# Growth phase diets diminish histone acetyltransferase Gcn5 function and shorten lifespan of Drosophila males

## TL;DR

Early-life diets rich in certain nutrients reduce the function of a key protein in fruit fly larvae, leading to shorter lifespans in male adults.

## Contribution

This study identifies a causal link between specific larval diets and reduced Gcn5 function, impacting adult male lifespan in Drosophila.

## Key findings

- A nat3 KO yeast diet rich in fatty acids and BCAAs reduces Gcn5 function in larvae.
- Supplementing control diets with oleic acid, valine, and acetic acid replicates the negative effects on Gcn5 and lifespan.
- Larval Gcn5 knockdown significantly shortens adult male lifespan.

## Abstract

The nutritional environment in early life, referred to as the nutrition history, exerts far-reaching health effects beyond the developmental stage. Here, with Drosophila melanogaster as a model, we fed larvae on diets consisting of a variety of yeast mutants and explored the resulting histories that impacted adult lifespan. A larval diet comprised of yeast nat3 KO shortened the lifespan of male adults; and remarkably, this diet diminished the function of histone acetyltransferase Gcn5 in larvae. Concordantly, perturbation of Gcn5-mediated gene regulation in the larval whole body or neurons significantly contributed to the earlier death of adults. The nat3 KO diet is much more abundant in long-chain fatty acids and branched-chain amino acids (BCAAs) than the control yeast diet. Supplementing the control diet with a combination of oleic acid, valine, and acetic acid recapitulated the effects of the nat3 KO diet on the larval transcriptome and the lifespan of males. Our findings strongly suggest a causal link between a fatty acids- and BCAA-rich diet in developmental stages and lifespan reduction via the adverse effect on the Gcn5 function.

Specific nutrition histories in Drosophila larval stages diminish the function of histone acetyltransferase Gcn5, which most likely contributes to the earlier death of male adults.

A larval diet of live yeast nat3 KO mutant shortens the lifespan of males.The nat3 KO diet diminishes Gcn5 function in larvae.Larval stage-specific Gcn5 knockdown dramatically shortens adult lifespan.The nat3 KO diet is rich in long-chain fatty acids and branched-chain amino acids.The nat3 KO diet alters metabolism and decreases in the acetyl-CoA level relative to other CoA-related metabolites in larvae.A diet, rich in oleic acid, valine and acetic acid, recapitulates the adverse effects of the nat3 KO diet on Gcn5 function and lifespan of males.

A larval diet of live yeast nat3 KO mutant shortens the lifespan of males.

The nat3 KO diet diminishes Gcn5 function in larvae.

Larval stage-specific Gcn5 knockdown dramatically shortens adult lifespan.

The nat3 KO diet is rich in long-chain fatty acids and branched-chain amino acids.

The nat3 KO diet alters metabolism and decreases in the acetyl-CoA level relative to other CoA-related metabolites in larvae.

A diet, rich in oleic acid, valine and acetic acid, recapitulates the adverse effects of the nat3 KO diet on Gcn5 function and lifespan of males.

Specific nutrition histories in Drosophila larval stages diminish the function of histone acetyltransferase Gcn5, which most likely contributes to the earlier death of male adults.