Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes

Moderate cold temperature extends lifespan, but the mechanisms involved are not fully understood. Here, the authors show that moderate cold temperature eliminates aggregation-prone proteins through PSME3-activated proteasomes in both C. elegans and human cells. Aging is a primary risk factor for neurodegenerative disorders that involve protein aggregation. Because lowering body temperature is one of the most effective mechanisms to extend longevity in both poikilotherms and homeotherms, a better understanding of cold-induced changes can lead to converging modifiers of pathological protein aggregation. Here, we find that cold temperature (15 degrees C) selectively induces the trypsin-like activity of the proteasome in Caenorhabditis elegans through PSME-3, the worm orthologue of human PA28 gamma/PSME3. This proteasome activator is required for cold-induced longevity and ameliorates age-related deficits in protein degradation. Moreover, cold-induced PA28 gamma/PSME-3 diminishes protein aggregation in C. elegans models of age-related diseases such as Huntington's and amyotrophic lateral sclerosis. Notably, exposure of human cells to moderate cold temperature (36 degrees C) also activates trypsin-like activity through PA28 gamma/PSME3, reducing disease-related protein aggregation and neurodegeneration. Together, our findings reveal a beneficial role of cold temperature that crosses evolutionary boundaries with potential implications for multi-disease prevention.

Automated summary

Moderate cold temperature extends lifespan by eliminating protein aggregation through PSME3-activated proteasomes. This mechanism is effective in both C. elegans and human cells, and it can ameliorate age-related deficits in protein degradation and reduce neurodegeneration.