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

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 •

••

•

• >

>

>>

Weight Loss

Sarcopenia

Strength


physical activity


••

•

• >

>

>>

Physiologic Vulnerability

Weight Loss

Sarcopenia

Strength


physical activity


••

•

• >

>

>>

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

Ph

ys

iolo

gic

al

Pa

ram

ete

r


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

ys

iolo

gic

al

Pa

ram

ete

r


65 100

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

Age

Ph

ys

iolo

gic

al

Pa

ram

ete

r


65 100

4. The “replacement therapy” approach postulates the disease model, but results are mostly disappointing

Age

Ph

ys

iolo

gic

al

Pa

ram

ete

r


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

Ph

ys

iolo

gic

al

Pa

ram

ete

r

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

>

> >MOLECULAR & GENETIC

Mitochondrial Dysfunction

>

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

>>

>

>


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


>

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?

[email protected]

Documents

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