Diet and Exercise Plus Metformin to Treat Frailty in Obese Seniors

Inclusion Criteria:

• BMI = or > 30 kg/m2

• Stable body weight (plus/minus 2 kg) during the past 6 months

• Sedentary (regular exercise <1 h/wk or <2 x/wk for the last 6 months)

• Willing to provide informed consent

Exclusion Criteria:

• Any major chronic diseases, or any condition that would interfere with exercise ordietary restriction, or use of metformin, in which exercise, dietary restrictions,or metformin are contraindicated, or that would interfere with interpretation ofresults

• Cardiopulmonary disease (e.g. recent MI, unstable angina, stroke) or unstabledisease (e.g., NYHA Class III or IV congestive heart failure, severe pulmonarydisease requiring steroid pills or the use of supplemental oxygen) that wouldcontraindicate exercise or dietary restriction

• Severe orthopedic (e.g. awaiting joint replacement) and/or neuromuscular (e.g.multiple sclerosis, active rheumatoid arthritis) disease or impairments that wouldcontraindicate participation in exercise

• Renal impairment as defined by an estimated glomerular filtration rate (eGFR of lessthan 30 mL/min/1.73 m2) in which metformin is contraindicated

• Other significant co-morbid disease that would impair ability to participate in theexercise intervention (e.g. severe psychiatric disorder [e.g. bipolar,schizophrenia], excess alcohol use [>14 drinks per week])

• Severe visual or hearing impairments that would interfere with following directions

• Significant cognitive impairment, defined as a known diagnosis of dementia orpositive screening test for dementia using the Mini-Mental State Exam (i.e. MMSEscore <24)69

• Uncontrolled hypertension (BP>160/90 mm Hg)

• History of malignancy during the past 5 years (except non-melanoma skin cancers)

• Current use of bone acting drugs (e.g. use of estrogen, or androgen containingcompound,raloxifene, calcitonin, parathyroid hormone during the past year orbisphosphonates during the last two years)

• Osteoporosis (T-score -2.5 and below on hip or spine scan) or history of fragilityfractures

• Known history of diabetes mellitus or any of the following:

• fasting blood glucose of 126 mg/dl, 2-h blood glucose 200 mg/dl in the OGTT, orHbA1c of 6.5% or >

• Terminal illness with life expectancy less than 12 months, as determined by aphysician

• Use of any drugs or natural products designed to induce weight loss within pastthree months

• History of excessive alcohol consumption (e.g. 8 or more drinks a week for women and 15 or more drinks a week for men)

• Positive exercise stress test for ischemia or any indication for early terminationof exercise stress testing

• Taking metformin or any other glucose lowering drug

• Lives outside of the study site or is planning to move out of the area in the next 2years