CoChat
Sign Up
Cited by 569Genetics, Aging, and Longevity in Model OrganismsHeat shock proteins researchAdvanced Proteomics Techniques and Applications

Widespread Proteome Remodeling and Aggregation in Aging C. elegans

Open access
Walther, Dirk M., Kasturi, Prasad, Zheng, Min, Pinkert, Stefan, Vecchi, Giulia, Ciryam, Prajwal, Morimoto, Richard I., Dobson, Christopher M. +3 more·2015·Cell
DOI 10.1016/j.cell.2015.03.032PMC PMC4643853
Open this paper in CoChat — free accountOpen PDF

Abstract

Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2015.03.032

Cites

88 of 88 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 31 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Proteins that increase at least twofold in aged C. elegans account for about half of total protein.

    “The proteins that increased by at least 2-fold amounted to approximately 50% of total protein in aged animals, as determined by label free absolute quantification (absolute LFQ values) (Schwanhausser et al., 2011) (Figure 1C).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Schwanhausser et al., 2011 source

      Not checked in the free run.

  • Findingown data

    In aging C. elegans, roughly one third of the quantified proteins change in abundance by at least twofold.

    “We find that one third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance.”
    • Also stated in: § Extensive Proteome Remodeling During Aging · plain
      “About one third of the quantified proteins increased or decreased in abundance by at least 2-fold, when equal amounts of total protein were analyzed (Figure 1B and Table S1B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Analyzing equal amounts of total protein normalizes for changes in cell number or tissue mass, so that measured protein abundance changes reflect proteome composition changes during aging.
  • Findingown data

    Among proteins increased more than twofold at day 22, 183 are extracellular proteins out of 490 quantified extracellular proteins.

    “Among the proteins that increased more than 2-fold in aged worms (22 days) were 183 extracellular proteins (out of 490 extracellular proteins quantified) (Figure S1E and Table S2B).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Proteins enriched in intestine, muscle, and hypodermis decline during aging.

    “In contrast, the levels of many proteins enriched in intestine, muscle and hypodermis decline (clusters 4–6), consistent with an age-related deterioration of these tissues.”
    Quote in the paperSubstantial claim
  • Findingown data

    Multiple transthyretin-like factors increase up to 100-fold during aging.

    “These included multiple transthyretin (TTR)-like factors, which increased up to 100-fold (Figure S1F), as well as all six of the vitellogenin egg storage proteins, despite egg formation having been completed before day 6.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 45
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    Neuronal-enriched proteins either increase throughout lifespan or after day 6.

    “Proteins enriched in neuronal cells either increase in abundance throughout lifespan or after day 6 (clusters 2 and 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    About 30% of proteins that increase more than twofold between day 6 and day 22 have elevated transcript levels in dicer mutants, and this rises to nearly 40% for proteins with more than fourfold change.

    “We find that ~30% of proteins that increased more than 2-fold between day 6 and 22 (99 of 357 proteins), i.e. after the worms have reproduced, have significantly elevated transcript levels in dicer mutants, and this proportion increases to nearly 40% for the subset of proteins with a more than 4-fold abundance change (50 out of 133 proteins) (Figure S1D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Welker et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Nucleolar ribosome biogenesis factors, various peroxisomal enzymes, and proteins involved in lipid glycosylation decline during aging.

    “Among the proteins that declined during aging are nucleolar ribosome biogenesis factors, various peroxisomal enzymes and proteins involved in lipid glycosylation (Figure S1E and Table S2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Protein abundance changes during C. elegans aging progress until day 22 and are seen in most cellular compartments.

    “Protein abundance changes were progressive until day 22 (Figure 1B, S1B and Table S2A) and were observed in most cellular compartments (Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Levels of many mitochondrial proteins decrease during aging, and respiratory chain complex I subunits decline gradually by up to 50%.

    “The levels of many mitochondrial proteins also decreased (Figure 1D). For example, subunits of respiratory chain complex I declined gradually by up to 50% during lifespan (Figure S1G), which may result in the production of reactive oxygen species.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Germline-enriched proteins strongly increase during the first 6 days of adulthood and then remain constant.

    “For example, proteins that are predominantly expressed in the germline strongly increase during the first 6 days of adulthood (cluster 1), when the animals reproduce, but surprisingly retain constant levels later in life.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In daf-2 mutants, the age-dependent increase in specific proteins is less pronounced than in WT, while in daf-16 mutants it is enhanced.

    “The increase in levels of specific proteins observed during aging of WT animals was considerably less pronounced in daf-2 mutant animals and enhanced in daf-16 mutant animals (Figure S3A, left panel), indicating that the long-lived daf-2 mutant strain is more effective in controlling the accumulation of surplus proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    20S and 19S proteasomal subunits increase with age, with 20S subunits about twofold higher at day 22.

    “In contrast to the effect on ribosomes, we observed an age-dependent increase in 20S and 19S proteasomal subunits (~2-fold at day 22 for 20S subunits) (Figure 2B), correlating with an increase in proteasome activity measured in worm lysates in vitro (Figure S2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ER proteostasis components show diverse age-related changes: PDI-2, C14B9.2, CRT-1, and HSP-3 decrease about twofold, while LET-268, DPY-18, and PHY-2 decrease about 3- to 10-fold.

    “For example, protein disulfide isomerases (PDI-2, C14B9.2), the chaperone calreticulin (CRT-1) as well as the HSP70 homolog HSP-3 decreased ~2-fold, and the pro-collagen modifying enzymes lysyl hydroxylase (LET-268) and prolyl-4-hydroxylase α (DPY-18, PHY-2) decreased ~3–10-fold.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The decrease in ribosomal proteins occurs at a similar rate in daf-2 mutants as in WT, but is strongly enhanced in daf-16 mutants.

    “The decrease in ribosomal proteins occurred at a similar rate in daf-2 mutant worms as in WT (Figure 3A), but was strongly enhanced in daf-16 mutant worms (Figure 3C), suggesting that DAF-16 is involved in ribosome maintenance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aged animals show pronounced imbalance in the relative subunit stoichiometry of cytosolic, but not mitochondrial, ribosomes, with several subunits decreasing more than 60% below median levels.

    “Interestingly, aged animals displayed a pronounced imbalance in the relative subunit stoichiometry of cytosolic, but not mitochondrial ribosomes, with several subunits decreasing more than 60% below median subunit levels (Figure 2A, left).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upregulation of proteasomal subunits begins earlier and is more pronounced in daf-2 mutants than in WT, and is less prominent in daf-16 and hsf-1 mutants.

    “The upregulation of proteasomal subunits commenced earlier during the lifespan of the daf-2 mutant and was more pronounced than in the WT worms (Figure 3A and B); such upregulation was instead less prominent in the short-lived daf-16 and hsf-1 mutant strains (Figures 3C and D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Long-lived daf-2 mutant worms also accumulate aggregates, and their aggregate load is significantly greater than that of age-matched WT animals.

    “However, in support of a beneficial role for aggregation, we found that the long-lived daf-2 mutant worms also accumulated aggregates and that their aggregate load was significantly greater than that of age-matched WT animals (Figures 5A, S6A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aggregation propensities of more than 2100 analyzed proteins vary by more than two orders of magnitude, with a median insoluble fraction per protein of about 9%.

    “The aggregation propensities of >2100 analyzed proteins varied by more than two orders of magnitude (Figure 4B), with the median insoluble fraction per individual protein amounting to ~ 9%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to WT, short-lived hsf-1 mutant worms accumulate more insoluble proteins and aggregation occurs earlier, between day 1 and day 6.

    “Indeed, compared to WT animals, the short-lived hsf-1 mutant worms accumulated more insoluble proteins and aggregation occurred earlier during aging (between day 1 and day 6) (Figures 5A and S6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All identified small HSPs, but not other chaperones, are highly insoluble at day 12 and accumulate in the aggregate fraction during aging.

    “Interestingly, all identified small HSPs, but not other chaperones, were highly insoluble at day 12 (Figure 4F), with a high rate of accumulation in the aggregate fraction during aging (Figure S5E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SIP-1 is already more abundant in young daf-2 mutants at day 1, and HSP-16.48 is markedly elevated in hsf-1 mutants.

    “Among the small HSPs, SIP-1 was already more abundant in young daf-2 mutant worms (day 1) and HSP-16.48 was markedly elevated in hsf-1 mutant animals (Figure S3D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There is a medium correlation (R = 0.43) between the age-dependent change in total abundance of proteins and their increase in the aggregate fraction, and this correlation becomes stronger as aging progresses.

    “Notably, we also observed a medium correlation (R = 0.43) between the age-dependent change in the total abundance of proteins and their increase in the aggregate fraction (Figure 4E), and this correlation became stronger as aging progressed (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Abundant proteins are more hydrophobic and more structured than less abundant proteins.

    “An analysis of the physicochemical properties of the abundant proteins based on their amino acid sequences revealed that they were more hydrophobic (Figure S5B) and more structured (data not shown) than the less abundant ones.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Proteins with relatively high aggregation propensity in aged animals are enriched in the nucleus, whereas abundant glycolytic enzymes and mitochondrial proteins tend to be highly soluble.

    “Gene ontology analysis showed that proteins with a relatively high aggregation propensity in aged animals are enriched in the nucleus, whereas abundant glycolytic enzymes and mitochondrial proteins tend to be highly soluble (Figure S5D and Table S4A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Increased aggregation in daf-2 mutants preferentially comprises cytosolic proteins and initiates between day 6 and day 12 as in WT.

    “The increased aggregation in daf-2 mutant animals comprised preferentially cytosolic proteins (Figure S6C and Table S4B) and initiated between day 6 and day 12 as in WT (Figure S6A), i.e. when the long-lived mutant worms are still youthful.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    26S proteasome complexes are enriched in insoluble fractions, most strongly in daf-2 mutants, but contribute only about 1% to total aggregate load.

    “Besides small HSPs, 26S proteasome complexes were enriched in the insoluble fractions (Figure 6B), most strongly in the daf-2 mutant strain, but contributed only ~1% to total aggregate load.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At day 12, total and soluble FlucDM-GFP levels were similar in WT and daf-2 mutants, but daf-2 mutants had ~4-fold more luciferase activity.

    “While similar levels of total and soluble FlucDM-GFP protein were present in day 12 WT and daf-2 mutant worms, the latter contained ~4-fold more luciferase activity (Figure S6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Actin architecture of muscle cells was well preserved in daf-2 mutants, while day 15 WT animals showed reduced structural integrity.

    “While the actin architecture of muscle cells was well preserved in daf-2 mutant animals, the muscles of day 15 WT animals showed a reduced structural integrity (Figure 6D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Several small HSPs are strongly increased in the insoluble fraction of daf-2 mutants, and these proteins contribute about 7% to total aggregate load.

    “Among the proteins that were strongly increased in the insoluble fraction of daf-2 mutant animals were several small HSPs (Figure 6A). These proteins contribute ~7% to total aggregate load, suggesting that they may be involved in a ‘protective aggregation response’.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Proteins that aggregate most in daf-2 mutants have significantly lower aggregation-propensity Z-scores, are more charged, display more structural disorder, and are less hydrophobic compared to proteins aggregating in WT.

    “Strikingly, the proteins that aggregate most in the daf-2 mutant animals are predicted to have significantly lower aggregation-propensity Z-scores, are more charged, display more structural disorder (coil average) and are less hydrophobic compared to the proteins aggregating in WT (Figure 5D–G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In daf-2 mutant aggregates, SIP-1 and HSP-16.1 contributed most by mass, whereas HSP-17 was most enriched in hsf-1 mutant aggregates.

    “SIP-1 and HSP-16.1 made the major contribution by mass to the aggregates in the daf-2 mutant, while HSP-17 was most enriched in the aggregates of hsf-1 mutant animals (Figure 6C and Table S1F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Small HSPs are also enriched in the insoluble fraction of hsf-1 mutants, although to a lesser extent, but not in aggregates of daf-16 mutants.

    “Small HSPs were also enriched in the insoluble fraction of hsf-1 mutant animals, although to a lesser extent, but not in the aggregates of the daf-16 mutant (Figure 6A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Proteasome subunit levels rose, and in vitro proteasome activity increased correspondingly.

    “In contrast, we observed an increase in the abundance of proteasome subunits and a corresponding increase of in vitro proteasome activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aggregation occurs across the proteome and begins mostly after day 6 of adulthood.

    “We found that aggregation is a proteome-wide process that initiates mainly after day 6 of adulthood.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    As they age, long-lived daf-2 mutants build up more insoluble protein, and this buildup tracks with their better maintenance of proteome composition.

    “We observed that long-lived daf-2 mutant animals accumulate increasing amounts of insoluble protein during aging, and that such accumulation correlates with their ability to maintain proteome composition more effectively (Figure 7C).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The decline in complex I subunits may lead to production of reactive oxygen species.

    “which may result in the production of reactive oxygen species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These findings suggest an age-dependent decline in ER quality control and collagen synthesis capacity.

    “These findings suggest an age-dependent decline in ER quality control and collagen synthesis capacity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Proteins with predicted transmembrane segments are not enriched in the insoluble fraction, indicating that lysis was efficient.

    “Proteins with predicted transmembrane segments were not enriched in the insoluble fraction (Figure S5A), indicating that lysis was efficient.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Recruitment of these chaperones into the insoluble fraction may reflect an attempt to sequester protein aggregates.

    “The recruitment of these chaperones into the insoluble fraction may reflect an attempt of the organism to sequester protein aggregates.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Declining proteostasis capacity is thought to cause accumulation of protein aggregates, consistent with reports of age-dependent aggregate formation in C. elegans.

    “Declining proteostasis capacity is thought to result in the accumulation of protein aggregates, consistent with recent reports of age-dependent aggregate formation in C. elegans (David et al., 2010; Reis-Rodrigues et al., 2012).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites David et al., 2010 source

      Not checked in the free run.

    • cites Reis-Rodrigues et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SOD-1 and SOD-2 are transcriptionally regulated by DAF-16.

    “consistent with their DAF-16-dependent transcriptional regulation (McElwee et al., 2003; Murphy et al., 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites McElwee et al., 2003 source

      Not checked in the free run.

    • cites Murphy et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    daf-2 mutants drive aberrant, potentially toxic proteins into aggregates, sequestering them and improving overall proteostasis.

    “Taken together these results suggest that daf-2 mutant animals drive aberrant, potentially toxic proteins into aggregates, thereby sequestering them and improving overall proteostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The imbalances mainly stem from altered protein translation and turnover, and lead to buildup of potentially harmful aggregation-prone species.

    “These imbalances are largely due to changes at the level of protein translation and turnover, and give rise to the accumulation of potentially harmful, aggregation-prone species (Figure 7A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    WT worms are predicted to have a larger soluble pool of abnormal, potentially toxic proteins than daf-2 mutants, ultimately depleting chaperones required for folding, conformational upkeep, and removal of misfolded proteins.

    “As a result, WT worms are expected to accumulate a larger soluble pool of aberrant, potentially toxic proteins than daf-2 mutant animals, eventually exhausting the available chaperone capacity needed for protein folding and conformational maintenance, and the clearance of misfolded polypeptides (Figure 7B and C).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: During normal C. elegans aging, the protective aggregation response is only partly engaged.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In neurodegenerative disease, soluble oligomers are considered the main toxic species, and depositing them into insoluble aggregates lowers toxicity.

    “This conclusion is consistent with the view that soluble oligomers are the major proteotoxic species in neurodegenerative diseases and that their sequestration into insoluble aggregates reduces proteotoxicity (Arrasate et al., 2004; Cohen et al., 2006; Cohen et al., 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Arrasate et al., 2004 source

      Not checked in the free run.

    • cites Cohen et al., 2006 source

      Not checked in the free run.

    • cites Cohen et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proteins present at high abundance tend to be more soluble and less intrinsically aggregation-prone than those at low abundance.

    “Highly abundant proteins are generally more soluble and display lower intrinsic aggregation-propensities than less abundant ones, as previously predicted (Tartaglia et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tartaglia et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aging in C. elegans involves broad proteome remodeling, unlike aged mouse tissues, which showed relatively small proteomic changes under a comparable method.

    “The extensive proteome remodeling during aging in C. elegans is contrary to observations in tissues of aged mice, where comparatively minor proteomic changes were detected with a similar experimental approach (Walther and Mann, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Walther and Mann, 2011

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mammals invest more in preserving proteome balance, so their proteostasis decline is more prolonged.

    “Evidently mammals devote greater resources to maintaining proteome balance, resulting in a more protracted proteostasis decline.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Earlier work showed that aged worms form insoluble protein aggregates.

    “Previous studies demonstrated the formation of insoluble protein aggregates in aged worms (David et al., 2010; Reis-Rodrigues et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites David et al., 2010 source

      Not checked in the free run.

    • cites Reis-Rodrigues et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Various small HSP forms might differ in their structural selectivity for endogenous proteins.

    “The co-existence of multiple small HSPs suggests that different forms may vary in their structural specificity for endogenous proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Knocking down individual small HSPs, such as SIP-1, by RNAi shortened lifespan by 25% in both WT and daf-2 mutants, while overexpression lengthened lifespan.

    “In support of this possibility, individual RNAi knock down of several small HSPs, including SIP-1, caused a 25 % shortening of lifespan in WT and daf-2 mutant worms (Hsu et al., 2003) and overexpression resulted in lifespan extension (Walker and Lithgow 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hsu et al., 2003 source

      Not checked in the free run.

    • cites Walker and Lithgow 2003

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Identifications of proteins and peptides were allowed at a 1% false discovery rate.

    “The minimal required peptide length was set to seven amino acids and both protein and peptide identifications were accepted at a false discovery rate of 1%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    For proteins measured in at least three of four biological replicates at days 1 and 12, Welch's t-test was applied and results filtered using a 5% permutation-based false discovery rate.

    “To identify aggregation-prone proteins that were significantly affected by aging, those proteins that were quantified in at least 3 out of 4 biological replicate experiments at day 1 and day 12 were subjected to a Welch’s t-test and filtered based on a 5% permutation-based false discovery rate threshold.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the aging brain, small HSPs show increased transcription, whereas most other major chaperones are reduced.

    “Notably, small HSPs are also transcriptionally induced in the aging brain, while most other major chaperone components are down-regulated (Brehme et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brehme et al., 2014 source

      Not checked in the free run.

50 of 50

  • The paper relies on this without support.

    Analyzing equal amounts of total protein normalizes for changes in cell number or tissue mass, so that measured protein abundance changes reflect proteome composition changes during aging.

    “About one third of the quantified proteins increased or decreased in abundance by at least 2-fold, when equal amounts of total protein were analyzed (Figure 1B and Table S1B).”

  • The authors state this as an assumption.

    During normal C. elegans aging, the protective aggregation response is only partly engaged.

    “We assume that this protective aggregation response is only partially activated during normal C. elegans aging.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Enhancement of UPS can improve healthy aging and longevity in disease and aged animals, although benefits to neurons and brain function remain elusive.

    “Accordingly, enhancement of UPS can improve healthy aging as well as longevity in disease and aged animals, although the specific benefits to neurons and brain function are still elusive (Saez and Vilchez, 2014; Walther et al., 2015).”

    From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Walther et al., 2015

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Olsen, 2009, Characterization of the Velos, an Enhanced LTQ Orbitrap, for Proteomics, Mol. Cell. Proteomics, 8, S40

Cited by

Sorted by citations

Authors
Walther, D. M., Kasturi, P., Zheng, M., Pinkert, S., Vecchi, G., Ciryam, P., Morimoto, R. I., Dobson, C. M., Vendruscolo, M., Mann, M., & Hartl, F. U.
Affiliations
  • Max Planck Institute of Biochemistry (DE)
  • University of Cambridge (GB)
  • Northwestern University (US)
Corresponding author
Hartl, F. Ulrich
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2015-05
Volume
161
Issue
4
Pages
919-932
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2015.03.032
PMC
PMC4643853
OpenAlex
W2151893314
Cited by
569
References
88
Citations by year
2026: 30 · 2025: 39 · 2024: 38 · 2023: 44 · 2022: 54 · 2021: 60 · 2020: 61 · 2019: 55 · 2018: 53 · 2017: 59 · 2016: 52 · 2015: 22
FWCI
24.94
Type
journal article
Language
en
Update notices
erratum (2017-02-23)
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • Wellcome Trust (094425/Z/10/Z)
  • National Institute on Aging (R37AG026647, R01AG026647, P01AG049665)
  • National Cancer Institute (P30CA060553)
  • National Institute of General Medical Sciences (T32GM008152, R01GM038109)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
aging, proteome remodeling, proteostasis, protein aggregation, Caenorhabditis elegans, lifespan, daf-2, DAF-16, ribosomal proteins, proteasome, heat shock proteins, molecular chaperones, protein stoichiometry, protein abundance
MeSH terms
Aging, Animals, Mutation, Caenorhabditis elegans, Proteome, Caenorhabditis elegans Proteins, Protein Aggregates

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review