More of Just one Component Part of a Proteasome Extends Life in Worms and Flies

Proteasomes are structures the cell, complex assemblies of a number of different proteins, that are responsible for breaking down damaged and excess proteins into small chunks that can be reused as raw materials. As is true of other cell maintenance processes, more proteasomal activity leads to better cell and tissue function, the creation of lesser amounts of downstream damage and dysfunction over time. Aging is modestly slowed. By way of following on from a recent review of upregulated proteasomal activity as a path to the treatment of aging, I'll point out this recent research in which scientists expand upon a very selective way to improve the operation of the proteasome. The production of more copies of just one component part of a proteasome improves overall function to a great enough degree to affect life span in short-lived species, an interesting finding.

Proteasome activity has been shown to decline with age and increasing proteasome function is known to provide benefits to lifespan. Given the multiple roles that the proteasome plays, however, including roles in metabolism, cell proliferation, and cell signaling, among others, discerning which aspects of proteasome function are limiting specifically for aging is necessary for further targeted investigations into the molecular consequences of aging. The major proteolytic activity associated with the proteasome is the chymotrypsin-like activity provided by the β5 subunit, and artificial impairment of only the chymotrypsin-like activity of the proteasome in mice has been shown to be sufficient to cause multiple early aging phenotypes, including shortened lifespans, reduced body weight, altered metabolism, muscle atrophy, and accumulation of ubiquitinated peptides.

The β5 subunit of the proteasome has been shown in worms and in human cell lines to be regulatory. In these models, β5 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 β5 overexpression and whether β5 overexpression can extend lifespan in other species.

To determine if adult-only overexpression of the β5 subunit can increase proteasome activity in a different model, we characterized phenotypes associated with β5 overexpression in Drosophila melanogaster adults. We find that adult-only overexpression of the β5 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 β5 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.

Link: https://doi.org/10.1038/s41598-019-39508-4

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