Center OverviewSeptember 2013

Jeremy Walston, MD, Principal InvestigatorKaren Bandeen-Roche, PhD, Co-Principal Investigator

Johns Hopkins UniversityClaude D. Pepper Older

Americans Independence Center

JHU OAIC Mission• To develop frailty as a clinical and research tool

that can lead to improved risk assessment and to the reduction in late life vulnerability to chronic disease and late life decline

• To identify frailty etiologies and potential pathways and targets for intervention

• To train the next generation of frailty focused investigators

Frailty• A geriatric syndrome of weakness, weight

loss, and low activity associated with adverse health outcomes

• An age-related, biological vulnerability to stressors that stems from alterations in multiple physiological systems

Frailty Phenotype Development• Weight loss • Weakness• Exhaustion• Slowed walking speed• Low activity

Fried, LP, et al, J Ger Med Sci, 2001

* Frail if 3 of 5 are present

Frailty Predicts Adverse OutcomesCHS WHAS

Incident Fall 1.29 (1.00 – 1.68)

1.18 (0.63, 2.19) (NS)

Worsening Mobility

1.50 (1.23, 1.82) 10.44 (3.51, 31.00)

Worsening ADL Disability

1.98 (1.54 – 2.55)

15.79 (5.83, 42.78)

First Hospitalizations

1.29 (1.09,1.54) 0.67 (0.33, 1.35) (NS)

Death 2.24 (1.51,3.33) 6.03 (3.00, 12.08)

Fried, L. P , et al, J Ger Med Sci, 2001Bandeen-Roche et al, J Ger Med Sci, 2006

Hazard Ratios Estimated Over 3 Years, covariate adjusted, p>0.01

Progress in Years 1-5 (2003-2008)

• Established frailty-focused leadership team• Developed and advanced a frailty model through

epidemiological discovery• Explored biological hypotheses in populations

– Inflammation– Multisystem studies

• Helped launch research careers focused on frailty– Leng, Boyd, Chaves, Xue, Seplaki, Makary, Walston, et al.

AgingMitochondrial declineDNA Methylation Senescence Cells DNA damage Apoptosis↓Telomere Length

Disease Depression Cognitive Decline Cancer Chronic Infection Cardiovascular Diabetes/Obesity

DependenceDisabilityMortality

Potential TriggersClinically Apparent

Outcomes

Genetic VariationEnvironment

FRAILTY

Physiology

Inflammation

Angiotensin system

HPA Axis

Sympathetic nervous system

↓ Decreased energy production

Weakness

Fatigue

Weight loss

Slowness

Pathophysiologic Model for Adverse Outcomes in Older Adults

• High Profile Frailty Science: Clinical– Precedence of frailty criteria onset (Xue)– Longitudinal strength phenotype (Xue)– Inflammation phenotype (Varadhan)– Simplified criterion assessment (Eckel)– FrDATA collaboration: nosology (Bandeen-Roche)– Frailty as Risk Assessment Tool (Makary, Leng, Segev)

Progress in Years 6-10 (2008-2013)

Use of Frailty as Clinical Tool

• Frailty predicts poor surgical outcomes– Makary, Segev, 2010

• Frailty predicts poor vaccine response– Leng, 2011

• Frailty predicts transplant rejection– Segev, 2012

• Clinical Risk and Etiological Studies– Influenza Vaccine Efficacy (Leng)– Inflammatory Phenotype (Varadhan)– Transplantation Risk (Segev, Pustavoitau)– Glucose Metabolism (Kalyani)– p16 as etiology (Pustavoitau)– CMV as etiology (Wang)– Vestibular Change and Fall Risk (Agrawal)

Progress in Years 6-10 (2008-2013)

• High Profile Science: Methods– Inflammation phenotype (Bandeen-Roche,

Varadhan)– Dynamical systems and dysregulation (Varadhan)

Progress in Years 6-10 (2008-2013)

Progress in Years 6-10 (2008-2013)• High Profile Biology Studies:

₋ Developed Frail Mouse Model that like humans has increased inflammation, lower strength and ATP in skeletal muscle, and increased risk for mortality (Walston, Ko, Akki)

₋ Mitochondrial angiotensin system (Abadir, PNAS 2011)₋ Losartan accelerates muscle healing and prevents disuse

atrophy in skeletal muscle (Burks, Science Transl. Medicine 2011)

₋ Novel Immunosenescence, Inflammation and chronic CMV findings (Wang, Science Transl. Medicine 2012; Yao, Vaccine 2011)

₋ Annual Frailty -themed GSA Symposium that highlights science from core faculty from all disciplines and from supported investigators

A Frail Mouse

IL-10tm/tm

C57Bl/6J

Walston J et al, Gerontology Med Sciences, 2008

0.0

00.2

50.5

00.7

51.0

0

0 20 40 60 80 100Time in weeks

Male C57BL/6J Female C57BL/6JMale IL-10tm/tm Female IL-10tm/tm

Kaplan-Meier survival estimatesEarly mortality for IL-10 -/- compared to controls

Ko F et al AGE 2011

MAS Dysregulation in Older Mice Recovers with Losartan Treatment

Abadir P M et al. PNAS 2011;108:14849-14854

©2011 by National Academy of Sciences

Losartan improves muscle remodeling and in vivo function in aging mice after injury

Burks T N et al. Sci Transl Med 2011;3:82ra37-82ra37Published by AAAS

Losartan Prevents Disuse Atrophy in Older Mice

Burks T N et al. Sci Transl Med 2011;3:82ra37-82ra37

• Pilot Intervention Development– Vitamin D Intervention (Chaves, Yasar)– Salsalate in Animal Models (Roy) – Rapamycin in Animal Models (Xue, Leng)– Wound Repair Studies (Harmon, Abadir)– Hearing Loss (Lin)– Anemia PACTEE Consortium (Roy, Chaves,

Walston)

Progress in Years 6-10 (2008-2013)

• Outstanding Supported Scholar Development– Research Career Development Core (RCDC)

• 8 funded K awards, 5 R awards

– Diversity Supplements• Graduate, Post-Doctoral, Junior Faculty participation

– PhD and Graduate Student Participation• Leverage T-32, Biology of Healthy Aging, Division of

Geriatric Medicine, Center on Aging and Health

Progress in Years 6-10 (2008-2013)

Moving Forward: 2013-2018

• Refunded for 5 Years starting July 2013• Frailty focus remains central • Increased emphasis on

– Deeper biological/etiology discovery (RAS, mitochondrial focus)

– Developing clinical interventions for frailty– Interdisciplinary training– Developing diverse interdisciplinary collaborations in

order to optimize science and resource utilization at JHU and across OAICs.

JHU OAIC and Aging-related Institutional Environment and Resources

Leadership and Administrative Core Leadership Council

Jeremy Walston, OAIC PIKaren Bandeen-Roche, OAIC Co-PI

External Advisory Board Independent Review

Panels

Research Career Development Core

Gary GerstenblithCore Leader

Pilot and Exploratory Studies Core

Neal FedarkoCore Leader

Resource Core-1 Biostatistics Core

Karen Bandeen-RocheCore Leader;Qian-Li Xue

Core Director

Resource Core-2 Biological Mechanisms Core

Aravinda Chakravarti,Core Leader;

Dan Arking and Jeremy Walston, Co-Directors

JHU OAIC Organizational Chart

Resource Core-3 Clinical Translation and

Recruitment CoreRobert Wise,Core Leader

Data Safety Monitoring Board

Resource Core 1: Biostatistics Core1) Mentors junior scholars and optimize their access

to analytic expertise and databases 2) Trains faculty in quantitative methods needed to

effect high quality research and effectiveness of collaboration with statistical colleagues

3) Provides data infrastructure and emerging computing technologies for frailty research

4) Provides analytic and data management support for research on frailty

5) Develops methodologies for analysis needed to translate research into clinical practice

Resource Core 2:Biological Mechanisms Core

1) Provides scientific expertise, technology and infrastructure necessary to facilitate efficient use of omics, other molecular approaches, and downstream computational technologies

2) Provides access to relevant biological samples from human subjects and animal models

3) Facilitates the translation of RC-2 frailty research findings into intervention- or prevention-focused clinical studies

4) Provides training, mentorship and guidance to promising junior investigators

5) Provides institutional, national, and international access and visibility for RC-2-related science and activities.

Resource Core 3:Clinical Translation and Recruitment Core

1) Provides mentorship and training in all aspects of human subjects research to OAIC supported investigators

2) Provides oversight necessary to ensure optimal and safe performance of clinical studies

3) Provides the clinical research infrastructure and services necessary to facilitate the successful conduct of frailty-related clinical studies

4) Maintains and continues to grow a research registry of older adults categorized by frailty

JHU OAIC RCDC Junior FacultyAwarded 2013-2014

Yuri Agrawal, MD,Assistant Professor, Department of

Otolaryngology-Head and Neck Surgery

Mara McAdams DeMarco, PhD, Instructor, Departments of

Transplantation Surgery and Epidemiology

Implications of specific vestibular impairments for postural instability, gait

impairments, frailty and falls for older adults

Clinical management of older ESRD patients and the development of adverse outcome metrics and risk

prediction related to frailty in older adults

Jessica Lee, MD, Clinical Research Fellow, Geriatric Medicine and Gerontology

Robert G. Weiss, MD, Professor of Medicine, Division of Cardiology

Honggang Cui, PhD, Assistant Professor, Department of

Chemical and Biomolecular Engineering

Safety and Efficacy of Losartan Treatment in Frailty:

A Phase II Pilot Study

Energy Production in Frailty: Skeletal Muscle ATP Kinetics

in Frail, Older Adults

The Specific Delivery of Pharmaceuticals into

Mitochondria

JHU OAIC Pilot Core InvestigatorsAwarded 2013-2014

JHU-OAICRC-1 and RC-2 Development Projects

2013-2014Qian-Li Xue, PhD,

Assistant Professor, Geriatric Medicine and Gerontology

Dan Arking, PhD,Associate Professor

McKusick-Nathans Institute of Genetic Medicine and Division of Cardiology

Resource Core 1 Development Project: Dysregulation in multiple physiological

systems as a frailty etiology

Resource Core 2 Development Project: Integrative omics analyses of the

IL10Tm/Tm frail mouse

JHU OAICDiversity Supplement Awards

2012- presentReyhan Westbrook, PhD,

Research Fellow, Geriatric Medicine and Gerontology

Rhondalyn McLean, MD,Cardiology (recently accepted position

at UPenn)

Adverse metabolic characteristics associated with aging and frailty in the

IL10Tm/Tm and normal mice

Cardiopulmonary Bypass, Frailty and Inflammation

JHU OAICOngoing Pilot Projects

Mary Armanios, PhD,Associate Professor of

Oncology

Qian-Li Xue, PhD,Assistant Professor, Geriatric Medicine and Gerontology

Sevil Yasar, MD, PhD, Assistant Professor,Geriatric Medicine

Telomere length and Clinical Outcomes in the Women’s

Health Aging Study

Effects of Rapamycin and Metformin on Muscle Quality and Function

Vitamin D, frailty, inflammation and functional outcomes

Acknowledgments– National Institutes of Aging

– Brian Buta, Research Program Administrator

– Katie Matthews, Research Service Analyst

– Denise Baldwin, Administrative Coordinator

– Partnerships with JHU Schools of Medicine, Public

Health and Nursing

– Highly Engaged and Happy Scholars, Students,

Collaborators, and Staff