Genetic mechanisms of metformin's pro-longevity and anti-cancer effects

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Metformin, best known as first line therapy for type 2 diabetes, also has myriad health benefits, including prolonging lifespan in model systems, and reducing cancer incidence and death. Although it is widely accepted that mitochondria are a primary site of metformin action, the mechanisms by which metformin promotes health downstream of mitochondria are not well understood. Our recent work provides an important clue about the mechanism of action of metformin in aging and cancer. We have shown that biguanides, the class of drug that includes metformin and the related drug phenformin, inhibit mitochondrial respiratory capacity, which restrains transit of the RagA/RagC heterodimer through the nuclear pore complex (NPC). RagC is thereby locked in the “off” state and is unable to activate mTORC1. The lack of mTORC1 activity in this context activates acyl-CoA dehydrogenase family member 10 (ACAD10), which is necessary and sufficient for metformin to extend lifespan and block growth in human cancer cells. However, critical gaps in our knowledge remain that prevent us from fully realizing the therapeutic potential of metformin. How do metformin effects on the mitochondria modulate NPC activity? What is the full spectrum of metformin effects on the NPC? How does ACAD10 modulate lifespan and control growth? There is a critical need to understand the full range of metformin's molecular effects in order to enable more intelligent therapies for cancer and aging-related diseases. The overall objective of this application is to determine the mechanisms by which metformin effects are translated into positive effects on health. The central hypothesis of this proposal is that metformin effects on mitochondria promote health by large-scale alteration of nuclear transport and induction of ACAD10-dependent metabolites. The rationale for this work is that completion of the project will illuminate unexpected elements of the metformin response pathway as therapeutic targets in aging and cancer. In Aim 1 we will determine the mechanisms by which metformin action are enhanced at mitochondria to enact changes in NPC transport. Aim 2 will fully characterize metformin effects on nuclear transport and their significance in aging and cancer. In Aim 3, we will identify the molecular mechanism by which ACAD10 drives positive health effects in response to biguanides. This project is significant because it will elucidate the molecular mechanisms by which biguanides mediate their positive effects on lifespan and on blocking cancer cell growth. We put forth conceptual and technical innovations that will allow unbiased genetic discovery of the most important aspects of the response to metformin. This project will leverage facile genetic discovery across model systems and ultimately validate our main hypothesis in animals and human cancer cells. Successful completion of this project will inform alternative ways to derive the health promoting benefits of biguanides without untoward effects, paving the way for a new generation of cancer therapeutics and agents that can reduce the onset or severity of aging related diseases.