Antecedent Metabolic Health and Metformin Aging Study

Aging is the number one risk factor for the majority of chronic diseases. There are no pharmaceutical treatments to slow aging and prolong healthspan. The anti-diabetic drug metformin is considered a likely pharmaceutical candidate to slow aging. In this study, the investigators hypothesize that metformin treatment in subjects free of type 2 diabetes will improve insulin sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and glucoregulation in insulin sensitive subjects. Further, the investigators hypothesize that long-term metformin treatment will remodel mitochondria in a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial function in subjects that are insulin resistant. The investigators will use a dual-site, 12- week drug intervention trial performed in a double-blind, placebo-controlled manner on 148 subjects recruited from two separate sites (Oklahoma Medical Research Foundation (OMRF) and University of Wisconsin-Madison (UWM)). After consent and initial subject screening for chronic disease, subjects will be stratified to insulin sensitive (IS) or insulin resistant (IR) groups. Over a 12- week intervention, half of each group will take metformin and half will take a placebo. Pre- and post--intervention, subjects will complete a series of procedures to assess insulin sensitivity, glucose regulation, and biomarkers of aging. The same subjects will provide a skeletal muscle biopsy pre-- and post-intervention to assess the change in mitochondrial function and mitochondrial remodeling with and without metformin treatment. By completion of this project, the investigators expect to provide evidence that helps further delineate who may benefit from metformin treatment to slow aging.

Inclusion Criteria: * 40-75 years of age (inclusive) * Free of chronic disease * Comprehension of the protocol as indicated by an ability to respond to questions about the study after reading the consent form. * Able to use and be contacted by telephone. * Able to speak, read, and understand English, and complete a questionnaire in English * Independently mobile Exclusion Criteria: * Pregnancy * Heart disease (history, abnormal ECG, abnormal stress ECG) * Cerebrovascular disease (history) * Cancer (history) * Chronic respiratory disease (history, forced expiratory volume at one second/forced vital capacity \[FEV1/FVC\] \< 70, FEV1 \< 80% predicted) * Chronic liver disease (history, alanine transaminase \[ALT\] \> 52 IU/L) * Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, oral glucose tolerance test \[OGTT\] ≥ 200 mg/dl at 2 hrs) * Impaired kidney function (eGFR ,45 mL/min) * B12 lab values outside of normal range (\982 pg/mL) * Alzheimer's (history) * Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine \> 1.4) * Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy) * Those on glucose lowering drugs * Those planning to have imaging that requires intravenous contrast dye (within 6 weeks) or are on any of the following medications since they are contraindicated with the use of metformin: Dofetilide, Lamotrigine, Pegvisomant, Somatropin, Trimethoprim, Trospium, Gatifloxacin, Cephalexin, Cimetidine, Dalfampridine * Tobacco use * Allergies to lidocaine or metformin