1. Center Overview September 2013 Jeremy Walston, MD, Principal Investigator Karen Bandeen-Roche, PhD, Co-Principal Investigator Johns Hopkins University Claude D. Pepper Older Americans Independence Center

2. 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

3. 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

4. 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

5. Frailty Predicts Adverse Outcomes CHSWHAS 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, 2001 Bandeen-Roche et al, J Ger Med Sci, 2006 Hazard Ratios Estimated Over 3 Years, covariate adjusted, p>0.01

6. 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.

7. Aging Mitochondrial decline DNA Methylation  Senescence Cells  DNA damage  Apoptosis ↓Telomere Length Disease Depression Cognitive Decline Cancer Chronic Infection Cardiovascular Diabetes/Obesity Dependence Disability Mortality Potential Triggers Clinically Apparent Outcomes Genetic Variation Environment 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

8. 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)

9. 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

10. 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)

11. High Profile Science: Methods – Inflammation phenotype (Bandeen-Roche, Varadhan) – Dynamical systems and dysregulation (Varadhan) Progress in Years 6-10 (2008-2013)

12. 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

13. A Frail Mouse IL-10 tm/tm C57Bl/6J Walston J et al, Gerontology Med Sciences, 2008

14. Early mortality for IL-10 -/- compared to controls Ko F et al AGE 2011

15. 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

16. Losartan improves muscle remodeling and in vivo function in aging mice after injury Burks T N et al. Sci Transl Med 2011;3:82ra37-82ra37 Published by AAAS

17. Losartan Prevents Disuse Atrophy in Older Mice Burks T N et al. Sci Transl Med 2011;3:82ra37-82ra37

18. 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)

19. 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)

20. 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.

21. JHU OAIC and Aging-related Institutional Environment and Resources

22. Leadership and Administrative Core Leadership Council Jeremy Walston, OAIC PI Karen Bandeen-Roche, OAIC Co-PI External Advisory Board Independent Review Panels Research Career Development Core Gary Gerstenblith Core Leader Pilot and Exploratory Studies Core Neal Fedarko Core Leader Resource Core-1 Biostatistics Core Karen Bandeen-Roche Core 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 Core Robert Wise, Core Leader Data Safety Monitoring Board

23. Resource Core 1: Biostatistics Core 1)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

24. 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.

25. 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

26. JHU OAIC RCDC Junior Faculty Awarded 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

27. 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 Investigators Awarded 2013-2014 JHU OAIC Pilot Core Investigators Awarded 2013-2014

28. JHU-OAIC RC-1 and RC-2 Development Projects 2013-2014 Qian-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

29. JHU OAIC Diversity Supplement Awards 2012- present Reyhan 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

30. JHU OAIC Ongoing 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

31. 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