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.