Abstract
Lowering the activity of the Insulin/IGF-1 Signaling (IIS) cascade results in elevated stress resistance, enhanced protein homeostasis (proteostasis) and extended lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), the longevity phenotype that stems from IIS reduction is entirely dependent upon the activities of a subset of transcription factors including the Forkhead factor DAF-16/FOXO (DAF-16), Heat Shock Factor-1 (HSF-1), SKiNhead/Nrf (SKN-1) and ParaQuat Methylviologen responsive (PQM-1). While DAF-16 determines lifespan exclusively during early adulthood and governs proteostasis in early adulthood and midlife, HSF-1 executes these functions foremost during development. Despite the central roles of SKN-1 as a regulator of lifespan and proteostasis, the temporal requirements of this transcription factor were unknown. Here we employed conditional knockdown techniques and discovered that in C. elegans, SKN-1 is primarily important for longevity and proteostasis during late larval development through early adulthood. Our findings indicate that events that occur during late larval developmental through early adulthood affect lifespan and proteostasis and suggest that subsequent to HSF-1, SKN-1 sets the conditions, partially overlapping temporally with DAF-16, that enable IIS reduction to promote longevity and proteostasis. Our findings raise the intriguing possibility that HSF-1, SKN-1 and DAF-16 function in a coordinated and sequential manner to promote healthy aging.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Caenorhabditis elegans / growth & development
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Forkhead Transcription Factors / metabolism
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Larva / drug effects
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Larva / growth & development
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Larva / metabolism
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Longevity*
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Peptides / pharmacology
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Proteostasis / physiology*
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RNA Interference
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RNA, Double-Stranded / metabolism
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Ribonuclease III / antagonists & inhibitors
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Ribonuclease III / genetics
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Ribonuclease III / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Caenorhabditis elegans Proteins
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Peptides
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RNA, Double-Stranded
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Transcription Factors
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daf-16 protein, C elegans
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heat shock factor-1, C elegans
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skn-1 protein, C elegans
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polyglutamine
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dcr-1 protein, C elegans
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Ribonuclease III
Grants and funding
This study was supported by the Israel Science Foundation (ISF#981/16) awarded to EC (isf.org.il). The Israeli Ministry of Science and Technology (MOST#80884) awarded to EC (
https://www.gov.il/en/Departments/ministry_of_science_and_technology) Henri J. and Erna D. Leir Chair for Research in Neurodegenerative Diseases - awarded to EC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.