Metformin extends C. elegans lifespan through lysosomal pathway

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.

Axin-mediated regulation of lifespan and muscle health inC. elegansinvolves AMPK-FOXO signaling

“…Thus, together with experiments involving genetic interactions, AAK-2::GFP expression, and pry-1 and aak-2 transcriptome analysis, the results collectively support the model of PRY-1 and AAK-2 functioning together, potentially forming a complex, to regulate DAF-16 activity for the maintenance of lifespan. It was reported previously that AXL-1, another Axin homolog in C. elegans, interacts with AAK-2 following Metformin treatment, although axl-1 mutants have no age-related phenotypes of their own (Chen et al, 2017). Thus, our work demonstrates that PRY-1 is the sole Axin family member in worms regulating lifespan as well as muscle health.…”

“…In this study, we report that the C. elegans Axin homolog PRY-1, which is necessary for the embryonic and larval processes, is also essential for the normal lifespan maintenance. Previously, metformin-mediated lifespan extension was shown to depend on another C. elegans Axin-like gene, axl-1, however, axl-1 does not play a role in aging and age-related processes (Chen et al, 2017). We found that animals lacking pry-1 function during adulthood had a shorter lifespan, which was due to deterioration in associated processes as judged by the analysis of age-linked markers.…”

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…Metformin, a biguanide used as a first-line drug for treating type 2 diabetes [138], was shown to extend the lifespan of C. elegans [139][140][141], D. melanogaster [142], and mice [143,144]. Moreover, it was shown to delay the onset of age-related diseases, such as cancer, metabolic syndrome [145], and cognitive disorders [146]. Its mechanism of action is associated with the activation of 5 AMP-activated protein kinase (AMPK) [147,148], inhibition of the mammalian target of rapamycin (mTOR) [149], reduction of DNA damage [150,151], and decreased insulin levels and IGF-1 signaling [152][153][154].…”

Metformin Modulates the Mechanisms of Ageing

“…Finally, a very recent pathway has been described by Chen et al [140]. The authors showed through genetic manipulation that metformin extends the Caenorhabditis elegans lifespan and attenuates age-related fitness decline via a mechanism that requires v-ATPase-Ragulator-AXIN/LKB1 of the lysosomal pathway [140].…”

“…In toto, the possible molecular mechanisms by which metformin exerts antiageing effects are [13, 91]: (1) inhibition of mitochondrial complex 1 in the electron transport chain and decrease of ROS production [139,141], (2) activation of AMPK [106,124,140,[142][143][144], (3) inhibition of mTOR [106,134,135,140], (4) NF-ĸB inhibition [101], and (5) reduced IGF-1 signalling [145].…”