Frailty from Bedside to Bench: Recommendations for a Research Agenda on Frailty Findings from the AGS/NIA- sponsored national conference on Frailty January, 2004
Jan 18, 2016
Frailty from Bedside to Bench: Recommendations for a Research
Agenda on FrailtyFindings 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
• 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 -
• 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:
• 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
2.24Death
1.29First Hospitalizations
1.98Worsening ADL Disability
1.50Worsening Mobility
1.29Incident Fall
Frail
Hazard Ratios* Estimated Over 3 Years
* 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
Sarcopenia
Strength
Exhaustion/ exercise tolerance Motor performance
physical activity
Clinical Presentation •
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Weight Loss
Sarcopenia
Strength
Exhaustion/ exercise tolerance Motor performance
physical activity
Clinical Presentation •
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Physiologic Vulnerability
Weight Loss
Sarcopenia
Strength
Exhaustion/ exercise tolerance Motor performance
physical activity
Clinical Presentation •
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Physiologic Vulnerability
Physiologic Dysregulation
Cellular Function,
Molecular and Genetic
Characteristics
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 FrailtyOperational Definitions for Studies on Aging
65 100
1. The aging process described decline of physiological parameters(The Nathan Shock Model)
Few examplesReaction Time (longer)Cognitive StatusNerve Conduction VelocityMuscle StrengthVisual AcuityMacro and Micronutrients intakeInsulin SensitivityTestosteroneEstrogensIGF-1Cytokines and APR (higher(ROS / AntioxidantsComplexity of CV reflexes
Age
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Aging, Homeostatic Mechanisms and FrailtyOperational Definitions for Studies on Aging
65 100
2. . . .but . . the rate of decline in cross-sectional studies is influenced by secular trends and the effect of diseases
Few examplesReaction Time (longer)Cognitive StatusNerve Conduction VelocityMuscle StrengthVisual AcuityMacro and Micronutrients intakeInsulin SensitivityTestosteroneEstrogensIGF-1Cytokines and APR (higher(ROS / AntioxidantsComplexity of CV reflexes
Age
Ph
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Aging, Homeostatic Mechanisms and FrailtyOperational Definitions for Studies on Aging
65 100
3. Additionally, information on patterns of functional decline in multiple physiological systems with age is scant
Age
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Aging, Homeostatic Mechanisms and FrailtyOperational Definitions for Studies on Aging
65 100
4. The “replacement therapy” approach postulates the disease model, but results are mostly disappointing
Age
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Aging, Homeostatic Mechanisms and FrailtyOperational Definitions for Studies on Aging
65 100
5. Frailty as accelerated decline in anatomical integrity and function across multiple physiological systems. The “replacement therapy” approach is unlikely to be effective.
Age
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Aging, Homeostatic Mechanisms and FrailtyFACING THE COMPLEXITY OF FRAILTY
Multiple Levels of Measure and Interaction
CNS
PNS
MUSCLES
BONE, JOINTS
ENERGY
FEEDBACK
Cognition, MotivationMotor Control, Plasticity, Adaptation
NCV and Neuromusc. Interaction
Strength, Power, Structure, Motor Units, Intramuscular Fat,Muscle Density
Pain, ROM, Struct. Changes Bone Quantity, Quality, 3D Structure
Cardiac Structure and Function, Arterial Compl,And IMT, Exercise Toller,VO2 max, Resp. Function, Nutritional Status, Anemia
Visual Acuity, Contrast, 3-D, Proprioc, Pallestesic, Thermal, Sensation, Space Perception, Body Image
Insulin, Ghrelin, Leptin, IGF-1, Testosterone, Estradiol, DHEAs,TSH, FT4, PTH,
PCR, IL-6, sIL-6R, TNF-alfa
HRV, ComplexityOf CV reflexes
?
Food Intake, VitD,VitB12, Folate, B6, VitE, Album.
Self-Report
Hormones
Inflammation
Autonomic
Nutrition
Phys Activity
Ox Stress
Balance
Gait
Endurance
Dexterity
Vitality
Body Shape
Gait Variability,Dynamic Posture,Mental Loading
Complexity and Noise
Exhaustion, and Tiredness vs. Dyspnea
Weight, BMI,Waist Circ., Kiphosis etc.
Upper ExtremityADLs and IADLs
Emotional Homeostasis
Aging, Homeostatic Mechanisms and FrailtyFACING THE COMPLEXITY OF FRAILTY
Compensations and Vicious Cycles
NeurologicalDysfunction
InsulinResistance
Inflammation
ImpairedExecutiveFunction
PoorWalking
Performance
ImpairedMotor Control
ReducedMuscle
Strength/Mass
ReducedPhysicalActivity
IGF-1
Aging, Homeostatic Mechanisms and FrailtyFrailty 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 changesGenetic variation
Secondary Causes of Frailty:DepressionCancerChronic InfectionCHF
Immune Dysfunction Sarcopenia HemoglobinNeuroendocrineDysregulation
Clinical Syndromeof Frailty
IL-6
IGF-1
DHEA-S
Altered hormones SNS activity
Hematopoiesis
Glucose intolerance
PHYSIOLOGIC
Free radicals
Cellular senescence DNA damage
Altered telomeres
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> >MOLECULAR & GENETIC
Mitochondrial Dysfunction
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Genetic Variation
Inflammation
Altered hormones, Environmental factors
Altered cellular metabolism
Molecular Alterations May Underlie Multisystem Change
Biology of Aging Meets Frailty:
• 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
Irreversible arrest of cell proliferation
Oxidative Stress
Oncogenes
Dysfunctional Telomeres
Chromatin Instability
DNA Damage
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
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Mitochondrial Dysfunction
Free Radicals
DNA Damage
Altered Telomeres
Cellular Senescence
Altered Cellular Metabolism
Genetic Variation
Altered Hormones, Environmental Factors
Altered hormones SNS activity
Hematopoiesis
Glucose intolerance
PHYSIOLOGIC
Free radicals
Cellular senescence DNA damage
Altered telomeres
>
> >MOLECULAR & GENETIC
Mitochondrial Dysfunction
>
Genetic Variation
Inflammation
Altered hormones, Environmental factors
Altered cellular metabolism
Molecular Alterations May Underlie Multisystem Change
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 AdultsTowards a Better Understanding of Physiology and
Etiology
Opportunities for Intervention
Anne B. Newman, MD, MPHUniversity of Pittsburgh
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
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.
Ver 21.02.04
Canadian Initiative on Frailty and Agingwww.frail-fragile.ca
Howard Bergman MDChristina Wolfson PhD
David Hogan MDFrançois Béland PhD
Sathya Karunananthan MSc (cand)for the Investigator Group
Version April 30 04 HB
Funding :Max Bell FoundationInstitute on Aging, CIHRQuebec Research Network on Aging (FRSQ)Gustav Levinschi FoundationIn partnership with Canadian, European, Israeli Research Groups
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 Investigators
History, concept, current definitions D. Hogan, C. Macknight, H. Bergman Biological basis T. Fulop, G. Duque, D. HoganSocial basis M. Penning, F. BélandPrevalence C. Wolfson, H. BergmanRisk factors G. Naglie, S. GillImpact B. Santos-Eggimann, L. Seematter-
BagnoudIdentification S. Sternberg, M. ClarfieldPrevention and Management C. Patterson, J. FeightnerEnvironment and Technology G. Fernie, B. RowHealth services M. Hollander, F. BélandHealth and social policy M. Hollander, N. Chappell, M. Prince
Literature search: 1516 abstracts
75abstracts retained
1435 abstracts
eliminated
6 reviews or editorials retained
13 articles pearled
54articles retained
20articles
eliminated
7review or editorials retained
20 retained asBackground
papers
54 articles forQuality assessment &
Data abstraction
Systematic Review Process: The example of Prevalence
Prevent/Delay FrailtyHealth Promotion and Prevention
Life-courseDeterminants: Biological (including genetic)PsychologicalSocial, SocietalEnvironment
Biological, Psychological,Social, societal modifiers/assets and deficits
A working framework in development
Delay Onset Delay/Prevent adverse outcomes, care
FRAILTY
Age Age
Adverse outcomes• Disability• Morbidity• Hospitalization• Institutionalization• Death
Disease
Decline in physiologic reserve
Candidate components
• Weight loss/under nutrition
• Weakness• Endurance• Physical activity• Slowness• Cognitive decline• Depressive symptoms
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?
Challenge: From a working framework to a model
1. Systematic review-understand/assess quality of evidence
2. Identification of candidate components3. Agreement on candidate components
– expert consensus4. 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
Canadian Initiative on Frailty and Aging / Initiative canadienne sur la fragilité et le vieillissementwww.frail-fragile.ca
What if it doesn’t work?
What if it all blows up in our faces?
What if somebody sees?
What happens ten years down the line
What happens if it works all too well?