Mistranslation Mutations Extend Lifespan in Reproducing Female Flies

Two genetic models that cause errors during protein production extended lifespan in mated female fruit flies, according to research reported in G3: Genes, Genomes, Genetics. The finding was unexpected because reproduction was expected to intensify the harmful effects of mistranslation on the flies’ non-reproductive tissues.

The study examined Drosophila melanogaster models in which valine was sometimes substituted for serine, or threonine was sometimes substituted for serine, during the conversion of RNA instructions into proteins. These are forms of “mistranslation,” meaning that the amino acid added to a growing protein does not match the genetic code.

Accurate protein production is generally important for organismal fitness, while translation errors can produce damaged or incorrectly functioning proteins and create proteotoxic stress. Earlier work with these fly models had shown a sex-specific longevity increase in virgin females. The researchers therefore predicted that reproduction would erase that benefit: because female flies prioritize reproductive tissues, the additional burden could have been expected to increase damage in somatic tissues and shorten lifespan.

Instead, both types of mistranslation were associated with longer lifespans in mated females compared with non-mistranslating controls. The researchers also reported that the flies’ risk of death declined by more than would be expected from simply adding the separate effects of mistranslation and reproduction.

The team measured longevity alongside egg laying and fecundity. The lifespan result could not be explained by reduced egg production or lower fertilization rates in the mistranslating females, according to the reported findings.

One proposed explanation had been that mistranslation might trigger a beneficial stress response, a phenomenon sometimes described as hormesis. However, the evidence presented in this study argued against a meaningful role for stress and stress responses in explaining the longevity effect. The reason the mutations extend lifespan remains unknown.

The research is a preclinical finding in fruit flies, not evidence that similar mutations would extend lifespan in humans. It also does not establish that deliberately inducing mistranslation would be beneficial. Instead, the results show that, in this fly model, the added protein-production stress did not worsen the lifespan costs of female reproduction and was associated with an unexpected longevity benefit.