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The long-term health of cells critically relies on selective protein degradation since damaged or aggregated proteins cause proteotoxic stress that can impair cell function and cause cell death. Many neuro-degenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s Disease, ALS and retinitis pigmentosa, are caused by the accumulation of protein aggregates. We recently discovered a novel mechanism that enables cells to avoid proteotoxic stress by stimulating the assembly of proteasomes, the multi-protein protease complex responsible for the regulated proteolysis of intracellular proteins. Significantly, this pathway is sensitive to diet, mitochondrial function, and oxidative stress. Furthermore, the activity of this pathway declines with age. Finally, polymorphisms in the central factor in this pathway, PI31 , are associated factor with Alzheimer’s Disease. Our findings suggest that insufficient availability of proteasomes contributes to the aging process and chronic neuro-degenerative diseases. Background reading: Bader, M. Benjamin, S. Wapinski O., Smith, DM., Goldberg, AL., and Steller, H. (2011). A conserved F-box-regulatory complex controls proteasome activity in Drosophila. Cell. 145, 371-82. Cho-Park, P., and Steller, H. (2013). Proteasome regulation by ADP -ribosylation. Cell, 153, 614–627.