Metformin Reshapes Cellular Stress Responses to Extend Worm Lifespan

Metformin, the world's most prescribed diabetes drug, has attracted intense interest as a potential longevity compound. Prior work in C. elegans and mice showed it can extend lifespan, but the precise cellular mechanisms—particularly its relationship to protein quality-control stress responses—remained poorly understood. This study set out to map how metformin interacts with two major stress-response systems: the mitochondrial unfolded protein response (UPRmt) and the endoplasmic reticulum unfolded protein response (UPRer).

The team used RNA interference to knock down four genes—tomm-22, cco-1, mdt-15, and tmem-131—each of which constitutively activates either UPRmt or UPRer while also shortening or lengthening worm lifespan. Fluorescent reporter strains (hsp-6::GFP for UPRmt; hsp-4::GFP for UPRer) allowed direct visualization of stress-pathway activity. Lifespan, thermotolerance, oxidative stress resistance, and locomotion were all measured with and without 50 mM metformin treatment.

Metformin extended lifespan in wild-type N2 worms and in tomm-22, cco-1, and tmem-131 knockdown worms, but shortened lifespan in mdt-15 knockdown worms. Critically, the direction of metformin's effect on UPR activation did not predict its effect on lifespan: in tomm-22 worms, metformin suppressed UPRmt yet still extended lifespan; in cco-1 worms, UPRmt was unaffected but lifespan still increased; in tmem-131 worms, UPRer was suppressed while lifespan extended; and in mdt-15 worms, UPRer was slightly elevated while lifespan shortened. These dissociations argue that metformin's longevity effects are not simply mediated through UPR activation or suppression.

Stress resistance results were equally nuanced. Metformin mildly improved thermotolerance and oxidative stress resistance in wild-type middle-aged worms, but these benefits did not consistently appear across UPR-activated backgrounds. Locomotion was enhanced by UPR activation itself—most notably in tomm-22 worms—but metformin treatment did not further improve or restore locomotor function in any strain tested.

These findings challenge a simple model in which metformin acts through a single conserved pathway. Instead, the drug appears to engage different molecular targets depending on the existing cellular stress context. The results also reinforce earlier evidence that UPRmt activation alone does not reliably predict longevity. For translational science, the data suggest that metformin's benefits in metabolically stressed or aging tissues may depend heavily on which stress pathways are already engaged—a consideration relevant to patient stratification in clinical longevity trials.