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Collapse of Proteostasis Represents an Early Molecular Event in Caenorhabditis elegans Aging

Anat Ben-Zvi, Elizabeth A. Miller, Richard I. Morimoto and Susan L. Lindquist
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 35 (Sep. 1, 2009), pp. 14914-14919
Stable URL: http://www.jstor.org/stable/40484529
Page Count: 6
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Collapse of Proteostasis Represents an Early Molecular Event in Caenorhabditis elegans Aging
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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 ail somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coïncides 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 thè ability of the celi 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.

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