The proteasome is just one part of the extensive cellular maintenance apparatus, many systems operating to keep a cell functioning correctly in the face of inappropriate chemical reactions, broken molecules, damaged cellular structures, and the like. Each proteasome is a very complex assembly of proteins that, collectively, are responsible for shredding excess or damaged or otherwise unwanted proteins into component parts that will be recycled into new proteins. Cellular processes identify unwanted proteins and tag them with ubiquitin, and this chemical change allows the proteasome to engage with and break down the tagged protein.
As is the case for other cellular maintenance processes, particularly autophagy, changes in proteasomal activity can influence the pace of aging and length of life in short-lived species. Further, proteasomal activity declines with age, impairing cells. Cellular stress produced via a range of approaches, including the restricted nutrient availability of calorie restriction, causes increased and more efficient proteasomal activity. Cells become less cluttered with unwanted proteins, and are more efficient and functional as a result. Scaled up, this leads to slowed aging. Unfortunately this is nowhere near as effective as a strategy in long-lived species such as our own. While calorie restriction allows mice to live 40% longer, it only adds a few years at most to human life span. Nonetheless, the research community is interested in establishing ways to upregulate proteasomal activity as a potential basis for therapies.
In recent years, researchers have shown that causing cells to produce more of the proteasomal β5 subunit protein has the effect of improving proteasomal function and extending life in nematode worms and flies. In effect, a similar outcome to stress response is being produced without the actual stress response. A paper published earlier this year demonstrated that global overexpression of the β5 subunit can slow aging in flies. Here, a different research group shows that only overexpressing the β5 subunit in neurons also extends life in flies, but their data shows no effect on lifespan for global overexpression. This sort of conflicting data is often an issue with mechanisms producing modest effect sizes.
With age, there is a progressive decline in 26S proteasome function in the nervous system of mammals as well as flies, with a corresponding increase in 20S proteasome levels but not activity, which either declines or is unchanged. These changes likely result from reduced capacity of the existing proteasome, diminished 26S assembly and disassembly of the 26S proteasome into free 20S to compensate for reduced 20S functionality. It has been shown that proteasome depletion and inhibition in mice can mirror brain aging phenotypes, producing neurodegeneration, cognitive deficits, and formation of Lewy-like bodies. The goal of this study is to establish whether age-related cognitive decline can be ameliorated by augmenting proteasome function.
The size and complexity of the proteasome has made manipulating its expression a challenge. Elevating the proteasome β5 subunit increases both expression of other subunits and whole proteasome assembly in mammalian cell cultures and Caenorhabditis elegans. We used the same approach in Drosophila melanogaster, utilizing UAS-Prosβ5 (fly ortholog of the β5 subunit). We used an inducible driver system to limit gene overexpression to adulthood, thereby removing developmental artifacts and allowing experiment and control animals to be genetically identical siblings.
We report that overexpression of the proteasome β5 subunit enhances proteasome assembly and function. Significantly, we go on to show that neuronal-specific proteasome augmentation slows age-related declines in measures of learning, memory, and circadian rhythmicity. Surprisingly, neuronal-specific augmentation of proteasome function also produces a robust increase of lifespan in Drosophila melanogaster. Our findings appear specific to the nervous system; ubiquitous proteasome overexpression increases oxidative stress resistance but does not impact lifespan and is detrimental to some healthspan measures. These findings demonstrate a key role of the proteasome system in brain aging.