
Identification
Prevention and Management
Environment and Technology
Health services
Health and social policy
Investigators
D. Hogan, C. Macknight, H. Bergman
T. Fulop, G. Duque, D. Hogan
M. Penning, F. Béland
C. Wolfson, H. Bergman
G. Naglie, S. Gill
B. Santos-Eggimann, L. SeematterBagnoud
S. Sternberg, M. Clarfield
C. Patterson, J. Feightner
G. Fernie, B. Row
M. Hollander, F. Béland
M. Hollander, N. Chappell, M. Prince
Systematic Review Process:
The example of Prevalence
Literature search: 1516 abstracts
1435
abstracts
eliminated
75
abstracts
retained
20
articles
eliminated
54
articles
retained
6 reviews or
editorials
retained
7
review or
editorials
retained
13 articles
pearled
54 articles for
Quality assessment &
Data abstraction
20 retained as
Background
papers
A working framework
in development
Age
Age
Prevent/Delay Frailty
Health Promotion and Prevention
Delay Onset
Delay/Prevent
adverse outcomes, care
FRAILTY
Life-course
Determinants:
Biological
(including genetic)
Psychological
Social, Societal
Environment
Disease
Decline in
physiologic
reserve
Candidate
components
• Weight loss/under
nutrition
• Weakness
• Endurance
• Physical activity
• Slowness
• Cognitive decline
• Depressive
symptoms
Adverse outcomes
• Disability
• Morbidity
• Hospitalization
• Institutionalization
• Death
Biological, Psychological,
Social, societal
modifiers/assets and deficits
Issues/Questions
•
Does frailty exist?
–
•
What is frailty?
–
–
–
•
a specific biological entity with defined pathway?
a syndrome with biological, psychological and cognitive characteristics
and multiple pathways?
a state of risk for adverse outcomes? e.g., metabolic syndrome X
Developing a working framework
–
–
•
or is it simply “accelerated” aging? “Flip” side of healthy aging?
relationship between biological, psychological and cognitive
components?
role of social and environmental factors?
How do we study candidate components of frailty within a
working framework?
Challenge:
From a working framework to a model
1. Systematic review-understand/assess quality of
evidence
2. Identification of candidate components
3. Agreement on candidate components
– expert consensus
4. Study
– How do the components cluster-do they present
together more often than you would expect if they
were independent?
– Which candidate components do you maintain?
– What is the relative importance of the components?
Perspectives
• Complete the systematic review (fall 2004)
• International working meeting (2005)
• Develop a working framework through this
process
• Move the research agenda ahead
– Opportunity to study frailty in planned longitudinal studies in
Europe, Canada, USA; Canadian Longitudinal Study on Aging
with an embedded study on frailty (2006)
– Exploitation of existing databases
– Funding and collaborative opportunities for biological, clinical
and population studies e.g., CIHR, NIA, other
What if
it doesn’t
work?
What if
it all blows
up in our
faces?
What
happens if it
works all too
well?
What if
somebody
sees?
What
happens ten
years down the line
[email protected]
Canadian Initiative on Frailty and Aging / Initiative canadienne sur la fragilité et le vieillissement
www.frail-fragile.ca