Expression of retrotransposons contributes to aging in Drosophila

Abstract

Retrotransposons are a class of transposable elements capable of self-replication and insertion into new genomic locations. Across species, the mobilization of retrotransposons in somatic cells has been suggested to contribute to the cell and tissue functional decline that occurs during aging. Retrotransposon expression generally increases with age, and de novo insertions have been observed to occur during tumorigenesis. However, the extent to which new retrotransposon insertions occur during normal aging and their effect on cellular and animal function remains understudied. Here we use a single nucleus whole genome sequencing approach in Drosophila to directly test whether transposon insertions increase with age in somatic cells. Analyses of nuclei from thoraces and indirect flight muscles using a newly developed pipeline, Retrofind, revealed no significant increase in the number of transposon insertions with age. Despite this, reducing the expression of two different retrotransposons, 412 and Roo, extends lifespan, without increasing stress resistance. This suggests a key role for transposon expression and not insertion in regulating longevity. Transcriptomic analyses revealed similar changes to gene expression in 412 and Roo knockdown flies and highlighted potential changes to genes involved in proteolysis and immune function as potential contributors to the observed changes in longevity. Combined, our data show a clear link between retrotransposon expression and aging. Author SummaryWith the onset of modern medicine, the average age of the population has significantly increased, leading to more individuals living with chronic health issues. Rather than treat each age-associated disorder individually, one approach to target multiple health concerns simultaneously might to be target aging itself. Genomic instability is a hallmark of aging cells that has been proposed to be a key contributor to age-associated cellular decline. Transposons are mobile genetic elements capable of inserting into new genomic locations, thus having the potential to increase genomic instability. Consistent with this, transposon expression generally increases with age. However, the extent to which transposon insertions accumulate to disrupt the genome of cells within aging individuals has remained an open question. We specifically answer this through single cell whole genome sequencing and find that transposon insertions do not increase with age. Even though insertions did not increase, the expression of transposons is linked to aging, as reducing the expression of individual transposons extended lifespan. Transcriptome studies of these long-lived flies revealed increased expression of genes linked to proteolysis genes and to functioning of the immune system. Our study therefore establishes transposon expression, and not insertion, as a critical contributor to animal aging.