Metformin Treatment in Old Rats and Effects on Mitochondrial Integrity

Abstract

Metformin, a commonly used well-tolerated treatment for type 2 diabetes, is being deployed in clinical trials to ameliorate aging in older nondiabetic humans. Concerningly, some experiments in model organisms have suggested that metformin use at old ages shortens life span and is toxic to mitochondria. The demonstrated safety of metformin therapy in humans and the conflicting data from model organisms compelled us to test the hypothesis that metformin treatment would be toxic to older rats. To define an effective dose in 30-month-old hybrid rats, we evaluated two doses of metformin (0.1%, 0.75% of the diet) and treated the rats for 4 months. Body mass decreased at the 0.75% dose. Neither dose affected mortality between 30 and 34 months of age. We assessed mitochondrial integrity by measuring mitochondrial DNA (mtDNA) copy number and deletion mutation frequency, and mitochondrial respiration in skeletal muscle and the heart. In skeletal muscle, we observed no effect of metformin on quadriceps mass, mtDNA copy number, or deletion frequency. In the heart, metformin-treated rats had higher mtDNA copy number, lower cardiac mass, with no change in mtDNA deletion frequency. Metformin treatment resulted in lower mitochondrial complex I-dependent respiration in the heart. We found that, in old rats, metformin did not compromise mtDNA integrity, did not affect mortality, and may have cardiac benefits. These data provide some reassurance that a metformin intervention in aged mammals is not toxic at appropriate doses.