# Metformin modulates the unfolded protein responses, altering lifespan and health-promoting effects in UPR-activated worms

## TL;DR

Metformin affects the unfolded protein response in worms, influencing lifespan and stress resistance in complex ways.

## Contribution

The study reveals metformin's differential modulation of UPRmt and UPRer in worms and its inconsistent effects on lifespan and stress resistance.

## Key findings

- Metformin extended lifespan in wild-type and UPRmt-activated worms without compromising UPRmt.
- Metformin suppressed UPRer in some worms but failed to induce lifespan extension in others.
- UPR activation improved worm movement, but metformin did not consistently correlate with stress resistance or locomotion.

## Abstract

Metformin has been demonstrated to extend lifespan in various model organisms, and its molecular effects are observed in the cytoplasm and multiple organelles, including mitochondria. However, its association with the unfolded protein response (UPR) and its impact on stress resistance and locomotion remain uncertain. In this study, metformin was found to exert differential influences on both UPRmt and UPRer. The correlation between metformin’s lifespan-mediating effect and its interaction with UPRs was also inconsistent. We identified a metformin-mediated lifespan extension in wild-type C. elegans and in UPRmt-activated tomm-22 and cco-1 RNAi worms. Metformin suppressed the UPRmt without compromising the lifespan extension observed in tomm-22 worms. Conversely, metformin did not affect the UPRmt but extended the lifespan of long-lived cco-1 RNAi worms. Furthermore, we investigated the effects of metformin on UPRer-activated nematodes. We observed that metformin exhibited a slight increase in the UPRer in mdt-15 RNAi worms and failed to induce lifespan extension. Surprisingly, metformin appeared to mediate lifespan extension in tmem-131 RNAi worms while suppressing the UPRer. Notably, the correlation between thermotolerance, oxidative stress resistance, and the lifespan effects of metformin in UPR-activated worms was inconsistent. Activation of UPRs, but not metformin treatment, enhanced the locomotor phenotype of these worms.