Unravelling protein homeostasis mechanisms for increased lifespan Proper regulation of protein homeostasis in cells is critical for the health of an organism. An EU-funded project showed that improving proteostasis in the endoplasmic reticulum (ER) promotes cellular stress resistance and can thus positively influence lifespan and health. Fundamental Research Health © aastock, Shutterstock Protein homeostasis describes processes within cells that regulate protein synthesis, folding, and degradation within the cell to maintain the health of the cellular proteome. Loss of homeostatic capacity has consequences for organismal lifespan, and can also lead to ageing of cells and age-related diseases in the elderly such as heart disease, diabetes and neurodegeneration. Within the ER certain processes and systems ensure that only correctly folded proteins are exported from the ER. In response to stress conditions, when unfolded proteins accumulate in the ER lumen, the ER initiates a series of unfolded protein response signal transduction pathways. These pathways play a critical role in restoring ER homeostasis. In the EU-funded project ER LONGEVITY (Improving protein homeostasis to extend health- and lifespan), scientists identified a novel longevity pathway in the model organism Caenorhabditis elegans, supporting the hypothesis that proteostasis in the ER contributes to stress resistance. The pathway utilises endogenous amino sugar metabolites to improve protein homeostasis and extend the nematode's lifespan. This pathway, called the hexosamine pathway, is controlled by an enzyme called GFAT-1. Scientists identified gain-of-function mutations in the GFAT-1 gene of C. elegans, resulting in elevated cellular levels of the pathway’s product, the aminosugar UDP-GlcNAc. Thus, the hexosamine pathway and UDP-GlcNAc are mediators of proteotoxic stress resistance and longevity. GFAT-1 activation extended the nematode's lifespan by improving proteostasis in the ER. Future work will focus on exploring the mechanisms that link UDP-GlcNAc concentration levels with improvements in protein quality control, also in the mammalian system. Elucidating novel mechanisms that coordinate protein homeostasis has positive implications for human age-related diseases and longevity. Project results have been published in journals. Keywords Protein homeostasis, lifespan, endoplasmic reticulum, stress resistance, ER LONGEVITY
