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

1. Frailty from Bedside to Bench: Recommendations for a Research Agenda on Frailty Findings from the AGS/NIA- sponsored national conference on Frailty January, 2004

2. 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

3. 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.

4. Goal for Frailty Conference • Define the state of knowledge of causes of frailty • Define the research needed to determine the causes of frailty

5. 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.

6. 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

7. Clinical Presentation of Frailty 3 case histories

8. The patient’s illness: • Contributors to health outcomes: • The disease • The underlying health status and vulnerability

9. #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 Two patients: 75 y/o men

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.

11. Physical Exam in ER • Cachectic; • Musculoskeletal: muscle wasting, DIP changes c/w OA • Neuro: diffuse weakness, cognition intact. • Unable to walk or transfer

12. 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.

13. 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

14. A: Resilient; Not frail B: Vulnerable; Poor recovery Decompensates with minor external stress. Onset of frailty Ho: Spectrum of resilience and frailty in older adults • C: • Frailty Syndrome; • Outcomes: • Loss of independence • D: Endstage frailty/ predeath

15. Clinical observations • Endstage frailty: • associated with death; • not remediable; • presentation: • malnutrition/undernutrition • severe weakness, sarcopenia • low albumin, cholesterol Verdery 1996

16. 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

17. (Fried and Walston, 1998)

18. Preliminary Clinical Criteria for Frailty Adopted by AGS Conference

19. 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

21. Hazard Ratios* Estimated Over 3 Years Frail Incident Fall 1.29 Worsening Mobility 1.50 Worsening ADL Disability 1.98 First Hospitalizations 1.29 Death 2.24 Baseline Frailty Status Predicting Adverse Outcomes Clinically Associated with Frailty * Covariate Adjusted, p  .05 (Fried et al, 2001)

23. 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.

24. Weight Loss • > • Clinical Presentation Sarcopenia • >  physical activity > • • > • Strength Exhaustion/  exercise tolerance  Motor performance

25. Weight Loss • > • Clinical Presentation Sarcopenia • >  physical activity > • • > • Strength Exhaustion/  exercise tolerance  Motor performance Physiologic Vulnerability

26. Weight Loss • > • Clinical Presentation Sarcopenia • >  physical activity > • • > • Strength Exhaustion/  exercise tolerance  Motor performance Physiologic Vulnerability Physiologic Dysregulation Cellular Function, Molecular and Genetic Characteristics

27. 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

28. Aging, Homeostatic Mechanisms and Frailty Operational Definitions for Studies on Aging Physiological Parameter Age • 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

29. Aging, Homeostatic Mechanisms and Frailty Operational Definitions for Studies on Aging Physiological Parameter Age • . . .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

30. Aging, Homeostatic Mechanisms and Frailty Operational Definitions for Studies on Aging Physiological Parameter Age • Additionally, information on patterns of functional decline in multiple physiological systems with age is scant 65 100

31. Aging, Homeostatic Mechanisms and Frailty Operational Definitions for Studies on Aging Physiological Parameter Age • The “replacement therapy” approach postulates the disease model, but results are mostly disappointing 65 100

32. Aging, Homeostatic Mechanisms and Frailty Operational Definitions for Studies on Aging Physiological Parameter Age • Frailty as accelerated decline in anatomical integrity and function across multiple physiological systems. The “replacement therapy” approach is unlikely to be effective. 65 100

33. 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 Balance CNS 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

34. 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

35. 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

36. Research into the Molecular Basis of Frailty and Potential for Animal Models Jeremy D. Walston, M.D Associate Professor of Medicine John Hopkins University

37. 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 Chronic Infection CHF

38. Molecular Alterations May Underlie Multisystem Change  SNS activity Altered hormones PHYSIOLOGIC Glucose intolerance Inflammation  Hematopoiesis Altered hormones, Environmental factors Mitochondrial Dysfunction > Altered cellular metabolism > > MOLECULAR & GENETIC  Free radicals > Cellular senescence  DNA damage Altered telomeres Genetic Variation

39. Biology of Aging Meets Frailty: • Oxidative stress & free radicals • Dysfunctional telomeres • DNA damage & repair • Cellular senescence & antagonistic pleiotropy

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

41. Induction of Cell Senescence Oxidative Stress Chromatin Instability Irreversible arrest of cell proliferation Oncogenes DNA Damage Dysfunctional Telomeres

42. The Senescent Cell Phenotype: Irreversible Growth Arrest Altered Differentiated Function Resistance to Apoptosis

43. Do Senescent Fibroblasts Promote Frailty? • Disruption in growth & differentiation of several cells • Secretion of inflammatory cytokines • Promotion of disease states

44. Hypothesized Molecular Pathway to Frailty Altered Hormones, Environmental Factors Mitochondrial Dysfunction > Altered Cellular Metabolism >  Free Radicals > >  DNA Damage Cellular Senescence Altered Telomeres Genetic Variation

45. Molecular Alterations May Underlie Multisystem Change  SNS activity Altered hormones PHYSIOLOGIC Glucose intolerance Inflammation  Hematopoiesis Altered hormones, Environmental factors Mitochondrial Dysfunction > Altered cellular metabolism > > MOLECULAR & GENETIC  Free radicals > Cellular senescence  DNA damage Altered telomeres Genetic Variation

46. Development of Animal & Cell Models • Critical need for molecular and physiological studies • Necessary first steps in development of intervention and prevention studies

47. 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

48. Recommendations for Animal Model Development • Further refinement of phenotypic measurements • Improved measurement of body composition • Phenotype candidate strains from already existing transgenics and knockouts.

49. 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

50. 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