Abstract
Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin. Elucidating the molecular mechanism of metformin regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.
Highlights
With the discovery that aging could be genetically regulated, numerous strategies have been employed to extend lifespan in model organisms, including pharmacologic and dietary interventions (Longo et al, 2015)
Intrigued by the discoveries that mechanistic target of rapamycin complex 1 (mTORC1) and AMPK share the common activator, v-ATPase-Ragulator complex (Zhang et al, 2014), and that metformin may directly act on the lysosomal pathway to promote AMPK activation (Zhang et al, 2016), we sought to set up a pure in vitro reconstitution system to explore the mechanism of metformin’s action (Figure 1)
To test if metformin’s effect on mTORC1 inhibition requires AMPK or not, we repeated the in vitro experiments in AMPK knockout MEF cells, and still observed the dissociation of Raptor (Figure 1—figure supplement 1). These results suggest that metformin inhibits mTORC1 through the lysosomal pathway independent of AMPK, possibly mimicking Concanavalin A (Con A) to inhibit v-ATPase
Summary
With the discovery that aging could be genetically regulated, numerous strategies have been employed to extend lifespan in model organisms, including pharmacologic and dietary interventions (Longo et al, 2015). Identification of a chemical or pharmacological manipulation that could target human aging and lower the risks associated with age-related diseases becomes a central goal of aging research. Administration of metformin, a first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan in C. elegans and mice (Anisimov et al, 2008; Cabreiro et al, 2013; De Haes et al, 2014; Martin-Montalvo et al, 2013; Onken and Driscoll, 2010; Wu et al, 2016). Metformin lowered the incidence of several other age-related diseases, such as cancer, metabolic syndrome and cognitive disorders (Foretz et al, 2014). Due to its broad range of health benefits and little side effects, a clinical trial named TAME (Targeting Aging with Metformin) was proposed to evaluate metformin’s protective effects against human aging and age-related diseases (Barzilai et al, 2016). Despite its intriguing benefits to promote healthy aging, the underlying mode of action of metformin is not well understood and a subject of extensive debate
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