title: Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging.
abstract: Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.
authors.affiliation: Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Zvi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Miller
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D029742:Caenorhabditis elegans Proteins
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