The DOI matches its Crossref record; 176 of the 177 references it cites were found in a registry or an index; 31 of the 61 sources its claims cite were checked for support.
Protein Homeostasis and Aging: the importance of exquisite quality control
Open accessAbstract
All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age and contributes to the functional loss characteristic of old organisms. Molecular chaperones and the proteolytic systems are responsible for this cellular quality control by assuring continuous renewal of intracellular proteins. When protein damage occurs, such as during cellular stress, the coordinated action of these cellular surveillance systems allows detection and repair of the damaged structures or, in many instances, leads to the complete elimination of the altered proteins from inside cells. Dysfunction of the quality control mechanisms and intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates occur in almost all tissues of an aged organism. Preservation or enhancement of the activity of these surveillance systems until late in life improves their resistance to stress and is sufficient to slow down aging. In this work, we review recent advances on our understanding of the contribution of chaperones and proteolytic systems to the maintenance of cellular homeostasis, the cellular response to stress and ultimately to longevity.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that age-related deterioration of protein quality control—molecular chaperones and proteolytic systems such as the ubiquitin/proteasome system and autophagy—contributes to loss of proteostasis and aging. Preserving or enhancing these surveillance systems can improve stress resistance and slow aging in model organisms.
Key findings
- Chaperones are central “gate keepers” of protein quality control; cytosolic sHSP and hsp70 family members are highly conserved (up to 50% amino acid identity among species), and their overexpression confers heat-shock resistance and stress tolerance in flies.
- Aging impairs chaperone responses: decreased hsp70 transcriptional upregulation occurs in senescent fibroblasts and old tissues across species up to monkeys, linked to HSF inability to bind the heat shock element; caloric restriction restores chaperone response, and cells from human centenarians preserve chaperone upregulation during stress.
- Longevity is linked to chaperones and proteolysis: extra copies of an hsp-70 family member or sHSPs make flies and worms long-lived, HSF overexpression increases nematode lifespan, and CHIP-defective mice have reduced longevity with accelerated aging, higher damaged proteins, and declined proteasome activity.
- Proteolytic systems decline with age: proteasome activity decreases in several tissues though not universally; CMA activity decreases in almost all tissues of old rodents and senescent human fibroblasts due to lower LAMP-2A; restoring CMA in mouse liver improves cellular homeostasis, stress response, and liver function comparable to young mice.
Methods
- Narrative review of recent advances; no primary experimental data, sample, or new analysis. It synthesizes biochemical and genetic studies in yeast, worms, flies, rodents, human cells/tissues, and centenarians.
- Discusses molecular chaperones (HSP families and organelle-specific chaperones), the ubiquitin/proteasome system, and autophagic/lysosomal pathways (macroautophagy, microautophagy, and chaperone-mediated autophagy) and their age-related changes and connections to longevity.
Limitations
- Stated: broad lack of knowledge on tissue-dependent characteristics of the proteostasis network and cross-talk among organs/tissues; species-specific differences (e.g., CMA is absent or has different components in unicellular organisms and invertebrates); need for genetic models with late-life impairment and better chemical modulators.
- Evident: as a narrative review, it does not systematically search or quantitatively synthesize evidence; many conclusions rely on diverse model systems and cited studies rather than uniform outcome measures.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
16 No full text of the sources · 12 Own interpretation · 10 Supported · 10 Partly supported · 6 No basis given · 3 Not checked yet · 2 Sources not found · 1 Supported so far · 1 Mixed support · 1 Couldn’t confirm · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Activation of macroautophagy is a common feature of all the long-lived mutant worms, including the models for dietary restriction (Hansen et al., 2008; Hars et al., 2007; Melendez et al., 2003; Tóth et al., 2008).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Disputedcites Hansen et al., 2008 sourceExperimental — accuracy not yet measured
The Results and Discussion support increased autophagy in long-lived dietary-restriction eat-2 mutants. But the Discussion reports no increase in the autophagy reporter’s foci in long-lived rsks-1 mutants, contrary to the claim that activation is a feature of all long-lived mutant worms. The authors note that autophagy in other tissues remains possible. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
- Partly supportedcites Hars et al., 2007 sourceExperimental — accuracy not yet measured
The paper’s Abstract reports that knocking down autophagy genes shortened the lifespan of long-lived daf-2 mutant worms, supporting a role for autophagy in their longevity. It does not show that macroautophagy is activated in all long-lived mutant worms or address dietary-restriction models; searches for dietary restriction and autophagy activation found no such result. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites Melendez et al., 2003 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Numerous studies support now that increased chaperone induction leads to increased longevity both in uni- and multicellular organisms (Lithgow et al., 1995; Shama et al., 1998; Tatar et al., 1997).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 3. Molecular Chaperones in protein quality control > 3.3. Molecular chaperones in longevity and aging
What the sources say
- Partly supportedcites Lithgow et al., 1995 sourceExperimental — accuracy not yet measured
The Results and Discussion report that mild thermal stress increased both thermotolerance and lifespan in C. elegans, a multicellular organism. But the Discussion treats lifespan extension through increased heat-shock-protein expression as a model and explicitly says that the causal prediction still needs testing. This paper does not establish the claimed effect of chaperone induction or report it in unicellular organisms. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites Shama et al., 1998 source
- Not checked — no full text of the sourcecites Tatar et al., 1997 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“and an E3 ligase (Hawse et al., 2004) have been reported in some aged tissues.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
- Could not verifycites Hawse et al., 2004 sourceExperimental — accuracy not yet measured
Section 3 (page unavailable) reports transcripts with decreased expression in aged human lens epithelia, but does not identify an E3 ligase among them. Searches for “E3,” “ligase,” and “ubiquitin” found no passage in our copy establishing age-related downregulation of an E3 ligase. (LLM, conf=0.73)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The increased content with age of mutant forms of ubiquitin due to molecular misreading could also be behind the inefficient clearance of polyubiquitinated proteins in aging (Tsirigotis et al., 2001).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
- Partly supportedcites Tsirigotis et al., 2001 sourceExperimental — accuracy not yet measured
The indexed passage labeled Abstract (page unavailable) reports that engineered K48R mutant ubiquitin-expressing cells accumulated high-molecular-weight ubiquitin conjugates and showed impaired proteolysis. It does not establish that mutant ubiquitin increases with age through molecular misreading or that this explains inefficient clearance in aging. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“studies in CHIP defective mice also support an important role for the UPS in longevity and health-span (Min et al., 2008)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
- Supportedcites Min et al., 2008 source
The Results report significantly reduced longevity in CHIP-deficient mice. The Discussion reports decreased UPS function alongside accelerated aging phenotypes and proposes impaired protein quality control as a possible mechanism affecting longevity. This supports the citing sentence’s qualified claim about longevity and health-span. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“mutations in the genes of the CUL-1 E3 ligase complex shorten the extended lifespan of different insulin signaling C. elegans mutants (Ghazi et al., 2007)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
- Partly supportedcites Ghazi et al., 2007 sourceExperimental — accuracy not yet measured
The Results report that RNAi depletion of cul-1 and skr-1/2 shortened the extended lifespan of several daf-2 mutant strains, and that a lin-23 mutation reduced lifespan extension in daf-2 mutants. The claim captures the lifespan finding but overstates the mutation evidence: the paper tested mutations in one CUL-1 complex gene, while it used RNAi to reduce the others. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the activity of other quality control mechanisms, such as macroautophagy and the UPS, is also improved in these animals (Zhang and Cuervo, 2008)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Supportedcites Zhang and Cuervo, 2008 source
The paper reports indirect evidence of improved macroautophagy in the livers of aged transgenic mice (passage 8, section labeled Abstract). It also reports that age-related declines in proteasome activity were absent in those mice and describes improved functioning of the proteolytic systems (passage 1, same section). (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“studies by other groups in worms and flies seem to support that functional macroautophagy is necessary to preserve normal lifespan (Juhasz et al., 2007; Morck and Pilon, 2006; Simonsen et al., 2007)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Supportedcites Juhasz et al., 2007 source
The Results section reports that loss of Atg7 reduced the lifespan of flies under normal conditions (Fig. 3E). The Abstract identifies Atg7 as a core autophagy regulator and says the mutants have severe autophagy defects. This paper supports the fly portion of the multi-citation claim; it does not need to establish the worm portion. (LLM, conf=0.93)
- Partly supportedcites Morck and Pilon, 2006 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) links increased autophagy in feeding-defective C. elegans mutants with increased longevity, but describes a role for autophagy in longevity as proposed. It does not show that functional autophagy is necessary to preserve normal lifespan. Its mention of flies in the Background concerns starvation-induced autophagy, not lifespan. (LLM, conf=0.84)
- Supportedcites Simonsen et al., 2007 source
In the paper’s discussion of Bchs-modifier mutants (page not supplied), Atg8a is identified as an autophagy-related gene, and Atg8a mutants are reported to have reduced adult lifespans in flies. This supports the fly portion of the multi-citation claim; the paper need not supply the worm evidence attributed collectively to the other citations. (LLM, conf=0.90)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The lifespan extension observed in worms mutant for the equivalent of the insulin-signaling pathway, such as daf-2, is drastically reduced when macroautophagy genes are knocked down (Hars et al., 2007; Melendez et al., 2003).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Supportedcites Hars et al., 2007 source
The results in the section labeled Abstract report that knocking down the autophagy genes atg-7 or atg-12 significantly shortened the lifespan of daf-2 mutant worms. Mean lifespan fell from about 18 days in controls to 13 or 11 days, respectively, supporting the claimed substantial reduction without implying that the lifespan advantage was eliminated. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites Melendez et al., 2003 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Functional macroautophagy has also proven necessary to attain the maximal lifespan extension mediated by mutations in other genes such as the nutrient-sensor TOR (Hansen et al., 2008), the tumor suppressor protein p53 (Tavernarakis et al., 2008) and even the lifespan prolonging effect of Sirt-1 (Morselli et al., 2010).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Supportedcites Hansen et al., 2008 source
Hansen et al. is cited for the TOR portion of the sentence, not the separately cited p53 or Sirt-1 portions. The Discussion (page not provided) states that autophagy genes are required for lifespan extension in TOR-pathway mutants. (LLM, conf=0.93)
- Supportedcites Tavernarakis et al., 2008 source
The p53 citation supports the p53 portion of the sentence, not the separately cited TOR or Sirt-1 portions. The Abstract reports that depleting the autophagy protein BEC-1 reduced the extended lifespan of C. elegans cep-1 mutants to approximately normal levels. (LLM, conf=0.93)
- Supportedcites Morselli et al., 2010 source
The citation to Morselli et al. is attached to the Sirt-1 portion of the sentence, not the TOR or p53 portions. In the section “The life span-prolonging effect of sirtuin-1 is mediated by autophagy” (page unavailable), the paper reports that sir-2.1 overexpression extends median and maximum lifespan in C. elegans, but that this gain is lost when the essential autophagy gene bec-1 is knocked down. (LLM, conf=0.94)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- It may state two separate claims as one. 17
- Probably not a substantial claim. 7
Every source the paper cites for this claim was checked and supports it.
In the paper
“worms lacking AIP-1, a homologue of the regulatory mammalian subunit AIRAP, exhibit shortened lifespan and hypersensitivity to misfolding proteins (Yun et al., 2008)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
- Supportedcites Yun et al., 2008 source
The Results report that aip-1 RNAi shortened mean worm lifespan from 16.6 to 10.6 days and accelerated paralysis caused by a misfolding-prone amyloid peptide. The paper identifies worm aip-1 as a homologue of mammalian AIRAP, a component of the proteasome’s 19S regulatory cap. The supplied passages do not provide page numbers. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“we have found that the activity of this autophagic pathway decreases in almost all tissues of old rodents and in senescent human fibroblasts in culture (Cuervo and Dice, 2000; Dice, 1982)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Partly supportedcites Cuervo and Dice, 2000 sourceExperimental — accuracy not yet measured
The Introduction says chaperone-mediated autophagy decreases in most tissues of old organisms, and the Discussion reports a decrease in senescent human fibroblasts in culture. The paper's own rodent results concern rat liver; it does not establish a decrease in almost all tissues of old rodents. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites Dice, 1982 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“marked increase in lifespan and enhance health-span in mice treated with rapamycin, a well-characterized inhibitor of mTOR (Harrison et al., 2009)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Partly supportedcites Harrison et al., 2009 sourceExperimental — accuracy not yet measured
The Abstract (page not provided) reports that rapamycin inhibits the mTOR pathway and extends median and maximal lifespan in male and female mice. It does not establish enhanced health-span: disease patterns did not differ from controls, and the authors say that determining whether ageing was slowed would require testing age-dependent changes in multiple tissues and processes. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Livers of mice with preserved CMA function show better cellular homeostasis, improved ability to respond to the cell damage induced by different stressors and their liver function is comparable to that of young mice (Zhang and Cuervo, 2008).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Supportedcites Zhang and Cuervo, 2008 source
The paper’s main text (indexed under Abstract; page unavailable) reports improved cellular homeostasis and ability to buffer cellular damage in aged mice with preserved CMA. It also reports that their recovery times in a liver-function assay were indistinguishable from those of young wild-type mice. The reference to different stressors is a broad paraphrase of the paper’s discussion of CMA responses to starvation, oxidation and other protein-damaging conditions. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Three different forms of autophagy have been described in mammalian cells: macroautophagy, microautophagy and chaperone-mediated autophagy (Fig. 3) (Cuervo, 2009; He and Klionsky, 2009; Mizushima et al., 2008).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Supportedcites Cuervo, 2009 source
The section “Autophagy: Cellular self-digestion with a purpose” states that three mechanisms coexist in most mammalian cells and names macroautophagy, microautophagy, and chaperone-mediated autophagy. The copy does not provide a page number for this passage. (LLM, conf=0.94)
- Partly supportedcites He and Klionsky, 2009 sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) describes autophagosomes in mammalian cells, supporting the macroautophagy portion of the claim. Our copy does not identify microautophagy or chaperone-mediated autophagy as the other two forms, or state the three-part classification (searched both terms and the three-form phrasing). (LLM, conf=0.84)
- Supportedcites Mizushima et al., 2008 source
The Abstract lists microautophagy, macroautophagy and chaperone-mediated autophagy as types of autophagy. Figure 1, “Different types of autophagy,” describes all three, supporting the cited classification; the supplied passages do not give page numbers. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“recent work in flies has shown that expression of specific autophagy genes prolongs lifespan and provides resistance to particular stressors (Simonsen et al., 2007)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Partly supportedcites Simonsen et al., 2007 sourceExperimental — accuracy not yet measured
The paper reports in its Abstract that mutations in several autophagy-related genes reduce adult fly lifespan, and its starvation-response section reports increased starvation sensitivity in atg8a mutants. These findings link the genes to longevity and stress response, but the paper does not show that expressing those genes prolongs lifespan or increases stress resistance. Its Bchs overexpression experiment concerns an eye phenotype, not either claimed benefit. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The two main components of this pathway, the ubiquitinization machinery – responsible for substrate targeting – and the proteasome core – where degradation takes place, undergo age-dependent changes that contribute to the lower efficiency of this system in old organisms and the consequent alterations in proteostasis.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“They have demonstrated the existence of a pool of metastable proteins in all cells, highly dependent on chaperones for their normal folding and function, and how these proteins can become unstable and aggregate in the presence of additional pathogenic proteins, such as those altered in protein conformational disorders (Gidalevitz et al., 2006).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 3. Molecular Chaperones in protein quality control > 3.3. Molecular chaperones in longevity and aging
What the sources say
- Not checked — no full text of the sourcecites Gidalevitz et al., 2006 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Many reports have shown different degrees of decrease in the activity of the proteasome with age in several tissues, although, in contrast to the lysosomal system, the decline in activity with age does not seem to be universal (Carrard et al., 2003; Ferrington et al., 2005; Keller et al., 2000 b; Shibatani et al., 1996).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Dysfunction of the quality control mechanisms and intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates occur in almost all tissues of an aged organism.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“In other tissues, constitutive levels of these enzymes are higher in the old animals that instead fail to upregulate their activity in response to stressors (Scrofano et al., 1998a)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.1. The ubiquitin/proteasome system
What the sources say
- Not checked — no full text of the sourcecites Scrofano et al., 1998a source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Preservation or enhancement of the activity of these surveillance systems until late in life improves their resistance to stress and is sufficient to slow down aging.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CMA is absent, or at least does not have the same components in unicellular organisms and invertebrates.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 5. Concluding remarks and the many open paths ahead
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The components of the quality control mechanisms are highly conserved through evolution, however, species-specific differences should be expected.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 5. Concluding remarks and the many open paths ahead
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is the first evidence in mammals that preventing the decline in autophagic activity slows down cellular aging and preserves organ function.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Cross-talk between chaperone families and among the different autophagic and non-autophagic pathways has been already demonstrated in different model systems.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 5. Concluding remarks and the many open paths ahead
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“although cargo sequestration by the double membrane vesicles still takes place in the old tissues, the elimination of these vesicles by fusion with the lysosomal compartment was severely impaired (Fig. 3) (Terman, 1995)”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
- Not checked — no full text of the sourcecites Terman, 1995 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Caloric restriction and treatment with lipogenic agents are able to prevent the dysregulation of macroautophagy in old rodents, although the mechanisms by which they exert their action is still subject of investigation (Cavallini et al., 2001; Donati et al., 2004).”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 4. Proteolytic systems > 4.2. The autophagic/lysosomal system
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“this coordinated function could explain why a small improvement in one of the components of the quality control in old organisms has such dramatic beneficial effects.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 5. Concluding remarks and the many open paths ahead
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Protein quality control is essential for proper cellular function and in the orchestration of an efficient cellular response to stress.”
§ Protein Homeostasis and Aging: the importance of exquisite quality control > 5. Concluding remarks and the many open paths ahead
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
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?
The cited source says what the claim attributes to it.
In the citing paper
“Proteostasis involves mechanisms for the stabilization of correctly folded proteins, most prominently the heat-shock family of proteins, and mechanisms for the degradation of proteins by the proteasome or the lysosome (Hartl et al., 2011; Koga et al., 2011; Mizushima et al., 2008).”
From The Hallmarks of Aging (2013) · cites this paper as Koga et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“Accordingly, many studies have demonstrated that proteostasis is altered with aging (Koga et al., 2011).”
From The Hallmarks of Aging (2013) · cites this paper as Koga et al., 2011
Citations
Cites
Aging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567
Autophagy fights disease through cellular self-digestion
Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008) · Nature · doi:10.1038/nature06639 · Cited by 6,452
Self-citationSignal integration in the endoplasmic reticulum unfolded protein response
Ron, D., & Walter, P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2199 · Cited by 6,431
Autophagy regulates lipid metabolism
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A. M., & Czaja, M. J. (2009) · Nature · doi:10.1038/nature07976 · Cited by 3,975
Self-citationSuppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006) · Nature · doi:10.1038/nature04724 · Cited by 3,882
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766
Regulation mechanisms and signaling pathways of autophagy
He, C., & Klionsky, D. J. (2009) · Annual Review of Genetics · doi:10.1146/annurev-genet-102808-114910 · Cited by 3,609
Loss of autophagy in the central nervous system causes neurodegeneration in mice
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-I., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006) · Nature · doi:10.1038/nature04723 · Cited by 3,500
Induction of autophagy and inhibition of tumorigenesis by beclin 1
Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., & Levine, B. (1999) · Nature · doi:10.1038/45257 · Cited by 3,347
The role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865
Cited by
Sorted by citations
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
Chiti, F., & Dobson, C. M. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045115 · Cited by 2,629
The amyloid state and its association with protein misfolding diseases.
Knowles, T. P. J., Vendruscolo, M., & Dobson, C. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3810 · Cited by 2,382
Genetics of longevity in model organisms: debates and paradigm shifts
Gems, D., & Partridge, L. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183712 · Cited by 499
Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock
Rando, T. A., & Chang, H. Y. (2012) · Cell · doi:10.1016/j.cell.2012.01.003 · Cited by 520
Metadata
- Authors
- Koga, H., Kaushik, S., & Cuervo, A. M.
- Affiliations
- Albert Einstein College of Medicine (US)
- Venue
- Ageing research reviews
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 10
- Issue
- 2
- Pages
- 205-215
- ISSN
- 1568-1637 (ISSN-L)
- PMC
- PMC2888802
- OpenAlex
- W2166415858
- Semantic Scholar
- 31476a7ef971f336d9599bbedc73d4e0b2b52147
- Cited by
- 476
- References
- 177
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 27 · 2023: 23 · 2022: 40 · 2021: 39 · 2020: 41 · 2019: 36 · 2018: 37 · 2017: 29 · 2016: 23 · 2015: 29 · 2014: 35 · 2013: 31 · 2012: 15
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (5t32ag023475-24)
- National Institute on Aging (P01 AG031782, R01AG021904, R37AG021904, 5U19AG023122, TG32 AG023475, AG-021904, AG031782)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK041918, P01 DK041918)
- National Institute of Neurological Disorders and Stroke (P50 NS038370, NS038370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- proteostasis, aging, protein quality control, molecular chaperones, proteolytic system, protein degradation, cellular stress response, protein aggregates, protein inclusions, longevity
- MeSH terms
- Aging, Autophagy, Homeostasis, Humans, Longevity, Proteins, Molecular Chaperones, Ubiquitin, Proteasome Endopeptidase Complex
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.
A language model drew the claims from the paper on 2026-10-21, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-21 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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 ›
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