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 PhD 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. RC1: Biostatistics and Data Management Core Paula Roberson, Ph.D., William Hogan, M.D. II. RC2: Nutrition, Metabolism, and Physiology Core Arny Ferrando, Ph.D., Gohar Azhar, M.D. III. RC3: 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 Geriatrics OAIC 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 RC1: 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 C3PR and LimeSurvey software applications. • Validates data entry and restricts modes of data entry to ensure data quality and security. RC2: Nutrition, Metabolism, and Physiology Core Arny Ferrando, Ph.D. Gohar Azhar, M.D. Nutrition, Metabolism, and Physiology Core (RC2) 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 RC2 support. Nutrition, Metabolism, and Physiology Core (RC2) 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, PhD 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, PhD Arny A. Ferrando, PhD 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-CoA 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 HMGB1 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 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 mTOR pathway. Hypothesis: Young and aged C2C12 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 mTOR-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 mM) w-3 fatty acids (60 uM EPA, 240 uM DHA) w-3 fatty acids + Leucine Serum and leucine deprivation for 6 hours B. Aged +/- rapamycin for 60 minutes Nutrient treatment for 60 minutes 2 1 Arbitrary Units 0 young aged 0.6 0.4 0.2 young Arbitrary Units mTOR P/Total mTOR Ser2448/Total p70S6K1 T389/Total 1.0 0.0 aged 0. 0 5 .5 C m m on M M tr ol L O Oeu Leu m m+ Le Le ega e rap u u -3 ga + + + -3 O O ra m m p eg eg a a +r ap 0. 0 5 .5 C m m on M M tr ol L O Oeu Leu + m Le Le ega me rap u u -3 ga + + + -3 O O ra m m p eg eg a a +r ap Arbitrary Units 3 0. 0 5 .5 C m m on M M tr ol L O Oeu Leu + m Le Le ega me rap u u -3 ga + + + -3 O O ra m m p eg eg a a +r ap 0. 0 5 .5 C o m m n M M tr ol L O Oeu Leu + m Le Le ega me rap u u -3 ga + + + -3 O O ra m m p eg eg a a +r ap 0. 0 5 .5 C m m on M M tr ol L O Oeu Leu + m Le Le ega me rap u u -3 ga + + + -3 O O ra m m p eg eg a a +r ap 0. 0 5 .5 C m m on M M tr ol L O Oeu Leu + m Le Le ega me rap u u -3 ga + + + -3 O O r m m ap eg eg a a +r ap Leucine and w-3 Fatty Acids Act Synergistically to Activate Translation Initiation 4E-BP1 hyperphosphorylation gform/Total 0.8 1.0 0.8 0.6 0.4 0.2 0.0 young aged Leadership and Administrative Core (LAC) Update Jeanne Wei, M.D., Ph.D. Robert Wolfe, Ph.D. RC3 Analytical Core Wolfe Stable radioisotope methodology, metabolomics and microRNA in cardiac and skeletal muscle RC1 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 RC2 Nutrition, UAMS TRI/CTSA Metabolism and Physiology core Ferrando, Azhar plus other support Leadership & Administrative core (LAC) Wei, Wolfe 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, PhD, “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, PhD, "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., PhD. RCDC trainees – Anna Czisar, Ph.D. – Ricki Fram, M.D. – Steven Rogers, Ph.D. – Valentina Todorova, Ph.D. V. Todorova Doxorubicin (DOX): Commonly used anti-cancer agent that may cause unpredictable cardiotoxicity, and irreversible cardiomyopathy and heart failure. Current clinical methods for detection of DOX cardio-toxicity show low sensitivity and low predictive power. 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. 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 (eNOS) is a cardinal feature of endothelial dysfunction and an independent predictor of cardiovascular disease risk. • Hyperglycemia and other stresses raise inducible NOS (iNOS), 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 (%) 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 40x Late Normal Glucose 40x Late High Glucose 40x Late High Glucose Metformin 40x 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.