Arkansas Claude D Pepper Older Americans Independence Center

Arkansas Claude D. Pepper Older Americans Independence Center at UAMS Center Update October 2013 Jeanne Y. Wei, M. D, Ph. D. , PI

The theme of the Arkansas OAIC at UAMS: “Translational research on cardiac and skeletal muscle dysfunction in aging and disease. ” The Donald W. Reynolds Department of Geriatrics: • is 1 of 9 depts. of geriatrics in the U. S. ; • cultivates trainees from the seedling level; • offers a Ph. D in the Biology of Aging; • has a mandatory 4 week geriatrics medical students rotation; • in an 8 -story building dedicated to Geriatrics - education, research, clinical care and community outreach for improving care of the elderly.

The Goals of the Arkansas OAIC: • Promote research that improves skeletal muscle function & cardiovascular performance with age • Train future geriatricians and gerontologists on improving functional independence I. RC 1: Biostatistics and Data Management Core Paula Roberson, Ph. D. , William Hogan, M. D. II. RC 2: Nutrition, Metabolism, and Physiology Core Arny Ferrando, Ph. D. , Gohar Azhar, M. D. III. RC 3: Analytical Core Robert Wolfe, Ph. D. IV. PESC: Pilot Exploratory Studies Core Robert J. Shmookler Reis, D. Phil. , Arny Ferrando, Ph. D. V. RCDC: Research and Career Development Core Gohar Azhar, M. D. , Jeanne Wei, M. D. , Ph. D. VI. LAC: Leadership and Administrative Core Jeanne Wei, M. D. , Ph. D. , Robert Wolfe, Ph. D.

College of Public Health UA Little Rock College of Health-Related Professions RIOA Clinical Programs Clinical Research Center for Clinical & Translational Research (CCTR/CTSA) Translational Research Department of Graduate Education Biology of Aging Medical Students Residents Geriatric Fellows OAIC Geriatrics Reynolds Oklahoma Center on Aging (ROCA) at OUHSC Basic Research Reynolds Institute on Aging Arkansas Children’s hospital CAVHS GRECC College of Medicine Geriatric Education Center College of Pharmacy Arkansas Aging Initiative AAI College of Nursing Hartford program Harding university University of Arkansas at Fayetteville RIOA Collaborations that augment the Arkansas OAIC

RC 1: Biostatistics and Data Management Paula K. Roberson, Ph. D. and William R. Hogan, M. D. Amy Schrader, M. S. and Nitin Kanaskar, M. S.

Research Design & Analysis • Work with pilot investigators regarding study design, sample size, power calculations, & data analysis • Develop procedural plans for patient enrollment, randomization & unified data management • Analyze case report forms used by investigators to identify common data elements & build draft versions of electronic case report forms • Analyze study data & participate in preparation of manuscripts, abstracts & posters

Data Management at Arkansas OAIC • Supports: – Pepper Center Subject Recruitment Registry – Data management for 9 studies to date, including participant registration, surveys/questionnaires, and electronic case report forms – Training of staff to use the registry Built in open-source C 3 PR and Lime. Survey software applications. • Validates data entry and restricts modes of data entry to ensure data quality and security.

RC 2: Nutrition, Metabolism, and Physiology Core Arny Ferrando, Ph. D. Gohar Azhar, M. D.

Nutrition, Metabolism, and Physiology Core (RC 2) Specific Aim 1. Provide standardization for comprehensive nutritional, metabolic, and functional assessments. Core utilization for 17 studies to date - 11 ongoing, 6 completed. This includes human and animal studies. • Specific Aim 2. Facilitate performance of complex methodologies derived to address the metabolic and functional implications of aging and its related health issues. • Methodologies utilized in 7 current projects - including 2 completed projects and 1 PESC 2013 project • To date, 17 publications and 4 invited presentations derived from RC 2 support.

Nutrition, Metabolism, and Physiology Core (RC 2) Specific Aim 3. Provide training opportunities for collaborative and translational research. • Recent collaboration on determination of protein and lipid metabolism with Arkansas Children’s Hospital Research Institute • Routine training of graduate students from UAMS-College of Health Professions and Department of Dietetics and Nutrition in assessment of body composition and in nutritional counseling & analyses. • Routine collaboration with UAMS TRI/CTSA for dietary counseling, planning, analyses, and metabolic kitchen.

Claude Pepper Older Americans Independence Center at UAMS Research Core 3 Robert R. Wolfe, Ph. D Core Director

Ongoing Projects Supported by Research Core 3 Utilizing Stable Isotope Tracer Methodology Investigator Project Title Sponsor Ayyadevara Role of amino acid deficiency in age related muscle atrophy Pepper OAIC Baum The role of leucine and omega-3 fatty acids in skeletal muscle function during aging Pepper OAIC Pilot Borsheim Essential amino acid and hypertriglyceridemia National Institutes of Health Kim Citrulline/blood flow pilot Pepper OAIC Hauer-jansen Lysine supplementation and glucose metabolism Translational Research Institute/UAMS Ferrando Dairy macronutrients on the metabolic system Diary Research Institute Ferrando Effect of dietary protein intake distribution on protein metabolism and skeletal muscle Dairy Research Institute, American Egg Board, National Cattlemen's Beef Association Washington The effect of leucine supplementation on aged skeletal muscle regenerative capacity Pepper OAIC Pilot Wolfe Is there a maximal anabolic response to beef intake? National Cattlemen's Beef Association Wolfe Determination of the optimal infusion rate of amino acids in seriously ill patients Baxter Healthcare Corporation

Pilot & Exploratory Studies Core Robert J. Shmookler Reis, Ph. D Arny A. Ferrando, Ph. D

Pilot Study Grant Recipients Cycle 1 (Sept. 2011) Martin Hauer-Jensen, UAMS, Arginine supplementation reverses muscle wasting due to deficient de novo arginine synthesis. Anna Csiszar, OUHSC, Improvement of cardiovascular function in rats by arginine supplementation. Sharda Singh, UAMS, Modulation by 4 -hydroxynonenal (4 -HNE) of the phosphorylation status of acetyl-Co. A carboxylase (ACC) as a regulator of ectopic fat levels in mouse skeletal muscle. Masil George, UAMS, Biologic factors influencing cardiac cachexia in the elderly. Cycle 2 (Mar. 2012) Valentina Todorova, UAMS, Transcriptional analysis of anthracycline-induced cardiotoxicity in elderly cancer patients. Srini Ayyadevara, UAMS, Role of amino-acid deficiency in aging-related muscle atrophy. Nukhet Aykin-Burns, UAMS, Role of radiation-induced oxidative stress in intracellular HMGB 1 trafficking. Sakeena Raza, UAMS, Improvement in functional capacity of obese elderly with heart failure. Cycle 3 (Sept. 2012) Jamie Baum, UA Fayetteville, The Role of Leucine and w-3 Fatty Acids in Skeletal Muscle Function During Aging. Cody Sipe, Harding University, Relationship of BMI, musculoskeletal performance and functional capacity in older patients with congestive heart failure. Tyrone Washington, U. A Fayetteville, The effect of leucine supplementation on aged skeletal muscle regenerative capacity. Cycle 4 (Sept. 2013) Il-Young Neil Kim, UAMS, Nutritional therapy in elderly with heart failure. Vladimir Zharov, UAMS, Photothermal nanodrugs for photothermal therapy of polyglutamine aggregates associated with neurological genetic disorders and muscle aging. Andrew Gardner, OUHSC, Diet and exercise interventions to treat claudication. Rtika Abraham, UAMS, Nutritional therapy for autonomic dysfunction in elderly HF patients.

Grants/Publications Since Pilot Funding Grants not funded Grants pending Peer-rev. pubs Reviews Book chapters 2011 1 3 2012 6 2 2013 11 24 2 28 1 4 2

The Role of Leucine and w-3 Fatty Acids in Skeletal Muscle Function During Aging Background: Mitochondria are essential for skeletal muscle function and mitochondrial function diminishes with age. Nutrients such as leucine and w -3 fatty acids may be able to improve mitochondrial function in muscle through the m. TOR pathway. Hypothesis: Young and aged C 2 C 12 myotubes treated with physiological doses of leucine and/or w -3 fatty acids will have improved skeletal muscle function by activating translation initiation, increasing mitochondrial biogenesis and improving cell bioenergetics in an m. TOR-dependent manner. Study Design: Young and aged cells were serum and leucine starved for 6 hours before treatment with leucine and/or w -3 fatty acids. One hour before treatment cells were treated with either rapamycin or a DMSO vehicle. A. Young Leucine (0. 5 m. M) w-3 fatty acids (60 u. M EPA, 240 u. M DHA) w-3 fatty acids + Leucine Serum and leucine deprivation for 6 hours B. Aged +/- rapamycin for 60 minutes Nutrient treatment for 60 minutes

Leucine and w-3 Fatty Acids Act Synergistically to Activate Translation Initiation m. TOR Ser 2448/Total young aged p 70 S 6 K 1 T 389/Total young aged 4 E-BP 1 hyperphosphorylation gform/Total young aged

Leadership and Administrative Core (LAC) Update Jeanne Wei, M. D. , Ph. D. Robert Wolfe, Ph. D.

RC 3 Analytical Core Wolfe Metabolism and Physiology core Ferrando, Azhar plus other support Stable radioisotope methodology, metabolomics and micro. RNA in cardiac and skeletal muscle Leadership & Administrative core (LAC) Wei, Wolfe RC 1 Statistical core Roberson, Hogan Study Design & Data Analysis Data Management and Training UAMS Graduate School Interdisciplinary Biomedical Sciences (IBS) Graduate Program with an Aging Track with MS or Ph. D. degree RC 2 Nutrition, UAMS TRI/CTSA Nutritional interventions and functional assessments of cardiac and skeletal muscle PESC Executive Committee(EC) Internal Advisory Committee (IAC) External Advisory Committee (EAC) Data Monitoring & Safety Board Minority Advisory Committee(MAC) IRB committees and Office of Research Compliance other OAIC leadership & national geriatric organizations Reynolds Institute on Aging at Oklahoma university of Health Sciences Center (OUHSC) Reis, Ferrando RCDC Wei, Azhar Didactics, Clinical and basic research experience, methodology, manuscript/grant writing External projects , UAMS, OUHSC, other OAICs

OAIC Pepper Seminars Arny A. Ferrando, Ph. D, “Recovery from Hip Arthroplasty: Effects of Nutritional • Supplementation and Muscle Inflammation” Sakeena Raza, MD, "Improvement of Functional Capacity in Obese Elderly with Heart Failure“ Robert Coker, Ph. D, "Nutritional Countermeasures Against Metabolic Disease“ Mark Supiano, MD, “What’s New in Hypertension in Older Adults: Implications for Practice” Dalane Kitzman, MD, “A new form of heart failure in older persons” • • Quarterly Community Advisory Board Meetings • • • Community members as stakeholders in improvement of health care research and delivery. Discussion of health issues important for patients and caregivers. Identification of barriers for provision of better health care in Arkansas. Suggestions to enhance partnerships with community members. Suggestions/comments on educational materials about heart failure.

Research Career Development Core (RCDC) Update Gohar Azhar M. D. Jeanne Wei, M. D. , Ph. D.

RCDC trainees – Anna Czisar, Ph. D. – Ricki Fram, M. D. – Steven Rogers, Ph. D. – Valentina Todorova, Ph. D.

V. Todorova Doxorubicin (DOX): Ø Commonly used anti-cancer agent that may cause unpredictable cardiotoxicity, and irreversible cardiomyopathy and heart failure. Ø Current clinical methods for detection of DOX cardio-toxicity show low sensitivity and low predictive power. Ø With the increasing number of cancer survivors and the individual variability in the tolerable DOX dose, there is a growing need for markers for pre-symptomatic identification of patients at risk. Ø Older age significantly increases the risk not only of cancer but also of developing DOX-induced congestive heart failure. Todorova et al. , 2012

Cancer & Aging: Peripheral Markers of Doxorubicin Cardiotoxity Todorova et al. , 2012

Cancer & Aging: Peripheral Blood Markers of Doxorubicin Cardiotoxity Todorova et al. , 2012

Diabetes, Heart Failure & Endothelial Dysfunction S. Rogers • Diabetes in the US now affects 11 million (27%) of those > 65 years. Both aging and hyperglycemia are associated with endothelial dysfunction and reduced nitric oxide function, & also cellular senescence. • Early replicative senescence is induced by stress. Endothelial cell function is essential for the homeostasis of the vascular system. • Loss of nitric oxide (e. NOS) is a cardinal feature of endothelial dysfunction and an independent predictor of cardiovascular disease risk. • Hyperglycemia and other stresses raise inducible NOS (i. NOS), which is associated with excessive nitric oxide (NO) and cellular damage. • Hypothesis: Low glucose may also impair endothelial function.

Senescence (%) Population doubling rate (PD/Day) Senescence and proliferation rate profiles of HUVECs exposed to high and/or low glucose over time Rogers et al 2013

High or Low Glucose Accelerates HUVEC Cell Senescence & Dysregulation of Nitric Oxide Synthase Rogers et al 2013

Cytoskeletal Morphology Early Normal Glucose 40 x Late High Glucose Metformin 40 x Rogers et al

Arkansas Pepper OAIC Update Summary 1. The research will broaden our understanding of cardiac & skeletal muscle weakness in seniors. 2. The findings will help to treat muscle weakness with nutritional & other novel approaches. 3. The OAIC will train new translational aging researchers in maintaining and improving functional independence of older Americans.