Mitochondrial Uncoupler BAM15 Modestly Extends Life in Flies

BAM15 is the result of attempts to produce a safe drug that induces mitochondrial uncoupling. Too much mitochondrial uncoupling will cause death by overheating, but modest degrees of this process can improve health and induce weight loss, as demonstrated in humans by the 20th century use of the somewhat dangerous mitochondrial uncoupler DNP. Here, researchers demonstrate a small extension of life in flies resulting from treatment with BAM15. Short-lived species exhibit a much greater plasticity of life span in response to interventions, so one shouldn't expect long-lived mammals such as humans to see any meaningful change in life span based on this work. Still, mitochondrial uncoupling does produce health benefits, provided it is constrained to a safe level.

Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age-related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle-aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity, citrate synthase, mitochondrial DNA content, gene expression, and protein expression were assessed in flight muscle homogenates of middle-aged flies fed vehicle or BAM15 ND.

The molar ratio of H2O2 and O2 (H2O2:O2) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity. Concurrently, BAM15 enhanced the mitochondrial H2O2 production rate, reverse electron flow from mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H2O2:O2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense.

In conclusion, BAM15-mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity.