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bioRxiv · 10.1101/2025.09.04.674084

Lifespan and fecundity impacts of reduced insulin signalling can be directed by mito-nuclear epistasis in Drosophila

Ibrahim, R.·Froschauer, C.·Broschk, S.·Sannino, D.·Dobson, A. J.
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Abstract

The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is leading example, which can extend healthy lifespan in a range of animals; but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for any putative translation. Here, in Drosophila, we test for genetic variation in lifespan response to a dominant-negative form of the insulin receptor, along with a metric of fecundity to evaluate corollary fitness costs/benefits. We also partition genetic variation between DNA variants in the nucleus (nDNA) and mitochondrial DNA (mtDNA), in a fully-factorial design that allows us to assess "mito-nuclear" epistasis. We show that reduced IIS can have either beneficial or detrimental effects on lifespan, depending on the combination of mtDNA and nDNA. This suggests that, while insulin signalling has a conserved effect on ageing among species, intraspecific effects can vary genetically, and the combination of mtDNA and nDNA can act as gatekeeper.

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Ibrahim, R., Froschauer, C., Broschk, S., Sannino, D., Dobson, A. J.. 2025-09-06. Lifespan and fecundity impacts of reduced insulin signalling can be directed by mito-nuclear epistasis in Drosophila. https://doi.org/10.1101/2025.09.04.674084

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