Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor

Hsu, Ao Lin; Murphy, Coleen T.; Kenyon, Cynthia

doi:10.1126/science.1083701

Cited by 1,333 publications

(1,399 citation statements)

References 27 publications

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“…The CNV approach highlighted an age‐dependent decrease in members of the cytosolic ribosome and an increase in the proteasome, relative to their respective cell compartment (Mann–Whitney test P < 0.01; Fig EV5 and Dataset EV6). Indeed, the same age‐related variations were observed by the authors of the original publication, and they are corroborated by other independent studies (Hsu et al , 2003; Golden & Melov, 2004; Vilchez et al , 2012; Kirstein‐miles et al , 2013). …”

Section: Resultssupporting

confidence: 85%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

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Section: Resultssupporting

confidence: 85%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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“…Consequently, restoring PQC by overexpression of small HSPs extends lifespan in D. melanogaster 67,68 . Furthermore, general upregulation of chaperones, either by a sublethal heat shock or by overexpression of HSF1, enhances the folding of aggregation prone proteins and extends lifespan in both C. elegans and D. melano gaster [69][70][71] . The opposite is also found: inhibition of the heat shock response through suppression of HSF1 expression during larval development causes C. elegans 78,79 Whereas the PQC network initially counteracts proteotoxicity by upregulation of chaperones and activation of the protein degradation pathways, the enduring stress drains their capacity, ultimately leading to degradation of the sarcomeric structure (FIG.…”

Section: Derailment During Normal Ageingmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

132

111

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…The HSR is highly conserved, and C. elegans HSF‐1 is associated with aging and longevity (Hsu, Murphy, & Kenyon, 2003; Morley & Morimoto, 2004; Morton & Lamitina, 2013). SIRT1‐regulated processes are also conserved in the worm and are mediated by SIR‐2.1.…”

Section: Introductionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat‐shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA‐bound state of HSF1 through deacetylation of the DNA‐binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell‐cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF‐1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR‐1. This negative regulation requires the SIRT1 homolog SIR‐2.1. In addition, knockdown of CCAR‐1 via ccar‐1 RNAi works through SIR‐2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.

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Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor

Cited by 1,333 publications

References 27 publications

Quantifying compartment‐associated variations of protein abundance in proteomics data

Quantifying compartment‐associated variations of protein abundance in proteomics data

Proteostasis in cardiac health and disease

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

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