Mitochondrial action of metformin in aging and longevity

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A growing body of evidence suggests that metformin effects on mitochondria are responsible for its ability to lower blood glucose and reduce the growth and incidence of cancer. In model systems, metformin prolongs lifespan, and observational studies in humans similarly suggest a longevity benefit for patients who take metformin. In spite of recent progress in the biology of metformin action, the mechanisms by which metformin exacts favorable effects on longevity and aging remain incompletely characterized. Our recent work provides evidence that metformin targets multiple, fundamental aspects of the aging process. In particular, we have shown that metformin-mediated inhibition of mitochondrial energetics restrains transport through the nuclear pore complex (NPC). Restrained NPC transport locks the pro-aging kinase mTORC1 in the inactive state. It is known that many cells obtain a “leaky” nucleus as they age, and our work is the first suggestion that metformin can target this leakiness through action on mitochondria. Our preliminary data and published studies indicate that metformin can also target mitochondrial leakiness that is mechanistically linked to aging. These exciting observations suggest that metformin is positioned to reverse multiple, pathological cellular changes that occur with aging. In doing so, the drug is poised to fulfill the geroscience principle: by reversing fundamental aspects of the aging process, metformin may target not one but many aging-associated diseases simultaneously. In spite of this tantalizing possibility, critical gaps in our knowledge remain that prevent us from fully realizing the therapeutic potential of metformin. In which tissues is metformin action needed to promote longevity? How are metformin effects at mitochondria transduced to effectors that mediate the drug’s geroprotective effects? What is the full spectrum of molecular events required for metformin effects in aging? The overall objective of this application is to determine the sites and mechanisms of metformin action in aging. The central hypothesis of this proposal is that metformin promotes healthy aging by targeting mitochondrial energetics in specific tissues, which signals through downstream effector pathways to promote longevity. The rationale for this work is that completion of the project will illuminate both specific effector sites of the drug and unexpected elements of the metformin response pathway. In Aim 1 we will define mechanisms by which metformin targets mitochondria to promote longevity. Aim 2 will characterize mechanisms by which metformin reduces mitochondrial permeability in aging. In Aim 3, we will probe a larger landscape of metformin response genes in order to understand the full spectrum of metformin’s direct and indirect cellular effects in aging. This project is significant because it will elucidate the molecular mechanisms by which biguanides mediate their positive effects on lifespan. We put forth conceptual and technical innovations that will allow discovery of the most important aspects of the response to metformin. Successful completion of this project will pave the way for a new generation of strategies that can promote healthy aging and reduce the onset and severity of aging-related diseases.