Protein Homeostasis and Aging: the importance of exquisite quality control

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).”

What the sources say

• Disputed

  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.

  cites Hansen et al., 2008 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Hars et al., 2007 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Melendez et al., 2003 source

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).”

What the sources say

• Partly supported

  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)

  cites Lithgow et al., 1995 sourceExperimental — accuracy not yet measured
• ?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

In the paper

“and an E3 ligase (Hawse et al., 2004) have been reported in some aged tissues.”

What the sources say

• ?Could not verify

  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)

  cites Hawse et al., 2004 sourceExperimental — accuracy not yet measured

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).”

What the sources say

• Partly supported

  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)

  cites Tsirigotis et al., 2001 sourceExperimental — accuracy not yet measured

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)”

What the sources say

• Supported

  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)

  cites Min et al., 2008 source

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)”

What the sources say

• Partly supported

  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)

  cites Ghazi et al., 2007 sourceExperimental — accuracy not yet measured

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)”

What the sources say

• Supported

  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)

  cites Zhang and Cuervo, 2008 source

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)”

What the sources say

• Supported

  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)

  cites Juhasz et al., 2007 source
• Partly supported

  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)

  cites Morck and Pilon, 2006 sourceExperimental — accuracy not yet measured
• Supported

  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)

  cites Simonsen et al., 2007 source

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).”

What the sources say

• Supported

  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)

  cites Hars et al., 2007 source
• ?Not checked — no full text of the sourcecites Melendez et al., 2003 source

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).”

What the sources say

• Supported

  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)

  cites Hansen et al., 2008 source
• Supported

  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)

  cites Tavernarakis et al., 2008 source
• Supported

  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)

  cites Morselli et al., 2010 source

In the paper

“the role of macroautophagy in lifespan extension mediated by caloric restriction has also been genetically confirmed in C. elegans (Jia and Levine, 2007)”

What the sources say

• Supported

  In “Autophagy and Dietary Restriction-Mediated Life Span Extension in C. elegans,” the authors call their results the first genetic evidence that autophagy is required for dietary restriction to extend C. elegans life span. The Abstract identifies the genetic basis: two essential autophagy genes are required for the longevity of a dietary-restriction mutant. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites Jia and Levine, 2007 source

In the paper

“our laboratory has recently prevented the age-dependent decrease of CMA in liver through genetic manipulations in mice (Zhang and Cuervo, 2008)”

What the sources say

• Supported

  The paper describes a transgenic mouse model that regulates liver expression of LAMP-2A (Abstract, Fig. 1a). With early activation, lysosomes from aged transgenic mice retained CMA substrate uptake rates similar to those of young wild-type mice (Fig. 1e–g), supporting prevention of the age-dependent decline in liver CMA. (LLM, conf=0.94)

  cites Zhang and Cuervo, 2008 source

In the paper

“Activation of an exogenously added copy of the CMA receptor in transgenic mice when its endogenous levels start to decrease prevents the decline in CMA activity in the old animals.”

What the sources say

• Supported

  The passage on early activation (labeled Abstract in our copy) says the added LAMP-2A gene was activated at six months, before the reported decline in receptor abundance at 9–12 months. It reports that liver lysosomes from aged transgenic mice retained CMA substrate uptake comparable to young wild-type mice, supporting preserved liver CMA activity. (LLM, conf=0.93)

  cites Zhang and Cuervo, 2008 source

In the paper

“decrease of some macroautophagy markers have been described in different tissues of rodents and in the aging human brain (Shibata et al., 2006)”

What the sources say

• Partly supported

  The section on Beclin 1 in post-mortem human brains reports that Beclin 1 mRNA and protein were about twofold lower in older than younger prefrontal cortex samples. The passages on rodent cells and mouse brains do not report an age-related decrease in macroautophagy markers across different rodent tissues, so that part of the claim is unsupported by our copy. (LLM, conf=0.87)

  cites Shibata et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

“Decreased macroautophagic activity with age has been described in different mammalian tissues (Cuervo, 2008; Cuervo et al., 2005).”

What the sources say

• Supported

  The section “Autophagy and aging: before the genetic dissection” explicitly reports reduced macroautophagic activity with age in rodent liver. “Enhancing autophagy as an anti-aging intervention” also discusses age-related changes in basal macroautophagy in heart and liver, supporting the claim that this has been described in different mammalian tissues. (LLM, conf=0.87)

  cites Cuervo, 2008 source
• Supported

  The section “WHO IS TO BLAME FOR THE AUTOPHAGIC DECLINE UPON AGING?” reports age-related decreases in autophagosome formation and elimination in different tissues of old animals. The “AGE-RELATED CHANGES IN AUTOPHAGY” section also says decreased macroautophagic proteolysis has been extensively reported. (LLM, conf=0.92)

  cites Cuervo et al., 2005 source

In the paper

“A step-by-step comparative analysis of CMA in livers of young and old rodents revealed a decrease with age in binding and lysosomal translocation of the substrate proteins, due to progressively lower levels of the CMA receptor at the lysosomal membrane with age (Cuervo and Dice, 2000).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Cuervo and Dice, 2000 source

In the paper

“recent studies with spermidine, a natural polyamine, have shown promising autophagy-dependent effects on yeast, flies and worms longevity and on mouse health-span (Eisenberg et al., 2009)”

What the sources say

• Partly supported

  The section on autophagy and lifespan extension reports that autophagy is crucial for spermidine-mediated longevity in yeast, flies and worms. The mouse experiment in the Articles section reports reduced age-related oxidative stress after spermidine supplementation, but does not establish that a mouse health-span benefit was autophagy-dependent. (LLM, conf=0.88)

  cites Eisenberg et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“All these examples support the hypothesis that a better capacity to adapt to various stresses, in which chaperones play a leading role, makes a major contribution to lifespan extension.”

In the paper

“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.”

In the paper

“Cultured fibroblasts from healthy centenarians have a more active proteasome (Chondrogianni et al., 2000)”

What the sources say

• ?Not checked — no full text of the sourcecites Chondrogianni et al., 2000 source

In the paper

“transcriptional downregulation of two ubiquitin-conjugating enzymes (Ruotolo et al., 2003)”

What the sources say

• ?Not checked — no full text of the sourcecites Ruotolo et al., 2003

In the paper

“Connections between longevity and the UPS have been established in different model systems.”

In the paper

“The reason behind the failure to upregulate chaperone transcription with age, at least in the case of hsp70, has been narrowed to the inability of HSF to bind the heat shock element on the chaperone gene promoter (Ambra et al., 2004; Heydari et al., 2000; Locke and Tanguay, 1996; Singh et al., 2006).”

What the sources say

• ?Not checked — no full text of the sourcecites Ambra et al., 2004 source
• ?Not checked — no full text of the sourcecites Heydari et al., 2000 source
• ?Not checked — no full text of the sourcecites Locke and Tanguay, 1996 source

In the paper

“Also in worms, defects in the regulatory components of the proteasome have an impact on lifespan.”

In the paper

“Proper proteasome function is required in the extension of lifespan observed in some of the long-lived worm mutants.”

In the paper

“A decrease in levels of free ubiquitin (Jahngen et al., 1990)”

What the sources say

• ?Not checked — no full text of the sourcecites Jahngen et al., 1990 source

In the paper

“In C. elegans, expression of RLE-1, an E3 ubiquitin ligase, regulates aging by determining degradation of DAF-16 by the UPS (Li et al., 2007).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Li et al., 2007

In the paper

“part of the anti-aging effect attained in human skin fibroblasts by hormesis through repeated exposure to mild stress could also be attributed to an increase in proteasome activities in these cells (Rattan and Ali, 2007)”

What the sources say

• ?Not checked — no full text of the sourcecites Rattan and Ali, 2007 source

In the paper

“In summary, functional decline of the UPS occurs with age”

In the paper

“A vast literature also supports that stress-induced synthesis of heat shock proteins is impaired in aging.”

In the paper

“cross-linked products that reach the lysosome through their sporadic fusion with the double membrane vesicles, exert a potent inhibitory effect on lysosomal proteolysis by directly inducing undesired posttranslational modifications in the enzymatic machinery and also by changing the properties of the intralysosomal milieu, normally optimal for functioning of these enzymes (Brunk and Terman, 2002;”

What the sources say

• ?Not checked — no full text of the sourcecites Brunk and Terman, 2002 source
• ?Not checked — no full text of the sourcecites Terman and Brunk 1998 source

In the paper

“The first genetic connection between autophagy and aging was established in worms.”

In the paper

“it is premature to attribute the beneficial effect observed with the rapamycin treatment to the stimulatory effect of this drug on macroautophagy, because inhibition of this major cellular kinase should also affect other cellular functions such as mRNA translation, ribosome biogenesis, angiogenesis, mitochondrial metabolism, adipogenesis and cellular growth (Dennis et al., 2001)”

What the sources say

• ?Not checked — no full text of the sourcecites Dennis et al., 2001 source

In the paper

“Studies on the regulation of macroautophagy, also in liver of old rodents, identified alterations in the hormonal regulation of this process (Bergamini and Kovacs, 1990).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Bergamini and Kovacs, 1990

In the paper

“Other factors that promote longevity in invertebrates, such as the Foxo family of Forkhead transcription factors, also upregulate macroautophagy (Salih and Brunet, 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Salih and Brunet, 2008 source

In the paper

“Changes with age in the lipid composition of the lysosomal membrane are likely behind the instability of LAMP-2A in old organisms (Kiffin et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Kiffin et al., 2007 source

In the paper

“the macroautophagic defect seems to be also tissue-dependent (Wohlgemuth et al., 2007)”

What the sources say

• ?Not checked — no full text of the sourcecites Wohlgemuth et al., 2007 source

In the paper

“the lack of information on this pathway in species commonly used for genetic manipulations such as flies and worms, has not permitted to generate genetic evidence linking this autophagic pathway with longevity”

In the paper

“Growing evidence supports that functional decline of the different components of the proteostasis network is one of the essential factors that contribute to cellular and organism aging.”

In the paper

“maintained UPS activity is required to attain maximal lifespan extension in long-lived mutants”

In the paper

“In old organisms the stimulatory effect of glucagon is compromised mostly due to increased basal signaling activity from the insulin receptor with age (Fig. 3) (Bergamini et al., 1994; Marino et al., 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Bergamini et al., 1994 source
• ?Not checked — no full text of the sourcecites Marino et al., 1998 source

In the paper

“underlying an important role for this proteolytic system in lifespan.”