Metformin extends C. elegans lifespan through lysosomal pathway

Area of Science:

• Cell Biology
• Metabolism
• Aging Research

Background:

• Metformin is a first-line T2D drug with known lifespan-extending properties.
• The precise molecular targets and mechanisms underlying metformin's effects on aging are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanism by which metformin extends lifespan.
• To identify the primary cellular pathway through which metformin exerts its effects on metabolic regulation and aging.

Main Methods:

• Utilized an in vitro reconstitution system to study metformin's action.
• Employed Caenorhabditis elegans models to investigate metformin's effects in vivo.
• Analyzed the interplay between metformin, v-ATPase, Ragulator, mTORC1, and AMPK signaling pathways.

Main Results:

• Demonstrated that metformin acts via the v-ATPase-Ragulator lysosomal pathway.
• Showed that metformin coordinates the activity of mTORC1 and AMPK, key metabolic regulators.
• Confirmed that v-ATPase-mediated mTORC1 inhibition and AMPK activation contribute to metformin's lifespan extension in C. elegans.

Conclusions:

• Metformin's healthspan-extending effects are mediated by the lysosomal v-ATPase-Ragulator pathway.
• This pathway coordinates mTORC1 and AMPK, offering a unified mechanism for metformin's action.
• Understanding this mechanism can enhance therapeutic applications of metformin for human aging and age-related diseases.