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Cited by 476Heat shock proteins researchGenetics, Aging, and Longevity in Model OrganismsUbiquitin and proteasome pathways

Protein Homeostasis and Aging: the importance of exquisite quality control

Open access
Koga, Hiroshi, Kaushik, Susmita, Cuervo, Ana Maria·2011·Ageing research reviews
DOI 10.1016/j.arr.2010.02.001PMC PMC2888802
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Abstract

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.

AI snapshot

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.

Integrity signals

Registry

Crossref · 10.1016/j.arr.2010.02.001

Cites

176 of 176 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

31 of 61 cited sources checked · 18 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Activation of macroautophagy is a common feature of all the long-lived mutant worms, including the models for dietary restriction.

    “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).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Hansen et al., 2008 source

      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.

      Experimental — accuracy not yet measured
    • cites Hars et al., 2007 source

      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)

      Experimental — accuracy not yet measured
    • cites Melendez et al., 2003 source
  • Premisecitation

    Increased chaperone induction leads to increased longevity both in uni- and multicellular organisms.

    “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).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Lithgow et al., 1995 source

      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)

      Experimental — accuracy not yet measured
    • cites Shama et al., 1998 source
    • cites Tatar et al., 1997 source
  • Premisecitation

    Transcriptional downregulation of an E3 ligase has been reported in some aged tissues.

    “and an E3 ligase (Hawse et al., 2004) have been reported in some aged tissues.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hawse et al., 2004 source

      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)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Increased content with age of mutant forms of ubiquitin due to molecular misreading could be behind the inefficient clearance of polyubiquitinated proteins in aging.

    “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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Tsirigotis et al., 2001 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    Studies in CHIP defective mice support an important role for the UPS in longevity and health-span.

    “studies in CHIP defective mice also support an important role for the UPS in longevity and health-span (Min et al., 2008)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Min et al., 2008 source
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    Worms lacking AIP-1, a homologue of the regulatory mammalian subunit AIRAP, exhibit shortened lifespan and hypersensitivity to misfolding proteins.

    “worms lacking AIP-1, a homologue of the regulatory mammalian subunit AIRAP, exhibit shortened lifespan and hypersensitivity to misfolding proteins (Yun et al., 2008)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Yun et al., 2008 source

  • May combine two claims.

    Premisecitation

    The activity of chaperone-mediated autophagy decreases in almost all tissues of old rodents and in senescent human fibroblasts in culture.

    “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)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Cuervo and Dice, 2000 source

      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)

      Experimental — accuracy not yet measured
    • cites Dice, 1982 source

  • May combine two claims.

    Premisecitation

    Mice treated with rapamycin, a well-characterized inhibitor of mTOR, show marked increase in lifespan and enhanced health-span.

    “marked increase in lifespan and enhance health-span in mice treated with rapamycin, a well-characterized inhibitor of mTOR (Harrison et al., 2009)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Harrison et al., 2009 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Livers of mice with preserved CMA function show better cellular homeostasis, improved ability to respond to cell damage induced by different stressors, and liver function comparable to that of young mice.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zhang and Cuervo, 2008 source

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

    Premisecitation

    Three different forms of autophagy have been described in mammalian cells: macroautophagy, microautophagy and chaperone-mediated autophagy.

    “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).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Cuervo, 2009 source
    • cites He and Klionsky, 2009 source

      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)

      Experimental — accuracy not yet measured
    • cites Mizushima et al., 2008 source

  • May combine two claims.

    Premisecitation

    In flies, expression of specific autophagy genes prolongs lifespan and provides resistance to particular stressors.

    “recent work in flies has shown that expression of specific autophagy genes prolongs lifespan and provides resistance to particular stressors (Simonsen et al., 2007)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Simonsen et al., 2007 source

      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)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    The ubiquitinization machinery and the proteasome core undergo age-dependent changes that contribute to the lower efficiency of the ubiquitin/proteasome system in old organisms and consequent alterations in proteostasis.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A pool of metastable proteins exists in all cells, highly dependent on chaperones for their normal folding and function, and these proteins can become unstable and aggregate in the presence of additional pathogenic proteins.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gidalevitz et al., 2006 source

  • May combine two claims.

    Premisecitation

    Many reports show different degrees of decrease in the activity of the proteasome with age in several tissues, although the decline in activity with age does not seem to be universal.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Carrard et al., 2003 source
    • cites Ferrington et al., 2005 source
    • cites Keller et al., 2000 b source

  • May combine two claims.

    Premisenone given

    Dysfunction of quality control mechanisms and intracellular accumulation of abnormal proteins in the form of inclusions and aggregates occur in almost all tissues of an aged organism.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In other tissues, constitutive levels of these enzymes are higher in old animals, which fail to upregulate their activity in response to stressors.

    “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)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Scrofano et al., 1998a source

  • May combine two claims.

    Interpretationnone given

    Preservation or enhancement of the activity of surveillance systems until late in life improves resistance to stress and is sufficient to slow down aging.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    CMA is absent, or at least does not have the same components, in unicellular organisms and invertebrates.

    “CMA is absent, or at least does not have the same components in unicellular organisms and invertebrates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The components of the quality control mechanisms are highly conserved through evolution, but species-specific differences should be expected.

    “The components of the quality control mechanisms are highly conserved through evolution, however, species-specific differences should be expected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    This is the first evidence in mammals that preventing the decline in autophagic activity slows down cellular aging and preserves organ function.

    “This is the first evidence in mammals that preventing the decline in autophagic activity slows down cellular aging and preserves organ function.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Cross-talk between chaperone families and among the different autophagic and non-autophagic pathways has been demonstrated in different model systems.

    “Cross-talk between chaperone families and among the different autophagic and non-autophagic pathways has been already demonstrated in different model systems.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In old rodent livers, cargo sequestration by double membrane vesicles still takes place, but elimination of these vesicles by fusion with the lysosomal compartment is severely impaired.

    “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)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Terman, 1995 source

  • May combine two claims.

    Premisecitation

    Caloric restriction and treatment with lipogenic agents are able to prevent the dysregulation of macroautophagy in old rodents, although the mechanisms are still under investigation.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Cavallini et al., 2001 source
    • cites Donati et al., 2004 source

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

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Protein quality control is essential for proper cellular function and in the orchestration of an efficient cellular response to stress.

    “Protein quality control is essential for proper cellular function and in the orchestration of an efficient cellular response to stress.”
    Quote in the paperNot a substantial claim
20 of 20

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Related

Authors
Koga, H., Kaushik, S., & Cuervo, A. M.
Affiliations
Albert Einstein College of Medicine (US)
ORCID
Venue
Ageing research reviews
Publisher
Elsevier BV
Published
2011-04
Volume
10
Issue
2
Pages
205-215
ISSN
1568-1637 (ISSN-L)
DOI
10.1016/j.arr.2010.02.001
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
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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

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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 2026-10-21.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-21.

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