Improved Autophagy and Proteosomal Function via USP14 Inhibition Slows Aging in Flies
Autophagy and the ubiquitin-proteosome system (UPS) serve similar purposes in the cell. Both flag unwanted materials in the cell for recycling, and then break them down into raw materials for further protein synthesis. In the case of autophagy, materials are wrapped in an autophagosome membrane and then conveyed to a lysosome that dismantles structures and proteins using the enzymes that it contains. In the case of the UPS, ubiquitination of a protein allows that protein to enter a proteasome, the interior of which breaks it apart.
Both of these processes are used to remove excess and damaged molecules that may harm a cell. Up to a point, greater activity of these maintenance processes produces healthier, more resilient cells. Repeated across the entire organism, this leads to a slowing of degenerative aging. A number of approaches have been shown to upregulate autophagy. Fewer improve proteasomal function. In today's research materials, scientists report on an approach that improves both, and demonstrate slowed aging in flies as a result.
Proteasomes are protein complexes that break down faulty proteins into smaller peptides. On the other hand, autophagy is a process by which cells degrade and recycle larger structures, including protein aggregates, through the formation of specialized vesicles. Both systems work in concert to maintain proteostasis, but the mechanism of their synergistic activation to mitigate the effects of aging is not well understood. "A few years ago, I learned from an academic conference that a certain drug called IU1 can enhance proteasomal activity, which encouraged our group to test its anti-aging effects."
The researchers employed an animal model for studying the aging process: fruit flies from the genus Drosophila. Since fruit flies have a short lifespan and their age-related muscle deterioration is quite similar to that in humans, Drosophila constitutes a valuable model for studying aging. They treated flies with the drug IU1 and measured various behavioral and proteostasis-related parameters. "Inhibiting the activity of ubiquitin specific peptidase 14 (USP14), a component of the proteasome complex, with IU1 enhanced not only proteasome activity but also autophagy activity simultaneously. We demonstrated that this synergistic mechanism could improve age-related muscle weakness in fruit flies and extend their lifespan."
Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging.
Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.