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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