ER LONGEVITY · Improving Protein Homeostasis to Extend Health- and Lifespan

Demographic changes result in ageing European populations and age-related diseases such as heart disease, diabetes, and neurodegeneration are serious health and societal challenges. Organismal ageing can be described as the progressive loss of homeostasis with time and, although ageing has a strong stochastic component, it is modulated by protective mechanisms that are conserved from simple organisms to mammals. Protein homeostasis, the combined processes that generate and maintain a functional proteome, is implicated in longevity and a deficiency is linked to various age-related diseases. Proteotoxic stress responses are compartmentalized and the cytosolic, mitochondrial and endoplasmic reticulum (ER) stress pathways are molecularly distinct. Both mitochondrial and cytosolic unfolded protein responses (UPR) are under systemic and cell-autonomous regulation in Caenorhabditis elegans. Endocrine ER-UPR modulation is currently unknown. I hypothesize that it is systemically coordinated through hormonal signals and that improving ER homeostasis will improve health and lifespan. I will use tissue-specific ER stress and heat-sensing-deficient mutants to investigate systemic ER-UPR regulation. Insulin signaling, which modulates stress resistance, and the ER-UPR are candidate pathways of cell-non-autonomous UPR. Next, unbiased whole genome screens will be used to identify new systemic and cell-autonomous regulators that enhance ER stress resistance and extend lifespan. To translate the findings from C. elegans work into the mammalian system, I will evaluate evolutionary conserved candidate genes in diverse murine and human cell lines during stress. I will use conditioned media to analyze non-cell-autonomous ER-UPR signaling in cytoprotection. Cultured cells will also be used for biochemical characterization of novel candidate genes. Elucidating novel mechanisms that coordinate protein homeostasis, my work will have implications for human age-related disease and longevity.