Resveratrol and Exercise to Treat Functional Limitations in Late Life
Phase: PHASE2
Conditions: Aging
Sponsor: University of Florida

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Protocol 
1. Project Title: 
Resveratrol and Exercise to Treat Functional Limitations in Late Life (RESTORES) 
2. Investigators: 
Thomas Buford, PhD 
Stephen Anton, PhD 
Christiaan Leeuwenburgh, PhD 
Marco Pahor, MD 
Bhanuprasad Sandesara, MD 
Samuel Wu, PhD 
3. Abstract:   
With persons aged ≥ 65 years representing the fastest growing segment of the U.S. population, the 
prevention of age-related functional decline and disability is an important public health priority. The loss of 
functional abilities in advanced age is associated with not only the onset of disability and the loss of 
independence but also with increased rates of morbidity and mortality. To date, physical exercise is the 
only intervention consistently demonstrated to improve physical function among older adults and is 
increasingly being considered the standard of cared for treating functional limitations. However, significant 
variability exists in responsiveness to exercise. As such, many individuals do not achieve clinically-
significant improvements in function despite good adherence. Accordingly, there is a need to identify 
adjuvant therapies capable of improving the efficacy of exercise in treating older adults with functional 
impairments. This project is a pilot study to investigate the potential of resveratrol, a commercially-
available nutritional product, to enhance the efficacy of physical exercise in improving physical function 
among older adults with functional limitations. The overarching objective of this project is to evaluate the 
safety and efficacy of an intervention combining resveratrol supplementation and physical exercise 
among sedentary persons aged 65 years objectively-measured functional limitations. A total of 60 
participants will be recruited to participate in this three month intervention study. All participants will 
engage in a center-based exercise program 2/days per week and will be randomly assigned to consume 
1) placebo, 2) 500 mg/day resveratrol, or 3) 1000 mg/day resveratrol. This study will provide critical 
information regarding the influence of the combination of resveratrol and exercise (REX) on objectively-
measured and self-assessed indices of physical function. The study will also provide biologic information 
regarding the relative effects of REX on skeletal muscle mitochondrial function.  
4. Background:  
The maintenance of one’s physical capabilities during older age is an essential part of healthy 
aging. Declines in physical abilities are associated with not only the onset of disability and the loss of 
independence but also with increased rates of morbidity and mortality.1-3 To date, physical exercise is 
the only intervention with consistent evidence supporting its use in treating age-related functional 
limitations. However, despite strong adherence to training, clinically-significant improvements in 
physical function are not obtained by many individuals.4,5 Thus exercise appears to be essential, but 
insufficient, for maintaining function among many seniors.6 Alternative strategies are therefore needed 
to improve the therapeutic efficacy of exercise in physically-limited older adults. Therefore, our long-
term goal is to develop interventions that optimize the efficacy of exercise as a strategy to prevent 
disablement among this high-risk population. 

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As our group has shown previously, skeletal muscle mitochondrial function declines with age and is 
a key factor in the maintenance of physical function among older adults.7,8 Moreover, several studies 
have demonstrated that mitochondrial adaptations to both acute and chronic exercise are attenuated in 
late life.9-12 Thus adjuvant therapies which stimulate mitochondrial function may hold promise for 
enhancing functional responses to exercise. Resveratrol, a polyphenol compound commonly found in 
the skin of red grapes, was previously suggested as a potential adjuvant to exercise due to its ability to 
stimulate mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma co-
activator 1 alpha (PGC-1α) activity.13 In a recently completed pilot study, we observed that 12 weeks of 
resveratrol supplementation was well tolerated by overweight older adults and induced a dose-
dependent (300 vs. 1000 mg/day) increase in resting muscle oxidative metabolism. Additionally, 30 
days of resveratrol supplementation (150 mg/day) was recently reported to increase skeletal muscle 
mitochondrial function and PGC-1α content in obese, middle-aged men.14  
Subsequent studies using animal models of aging have reported that improvements in physical 
performance are greater in response to the combination of exercise and resveratrol than from either 
treatment alone.15-18 These studies overwhelmingly suggest that improvements in performance likely 
manifest as a result of enhanced skeletal muscle mitochondrial function. Thus, resveratrol appears to 
specifically target a key physiologic mechanism through which exercise improves physical function 
among older adults. We hypothesize that enhancing mitochondrial function may enhance physiologic 
adaptations to exercise such as aerobic fitness and skeletal muscle endurance. However, despite the 
promising findings from pre-clinical models, experimental data are sparse regarding the effects of this 
combined approach in humans. Consequently, well-controlled studies are needed to determine if the 
benefits of combining resveratrol with exercise demonstrated in pre-clinical studies can be translated to 
humans. Therefore, the purpose here, as the next step in pursuit of our long-term goal, is to evaluate 
the relative efficacy of combining physical exercise with oral resveratrol supplementation for improving 
the physical function of older adults at risk for disability.  
5. Specific Aims: 
The objective of this study is to conduct a pilot study to refine and finalize elements critical to 
conducting a future, definitive randomized, controlled trial (RCT). We propose to recruit 60 persons 
aged ≥ 65 years with functional limitations and follow them for 12 weeks. Participants will be randomly 
assigned to receive either (1) placebo plus 2 days/week of supervised, center-based, multi-modal 
exercise (EX), or (2) the same exercise program combined with either 500 or 1000 mg/day of 
resveratrol (REX). We will also collect skeletal muscle biopsies at baseline and 12 weeks from willing 
participants (i.e. optional for study participation) to evaluate skeletal muscle mitochondrial adaptations 
to the interventions. This study will enable us to address the following aims, all of which are of critical 
importance for designing a full-scale trial. 
1. To obtain critical data necessary to project the sample size needed for a full-scale trial using the 
change in 4m usual gait speed, a key predictor of health and survival in older adults,2,19,20 as the 
primary outcome. 
2. To determine the variance of secondary outcomes and short-term effects of the intervention on 
these outcomes, including: (1) exercise capacity, evaluated by distance walked during the 6-minute 
walk test, (2) lower-extremity function, assessed by the Short Physical Performance Battery 
(SPPB), (3) skeletal muscle strength and endurance, assessed by isokinetic muscle testing, and 4) 
self-assessed functional limitations, evaluated by the Late-Life Disability Questionnaire. 
3. To (a) assess the effects of resveratrol on exercise-induced changes in key indices of skeletal 
muscle mitochondrial function and quantity, and (b) determine the extent of association between 
changes in these mitochondrial outcomes and changes in measures of physical function.  

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6. Research Plan: 
 
We propose to conduct a randomized, controlled pilot trial to test that resveratrol improves functional 
responses of physically-limited older adults to chronic exercise training. Following study entry, participants 
(N = 60) will be randomly assigned to either EX or one of two REX groups for 12 weeks. Each condition 
will consist of two center-based resistance training sessions per week.  
 
6.1 Participants: Eligible participants will be males or females  ≥ 65 years of age with a sedentary lifestyle 
and objectively-measured functional limitations.  
 
Table 6.1. Inclusion and exclusion criteria 
Inclusion Criteria  
• 
Age 65 years  
• 
> 290 seconds needed to complete long-distance corridor walk test, as an indicator of functional 
limitation and moderate to low aerobic fitness3  
• 
Sedentary lifestyle, defined as <150 min/wk of moderate physical activity as assessed by 
CHAMPS questionnaire21 
• 
Willingness to be randomized to either treatment group 
• 
Willingness to participate in all study procedures 
Exclusion criteria  
• 
Failure to provide informed consent; 
• 
Regular consumption of a resveratrol supplement  
• 
Current involvement in supervised rehabilitation program  
• 
Absolute contraindication(s) to exercise training according to American College of Sports Medicine 
guidelines22 
• 
Pain classification > Grade 3 on Graded Chronic Pain Scale23  
• 
Peripheral vascular disease; peripheral neuropathy; retinopathy 
• 
Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically 
significant aortic stenosis, history of cardiac arrest, use of a cardiac defibrillator, or uncontrolled 
angina;   
• 
Myocardial infarction or stroke within past year 
• 
Significant cognitive impairment, including known dementia diagnosis or a Mini-Mental State 
Examination exam score < 24  
• 
Progressive, degenerative neurologic disease, e.g., Parkinson’s Disease, multiple sclerosis, ALS; 
• 
Severe rheumatologic or orthopedic diseases, e.g., awaiting joint replacement, active inflammatory 
disease; 
• 
Severe pulmonary disease, requiring either steroid pills or injections or the use of supplemental 
oxygen; 
• 
Hip fracture, hip or knee replacement, or spinal surgery within past 4 mos.; 
• 
Other significant co-morbid conditions that would impair ability to participate in the exercise-based 
intervention 
• 
Simultaneous participation in another intervention trial 
 
FOR MUSCLE BIOPSY ONLY  
• 
Use of prescription anti-platelet medications (not including aspirin) 
• 
Prescription anti-coagulant use (e.g. warfarin) 
• 
Conditions which reduce wound healing, e.g. peripheral vascular disease, venous stasis 
• 
Known allergy to lidocaine 
 

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6.2 Recruitment: Participant recruitment will be coordinated in conjunction with the OAIC Clinical 
Research Core, led by co-investigator Dr. Stephen Anton. We will develop a targeted recruitment 
approach based on previous experiences utilizing methods of recruitment that include direct mailings, 
newspaper classified and print ads, community luncheons and health fairs, as well as clinic referrals. We 
have extremely successful in implementing this approach in past studies 
 
6.3 Screening and Study Entry: Interested individuals will initially complete a pre-screening interview by 
phone. Participants deemed eligible based on the pre-screening invited to an in-person screening visit. 
During this visit, potential participants will first be asked to give their informed consent and then will be 
screened for study entry criteria. Initial screening procedures will include a review of their medical history, 
physical activity habits, medication use, cognitive function (assessed by the Mini Mental State Exam), and 
a physical exam performed by a study physician. The study physician will review collected information 
relevant to potential participant’s health and make recommendation on this individual’s participation in this 
trial. 
Participants will then be asked to complete the long-distance corridor walk test to evaluate functional 
status and aerobic fitness. If all study entry criteria are met, participants will be scheduled to return to the 
clinic for baseline assessments. In addition, the study participants will be asked to sign Medical Records 
Release Authorization. This Authorization will be used exclusively to obtain medical records to acquire 
facts, details, and outcomes of Serious Adverse Events that occurred during the study and have to be 
reported to the sponsor and/or IRB. 
 
6.4 Baseline Assessment and Randomization: If all study entry criteria are met, participants will be 
scheduled to return to the clinic for baseline assessments prior to randomization. During this visit, 
participants will be asked to complete validated study questionnaires, including the Late-Life Disability 
Instrument24 and provide a fasting blood sample for evaluation of clinical safety lab values. Participants 
will also complete the Short Physical Performance Battery (SPPB), a 6-minute walk test, and 
assessments of muscle strength. Finally, the study coordinator will provide participants with an 
armband physical activity monitor and dietary intake form to take home to objectively evaluate baseline 
physical activity and dietary habits. Staff members will then discuss randomization procedures with 
participants. Participants who agree to participate in the muscle biopsy procedure will be scheduled for 
a separate visit prior to initiation of study interventions.  
 
6.5 Exercise Intervention: After random assignment to either the EX or the REX groups, participants will 
engage in a two days a week, center based resistance exercise intervention for 12 weeks. Following a 
brief warm-up, participants will be instructed to walk for 30 minutes at a 5-6 on the CR10 scale with 
encouragement for 10 minutes to be vigorous (7-8 on CR10 scale). Sessions will also include 30 
minutes of strength exercises for both lower- and upper-body followed by flexibility exercises and 
balance training to promote cool-down. Participants will be introduced to exercises in such a way that 
they begin with lighter intensity and gradually increase. The progressive nature of the intervention is 
designed to minimize discomfort and prevent injury. During the first week of the intervention, resistance 
exercises will be performed using lighter resistance where the focus will be on learning proper 
technique. Resistance training will be performed using standard isotonic resistance training equipment.  
 
Participants in the REX groups will be randomly assigned to receive, in a double-blind fashion, either 
500 or 1000 mg/day of encapsulated resveratrol or placebo. The company Reserveage Organics 
(Gainesville, FL) provided the resveratrol and placebo capsules for our previous study and will 
provide both the resveratrol and placebo capsules for the proposed study. Placebo capsules will be 
identical to those including resveratrol. Our 12-week resveratrol pilot study demonstrated that 
resveratrol supplementation at a dose of 1000 mg/day was safe and improved markers of 
metabolic function (i.e., blood glucose) in overweight, older adults. This dosage is also in line with 

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another recent pilot study by Crandall et al. (2012) which demonstrated safety and improvements 
in glucose metabolism and insulin sensitivity in older adults (mean age = 72 years) following 1000 
mg/day of resveratrol.25 The low dose has been previously shown to be sufficient for improving 
mitochondrial function3 and will allow for comparison with findings from the only human study of 
REX to our knowledge published to date.26,27   
 
Data from the exercise interventions will be collected and stored in the study database. Following each 
session, participants will be asked to provide a rating of perceived exertion (RPE) for the session 
according to the Borg CR10 scale. Additional data collected includes session attendance, 1 repetition 
maximum, and repetitions completed for each exercise per session.  
 
6.6 Adherence to interventions. To enhance adherence to the study interventions (compliance), we will 
utilize empirically-supported techniques which we have successfully utilized in prior studies. Our first 
step will to fully inform participants of study requirements before randomization and enroll only those 
persons who are willing to complete all study procedures. Undoubtedly, however, issues arise after 
randomization with the potential to limit compliance. Common causes of poor compliance include 
vacations, spouse care, fatigue, and fluctuations in motivation, perceived lack of benefit, physical 
discomfort, and adverse health experiences. First, we have designed the trial, including the 
inclusion/exclusion criteria and physician monitoring, to limit the likelihood of experiencing adverse 
health events in response to the interventions. In addition, care will be taken by the interventionists to 
promote the safe engagement in the exercise intervention. For other issues of non-compliance, we will 
approach this potential problem using a social problem solving model (“toolbox”) approach in dealing 
with individual adherence problems.28 This approach assumes that the process of changing behavior is 
a collaborative effort between the participant and the interventionists, and that behavior change can be 
readily undertaken during the regular weekly contacts that intervention staff will initiate throughout the 
course of the intervention, as well as during face-to-face visits. Our team has successfully applied this 
type of problem-solving approach in promoting adherence to behavioral interventions in prior studies. 
 
6.7 Follow-up and Close-out visits. In addition to baseline and screening visits, assessment visits will be 
conducted at 6 weeks (follow-up) and 12 weeks post-randomization. During the 6-week assessment 
visit, the research team will evaluate participant vital signs, collect blood samples, inquire about any 
adverse experiences since the last visit, and perform tests of physical performance evaluated 
performed at baseline. During the close-out (12 week) visit, the team will perform the same evaluations 
as during the 6-week visit, as well as administer study questionnaires, perform the SPPB, and collect 
home-based physical activity and dietary information from participants. Skeletal muscle biopsies will 
also be collected at 12 weeks from willing participants.  
 
6.8. Primary and Secondary Outcome Measures.  
Walking 
speed 
We will assess walking speed by asking the participants to walk at their usual pace 
over a 4 m course. Participants will be instructed to stand with both feet touching the 
starting line and to start walking after a specific verbal command. Timing will begin 
when the command is given, and the time needed to complete the entire distance will 
be recorded. The faster of two walks will be used. The reliability of the 4 m walk test is 
excellent – with an intraclass correlation coefficient (ICC) > 0.9.29  
Lower-
extremity 
function 
(SPPB) 
The SPPB is based on the 4m walk (above), repeated chair stands and a balance test. 
This test is reliable30 and valid for predicting institutionalization, hospital admission, 
mortality and disability.31,32-34 Each task is scored from 0 to 4, with 4 indicating best 
level of performance and 0 the inability to complete the test. A summary score (0-12) 
is then calculated. 

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6.9 Mitochondrial Outcome Measures.  
Measurement of skeletal muscle (1) in situ mitochondrial respiration, (2) proliferative activated receptor-
γ coactivator 1α (PGC-1α), (3) mitochondrial DNA, (4) citrate synthase (CS) activity, and (5) 
cytochrome C oxidase (COX) activity will be completed the OAIC Metabolism and Translational 
Science Core, led by co-investigator Dr. Christiaan Leeuwenburgh. Mitochondrial respiration will be 
determined immediately on freshly saponin-permeabilized muscle fibers as published previously8 using 
the high-resolution Oxygraph-2k (Oroboros, Innsbruck, Austria). Skeletal muscle PGC-1α, 
mitochondrial DNA content, as well as CS and COX activities will be determined using well-
standardized, validated methods with excellent test re-test reliability in the Core laboratory.42 
 
6.10 Sample size justification. This study will help generate precise estimates of effect variance in 
the population in which a subsequent larger-scale study will be conducted. Published 
recommendations for the design of pilot studies indicate that a sample of 15-20 participants per 
randomized arm is typically sufficient to estimate a parameter for a future trial.43-45 The enrollment 
sample of 60 participants is intended to provide preliminary data necessary to indicate feasibility of 
a larger trial and to provide descriptive estimates of effects. It will also provide for nominal 
estimation (using a 95% CI) of mean changes in dependent variables within each arm. While it is 
possible that statistically significant differences between arms may be observed, this pilot trial is not 
intended to be powered to observe such differences with high probability. For aims 1 and 2, assuming 
α = 0.05, we will have 80% power to detect an effect size of 0.74 for outcomes with three 
assessments (walking speed, muscle function, exercise capacity) and 0.79 for outcomes with two 
assessments (SPPB, self-assessed function, mitochondrial measurements), assuming a repeated 
measures correlation of 0.5. For the primary outcome of walking speed, we expect this detectable 
difference to be 0.12 m/sec based on a SD of 0.16 m/sec observed in the LIFE studies. For 
secondary aims, the following detectable effects sizes are expected based on our prior experience 
in LIFE and LIFE-P: SPPB, 1.3 points; 6-minute walk distance, 22.2 m; isokinetic peak torque, 27.8 
Nm; and Late Life Disability Instrument Score; 3.8 points.  
 
6.11 Safety monitoring plan. To ensure participant safety in the proposed study, we will adapt procedures 
that we have implemented successfully in other studies including LIFE,46,47 Weight Loss + Exercise,48 and 
Task Specific Exercise.49 As he has for a number of our prior studies, Dr. Bhanuprasad Sandesara will 
serve as the Study Physician who is responsible for assessment, monitoring and interventions for health 
events. To maximize participant safety we will follow a standardized screening protocol. Accordingly, all 
Skeletal 
muscle 
function 
Isokinetic strength and endurance of the knee flexors and extensors of the dominant 
limb will be assessed by a standard dynamometer as published previously.35,36  
Exercise 
capacity 
We will assess exercise capacity of participants using the six-minute (6-min) walk test, 
a safe and reliable test of aerobic endurance in older persons and those with 
cardiovascular conditions.37,38 This test has strong reproducibility, with intra-subject 
coefficients of variation averaging < 10%, and has a modest correlation with peak 
VO2.39 Participants will be asked to walk as far and fast as possible for 6-min on a 60 
m track. 
Self-
assessed 
physical 
function 
We will document self-assessed functional status using the Late Life Function and 
Disability Instrument.40,41 The instrument includes 16 tasks representing a broad range 
of disability indicators that assesses both frequency of doing a task and perceived 
limitation. The instrument uses a scale from 0 to 100, with higher scores indicating 
higher levels of function. The scale has strong concurrent and predictive validity with 
physical performance.24  

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potential participants will undergo screening for cardiovascular and other major diseases by means of a 
health questionnaire, medication inventory, and physical exam. Those with conditions that meet the 
exclusion criteria described in section 6.1 as determined by Dr. Sandesara will be excluded. Dr. 
Sandesara will also review clinically significant abnormal laboratory values and indicate the need for 
study withdrawal if he deems it necessary. Each participant will be instructed to report the occurrence of 
an adverse event at scheduled data collection times (scheduled clinical exams or phone interviews). 
Participants also have access to study clinic personnel at other times to report serious adverse events or 
concerns about the safety of participating in the study. If necessary, Release of Medical Records 
Authorizations signed by the study participants will be used to obtain medical records to collect details 
and outcomes of SAEs for safety and reporting purposes. 
Venipuncture will be performed by a trained and experienced phlebotomist using standard techniques. 
Participants will always have venipuncture performed while seated upright with both feet on the floor. 
Muscle biopsies will be performed by a licensed physician trained in the technique. A detailed description 
of the procedure is provided below. 
Muscle Biopsy Procedure – Vastus Lateralis 
• 
Participant should lie comfortably in a reclined position with both legs outstretched. Support can 
be added for calves/feet with pillows to maintain relaxed position 
• 
The participant is asked if they are allergic to latex, and if so, alternative material gloves must be 
used. 
• 
The muscle biopsy will be obtained approximately midway between the patella and iliac crest on 
the lateral thigh. See figure below. This distance was chosen so each participant will receive the 
biopsy at the same relative length of their lower extremity.  
 
• 
If necessary, an area of skin can be shaved to prevent hair from entering the incision and to 
improve adhesion of the sterile bandage 
• 
The skin is cleaned with an alcohol-based solution such as ChloraPrep® Swab, starting from 
the anticipated biopsy site in a circular motion extending to a diameter of approximately 4-5 
inches. 
• 
1 to 2 ml of 2% lidocaine is injected intradermally and subcutaneously. A brief period (i.e. 30-60 
seconds) allows for the skin to numb before injecting the remaining volume more deeply. The 
needle is inserted to just below the fascia, a small amount of lidocaine is injected starting below 
the fascia and injection is continued while the needle is drawn straight up through the 
subcutaneous tissue. This step is repeated in a star pattern.  
• 
8 to 10 minutes are allowed to pass after injection of the lidocaine before proceeding, to ensure 
maximal participant comfort. 
• 
Scalpel skin test: Using a blade scalpel, gently touch the scalpel to the anticipated site and ask 
the patient if they can feel anything where touched. It may help to have the patient close their 

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eyes. If they can feel the scalpel, allow more time and retest in 5 minutes. If the participant can 
still feel the blade touch, consider switching to carbocaine. 
• 
When the participant’s area of the leg is properly numbed, approximately 5 mm incision is made 
in the skin down through the muscle fascia.  The biopsy needle trocar is inserted through the 
incision, and through the fascia, advancing it into the muscle belly to obtain the muscle sample.  
If the yield is insufficient with study participant’s consent the trocar may re-inserted up to three 
times through the same hole in the fascia but at slightly different angles in the numbed area, as 
long as the participant is comfortable. 
• 
After completing the procedure, the study physician holds firm direct pressure over incision site 
for at least 5 minutes or longer until external bleeding has ceased. He/she then closes the 
incision with a sterile liquid bonding agent (such as Dermabond) or butterfly bandage. This will 
help prevent bleeding and scarring. Finally, the physician will apply a small amount of antibiotic 
and a sterile gauze pad over the incision and cover with a waterproof transparent dressing.  
The study participant will be provided with detailed instructions (discussion and a leaflet) on how to take 
care of the incision site. Study staff will make follow-up phone calls in the days following the procedure 
to monitor healing and any potential adverse events. 
Center-based assessments and interventions will be conducted and supervised by trained staff who will 
monitor potential adverse experiences and symptoms. All assessors and interventionists receive CPR 
training and training on management of acute events including syncope, chest pain, acute dyspnea, focal 
neurological symptoms and abnormal vital signs. Portable defibrillators are available at each intervention 
and assessment site and all study staff have on-call access to the study physician and contact numbers 
for emergency services are. Institutional and community EMS services will be activated if needed. As 
indicated previously, participants will be taught the importance and proper method of warming-up prior to 
and cooling-down following structured activity sessions. If at any point during an exercise session, 
participants develop chest pain, shortness of breath, or dizziness, they will be instructed to rest and to 
contact the center and their physicians if these symptoms persist or recur with further exercise.  
Blood pressure and heart rate will be measured before and after the resistance training at each center 
based session in participants who had experienced any of the following during a previous exercise 
session: decrease in diastolic blood pressure 20 mm Hg during the activity, increase in systolic blood 
pressure to 250 mm Hg or in diastolic blood pressure 115 mm Hg during the activity, increase in heart 
rate 90% of age predicted maximum, unusual or severe shortness of breath, chest pain or discomfort, 
palpitations, light headedness, dizziness or feeling about to faint, a session had to be discontinued 
because of other symptoms, excluding musculoskeletal symptoms (e.g., knees, ankles, hips), reported by 
the participant.  
 
Procedures to minimize discomfort include warm-up and cool-down activities that include cycling and 
flexibility exercises. The participants will also be introduced to the intervention exercises in a structured 
way, such that they begin with lighter resistance and gradually increase over the course of the first 2-3 
wks. During the intervention visits, participants will be supervised at all times and instructed on correct 
exercise techniques. Participants will also be instructed to move slowly when rising from a seated or lying 
position to reduce the risk of experiencing orthostatic hypotension. Study staff will be instructed to stand 
in a supportive position when participants are rising to prevent a fall in case of syncope. Participants will 
be instructed to talk with the interventionists about any muscle soreness. Exercise will be stopped if the 
participant reports pain, tightness or pressure in the chest, significant shortness of breath, feeling faint, 
lightheaded or dizzy, or significant other medical problems.  
Any significant adverse events will be reported promptly to the IRB and to the OAIC Data Safety 
Monitoring Board (DSMB). Otherwise, annual reports will be prepared for both. The OAIC DSMB 
consists of an established board which has reviewed all studies conducted within the University of 
Florida’s Pepper center during bi-annual conference calls for the past seven years. This board consists 

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of the following individuals: (1) Stephen Kritchevsky, Ph.D., Chair, an epidemiologist who has been 
involved in research for many years, (2) Jing Cheng, Ph.D., a biostatistician who has been involved 
with a number of clinical trials, and (3) John Meuleman, M.D., a physician who has been involved in the 
conduct of clinical research for many years.   
Again, written informed consent will be obtained after explanation to subjects of all procedures and time 
commitments. The study interviewers will explain to prospective participants the purpose, methods and 
extent of the study. Potential participants will be asked to read the informed consent form and to ask 
questions. The form will be written in simple, easy-to-understand language. Staff members will also 
review all key aspects of the study verbally.  
Confidentiality of data will be maintained by using research identification numbers that uniquely identify 
each individual. Data will be used only in aggregate and no identifying characteristics of individuals will 
be published or presented. Safeguards will be established to ensure the security and privacy of 
participants’ study records. The information collected from participants in this study has a low potential 
for abuse, since the data do not address sensitive issues. Nevertheless, appropriate measures will be 
taken to prevent unauthorized use of study information. The research records will be kept in a locked 
room at the Institute on Aging. The files matching participants' names and demographic information 
with research ID numbers will be kept in a separate room and will be stored in a locked file that uses a 
different key from that of all other files. Only study personnel will have access to these files, and they 
will be asked to sign a document that they agree to maintain the confidentiality of the information. 
After the study is completed, local data will be stored with other completed research studies in a 
secured storage vault. In compliance with the Health Insurance Portability and Accountability Act 
(HIPAA) and the Standards for Privacy of Individually Identifiable Health Information of the Department 
of Health and Human Services, we will access personal health information and medical records only 
after receiving signed informed consent, as described above.  
Finally, the study protocol will be registered at www.ClinicalTrials.gov before study enrollment begins. 
7. Possible Discomforts and Risks: 
Potential risks are those associated with health information privacy, venipuncture, muscle biopsies, and 
participation in exercise training and testing.  
Venipuncture can be associated with pain, bruising, hematoma formation, superficial phlebitis, and rarely 
cellulitis or fainting. The potential risks of the muscle biopsy procedure include infection, mild muscle 
soreness, scarring from the incision, mild nerve damage, swelling, and bleeding. The primary risk 
associated with moderate-intensity exercise training is skeletal muscle soreness. There are also other 
risks that relate to soft tissue injury, falls and fractures, exacerbation of arthritis and other joint conditions, 
post-exercise hypotension, and cardiovascular events.  There is a risk that a participant may trip, stumble, 
or fall during the physical performance tests and experience shortness of breath, dizziness, palpitations, 
chest pain or discomfort, heartburn, light headedness, or feeling about to faint. Strength training may 
involve a minimal risk of increasing intraocular and systemic pressures associated with use of the 
Valsalva maneuver to levels that may cause injury.  
8. Possible Benefits: 
Importantly, the proposed project should have tangible benefits for participants. These benefits include 
information about their health and assessments of their functional status. All study participants will be 
encouraged to communicate the results from the study to their primary care providers. Moreover, all 
participants – regardless of randomized group– will receive supervised exercise training and instruction 
about how to maintain exercise habits at home. We expect that these benefits will improve quality of life 
for all participants.    

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9. Conflict of Interest: 
Dr. Anton, a Sub-Investigator, is a paid adviser to Reserveage Organics that makes the 
resveratrol product that will be used in the study. 
 
 

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