# Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito‐Nuclear Epistasis in Drosophila

## TL;DR

Reduced insulin signaling can either extend or shorten lifespan in fruit flies, depending on interactions between mitochondrial and nuclear DNA.

## Contribution

The study reveals mito-nuclear epistasis as a key factor influencing lifespan and fecundity effects of reduced insulin signaling in Drosophila.

## Key findings

- Reduced insulin signaling can have beneficial or detrimental effects on lifespan depending on mtDNA and nDNA combinations.
- Mito-nuclear interactions act as a gatekeeper for the effects of insulin signaling on aging.
- Genetic variation within species influences the response to reduced insulin signaling.

## 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 a 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 a gatekeeper.

Insulin signalling extends lifespan across species but, in Drosophila, this effect can vary among populations. This variable response is underpinned by epistasis between mtDNA and nDNA.