Phenformin’s impact on lifespan inC. elegansis resilient to environmental factors that inhibit metformin-induced longevity downstream ofskn-1/Nrf and AMP-activated protein kinase

Abstract

AbstractDespite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models, and to reduce the impact of aging-associated diseases such as cancer. While there have been conflicting results in studies involving rodents and humans, consistent evidence from laboratories worldwide, including our own, indicates metformin and phenformin’s ability to significantly extend lifespan inC. elegans. However, the pro-longevity effect of metformin can vary depending on environmental conditions. Specifically, the choice of agar from different manufacturers or batches influences metformin’s ability to extend lifespan inC. elegans. We traced ability of certain agar batches to interfere with metformin-prompted lifespan extension to the presence of a factor that acts directly in the worm, independently of the bacterial food source, that prevents longevity promoting effects downstream of longevity effectorsskn-1and AMPK. In contrast, phenformin prompts robust lifespan extension in the face of environmental changes and exhibits broad positive effects in aging across genetically diverseCaenorhabditisspecies where the impact of metformin is highly variable. Thus metformin effects in aging are impacted by heretofore unappreciated environmental factors. Phenformin may represent a more robust agent with which to understand the longevity promoting mechanisms downstream of biguanides.