Mitochondrial stress extends lifespan in worms through ELT-2 and lysosomal clearance

Genetically reducing mitochondrial respiration extended the lifespan of worms by preserving lysosomal function, which cells use to break down proteins

On August 12, researchers reported experiments in C. elegans in a Science Advances article. This small, transparent roundworm is widely used to study aging. Genetically reducing mitochondrial function preserved lysosomal acidity and degradative activity in older animals. ELT-2, a regulatory protein in the worm intestine, activated genes encoding the required enzymes.

Mitochondria supply cells with energy. Lysosomal enzymes require an acidic environment to break down damaged and excess proteins. In older worms, lysosomes become less acidic and their degradative activity declines. Genetically reducing respiration mitigated this age-related loss of function.

ELT-2 binds to DNA near genes and activates them in intestinal cells. A 2016 study showed that ELT-2 levels in worms begin to decline by middle age and that increased expression of this protein extends their lifespan. In a 2025 study, some of the authors of the current article described an ELT-2-dependent lysosomal program triggered by reduced acidity in the intestine. The new study tested whether reducing mitochondrial respiration activates the same pathway.

In the regulatory regions of DNA upstream of genes activated by this stress, the authors identified a short sequence that typically binds GATA proteins. Testing 14 of these regulatory regions identified ELT-2 as the relevant factor. When ELT-2 was suppressed, genes encoding lysosomal enzymes were activated less strongly. DNA binding analysis showed that reduced respiration increased ELT-2 binding to regions upstream of these genes.

The researchers then tested whether cellular clearance was required for the effect. When lysosomal acidity was chemically reduced, the worms became less effective at clearing model protein aggregates and no longer gained additional lifespan from reduced respiration. Disabling either of two lysosomal enzymes partially restored protein aggregates and reduced the increase in lifespan. Controlled suppression of ELT-2 almost completely prevented both the activation of these genes and the extension of lifespan.

In experiments with C. elegans, mild inhibition of mitochondrial respiration helped older worms maintain their protein clearance program. ELT-2 connected the mitochondrial signal to lysosomal enzymes. The activity of these enzymes was associated with fewer protein aggregates and a longer lifespan in the worms.