Proteasome β5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster

The beta 5 subunit of the proteasome has been shown in worms and in human cell lines to be regulatory. In these models, beta 5 overexpression results in upregulation of the entire proteasome complex which is sufficient to increase proteotoxic stress resistance, improve metabolic parameters, and increase longevity. However, fundamental questions remain unanswered, including the temporal requirements for beta 5 overexpression and whether beta 5 overexpression can extend lifespan in other species. To determine if adult-only overexpression of the beta 5 subunit can increase proteasome activity in a different model, we characterized phenotypes associated with beta 5 overexpression in Drosophila melanogaster adults. We find that adult-only overexpression of the beta 5 subunit does not result in transcriptional upregulation of the other subunits of the proteasome as they do in nematodes and human cell culture. Despite this lack of a regulatory role, boosting beta 5 expression increases the chymotrypsin-like activity associated with the proteasome, reduces both the size and number of ubiquitinated protein aggregates in aged flies, and increases longevity. Surprisingly, these phenotypes were not associated with increased resistance to acute proteotoxic insults or improved metabolic parameters.