Frailty from Bedside to Bench: Recommendations for a Research Agenda on Frailty

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Frailty from Bedside to Bench Recommendations
for a Research Agenda on Frailty

• Findings from the AGS/NIA- sponsored national
  conference on Frailty
• January, 2004

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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

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Organizing Committee, Conference on Frailty

• 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.

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Goal for Frailty Conference

• Define the state of knowledge of causes of
  frailty
• Define the research needed to determine the
  causes of frailty

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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.

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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

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Clinical Presentation of Frailty

• 3 case histories

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The patients illness

• Contributors to health outcomes
• The disease
• The underlying health status and vulnerability

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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

10
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.

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Physical Exam in ER

• Cachectic
• Musculoskeletal muscle wasting, DIP changes c/w
  OA
• Neuro diffuse weakness, cognition intact.
• Unable to walk or transfer

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• 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.

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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

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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

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Clinical observations

• Endstage frailty
• associated with death
• not remediable
• presentation
• malnutrition/undernutrition
• severe weakness, sarcopenia
• low albumin, cholesterol
• Verdery 1996

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Clinical Manifestations of Frailty- Consensus of
Working Groups -

• 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

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(Fried and Walston, 1998)
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Preliminary Clinical Criteria for Frailty Adopted
by AGS Conference
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Formalized phenotype definition and validation
of the clinical syndrome of frailty Multiple
(3-5/5) criteria present

• Weight loss
• Weakness
• Exhaustion
• Slowed walking speed
• Low activity
• Fried, Tangen, Walston, Newman, Tracy, et al, J
  Ger Med Sci, 2001

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Baseline Frailty Status Predicting Adverse
Outcomes Clinically Associated with Frailty
Covariate Adjusted, p ? .05
(Fried et al, 2001)
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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.

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Weight Loss

gt

Sarcopenia
Clinical Presentation

gt
? physical activity
gt


gt

• Strength
• Exhaustion/ ? exercise tolerance

? Motor performance
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Weight Loss

gt

Sarcopenia
Clinical Presentation

gt
? physical activity
gt


gt

• Strength
• Exhaustion/ ? exercise tolerance

? Motor performance
Physiologic Vulnerability
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Weight Loss

gt

Sarcopenia
Clinical Presentation

gt
? physical activity
gt


gt

• Strength
• Exhaustion/ ? exercise tolerance

? Motor performance
Physiologic Vulnerability
Physiologic Dysregulation
Cellular Function, Molecular and Genetic
Characteristics
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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

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• 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
100
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• . . .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
100
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• Additionally, information on patterns of
  functional decline in multiple physiological
  systems with age is scant

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100
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• The replacement therapy approach postulates the
  disease model, but results are mostly
  disappointing

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100
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• Frailty as accelerated decline in anatomical
  integrity and function across multiple
  physiological systems. The replacement therapy
  approach is unlikely to be effective.

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100
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Aging, Homeostatic Mechanisms and Frailty
FACING THE COMPLEXITY OF FRAILTY Multiple Levels
of Measure and Interaction
Insulin, Ghrelin, Leptin, IGF-1, Testosterone,
Estradiol, DHEAs, TSH, FT4, PTH,
Cognition, Motivation Motor Control, Plasticity,
Adaptation
Complexity and Noise
CNS
Balance
Hormones
Gait Variability, Dynamic Posture, Mental Loading
NCV and Neuromusc. Interaction
PCR, IL-6, sIL-6R, TNF-alfa
PNS
Inflammation
Gait
Strength, Power, Structure, Motor Units,
Intramuscular Fat, Muscle Density
Exhaustion, and Tiredness vs. Dyspnea
HRV, Complexity Of CV reflexes
MUSCLES
Endurance
Autonomic
Body Shape
Pain, ROM, Struct. Changes Bone Quantity,
Quality, 3D Structure
Weight, BMI, Waist Circ., Kiphosis etc.
BONE, JOINTS
?
Ox Stress
Cardiac Structure and Function, Arterial
Compl, And IMT, Exercise Toller, VO2 max, Resp.
Function, Nutritional Status, Anemia
Food Intake, VitD, VitB12, Folate, B6, VitE,
Album.
Upper Extremity ADLs and IADLs
ENERGY
Dexterity
Nutrition
Visual Acuity, Contrast, 3-D, Proprioc,
Pallestesic, Thermal, Sensation, Space
Perception, Body Image
Emotional Homeostasis
FEEDBACK
Vitality
Phys Activity
Self-Report
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Aging, Homeostatic Mechanisms and Frailty
FACING THE COMPLEXITY OF FRAILTY Compensations
and Vicious Cycles
Reduced Physical Activity
Reduced Muscle Strength/Mass
Poor Walking Performance
IGF-1
Impaired Executive Function
Impaired Motor Control
Inflammation
Insulin Resistance
Neurological Dysfunction
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Aging, Homeostatic Mechanisms and Frailty
Frailty is parallel, accelerated decline in
multiple systems

• CONCLUSIONS
• 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.
• Information on multiple physiological parameters
  may be required to identify persons that may
  benefit from specific Replacement Therapy
• Frailty is characterized by accelerated decline
  of multiple physiological parameters
• The identification of compensatory mechanisms
  and vicious cycles is central to translational
  research

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Research into the Molecular Basis of Frailty and
Potential for Animal Models

• Jeremy D. Walston, M.D
• Associate Professor of Medicine
• John Hopkins University

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Frailty Potential Causal Pathway(s)
Primary Causes of Frailty Age-related molecular
changes Genetic variation
Clinical Syndrome of Frailty
IL-6
Immune Dysfunction
Sarcopenia ?
Hemoglobin Neuroendocrine Dysregulation
IGF-1 DHEA-S
Secondary Causes of Frailty Depression Cancer Chr
onic Infection CHF
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Molecular Alterations May Underlie Multisystem
Change
? SNS activity
Altered hormones
PHYSIOLOGIC
Glucose intolerance
Inflammation
? Hematopoiesis
Altered hormones, Environmental factors
Mitochondrial Dysfunction
gt
Altered cellular metabolism
gt
gt
MOLECULAR GENETIC
? Free radicals
gt
Cellular senescence
? DNA damage
Altered telomeres
Genetic Variation
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Biology of Aging Meets Frailty

• Oxidative stress free radicals
• Dysfunctional telomeres
• DNA damage repair
• Cellular senescence antagonistic pleiotropy

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Free Radicals

• Oxidize proteins, impair protein synthesis, and
  damage DNA
• Alter redox dependent signaling and gene
  expression
• Activate NFkB signal transduction and inflammation

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Induction of Cell Senescence
Oxidative Stress
Chromatin Instability
Irreversible arrest of cell proliferation
Oncogenes
DNA Damage
Dysfunctional Telomeres
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The Senescent Cell Phenotype
Irreversible Growth Arrest
Altered Differentiated Function
Resistance to Apoptosis
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Do Senescent Fibroblasts Promote Frailty?

• Disruption in growth differentiation of several
  cells
• Secretion of inflammatory cytokines
• Promotion of disease states

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Hypothesized Molecular Pathway to Frailty
Altered Hormones, Environmental Factors
Mitochondrial Dysfunction
gt
Altered Cellular Metabolism
gt
? Free Radicals
gt
gt
? DNA Damage
Cellular Senescence
Altered Telomeres
Genetic Variation
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Molecular Alterations May Underlie Multisystem
Change
? SNS activity
Altered hormones
PHYSIOLOGIC
Glucose intolerance
Inflammation
? Hematopoiesis
Altered hormones, Environmental factors
Mitochondrial Dysfunction
gt
Altered cellular metabolism
gt
gt
MOLECULAR GENETIC
? Free radicals
gt
Cellular senescence
? DNA damage
Altered telomeres
Genetic Variation
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Development of Animal Cell Models

• Critical need for molecular and physiological
  studies
• Necessary first steps in development of
  intervention and prevention studies

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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

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Recommendations for Animal Model Development

• Further refinement of phenotypic measurements
• Improved measurement of body composition
• Phenotype candidate strains from already existing
  transgenics and knockouts.

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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

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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

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Research Agenda for Frailty in Older
AdultsTowards a Better Understanding of
Physiology and Etiology

• Opportunities for Intervention

Anne B. Newman, MD, MPH University of Pittsburgh
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Types of Intervention Studiesthat 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

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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

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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

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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

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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.

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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

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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.

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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

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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

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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

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Frailty from bedside to bench. Findings from the
NIA R13 Conference Grant

• Frailty
• Recommendations and Research Questions
• Stephanie A. Studenski, MD, MPH

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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

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Vulnerability

• Define- predictors, measures
• Provocative tests?
• ? critical risk periods
• Factors that precipitate frailty

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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

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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

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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.

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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
Version April 30 04 HB
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The Canadian Initiative on Frailty and Aging
Objectives 2002-2006

• Investigators and collaborators from Canada,
  Europe, USA, Japan
• 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
• Identify research priorities and develop a
  research program
• Propose to clinicians evidence based
  recommendations on interventions which may
  prevent or delay onset or slow progression of
  frailty
• Propose recommendations to policy makers and the
  population

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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 persons
  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 200231285-293
• Societal
• A population approach health promotion and
  policy
• Develop a working framework through the process

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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
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Systematic ReviewThe Questions and the
Investigators
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Systematic Review Process The example of
Prevalence
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A working framework in development
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Issues/Questions

• Does frailty exist?
• or is it simply accelerated aging? Flip side
  of healthy aging?
• 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
• 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?

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Challenge From a working framework to a model

• Systematic review-understand/assess quality of
  evidence
• Identification of candidate components
• Agreement on candidate components
• expert consensus
• 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?

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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

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What happens if it works all too well?
What if it doesnt work?
What if somebody sees?
What if it all blows up in our faces?
What happens ten years down the line
howard.bergman_at_mcgill.ca