DNA Repair, Genome Stability, and Aging
Open accessAbstract
Aging can be defined as progressive functional decline and increasing mortality over time. Here, we review evidence linking aging to nuclear DNA lesions: DNA damage accumulates with age, and DNA repair defects can cause phenotypes resembling premature aging. We discuss how cellular DNA damage responses may contribute to manifestations of aging. We review Sir2, a factor linking genomic stability, metabolism, and aging. We conclude with a general discussion of the role of mutant mice in aging research and avenues for future investigation.
Verified 2026-10-06 · 29 references not checked yet
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that nuclear DNA damage accumulates with age and that defects in DNA repair produce premature-aging phenotypes in mice and humans, with p53-mediated senescence and apoptosis as a shared downstream mechanism. It also reviews Sir2/SIRT1 as a link between genome stability, metabolism, and life span.
Key findings
- DNA damage and mutations accumulate with age in mammals; cytogenetically visible lesions (translocations, insertions, dicentrics, acentric fragments) increase in aging cells, and mutation spectra vary considerably between tissues.
- Many premature-aging syndromes arise from mutations in DNA repair genes: ATM (Ataxia-Telangiectasia), CSA/CSB (Cockayne syndrome), XPD (trichothiodystrophy), WRN (Werner syndrome), plus mouse hypomorphs in Rad50 and BRCA1 and NHEJ mutants (Ku80, DNA-PKcs).
- Aging-like phenotypes in Rad50s/s, BRCA1Δ11/Δ11/p53+/−, and several NHEJ mutants are largely p53-dependent responses to unrepaired damage rather than direct consequences of the lesions; p53 deficiency rescues premature senescence and neuronal apoptosis but not small size.
- Sir2 links genome stability, metabolism, and life span: loss of Sir2 increases rDNA recombination and shortens yeast life span, while an extra copy extends it; overexpression or pharmacologic activation of Sir2 extends life span in worms and flies.
Methods
- Narrative review, not primary research. The authors synthesize evidence from yeast, C. elegans, Drosophila, mouse models, and human progeroid syndromes.
- Focus is on nuclear (not mitochondrial) DNA damage in mammalian aging, emphasizing recent mouse models; mitochondrial ROS is deferred to the companion Balaban et al. review in the same issue.
- Key evidence discussed includes mouse DNA repair/metabolism mutants with aging features (Table 1), features of normal aging in wild-type mice (Table 2), and pathway diagrams for DSB repair (NHEJ, HR) and NER.
Limitations
- Stated: the evidence that cellular senescence plays a role in aging is correlative, and "a causal relationship between cellular senescence and organismal aging has yet to be proved."
- Stated: premature aging models are "segmental progerias" that reproduce only some aspects of aging, and the histopathology of normal aging corresponds poorly with changes in these models; genetic background, housing, infection, and diet likely modify phenotypes.
- Stated: it is unclear why only certain DNA repair mutants in particular pathways show progeroid phenotypes, and many implicated factors have roles beyond DNA repair; measurement of ROS and oxidative damage is experimentally difficult, with discrepant estimates of oxidatively damaged DNA.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 153 cited sources checked · 0 supported · 0 flagged
- Premisecitation§ Introduction
Uncapped telomeres are recognized by the cell cycle checkpoint machinery as DNA damage, leading to cell cycle arrest.
“Such uncapped telomeres are then recognized by the cell cycle checkpoint machinery as DNA damage, leading to cell cycle arrest (Ben-Porath and Weinberg, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ben-Porath and Weinberg, 2004 source
Not checked in the free run.
- Premisecitation§ Introduction
Caloric restriction likely decreases ROS production.
“Caloric restriction, an intervention that extends life span in many organisms, likely decreases ROS production (Barja, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Barja, 2004 source
Not checked in the free run.
- Premisecitation§ Introduction
In many primary human cell lines, replicative senescence occurs secondary to attrition of telomeres, in a process termed intrinsic senescence.
“In many primary human cell lines, replicative senescence occurs secondary to attrition of the ends of the chromosomes, the telomeres, in a process termed “intrinsic senescence” (Itahana et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Itahana et al., 2004 source
Not checked in the free run.
- Premisecitation§ Introduction
Many mutations in DNA repair genes that cause premature aging phenotypes also confer premature replicative senescence.
“many mutations in DNA repair genes that cause premature aging phenotypes also confer premature replicative senescence (Table 1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table 1
Not checked in the free run.
- Premisecitation§ Introduction
Mutation spectra vary considerably between different tissues.
“Such analyses have revealed considerable variation in mutation spectra between different tissues.”
Quote in the paperNot a substantial claim
- Premisecitation§ Introduction
In model organisms, many mutations that promote longevity concomitantly increase oxidative stress resistance.
“In model organisms, many mutations that promote longevity concomitantly increase oxidative stress resistance (Finkel and Holbrook, 2000”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Finkel and Holbrook, 2000
Not checked in the free run.
- Premisecitation§ Introduction
Terc deficiency in mice leads to progressive telomere attrition in successive mouse generations.
“Terc deficiency in mice leads to progressive telomere attrition in successive mouse generations”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Espejel and Blasco, 2002
Not checked in the free run.
- Interpretationreasoning§ Introduction
It is difficult to accurately measure ROS and oxidative damage experimentally.
“This highlights the difficulty of accurately measuring ROS and oxidative damage experimentally.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
Late-generation Terc-deficient mice show some signs of accelerated aging.
“Of note, late-generation Terc-deficient mice show some signs of accelerated aging (Lee et al., 1998; Rudolph et al., 1999”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ Introduction
Critically short telomeres trigger the onset of senescence through a process that may involve loss of the t loop structure and/or loss of protective proteins.
“Critically short telomeres trigger the onset of senescence through a process that may involve loss of the t loop structure and/or loss of protective proteins (referred to as “uncapping”).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ben-Porath and Weinberg, 2004 source
Not checked in the free run.
- Interpretationnone given§ Introduction
The efficiency of cellular DNA repair machinery itself may decline with age.
“As outlined below, the efficiency of cellular DNA repair machinery itself may decline with age.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Levels of 8-oxoguanine (oxo8dG), a major product of oxidative damage to DNA, accumulate with age.
“In addition, levels of 8-oxoguanine (oxo8dG), a major product of oxidative damage to DNA, accumulate with age (Hamilton et al., 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hamilton et al., 2001 source
Not checked in the free run.
- Premisecitation§ Introduction
Cytogenetically visible lesions such as translocations, insertions, dicentrics, and acentric fragments accumulate in aging mammalian cells.
“Cytogenetically visible lesions such as translocations, insertions, dicentrics, and acentric fragments also accumulate in aging mammalian cells.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vijg, 2000 source
Not checked in the free run.
- Premisecitation§ Introduction
There is some evidence that the intrinsic fidelity and activity of DNA repair systems in different species may influence the rate of age-associated functional decline.
“There is some evidence that the intrinsic fidelity and activity of such systems in different species may influence the rate of age-associated functional decline (Hart and Setlow, 1974”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hart and Setlow, 1974 source
Not checked in the free run.
- Premisecitation§ Introduction
Mice heterozygous for a mutation in Sod2 accumulate higher levels of nuclear and mitochondrial 8oxodG with age.
“despite accumulating higher levels of nuclear and mitochondrial 8oxodG with age (Van Remmen et al., 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Van Remmen et al., 2003 source
Not checked in the free run.
- Interpretationcitation§ Introduction
The high levels of oxidative DNA damage found by Lu et al. are at odds with other much lower estimates of the amount of oxidatively damaged DNA in cells.
“However, the high levels of oxidative DNA damage found by these investigators is at odds with other much lower estimates of the amount of oxidatively damaged DNA in cells (Hamilton et al., 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hamilton et al., 2001 source
Not checked in the free run.
- Premisecitation§ Introduction
Perturbations in ATM function can lead to symptoms of accelerated aging.
“Perturbations in ATM function can lead to symptoms of accelerated aging.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Shiloh and Kastan, 2001
Not checked in the free run.
- Premisecitation§ Introduction
ROS and many other DNA-damaging agents can cause cells to enter senescence.
“ROS and many other DNA-damaging agents can cause cells to enter a state of irreversible cell cycle arrest accompanied by characteristic morphologic and functional alterations, termed senescence (Ben-Porath and Weinberg, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ben-Porath and Weinberg, 2004 source
Not checked in the free run.
- Premisecitation§ Introduction
Among long-lived mutants, the correlation with oxidative stress resistance is frequent but not universal.
“Among long-lived mutants, the correlation with oxidative stress resistance is a frequent but not universal one”
Quote in the paperNot a substantial claim - Premisenone given§ Introduction
An important target of ATM is the p53 protein.
“An important target of ATM is the p53 protein, which plays a role in the cellular response to numerous genotoxic insults including DSBs.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
Telomere shortening in human cells is accelerated by elevated levels of oxidative stress.
“and telomere shortening in these cells is itself accelerated by elevated levels of oxidative stress.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
In some mutants, longevity occurs despite unchanged resistance to ROS or other forms of stress.
“in some mutants, longevity occurs despite unchanged resistance to ROS or other forms of stress.”
Quote in the paperNot a substantial claim - Premisenone given§ Introduction
In many types of human cells, including fibroblasts, telomeres shorten with each successive generation.
“In many types of human cells, including fibroblasts, telomeres shorten with each successive generation.”
Quote in the paperNot a substantial claim - Premisenone given§ Introduction
In mice and humans, mutations in certain DNA repair genes lead to phenotypes that, in some respects, caricature aging.
“In mice and humans, mutations in certain DNA repair genes lead to phenotypes that, in some respects, caricature aging.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Table 1
Not checked in the free run.
- cites Table 2
Not checked in the free run.
- Premisecitation§ Introduction
Terc deficiency in mice leads to rapid senescence in embryonic fibroblasts derived from late-generation animals.
“and rapid senescence in embryonic fibroblasts derived from late-generation animals (Espejel and Blasco, 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Espejel and Blasco, 2002
Not checked in the free run.
- Premisenone given§ Introduction
Bmi1 appears to control levels of hematopoietic stem cells via negatively regulating the induction of senescence specifically in these stem cells.
“the Polycomb group repressor Bmi1 appears to control levels of hematopoietic stem cells via negatively regulating the induction of senescence specifically in these stem cells.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
Many mouse and human models of premature aging are accompanied by premature cellular senescence in vitro.
“and many mouse and human models of premature aging are accompanied by premature cellular senescence in vitro (Table 1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table 1
Not checked in the free run.
- Premisecitation§ Introduction
Senescence of wild-type MEFs occurs primarily in response to oxidative DNA damage incurred during cell culture.
“Instead, senescence of wild-type MEFs occurs primarily in response to oxidative DNA damage incurred during cell culture (Parrinello et al., 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Parrinello et al., 2003 source
Not checked in the free run.
- Interpretationreasoning§ Introduction
Senescence can be induced by a variety of different types of cellular injury.
“It is now clear that senescence can be induced by a variety of different types of cellular injury (Figure 1).”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Introduction
MEFs ordinarily do not senesce due to telomeric attrition.
“Thus, MEFs ordinarily do not senesce due to telomeric attrition.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Introduction
Differences in mutation spectra between tissues likely reflect functional characteristics of those tissues, such as mitotic rate, transcriptional activity, metabolism, and the action of specific DNA repair systems.
“These differences likely reflect functional characteristics of those tissues, such as mitotic rate, transcriptional activity, metabolism, and the action of specific DNA repair systems.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
Mice heterozygous for a mutation in Sod2 live out a normal lifespan.
“Additionally, mice heterozygous for a mutation in the mitochondrial enzyme that processes superoxide, Sod2, live out a normal lifespan”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Van Remmen et al., 2003 source
Not checked in the free run.
- Interpretationcitation§ Introduction
Various lines of evidence suggest that p53 plays opposing roles in the aging process.
“Various lines of evidence suggest that p53 plays opposing roles in the aging process.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Introduction
The premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants occur as a response to, rather than as a direct consequence of, unrepaired DSBs.
“Thus, the former phenotypes occur as a response to, rather than as a direct consequence of, unrepaired DSBs (Ferguson and Alt, 2001”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ferguson and Alt, 2001 source
Not checked in the free run.
- Premisecitation§ Introduction
The phenotypes of ATM deficiency are influenced by environmental conditions.
“The phenotypes of ATM deficiency are influenced by environmental conditions.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Introduction
NHEJ promotes telomeric fusions in some circumstances.
“NHEJ also promotes telomeric fusions in some circumstances.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Espejel et al., 2002a, 2002b; Smogorzewska et al., 2002
Not checked in the free run.
- Interpretationreasoning§ Introduction
p53 function may display antagonistic pleiotropy.
“Thus, p53 function may display antagonistic pleiotropy (Campisi, 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Campisi, 2002 source
Not checked in the free run.
- Premisecitation§ Introduction
Targeted ablation of Ku70 results in dramatically reduced Ku80 levels.
“targeted ablation of Ku70 results in dramatically reduced Ku80 levels (Gu et al., 1997”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gu et al., 1997
Not checked in the free run.
- Premisecitation§ Introduction
p66Shc promotes cell death in response to oxidative stress.
“it promotes cell death in response to oxidative stress”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Migliaccio et al., 1999 source
Not checked in the free run.
- Premisecitation§ Introduction
The premature cellular senescence phenotype of ATM deficiency is rescued by p53 deficiency.
“In this context, the premature cellular senescence phenotype of ATM deficiency is rescued by p53 deficiency (Xu et al., 1998”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xu et al., 1998
Not checked in the free run.
- Premisecitation§ Introduction
p66Shc increases constitutive intracellular ROS levels.
“it increases constitutive intracellular ROS levels”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Migliaccio et al., 1999 source
Not checked in the free run.
- Premisecitation§ Introduction
A line of Ku80-deficient mice prematurely exhibits age-specific changes including osteopenia, atrophic skin, liver lesions, and shortened life span.
“a line of Ku80-deficient mice prematurely exhibits age-specific changes including osteopenia, atrophic skin, liver lesions, and shortened life span (Vogel et al., 1999”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vogel et al., 1999 source
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
- Premisecitation§ Introduction
Increased telomere end-to-end fusions in the setting of telomeric attrition associated with Terc deficiency or inhibition of TRF2 are eliminated in NHEJ-deficient backgrounds.
“Increased telomere end-to-end fusions are observed in the setting of the telomeric attrition associated with Terc deficiency or inhibition of TRF2, a protein thought to function in end capping, and these end-to-end fusions are eliminated in NHEJ-deficient backgrounds (Espejel et al., 2002a, 2002b; Smogorzewska et al., 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Espejel et al., 2002a, 2002b; Smogorzewska et al., 2002
Not checked in the free run.
- Premisecitation§ Introduction
p53-dependent responses are critical in mediating the premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants.
“p53-dependent responses are critical in mediating the premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants (Ferguson and Alt, 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ferguson and Alt, 2001 source
Not checked in the free run.
- Interpretationreasoning§ Introduction
Genomic instability or DNA repair defects of ATM deficiency could contribute to the aging-like features of this disorder.
“Genomic instability or DNA repair defects of ATM deficiency could contribute to the aging-like features of this disorder (see below).”
Quote in the paperSubstantial claim - Interpretationcitation§ Introduction
The lack of a consistent aging-like phenotype in other lines of long-lived Ku-, DNA-PKcs-, or Artemis-deficient mice is difficult to explain if NHEJ plays a general role in delaying manifestations of aging.
“the lack of a consistent aging-like phenotype in other lines of long-lived Ku-, DNA-PKcs-, or Artemis-deficient mice is difficult to explain if NHEJ plays a general role in delaying manifestations of aging (Karanjawala and Lieber, 2004”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Karanjawala and Lieber, 2004
Not checked in the free run.
- Interpretationcitation§ Introduction
Only nonphysiologic activation of p53 leads to progeria.
“Only nonphysiologic activation of p53 leads to progeria, as mice expressing extra copies of wild-type p53 under the control of its own promoter do not show signs of premature aging (Garcia-Cao et al., 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Garcia-Cao et al., 2002 source
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
- Premisecitation§ Introduction
Mice with targeted inactivating mutations in NHEJ genes display phenotypes that reflect loss of these functions.
“Mice with targeted inactivating mutations in NHEJ genes display phenotypes that reflect loss of these functions (Ferguson and Alt, 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ferguson and Alt, 2001 source
Not checked in the free run.
- Interpretationcitation§ Introduction
Human AT patients may show aging-like effects, at least in part, as a consequence of telomeric dysfunction, an effect that ordinarily may be masked in the mouse due to the long telomeres of this organism.
“Thus, human AT patients may show aging-like effects, at least in part, as a consequence of telomeric dysfunction, an effect that ordinarily may be masked in the mouse due to the long telomeres of this organism.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Phenotypes resembling accelerated aging have been described in one strain each of Ku80- and DNA-PKcs-deficient mice.
“The observation that phenotypes resembling accelerated aging have been described in one strain each of Ku80- and DNA-PKcs-deficient mice potentially supports this model.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Vogel et al., 1999 source
Not checked in the free run.
- cites Espejel et al., 2004b
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
- Interpretationreasoning§ Introduction
Given the lack of an AT-like phenotype of the Sod2+/− mouse, progeroid features of ATM deficiency likely reflect more than increased ROS levels.
“However, given the lack of an AT-like phenotype of the Sod2+/− mouse, progeroid features of ATM deficiency likely reflect more than increased ROS levels.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
The frequency of thymic lymphoma varies among different strains of ATM-deficient mice.
“Additionally, the frequency of thymic lymphoma varies among different strains of ATM-deficient mice, a finding that might reflect different background mutations and/or housing conditions and the types of pathogens present (Petiniot et al., 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Petiniot et al., 2002 source
Not checked in the free run.
- Premisecitation§ Introduction
Genetic studies support the notion that NHEJ plays an important role in the repair of ROS-induced DNA lesions.
“genetic studies support the notion that NHEJ plays an important role in the repair of ROS-induced DNA lesions (Karanjawala and Lieber, 2004”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Karanjawala and Lieber, 2004
Not checked in the free run.
- Premisecitation§ Introduction
MEFs deficient for XRCC4, Ligase IV, Ku70, or Ku80 (but not DNA-PKcs or Artemis) senesce prematurely in culture.
“MEFs deficient for XRCC4, Ligase IV, Ku70, or Ku80 (but not DNA-PKcs or Artemis) senesce prematurely in culture”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ferguson and Alt, 2001 source
Not checked in the free run.
- Premisecitation§ Introduction
Ku80-deficient mice have a low rate of mutations at a marker locus.
“Ku80-deficient mice are found to have a low rate of mutations at a marker locus (Rockwood et al., 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Rockwood et al., 2003 source
Not checked in the free run.
- Interpretationreasoning§ Introduction
By ligating uncapped telomeres, NHEJ may promote genomic instability.
“Thus, by ligating uncapped telomeres, NHEJ may actually promote genomic instability.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Neurological dysfunction in the ATM-deficient mouse model can be ameliorated via antioxidant treatment.
“Neurological dysfunction in this model can similarly be ameliorated via antioxidant treatment (Browne et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Browne et al., 2004 source
Not checked in the free run.
- Premisecitation§ Introduction
At least three core NHEJ factors, namely Ku70, Ku80, and DNA-PKcs, localize to telomeres.
“at least three core NHEJ factors, namely Ku70, Ku80, and DNA-PKcs, localize to telomeres (d'Adda di Fagagna et al., 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites d'Adda di Fagagna et al., 2001 source
Not checked in the free run.
- Premisecitation§ Introduction
In the ATM-deficient mouse, the onset of T cell lymphoma can be delayed by treatment with an antioxidant.
“In the ATM-deficient mouse, the onset of T cell lymphoma can be delayed by treatment with an antioxidant, suggesting that dietary factors impact on the expression of this condition (Schubert et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schubert et al., 2004 source
Not checked in the free run.
- Premisecitation§ Introduction
Stalled RNA polymerase provides a signal for activation of p53-dependent apoptosis.
“Stalled RNA polymerase provides a signal for activation of p53-dependent apoptosis (Ljungman and Lane, 2004”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ljungman and Lane, 2004
Not checked in the free run.
- Premisecitation§ Introduction
TTD patients show defects in transcription of hair- and skin-specific transcripts (and perhaps other mRNAs).
“These patients show defects in transcription of hair- and skin-specific transcripts (and perhaps other mRNAs) (Bergmann and Egly, 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bergmann and Egly, 2001
Not checked in the free run.
- Premisecitation§ Introduction
Late generation Terc-deficient mice have an uncharacterized DSB repair defect.
“Late generation Terc-deficient mice have an uncharacterized DSB repair defect (Wong et al., 2000”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wong et al., 2000 source
Not checked in the free run.
- Premisecitation§ Introduction
Baseline p53 protein levels are higher in BRCA1Δ11/Δ11/p53+/− mice than in p53+/− control animals.
“Baseline p53 protein levels are higher in BRCA1Δ11/Δ11/p53+/− mice than in p53+/− control animals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cao et al., 2003b
Not checked in the free run.
- Premisecitation§ Introduction
Ku80/Terc and DNA-PKcs/Terc double deficient mice show exacerbation of intestinal atrophy and other aging-like phenotypes of Terc deficiency.
“Ku80/Terc and DNA-PKcs/Terc double deficient mice show exacerbation of intestinal atrophy and other aging-like phenotypes of Terc deficiency (Espejel et al., 2004a”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Espejel et al., 2004a
Not checked in the free run.
- Interpretationcitation§ Introduction
In the setting of impaired transcription and/or TC-NER, a total lack of NER is extremely deleterious.
“suggesting that in the setting of impaired transcription and/or TC-NER, a total lack of NER is extremely deleterious.”
Quote in the paperSubstantial claim- Rests on an assumption: XPDTTD/XPA double mutants show a much more rapid degenerative phenotype than XPDTTD single mutants.
- Premisecitation§ Introduction
Some human patients and mouse strains with defects in different NER factors have phenotypes reminiscent of premature aging.
“Numerous human patients and mouse strains with defects in different NER factors exist, and some have phenotypes reminiscent of premature aging (Mitchell et al., 2003”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Mitchell et al., 2003 source
Not checked in the free run.
- Premisecitation§ Introduction
The human disease WS represents the best model for premature aging in humans.
“The human disease WS represents the best model for premature aging in humans (Goto, 1997”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Goto, 1997 source
Not checked in the free run.
- Interpretationreasoning§ Introduction
These observations argue against a simple relationship between mitotic status and dependence on NHEJ in the suppression of aging.
“These observations argue against a simple relationship between mitotic status and dependence on NHEJ in the suppression of aging.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
CSA- and CSB-deficient mice show much milder phenotypes than their human counterparts.
“CSA- and CSB-deficient mice show much milder phenotypes than their human counterparts (Mitchell et al., 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mitchell et al., 2003 source
Not checked in the free run.
- Premisecitation§ Introduction
WS cells senesce prematurely in culture.
“WS cells senesce prematurely in culture.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Goto, 1997 source
Not checked in the free run.
- Interpretationreasoning§ Introduction
In both Rad50s/s and BRCA1Δ11/Δ11/p53+/− mice, signs of premature aging occur as a consequence of p53-mediated responses to unrepaired DNA damage.
“Thus, in both the Rad50s/s and BRCA1Δ11/Δ11/p53+/− mice, signs of premature aging occur as a consequence of the p53-mediated responses to unrepaired DNA damage.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
WRN may be involved in multiple DNA repair pathways.
“WRN plays a role in the maintenance of overall genomic stability, and WRN may be involved in multiple DNA repair pathways (Bachrati and Hickson, 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bachrati and Hickson, 2003
Not checked in the free run.
- Premisenone given§ Introduction
Rad50 and BRCA1 appear linked to aging-like phenotypes in mouse models.
“Two factors with roles in HR, Rad50 and BRCA1 (breast cancer susceptibility gene-1), appear linked to aging-like phenotypes in mouse models.”
Quote in the paperNot a substantial claim- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
- Premisecitation§ Introduction
Homozygous inactivation of BRCA1 results in early embryonic lethality.
“Homozyogous inactivation of BRCA1 results in early embryonic lethality (Valerie and Povirk, 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Valerie and Povirk, 2003
Not checked in the free run.
- Premisecitation§ Introduction
Mice bearing a targeted mutation in XPD that recapitulates a human TTD mutation show similar manifestations to human TTD patients.
“Mice bearing a targeted mutation in XPD that recapitulates a human TTD mutation show similar manifestations to human TTD patients.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites de Boer et al., 2002 source
Not checked in the free run.
- Interpretationreasoning§ Introduction
Multiple functions of XPD are defective in TTD patients.
“suggesting that multiple functions of XPD are defective in these individuals.”
Quote in the paperSubstantial claim- Rests on an assumption: Cells derived from TTD patients show NER defects.
- Premisecitation§ Introduction
WRN-deficient mice do not recapitulate human WS.
“WRN-deficient mice do not recapitulate human WS (Bachrati and Hickson, 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bachrati and Hickson, 2003
Not checked in the free run.
- Premisecitation§ Introduction
Introduction of telomerase into WS fibroblasts can rescue their premature senescence.
“introduction of telomerase into WS fibroblasts can rescue their premature senescence (Wyllie et al., 2000”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wyllie et al., 2000 source
Not checked in the free run.
- Interpretationcitation§ Introduction
Recent experiments using mice bearing targeted mutations in WRN provide evidence that, with respect to aging, the most relevant sites of WRN function are the telomeres.
“Recent experiments using mice bearing targeted mutations in WRN provide evidence that, with respect to aging, the most relevant sites of WRN function are the telomeres.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Introduction
The aging-like phenotypes in human CS patients and in XPDTTD, XPDTTD/XPA, and CSB/XPA mouse mutants may be explained by failure to repair lesions in transcribed genes causing cell death, tissue attrition, and aging.
“The aging-like phenotypes in human CS patients and in XPDTTD, XPDTTD/XPA, and CSB/XPA mouse mutants may be explained by the fact that a failure to repair lesions in transcribed genes can result in cell death, leading to tissue attrition and aging.”
Quote in the paperSubstantial claim - Premisenone given§ Introduction
Lesions in some factors involved in NER can lead to premature aging syndromes in mice and humans.
“lesions in some factors involved in NER can lead to premature aging syndromes in mice and humans.”
Quote in the paperSubstantial claim- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
- Interpretationcitation§ Introduction
Failure to repair lesions in transcribed genes can result in cell death.
“a failure to repair lesions in transcribed genes can result in cell death”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
The attrition of the hematopoietic and male germ cell lineages in Rad50s/s mice occurs in large measure due to p53-mediated signaling triggered by genomic instability.
“The attrition of the hematopoietic and male germ cell lineages occurs in large measure due to p53-mediated signaling triggered by genomic instability (Bender et al., 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bender et al., 2002 source
Not checked in the free run.
- Premisecitation§ Introduction
Targeted inactivation of either Ku80 or DNA-PKcs, but not Ligase IV or XRCC4, demonstrates synthetic lethality with ATM deficiency.
“targeted inactivation of either Ku80 or DNA-PKcs, but not in Ligase IV or XRCC4, demonstrates synthetic lethality with ATM deficiency.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sekiguchi et al., 2001 source
Not checked in the free run.
- Premisenone given§ Introduction
Degenerative changes in afflicted strains of DNA-PKcs- and Ku80-deficient mice affect only a limited subset of organs.
“The degenerative changes in afflicted strains of DNA-PKcs- and Ku80-deficient mice affect only a limited subset of organs.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
WRN plays a role in the maintenance of overall genomic stability.
“WRN plays a role in the maintenance of overall genomic stability, and WRN may be involved in multiple DNA repair pathways (Bachrati and Hickson, 2003”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bachrati and Hickson, 2003
Not checked in the free run.
- Premisecitation§ Introduction
The phenotype of BRCA1Δ11/Δ11/p53+/− mice results from p53-dependent responses to unrepaired DNA damage.
“There is compelling evidence that this phenotype results from p53-dependent responses to unrepaired DNA damage (Cao et al., 2003b”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cao et al., 2003b
Not checked in the free run.
- Premisecitation§ Introduction
Mice deficient in both CSB and XPA die within a few weeks after birth.
“Similarly, mice deficient in both CSB and XPA also die within a few weeks after birth”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Murai et al., 2001 source
Not checked in the free run.
- Interpretationnone given§ Introduction
Defects in proteins with less well-defined functions in DNA repair can lead to aging phenotypes.
“Defects in proteins with less well-defined functions in DNA repair can lead to aging phenotypes as well.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
Human WS cells show telomeric instability.
“human WS cells show telomeric instability (Schulz et al., 1996; Tahara et al., 1997”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Introduction
Genomic instability is detectable in cells derived from Rad50s/s mice.
“Genomic instability is detectable in cells derived from this animal.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bender et al., 2002 source
Not checked in the free run.
- Premisecitation§ Introduction
Sir2-driven increased longevity in C. elegans requires the Daf-16 transcription factor.
“Sir2-driven increased longevity in C. elegans requires the Daf-16 transcription factor (Tissenbaum and Guarente, 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tissenbaum and Guarente, 2001
Not checked in the free run.
- Premisecitation§ Introduction
Premature senescence of human WS fibroblasts is p53 dependent.
“the premature senescence of human WS fibroblasts is p53 dependent (Davis et al., 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Davis et al., 2003 source
Not checked in the free run.
- Premisecitation§ Introduction
The excision and replication of rDNA circles is an important cause of mortality in yeast when life span is measured by number of divisions a mother cell undergoes.
“The excision and replication of rDNA circles is an important cause of mortality in yeast when life span is measured in this fashion (Sinclair and Guarente, 1997”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sinclair and Guarente, 1997 source
Not checked in the free run.
- Interpretationreasoning§ Conclusions
The impact of DNA lesions may be enhanced by age-related compromise of DNA repair.
“the impact of such lesions may be enhanced by age-related compromise of DNA repair.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Introduction
Cellular checkpoint functions may be involved in producing the clinical features of WS.
“The latter observation suggests that cellular checkpoint functions may be involved in producing the clinical features of WS.”
Quote in the paperNot a substantial claim - Interpretationnone given§ Introduction
In the models discussed above, decreased genomic stability is associated with shortened life span.
“In the models discussed above, decreased genomic stability is associated with shortened life span.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Conclusions
p53-mediated senescence and apoptosis, in response to DNA damage, also likely contribute to aging.
“In addition, p53-mediated senescence and apoptosis, in response to DNA damage, also likely contribute to aging (Figure 6).”
Quote in the paperSubstantial claim - Interpretationnone given§ Conclusions
ROS are likely to be one important source of nuclear DNA damage.
“While ROS are likely to be one important source of this damage, there are numerous other cellular and environmental sources of damage”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
When nutrients are scarce, yeast cells preferentially employ respiration rather than fermentation to generate ATP.
“When nutrients are scarce, yeast cells preferentially employ respiration rather than fermentation to generate ATP (Lin et al., 2002”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lin et al., 2002 source
Not checked in the free run.
- Premisecitation§ Introduction
WRN can be detected at the telomeres in the absence of telomerase function in mammalian cells.
“WRN can be detected at the telomeres in the absence of telomerase function in mammalian cells (Johnson et al., 2001; Opresko et al., 2004”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning§ Conclusions
The hypothesis that nuclear DNA is an important target of age-related change is supported by evidence that nuclear DNA damage and mutations accumulate with age.
“The hypothesis that nuclear DNA, a critically important cellular constituent that cannot be replaced, is an important target of age-related change is supported by evidence that nuclear DNA damage and mutations accumulate with age.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
In WRN/Terc double deficient animals, phenotypes reminiscent of human WS that are not observed in either single mutant are present: osteopenia, diabetes, and sarcomas.
“In the WRN/Terc double deficient animals, phenotypes reminiscent of human WS that are not observed in either single mutant are present: osteopenia, diabetes, and sarcomas.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Chang et al., 2004 source
Not checked in the free run.
- cites Du et al., 2004
Not checked in the free run.
- Premisecitation§ Introduction
Caloric restriction is an intervention capable of extending life span in many different organisms from yeast to mammals.
“an intervention capable of extending life span in many different organisms from yeast to mammals (Cohen et al., 2004; Howitz et al., 2003; Lin et al., 2000; Rogina and Helfand, 2004; Wood et al., 2004”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ Conclusions
Accumulation of mutations in critical genes may be one general mechanism by which compromised DNA repair could contribute to aging.
“Accumulation of mutations in critical genes may be one general mechanism by which compromised DNA repair could contribute to aging.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Sgs1p, the S. cerevisiae WRN homolog, is required for recombinational telomere maintenance in telomerase-deficient cells in yeast.
“Sgs1p, the S. cerevisiae WRN homolog, is required for recombinational telomere maintenance in telomerase-deficient cells in yeast (Cohen and Sinclair, 2001; Huang et al., 2001; Johnson et al., 2001”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Introduction
In S. cerevisiae, Sir2 functions as an NAD-dependent histone deacetylase.
“In S. cerevisiae, the chromatin regulatory factor Sir2 (silent information regulator-2) functions as an NAD-dependent histone deacetylase (Imai et al., 2000”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Imai et al., 2000 source
Not checked in the free run.
- Interpretationnone given§ Conclusions
Genetic background effects almost certainly play an important role in modifying the aging-like manifestations of DNA repair deficiencies.
“However, genetic background effects almost certainly play an important role in modifying the aging-like manifestations of DNA repair deficiencies.”
Quote in the paperNot a substantial claim - Premisecitation§ Introduction
The Sir2 family of proteins provides an example in which increased genomic stability extends life span.
“The Sir2 family of proteins provides an example in which increased genomic stability extends life span (Blander and Guarente, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blander and Guarente, 2004
Not checked in the free run.
- Premisecitation§ Conclusions
Most premature aging syndromes are caused by mutations in genes encoding proteins involved in DNA repair.
“most premature aging syndromes are caused by mutations in genes encoding proteins involved in DNA repair (Karanjawala and Lieber, 2004”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Karanjawala and Lieber, 2004
Not checked in the free run.
- Interpretationcitation§ Introduction
SIRT2 and SIRT3 are unlikely to play the role of true mammalian functional ortholog of Sir2, because these proteins are cytoplasmic and mitochondrial, respectively, rather than chromatin associated.
“SIRT2 and SIRT3 are unlikely to play this role, because these proteins are cytoplasmic and mitochondrial, respectively, rather than chromatin associated (Blander and Guarente, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blander and Guarente, 2004
Not checked in the free run.
- Interpretationreasoning§ Conclusions
The fact that lesions in several disparate repair systems cause phenotypes that are broadly similar to one another is consistent with the notion that the specific chemical nature of the accumulated DNA lesions may be less important than their ability to activate the common cellular checkpoint machinery.
“Indeed, the fact that lesions in several disparate repair systems cause phenotypes that are broadly similar to one another (Table 1) is consistent with the notion that the specific chemical nature of the accumulated DNA lesions may be less important than their ability to activate the common cellular checkpoint machinery.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Introduction
WRN may play a role in providing telomeric access to other factors involved in telomere maintenance.
“These observations suggest that WRN may play a role in providing telomeric access to other factors involved in telomere maintenance (Machwe et al., 2004; Opresko et al., 2004; Orren et al., 2002”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ Introduction
Overexpression or pharmacologic activation of Sir2 in worms and flies extends life span.
“Strikingly, overexpression or pharmacologic activation of Sir2 in worms and flies also extends life span (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001; Wood et al., 2004”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationcitation§ Introduction
The hypothesis that WRN-deficient mice may not demonstrate a strong phenotype due to abundant mouse telomere reserve has been proven correct by generation of mice deficient in both WRN and Terc.
“This hypothesis has been proven correct by the generation of mice deficient in both WRN and Terc (Chang et al., 2004; Du et al., 2004”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Chang et al., 2004 source
Not checked in the free run.
- cites Du et al., 2004
Not checked in the free run.
- Interpretationreasoning§ Conclusions
Aging is likely the outcome of a complex interplay between the genetic endowment of an organism and the stresses placed upon it by its particular environment.
“Thus, aging is likely the outcome of a complex interplay between the genetic endowment of an organism and the stresses placed upon it by its particular environment.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Conclusions
Factors implicated in organismal decline in genetic models might not play a role in the normal aging processes.
“Factors implicated in organismal decline in genetic models might not play a role in the normal aging processes.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Conclusions
The myriad histopathologic changes of normal aging correspond poorly with the changes that occur in models of premature aging.
“In this regard, the myriad histopathologic changes of normal aging (Table 2) correspond poorly with the changes that occur in models of premature aging (Table 1).”
Quote in the paperSubstantial claim - Interpretationreasoning§ Conclusions
Genetic models of extended life span are likely to be more informative than models with reduced longevity with respect to physiologically relevant causes of decline and mortality.
“For these reasons, genetic models of extended life span are likely to be more informative than models with reduced longevity with respect to physiologically relevant causes of decline and mortality; in such long-lived organisms, life span-limiting factors must of necessity be counteracted.”
Quote in the paperNot a substantial claim
- May combine two claims. 54
- Classified as probably not a substantial claim. 22
- The quote only partly states this claim. 1
May combine two claims.
Premisenone given§ IntroductionPhosphorylation of p53 by ATM and kinases downstream of ATM is a major mechanism leading to upregulation of p53 levels and activity, although p53 also can be activated via ATM-independent mechanisms.
“Phosphorylation of p53 by ATM and kinases downstream of ATM is a major mechanism leading to upregulation of p53 levels and activity, although p53 also can be activated via ATM-independent mechanisms.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ IntroductionReplicative life span of human cells is altered by culture under different oxygen tensions.
“Replicative life span of human cells is altered by culture under different oxygen tensions”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Introductionp53 triggers arrest/senescence or apoptosis.
“p53, through modulation of various downstream targets, triggers arrest/senescence or apoptosis (Meek, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Meek, 2004 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionReactive oxygen species are a potential source of chronic, persistent DNA damage in all cells and may contribute to aging.
“As normal byproducts of metabolism, ROS are a potential source of chronic, persistent DNA damage in all cells and may contribute to aging (Sohal and Weindruch, 1996”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sohal and Weindruch, 1996
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionThe initial step in DSB repair is detection of the lesion, and this step involves the ATM kinase, other related PIKKs, and other proteins.
“The initial step in DSB repair is detection of the lesion, and this step involves the ataxia-telangiectasia mutated (ATM) kinase, other related phosphatidylinositol 3-kinase-like kinases (PIKKs), and other proteins (Figure 2; Bassing and Alt, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bassing and Alt, 2004
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionMEFs derived from M. musculus possess long telomeres and easily detectable telomerase activity.
“MEFs derived from M. musculus possess long telomeres and easily detectable telomerase activity (Itahana et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Itahana et al., 2004 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionThe G strand overhang is the substrate for telomerase, which employs an RNA template, Terc, to extend telomeres during S phase, thereby countering the natural shortening of telomeres that would otherwise occur with each cell division.
“The G strand overhang is the substrate for the enzyme telomerase, which employs an RNA template, Terc, to extend telomeres during S phase, thereby countering the natural shortening of telomeres that would otherwise occur with each cell division.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionActivated ATM phosphorylates numerous proteins involved in the G1/S, intra-S, and G2/M checkpoint responses and additionally phosphorylates factors involved in DNA repair.
“Activated ATM phosphorylates numerous proteins involved in the G1/S, intra-S, and G2/M checkpoint responses and additionally phosphorylates factors involved in DNA repair (Bassing and Alt, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bassing and Alt, 2004
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionIn mammalian cells, the ends of the chromosomes consist of a terminal 3′ single-stranded tail, the G strand overhang, which is buried into adjacent double-stranded repetitive telomeric DNA, forming a protective t loop higher-order structure.
“In mammalian cells, the ends of the chromosomes consist of a terminal 3′ single-stranded tail, the G strand overhang, which is buried into adjacent double-stranded repetitive telomeric DNA, forming a protective “t loop” higher-order structure (de Lange, 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites de Lange, 2002 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionMany nuclear genes involved in critical neural functions show reduced expression after age 40, concomitant with elevated levels of oxo8dG and DNA damage in their promoters.
“which found that many nuclear genes involved in critical neural functions show reduced expression after age 40, concomitant with elevated levels of oxo8dG and DNA damage in their promoters.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lu et al., 2004
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionActivated p53 stimulates or represses transcription of many target genes and coordinates checkpoint, senescence, and apoptosis pathways in response to DSBs and other signals.
“Activated p53 stimulates or represses transcription of many target genes and coordinates checkpoint, senescence, and apoptosis pathways in response to DSBs and other signals.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Meek, 2004 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionSenescent stromal cells can promote the growth of epithelial cancers, malignancies that occur with increased incidence in the elderly.
“However, senescent stromal cells can actually promote the growth of epithelial cancers, malignancies that occur with increased incidence in the elderly.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Krtolica and Campisi, 2002
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionUnrepaired or improperly repaired DSBs have serious potential consequences for the cell: cell death, senescence, dysregulation of cellular functions, genomic instability, and oncogenic transformation.
“Unrepaired or improperly repaired DSBs have serious potential consequences for the cell: cell death, senescence, dysregulation of cellular functions, genomic instability, and, in higher organisms, oncogenic transformation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bassing and Alt, 2004
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionSenescent cells accumulate in vivo in mammals with increasing age and at sites of pathology.
“senescent cells accumulate in vivo in mammals with increasing age and at sites of pathology (Itahana et al., 2004”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Itahana et al., 2004 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionLonger-lived species generally show higher cellular oxidative stress resistance and lower levels of mitochondrial ROS production than shorter-lived species.
“In brief, longer-lived species generally show higher cellular oxidative stress resistance and lower levels of mitochondrial ROS production than shorter-lived species.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Balaban et al., 2005 source
Not checked in the free run.
May combine two claims.
Premisecitation§ AbstractDNA damage and mutations accumulate with age in mammals.
“DNA damage accumulates with age”
- Also stated in: § Introduction · boosted
“A large body of evidence argues that DNA damage and mutations accumulate with age in mammals (Vijg, 2000”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Vijg, 2000 source
Not checked in the free run.
- Also stated in: § Introduction · boosted
May combine two claims.
Premisecitation§ IntroductionA strain of DNA-PKcs-deficient mice exhibits age-related pathologies, with osteopenia, intestinal atrophy, thymic lymphoma, and reduced longevity.
“a strain of DNA-PKcs-deficient mice recently has been noted to exhibit age-related pathologies, with osteopenia, intestinal atrophy, thymic lymphoma, and reduced longevity (Espejel et al., 2004b”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Espejel et al., 2004b
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationcitation§ IntroductionThe variation in thymic lymphoma frequency among ATM-deficient mouse strains might reflect different background mutations and/or housing conditions and the types of pathogens present.
“a finding that might reflect different background mutations and/or housing conditions and the types of pathogens present (Petiniot et al., 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Petiniot et al., 2002 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionATM plays an important role in telomere maintenance; AT cells show shortened telomeres and an increased incidence of telomeric fusions.
“Finally, ATM plays an important role in telomere maintenance; AT cells show shortened telomeres and an increased incidence of telomeric fusions (Pandita, 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pandita, 2002 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionMice deficient for XRCC4, Ligase IV, Ku70, or Ku80 are very small and show widespread neuronal apoptosis during embryogenesis.
“mice deficient for these four factors are very small and show widespread neuronal apoptosis during embryogenesis”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ferguson and Alt, 2001
Not checked in the free run.
May combine two claims.
Interpretationcitation§ IntroductionNHEJ plays a critical role in general DNA DSB repair and in the maintenance of genomic stability.
“NHEJ plays a critical role in general DNA DSB repair and, correspondingly, in the maintenance of genomic stability.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionATM-deficient cells manifest sensitivity to DSB-inducing agents and have marked genomic instability; they also grow poorly and senesce prematurely in culture.
“In particular, such cells manifest sensitivity to DSB-inducing agents and have marked genomic instability; they also grow poorly and senesce prematurely in culture (Barzilai et al., 2002”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Barzilai et al., 2002 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionPremature senescence and neuronal apoptosis, but not small size, are relieved by p53 deficiency.
“Premature senescence and neuronal apoptosis, but not small size, are relieved by p53 deficiency.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ferguson and Alt, 2001
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ IntroductionOther aspects of the ATM-deficient phenotype, including the premature aging observed in human patients, may be influenced by environment.
“These observations raise the possibility that other aspects of the ATM-deficient phenotype, including the premature aging observed in human patients, may be influenced by environment.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionPatients with mutations in the ATM gene suffer from Ataxia-Telangiectasia, a condition characterized by a prematurely aged (progeroid) appearance, immunodeficiency, cerebellar degeneration, and cancer.
“Patients with mutations in the ATM gene suffer from Ataxia-Telangiectasia (AT), a condition characterized by a prematurely aged (progeroid) appearance, immunodeficiency, cerebellar degeneration, and cancer (Shiloh and Kastan, 2001”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shiloh and Kastan, 2001
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionA null mutation in p66Shc confers oxidative stress resistance and extends mouse life span.
“a null mutation in a gene functioning downstream of p53 in the induction of apoptosis, p66Shc, confers oxidative stress resistance and extends mouse life span (Migliaccio et al., 1999”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Migliaccio et al., 1999 source
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
May combine two claims.
Interpretationreasoning§ IntroductionNHEJ plays crucial roles in general and site-specific DSB repair, in telomere maintenance, and in maintenance of genomic stability.
“In summary, NHEJ plays crucial roles in general and site-specific DSB repair, in telomere maintenance, and in maintenance of genomic stability.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionNHEJ is one of the two major DSB repair pathways in mammalian cells.
“NHEJ is one of the two major DSB repair pathways in mammalian cells (Bassing and Alt, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bassing and Alt, 2004
Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationcitation§ IntroductionPersistently elevated ROS levels in AT cells might cause chronic damage to DNA and other cellular macromolecules.
“Persistently elevated ROS levels in AT cells might cause chronic damage to DNA and other cellular macromolecules.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Premisecitation§ IntroductionATM functions in regulating intracellular ROS levels and sensitivity to these molecules.
“Another potential function for ATM in suppressing progeroid phenotypes may be related to reported ATM functions in regulating intracellular ROS levels and sensitivity to these molecules (Barzilai et al., 2002; Ito et al., 2004”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationcitation§ Introductionp53 promotes cellular senescence and apoptosis in response to DNA damage, potentially contributing to the clinical changes of aging.
“at the same time it promotes cellular senescence and apoptosis in response to DNA damage, potentially contributing to the clinical changes of aging.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionATM deficiency in mice recapitulates many of these phenotypes, although the progeroid features of the mouse models are less prominent than in the human disease.
“ATM deficiency in mice recapitulates many of these phenotypes, although the progeroid features of the mouse models are less prominent than in the human disease.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionMice lacking both ATM and Terc have higher levels of telomeric dysfunction than generation-matched Terc-deficient mutants, as well as proliferative defects in multiple tissues, decreased survival, and clinical evidence of premature aging.
“Moreover, mice lacking both ATM and Terc have higher levels of telomeric dysfunction than generation-matched Terc-deficient mutants, as well as proliferative defects in multiple tissues, decreased survival, and clinical evidence of premature aging (Wong et al., 2003”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wong et al., 2003 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionTwo mouse strains that express C-terminal p53 fragments along with full-length p53 show accelerated aging phenotypes and a lower incidence of malignancy.
“However, two mouse strains that express C-terminal p53 fragments along with full-length p53 have been reported to show accelerated aging phenotypes and a lower incidence of malignancy (Maier et al., 2004; Tyner et al., 2002”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Maier et al., 2004 source
Not checked in the free run.
- cites Tyner et al., 2002 source
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
May combine two claims.
Premisecitation§ IntroductionBRCA1Δ11/Δ11 MEFs show increased chromosomal abnormalities and premature cellular senescence, and BRCA1Δ11/Δ11 embryos show tissue SA-β-galactosidase activity.
“BRCA1Δ11/Δ11 MEFs show increased chromosomal abnormalities and premature cellular senescence, and BRCA1Δ11/Δ11 embryos show tissue SA-β-galactosidase activity, a marker of senescence.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cao et al., 2003b
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionOnly cerebellar defects have been described in detail in CSB/XPA double-deficient mice.
“although only cerebellar defects have been described in detail in these animals (Murai et al., 2001”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Murai et al., 2001 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionXPDTTD mice show aging-associated changes such as wasting, scoliosis, osteoporosis, and melanocyte loss.
“Additionally, these XPDTTD mice show aging-associated changes such as wasting, scoliosis, osteoporosis, and melanocyte loss (de Boer et al., 2002”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites de Boer et al., 2002 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionNER can be subdivided into two pathways, global genome NER (GG-NER) and transcription-coupled NER (TC-NER), which differ with respect to the lesion detected and some of the factors involved.
“NER can be subdivided into two pathways, global genome NER (GG-NER) and transcription-coupled NER (TC-NER), which differ with respect to the lesion detected and some of the factors involved (Mitchell et al., 2003; Figure 5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mitchell et al., 2003 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionMice homozygous for a BRCA1 hypomorphic allele and haploinsufficient for p53 (BRCA1Δ11/Δ11/p53+/−) are viable and have many features reminiscent of accelerated aging: wasting, skin atrophy, osteopenia, and malignancy.
“mice homozygous for a BRCA1 hypomorphic allele and haploinsufficient for p53 (BRCA1Δ11/Δ11/p53+/−) are viable and have many features reminiscent of accelerated aging: wasting, skin atrophy, osteopenia, and malignancy (Cao et al., 2003b”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cao et al., 2003b
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
May combine two claims.
Premisecitation§ IntroductionCells deficient in Ligase IV and ATM or Terc and ATM show high levels of genomic instability and very rapid senescence.
“cells deficient in Ligase IV and ATM or Terc and ATM show high levels of genomic instability and very rapid senescence (Sekiguchi et al., 2001; Wong et al., 2003”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sekiguchi et al., 2001; Wong et al., 2003
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ IntroductionHomozygosity for a Rad50 hypomorphic allele (Rad50s/s) permits viability; Rad50s/s mice show a shortened life span, cancer predisposition, and hematopoietic stem cell and spermatogenic failure.
“homozygosity for a Rad50 hypomorphic allele (Rad50s/s) permits viability; Rad50s/s mice show a shortened life span, cancer predisposition, and hematopoietic stem cell and spermatogenic failure (Bender et al., 2002”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bender et al., 2002 source
Not checked in the free run.
- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
May combine two claims.
Interpretationreasoning§ IntroductionAging phenotypes likely do not result from a failure of DSB repair alone but instead from a loss of other functions or combinations of functions of these proteins, perhaps in concert with environmental factors.
“Current findings suggest, however, that aging phenotypes likely do not result from a failure of DSB repair alone but instead from a loss of other functions or combinations of functions of these proteins, perhaps in concert with environmental factors, such as housing conditions and/or infection and/or background mutations.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ IntroductionImpaired transcription of critical genes may play a role in causing progeroid phenotypes in XPD and CSB mutants, perhaps interacting with repair defects.
“Alternatively, the involvement of XPD and the CSB proteins in transcription suggests that impaired transcription of critical genes may play a role in causing these progeroid phenotypes, perhaps interacting with the repair defects in a complicated fashion.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionWS patients develop premature graying, cataract, loss of subcutaneous fat, skin atrophy, osteoporosis, diabetes, atherosclerosis, and malignancies.
“WS patients develop premature graying, cataract, loss of subcutaneous fat, skin atrophy, osteoporosis, diabetes, atherosclerosis, and malignancies.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Goto, 1997 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionDefects in Rad50 or BRCA1 cause progeroid phenotypes.
“Defects in Rad50 or BRCA1 cause progeroid phenotypes.”
Quote in the paperSubstantial claim- Rests on an assumption: Mouse models of accelerated aging phenotypes are informative about normal aging processes.
May combine two claims.
Premisecitation§ IntroductionMutations in genes involved in BER do not produce aging manifestations: they are either lethal or confer no obvious phenotypes.
“mutations in genes involved in this pathway do not produce aging manifestations: they are either lethal or confer no obvious phenotypes (Hasty et al., 2003”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hasty et al., 2003 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Interpretationreasoning§ IntroductionSuch complexities may likely apply to other DNA repair proteins implicated in the suppression of aging as well.
“Such complexities also may likely apply to other DNA repair proteins implicated in the suppression of aging as well”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionDefects in the TC-NER-specific factors CSA or CSB lead to Cockayne syndrome in humans, a severely debilitating disorder with striking progeroid features.
“Defects in the TC-NER-specific factors CSA or CSB lead to Cockayne syndrome in humans, a severely debilitating disorder with striking progeroid features.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mitchell et al., 2003 source
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionDeficiency of Mre11, Nbs1, or Rad50 is not compatible with cellular survival.
“Deficiency of Mre11, Nbs1, or Rad50 is not compatible with cellular survival (Stracker et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Stracker et al., 2004 source
Not checked in the free run.
May combine two claims.
Premisenone given§ IntroductionDegenerative changes in these models occur in both highly proliferative (intestine and skin) and relatively less proliferative (bone and liver) tissues, apparently sparing many other tissues of both types.
“degenerative changes in these models occur in both highly proliferative (intestine and skin) and relatively less proliferative (bone and liver) tissues, apparently sparing many other tissues of both types.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Interpretationcitation§ IntroductionCell death from unrepaired lesions in transcribed genes leads to tissue attrition and aging.
“leading to tissue attrition and aging.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionSIRT1, like Sir2, has recently been shown to directly modify chromatin and silence transcription.
“Additionally, SIRT1, like Sir2, has recently been shown to directly modify chromatin and silence transcription (Vaquero et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Vaquero et al., 2004 source
Not checked in the free run.
Classified as probably not a substantial claim.
Interpretationcitation§ IntroductionWRN-deficient mice may not demonstrate a strong phenotype due to the abundant mouse telomere reserve.
“it was proposed that WRN-deficient mice may not demonstrate a strong phenotype due to the abundant mouse telomere reserve (Lombard et al., 2000”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lombard et al., 2000 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone given§ ConclusionsEnvironmental factors including housing conditions, infectious agents, diet, and many other influences likely play a significant role in the expression of aging phenotypes in mouse models and, perhaps, in humans as well.
“In addition, as discussed above, environmental factors including housing conditions, infectious agents, diet, and many other influences, also likely play a significant role in the expression of aging phenotypes in mouse models and, perhaps, in humans as well.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionSir2 suppresses recombination and turns off transcription at multiple genomic loci.
“to suppress recombination and turns off transcription at multiple genomic loci (Blander and Guarente, 2004”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Blander and Guarente, 2004
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionThe role of SIRT1 in mammalian longevity has not yet been directly tested, because on a pure strain background SIRT1-deficient animals die very early as a consequence of multiple developmental defects.
“The role of SIRT1 in mammalian longevity has not yet been directly tested, since on a pure strain background SIRT1-deficient animals die very early as a consequence of multiple developmental defects (Cheng et al., 2003; McBurney et al., 2003”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ IntroductionAn extra genomic copy of Sir2 increases rDNA stability and extends life span.
“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kaeberlein et al., 1999 source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ IntroductionThe phenotype of the WRN/Terc double knockout mouse argues that defective telomere maintenance is an important factor in producing the premature aging-like aspects of WS in humans, although it does not exclude a role for other functions of WRN at nontelomeric sites.
“Overall, the phenotype of the WRN/Terc double knockout mouse argues that defective telomere maintenance is an important factor in producing the premature aging-like aspects of WS in humans, although it does not exclude a role for other functions of WRN at nontelomeric sites.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ ConclusionsMany DNA repair genes and factors implicated in suppressing aging also play roles in cellular processes other than DNA repair, and therefore aging-like phenotypes might be enhanced by impairment of other cellular functions in conjunction with altered DNA repair.
“Also, it must be remembered that many of the DNA repair genes and factors implicated in suppressing aging also play roles in cellular processes other than DNA repair, and therefore aging-like phenotypes might be enhanced by impairment of other cellular functions in conjunction with altered DNA repair.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationcitation§ IntroductionThe metabolic switch to respiration alters metabolism, increasing the NAD/NADH ratio and/or decreasing levels of the Sir2 inhibitor nicotinamide, in turn activating Sir2 and increasing rDNA stability.
“This metabolic switch alters the metabolism of the cell, increasing the NAD/NADH ratio and/or decreasing levels of the Sir2 inhibitor nicotinamide, in turn activating Sir2 and increasing rDNA stability (reviewed in Blander and Guarente, [2004]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blander and Guarente, 2004
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionSIRT1 possesses a large and growing list of targets, some of which, including p53 and forkhead transcription factors, modulate cellular resistance to oxidative and genotoxic stress.
“SIRT1 possesses a large and growing list of targets, some of which, including p53 and forkhead transcription factors (mammalian homologs of Daf-16), modulate cellular resistance to oxidative and genotoxic stress (Blander and Guarente, 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Blander and Guarente, 2004
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ IntroductionSir2 family members may play a general role in mediating caloric restriction.
“Sir2 family members may play a general role in mediating caloric restriction (Sohal and Weindruch, 1996”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sohal and Weindruch, 1996
Not checked in the free run.
May combine two claims.
Premisecitation§ IntroductionWRN interacts with the telomeric protein TRF2 and can unwind and degrade telomeric D loop structures.
“WRN also interacts with the telomeric protein TRF2 and can unwind and degrade telomeric D loop structures.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ IntroductionLoss of Sir2 increases rDNA recombination and shortens life span.
“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kaeberlein et al., 1999 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionSir2 activity ties the energy status of the yeast cell to longevity.
“It has been proposed that Sir2 activity ties the energy status of the yeast cell to longevity (Blander and Guarente, 2004; Lin et al., 2000”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Blander and Guarente, 2004
Not checked in the free run.
- cites Lin et al., 2000 source
Not checked in the free run.
May combine two claims.
Premisenone given§ IntroductionPhenotypes ordinarily seen in late-generation Terc-deficient animals also occur earlier in WRN/Terc compound mutants and are associated with a greater degree of telomeric dysfunction.
“Phenotypes ordinarily seen in late-generation Terc-deficient animals also occur earlier in the compound mutants and are associated with a greater degree of telomeric dysfunction.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionIn mammals, there are seven Sir2 family members, designated SIRT1-SIRT7.
“In mammals, there are seven Sir2 family members, designated SIRT1–SIRT7 (Frye, 2000”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Frye, 2000 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionIn yeast, the involvement of Sir2 in caloric restriction appears to be strain specific.
“although in yeast the involvement of Sir2 in CR appears to be strain specific (Kaeberlein et al., 2004”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kaeberlein et al., 2004 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Premisecitation§ ConclusionsAging encompasses a wide spectrum of degenerative processes, many of which are quite nonspecific, both clinically and pathologically.
“Aging encompasses a wide spectrum of degenerative processes, many of which are quite nonspecific, both clinically and pathologically (Harrison, 1994”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Harrison, 1994 source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ ConclusionsMammalian aging is not likely a single process but rather the decline of many somatic functions, heavily influenced by the environment.
“Mammalian aging is not likely a single process but rather the decline of many somatic functions, heavily influenced by the environment; this is a complex interplay that is extremely difficult to model accurately.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ ConclusionsPremature aging models fail to recapitulate all aspects of aging but are instead "segmental progerias".
“A related difficulty is that premature aging models fail to recapitulate all aspects of aging but are instead “segmental progerias” (Hasty and Vijg, 2004; Miller, 2004”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hasty and Vijg, 2004
Not checked in the free run.
- cites Miller, 2004 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ ConclusionsIn long-lived organisms, life span-limiting factors must of necessity be counteracted.
“For these reasons, genetic models of extended life span are likely to be more informative than models with reduced longevity with respect to physiologically relevant causes of decline and mortality; in such long-lived organisms, life span-limiting factors must of necessity be counteracted.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone given§ ConclusionsIn models of premature aging, the most vulnerable system fails first, leading to death and precluding gain of insights from effects on other, potentially more relevant, organ systems.
“In models of premature aging, the most vulnerable system fails first, leading to death and precluding gain of insights from effects on other, potentially more relevant, organ systems.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone given§ ConclusionsAll mouse models that link DNA repair to aging possess defects in DNA repair and have shortened life spans.
“All mouse models that link DNA repair to aging possess defects in DNA repair and have shortened life spans.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The induction of senescence depends on pathways involving the p53 and Rb proteins.
“The induction of senescence depends on pathways involving the p53 and Rb proteins (Figure 1).”
The paper relies on this without support.
The accurate maintenance of nuclear DNA is critical to cellular and organismal function.
“The accurate maintenance of nuclear DNA is critical to cellular and organismal function, and therefore, numerous DNA repair systems have evolved.”
The paper relies on this without support.
p53 suppresses the onset of malignancy and thereby extends life span.
“While p53 suppresses the onset of malignancy and thereby extends life span”
The paper relies on this without support.
The role of p53 in aging cannot be directly tested using p53-deficient mice because they die of malignancy before age-related changes become manifest.
“The role of p53 in aging cannot be directly tested using p53-deficient mice, as such animals invariably die of malignancy before age-related changes become manifest.”
The paper relies on this without support.
Mouse models of accelerated aging phenotypes are informative about normal aging processes.
“phenotypes resembling accelerated aging have been described in one strain each of Ku80- and DNA-PKcs-deficient mice”
The paper relies on this without support.
Patients with specific mutations in XPD suffer from trichothiodystrophy (TTD), a disease characterized by photosensitivity, brittle hair, skin defects, and a shortened life span.
“Patients with specific mutations in XPD suffer from trichothiodystrophy (TTD), a disease characterized by photosensitivity, brittle hair, skin defects, and a shortened life span.”
The paper relies on this without support.
Cells derived from TTD patients show NER defects.
“In addition, cells derived from TTD patients show NER defects”
The paper relies on this without support.
XPDTTD/XPA double mutants show a much more rapid degenerative phenotype than XPDTTD single mutants.
“XPDTTD/XPA double mutants show a much more rapid degenerative phenotype”
The paper relies on this without support.
The gene defective in WS, WRN, encodes a helicase of the RecQ family.
“The gene defective in WS, WRN, encodes a helicase of the RecQ family (a group defined by its similarity to E. coli RecQ helicase).”
The paper relies on this without support.
WRN possesses an exonuclease domain.
“WRN also possesses an exonuclease domain.”
The paper relies on this without support.
SIRT1 is the most highly related mammalian Sir2 family member to S. cerevisiae Sir2.
“SIRT1 is the most highly related to S. cerevisiae Sir2.”
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?
Quiescent stem cells can suffer DNA damage during normal homeostatic turnover and depend on DNA repair mechanisms for survival.
“quiescent stem cells can also be subjected to DNA damage during normal homeostatic turnover, and quiescent stem cells depend on DNA repair mechanisms for survival123.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [123]
Defects in DSB repair can cause cell cycle arrest, apoptosis or genomic aberrations and have been linked to disease progression and premature aging phenotypes.
“Defects in DSB repair can result in cell cycle arrest, apoptosis or genomic aberrations and have been linked to both disease progression and a premature onset of aging phenotypes (2,3).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [3]
Many mouse models with deletions of genes linked to repairing or sensing DNA damage can exhibit both cancer susceptibility and progeroid features.
“so many mouse models with deletions of genes linked to repairing or sensing DNA damage can exhibit both cancer susceptibility and progeroid features 40”
From The common biology of cancer and ageing (2007) · cites this paper as [40]
Cites
Oxidants, oxidative stress and the biology of ageing
Finkel, T., & Holbrook, N. J. (2000) · Nature · doi:10.1038/35041687 · Cited by 9,413 · see citing works
Mitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388 · see citing works
Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., et al. (2003) · Nature · doi:10.1038/nature01960 · Cited by 3,796 · see citing works
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510 · see citing works
Oxidative Stress, Caloric Restriction, and Aging
Sohal, R. S., & Weindruch, R. H. (1996) · Science · doi:10.1126/science.273.5271.59 · Cited by 3,133 · see citing works
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734 · see citing works
Kaeberlein, M., McVey, M., & Guarente, L. (1999) · Genes & Development · doi:10.1101/gad.13.19.2570 · Cited by 2,253 · see citing works
Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase
Cohen, H. Y., Miller, C., Bitterman, K. J., Wall, N. R., Hekking, B., Kessler, B., Howitz, K. T., Gorospe, M., de Cabo, R., & Sinclair, D. A. (2004) · Science · doi:10.1126/science.1099196 · Cited by 1,924 · see citing works
Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
Tissenbaum, H. A., & Guarente, L. (2001) · Nature · doi:10.1038/35065638 · Cited by 1,918 · see citing works
Gene regulation and DNA damage in the ageing human brain
Lu, T., Pan, Y., Kao, S.-Y., Li, C., Kohane, I., Chan, J., & Yankner, B. A. (2004) · Nature · doi:10.1038/nature02661 · Cited by 1,874 · see citing works
Sirtuin activators mimic caloric restriction and delay ageing in metazoans
Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004) · Nature · doi:10.1038/nature02789 · Cited by 1,868 · see citing works
Lin, S.-J., Defossez, P.-A., & Guarente, L. (2000) · Science · doi:10.1126/science.289.5487.2126 · Cited by 1,775 · see citing works
The p66shc adaptor protein controls oxidative stress response and life span in mammals
Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandolfi, P. P., Lanfrancone, L., & Pelicci, P. G. (1999) · Nature · doi:10.1038/46311 · Cited by 1,712 · see citing works
Extrachromosomal rDNA circles—a cause of aging in yeast
Sinclair, D. A., & Guarente, L. (1997) · Cell · doi:10.1016/s0092-8674(00)80493-6 · Cited by 1,500 · see citing works
The Sir2 Family of Protein Deacetylases
Blander, G., & Guarente, L. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073651 · Cited by 1,496 · see citing works
p53 mutant mice that display early ageing-associated phenotypes
Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., et al. (2002) · Nature · doi:10.1038/415045a · Cited by 1,459 · see citing works
Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins
Frye, R. A. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3000 · Cited by 1,409 · see citing works
Sir2 mediates longevity in the fly through a pathway related to calorie restriction
Rogina, B., & Helfand, S. L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404184101 · Cited by 1,361 · see citing works
Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice
Rudolph, K. L., Chang, S., Lee, H.-W., Blasco, M., Gottlieb, G. J., Greider, C., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80580-2 · Cited by 1,349 · see citing works
Essential role of mouse telomerase in highly proliferative organs
Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998) · Nature · doi:10.1038/33345 · Cited by 1,270 · see citing works
Takata, M., Sasaki, M. S., Sonoda, E., Morrison, C., Hashimoto, M., Utsumi, H., Yamaguchi‐Iwai, Y., Shinohara, A., & Takeda, S. (1998) · The EMBO Journal · doi:10.1093/emboj/17.18.5497 · Cited by 1,229 · see citing works
Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle
Rothkamm, K., Krüger, I., Thompson, L. H., & Lübrich, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.16.5706-5715.2003 · Cited by 1,187 · see citing works
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., et al. (2004) · Nature · doi:10.1038/nature02989 · Cited by 1,175 · see citing works
Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts
Parrinello, S., Samper, E., Krtolica, A., Goldstein, J., Melov, S., & Campisi, J. (2003) · Nature Cell Biology · doi:10.1038/ncb1024 · Cited by 1,116 · see citing works
Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice
Cheng, H.-L., Mostoslavsky, R., Saito, S., Manis, J. P., Gu, Y., Patel, P., Bronson, R., Appella, E., Alt, F. W., & Chua, K. F. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1934713100 · Cited by 1,095 · see citing works
Self-citationCalorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration
Lin, S.-J., Kaeberlein, M., Andalis, A. A., Sturtz, L. A., Defossez, P.-A., Culotta, V. C., Fink, G. R., & Guarente, L. (2002) · Nature · doi:10.1038/nature00829 · Cited by 1,057 · see citing works
Protection of mammalian telomeres
de Lange, T. (2002) · Oncogene · doi:10.1038/sj.onc.1205080 · Cited by 942 · see citing works
Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.
Vaquero, A., Scher, M., Lee, D., Erdjument-Bromage, H., Tempst, P., & Reinberg, D. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.08.031 · Cited by 916 · see citing works
The evolution of ageing and longevity
Kirkwood, T. B. L., & Holliday, R. (1979) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1979.0083 · Cited by 900 · see citing works
Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks
Sedelnikova, O. A., Horikawa, I., Zimonjic, D. B., Popescu, N. C., Bonner, W. M., & Barrett, J. C. (2004) · Nature Cell Biology · doi:10.1038/ncb1095 · Cited by 790 · see citing works
Does oxidative damage to DNA increase with age?
Hamilton, M. L., Van Remmen, H., Drake, J. A., Yang, H., Guo, Z. M., Kewitt, K., Walter, C. A., & Richardson, A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171202698 · Cited by 768 · see citing works
Hart, R. W., & Setlow, R. B. (1974) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.71.6.2169 · Cited by 739 · see citing works
Van Remmen, H., Ikeno, Y., Hamilton, M., Pahlavani, M., Wolf, N., Thorpe, S. R., Alderson, N. L., Baynes, J. W., Epstein, C. J., Huang, T.-T., et al. (2003) · Physiological Genomics · doi:10.1152/physiolgenomics.00122.2003 · Cited by 734 · see citing works
BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice
Baker, D. J., Jeganathan, K. B., Cameron, J. D., Thompson, M., Juneja, S., Kopecka, A., Kumar, R., Jenkins, R. B., de Groen, P. C., Roche, P., et al. (2004) · Nature Genetics · doi:10.1038/ng1382 · Cited by 731 · see citing works
Barja, G. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.07.005 · Cited by 653 · see citing works
The Mammalian SIR2α Protein Has a Role in Embryogenesis and Gametogenesis
McBurney, M. W., Yang, X., Jardine, K., Hixon, M., Boekelheide, K., Webb, J. R., Lansdorp, P. M., & Lemieux, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.38-54.2003 · Cited by 611 · see citing works
Modulation of mammalian life span by the short isoform of p53
Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., Sutherland, A., Thorner, M., & Scrable, H. (2004) · Genes & Development · doi:10.1101/gad.1162404 · Cited by 586 · see citing works
Regulation and mechanisms of mammalian double-strand break repair
Valerie, K. C., & Povirk, L. F. (2003) · Oncogene · doi:10.1038/sj.onc.1206679 · Cited by 572 · see citing works
Aging and Genome Maintenance: Lessons from the Mouse?
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., & Vijg, J. (2003) · Science · doi:10.1126/science.1079161 · Cited by 553 · see citing works
Premature Aging in Mice Deficient in DNA Repair and Transcription
de Boer, J., Andressoo, J. O., de Wit, J., Huijmans, J., Beems, R. B., van Steeg, H., Weeda, G., van der Horst, G. T. J., van Leeuwen, W., Themmen, A. P. N., et al. (2002) · Science · doi:10.1126/science.1070174 · Cited by 545 · see citing works
Barja, G., & Herrero, A. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.2.312 · Cited by 540 · see citing works
'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally
García‐Cao, I., García‐Cao, M., Martín‐Caballero, J., Criado, L. M., Klatt, P., Flores, J. M., Weill, J., Blasco, M. A., & Serrano, M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf595 · Cited by 529 · see citing works
Essential role of limiting telomeres in the pathogenesis of Werner syndrome
Chang, S., Multani, A. S., Cabrera, N. G., Naylor, M. L., Laud, P., Lombard, D., Pathak, S., Guarente, L., & DePinho, R. A. (2004) · Nature Genetics · doi:10.1038/ng1389 · Cited by 462 · see citing works
Self-citationGrowth Retardation and Leaky SCID Phenotype of Ku70-Deficient Mice
Gu, Y., Seidl, K. J., Rathbun, G. A., Zhu, C., Manis, J. P., van der Stoep, N., Davidson, L., Cheng, H.-L., Sekiguchi, J., Frank, K. M., et al. (1997) · Immunity · doi:10.1016/s1074-7613(00)80386-6 · Cited by 451 · see citing works
Self-citationSir2-Independent Life Span Extension by Calorie Restriction in Yeast
Kaeberlein, M., Kirkland, K. T., Fields, S., & Kennedy, B. K. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020296 · Cited by 441 · see citing works
When cells get stressed: an integrative view of cellular senescence
Ben-Porath, I., & Weinberg, R. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420663 · Cited by 404 · see citing works
Weeda, G., Donker, I., de Wit, J., Morreau, H., Janssens, R. C., Vissers, C. J., Nigg, A. L., STEEG, H. V., Bootsma, D., & Hoeijmakers, J. H. J. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00190-4 · Cited by 380 · see citing works
DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2
Smogorzewska, A., Karlseder, J., Holtgreve-Grez, H., Jauch, A. S., & de Lange, T. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01179-x · Cited by 377 · see citing works
Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing
Wong, K.-K., Maser, R. S., Bachoo, R. M., Menon, J., Carrasco, D. R., Gu, Y., Alt, F. W., & DePinho, R. A. (2003) · Nature · doi:10.1038/nature01385 · Cited by 375 · see citing works
Self-citationRecQ helicases: suppressors of tumorigenesis and premature aging
Bachrati, C. Z., & Hickson, I. D. (2003) · Biochemical Journal · doi:10.1042/bj20030491 · Cited by 372 · see citing works
Deletion of Ku86 causes early onset of senescence in mice
Vogel, H., Lim, D.-S., Karsenty, G., Finegold, M., & Hasty, P. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.19.10770 · Cited by 368 · see citing works
ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage
Barzilai, A. (2002) · DNA Repair · doi:10.1016/s1568-7864(01)00007-6 · Cited by 359 · see citing works
Mechanisms of cellular senescence in human and mouse cells.
Itahana, K., Campisi, J., & Dimri, G. P. (2004) · Biogerontology · doi:10.1023/b:bgen.0000017682.96395.10 · Cited by 338 · see citing works
DNA double strand break repair and chromosomal translocation: Lessons from animal models
Ferguson, D. O., & Alt, F. W. (2001) · Oncogene · doi:10.1038/sj.onc.1204767 · Cited by 333 · see citing works
Self-citationTelomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts
Wyllie, F. S., Jones, C. J., Skinner, J. W., Haughton, M. F., Wallis, C., Wynford-Thomas, D., Faragher, R. G. A., & Kipling, D. (2000) · Nature Genetics · doi:10.1038/71630 · Cited by 332 · see citing works
The p53 response to DNA damage
Meek, D. W. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.027 · Cited by 329 · see citing works
McWhir, J., Selfridge, J., Harrison, D. J., Squires, S., & Melton, D. W. (1993) · Nature Genetics · doi:10.1038/ng1193-217 · Cited by 322 · see citing works
Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation
Wong, K.-K., Chang, S., Weiler, S. R., Ganesan, S., Chaudhuri, J., Zhu, C., Artandi, S. E., Rudolph, K. L., Gottlieb, G. J., Chin, L., et al. (2000) · Nature Genetics · doi:10.1038/79232 · Cited by 309 · see citing works
Self-citationOpresko, P. L., Otterlei, M., Graakjær, J., Bruheim, P., Dawut, L., Kølvraa, S., May, A., Seidman, M. M., & Bohr, V. A. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.05.023 · Cited by 305 · see citing works
Lebel, M., & Leder, P. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.22.13097 · Cited by 304 · see citing works
The cellular response to general and programmed DNA double strand breaks
Bassing, C. H., & Alt, F. W. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.06.001 · Cited by 301 · see citing works
Self-citationATM: Genome stability, neuronal development, and cancer cross paths
(2001) · Advances in Cancer Research · doi:10.1016/s0065-230x(01)83007-4 · Cited by 299 · see citing works
Cancer and aging: a model for the cancer promoting effects of the aging stroma
Krtolica, A., & Campisi, J. (2002) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00053-5 · Cited by 295 · see citing works
d'Adda di Fagagna, F., Hande, M. P., Tong, W.-M., Roth, D., Lansdorp, P. M., Wang, Z.-Q., & Jackson, S. P. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00328-1 · Cited by 293 · see citing works
Cao, L., Li, W., Kim, S., Brodie, S. G., & Deng, C.-X. (2003) · Genes & Development · doi:10.1101/gad.1050003 · Cited by 293 · see citing works
DNA end joining becomes less efficient and more error-prone during cellular senescence
Seluanov, A., Mittelman, D., Pereira-Smith, O. M., Wilson, J. H., & Gorbunova, V. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400726101 · Cited by 278 · see citing works
Dong, Y., Hakimi, M., Chen, X., Kumaraswamy, E., Cooch, N. S., Godwin, A. K., & Shiekhattar, R. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00424-6 · Cited by 274 · see citing works
Johnson, F. B., Marciniak, R. A., McVey, M., Stewart, S. A., Hahn, W. C., & Guarente, L. (2001) · The EMBO Journal · doi:10.1093/emboj/20.4.905 · Cited by 269 · see citing works
Stracker, T. H., Theunissen, J.-W. F., Morales, M., & Petrini, J. H. J. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.014 · Cited by 263 · see citing works
Somatic mutations and aging: a re-evaluation
Vijg, J. (2000) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/s0027-5107(99)00202-x · Cited by 243 · see citing works
Hierarchical deterioration of body systems in Werner's syndrome: Implications for normal ageing
Goto, M. (1997) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(97)00111-5 · Cited by 240 · see citing works
Transcription — guarding the genome by sensing DNA damage
Ljungman, M. E., & Lane, D. P. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1435 · Cited by 237 · see citing works
Schulz, V. P., Zakian, V. A., Ogburn, C. E., McKay, J., Jarzebowicz, A. A., Martin, G. M., & Edland, S. D. (1996) · Human Genetics · doi:10.1007/bf02346184 · Cited by 221 · see citing works
Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres
Espejel, S., Franco, S., Rodríguez, S., Bouffler, S. D., Cigudosa, J. C., & Blasco, M. A. (2002) · The EMBO Journal · doi:10.1093/emboj/21.9.2207 · Cited by 215 · see citing works
Self-citationTelomere Shortening Exposes Functions for the Mouse Werner and Bloom Syndrome Genes
Du, X., Shen, J., Kugan, N., Furth, E. E., Lombard, D. B., Cheung, C., Pak, S., Luo, G., Pignolo, R. J., DePinho, R. A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.19.8437-8446.2004 · Cited by 213 · see citing works
Self-citationCancer predisposition and hematopoietic failure in <i> Rad50 <sup>S/S</sup> </i> mice
Bender, C. F., Sikes, M. L., Sullivan, R., Huye, L. E., Le Beau, M. M., Roth, D. B., Mirzoeva, O. K., Oltz, E. M., & Petrini, J. H. J. (2002) · Genes & Development · doi:10.1101/gad.1007902 · Cited by 213 · see citing works
An Age-Induced Switch to a Hyper-Recombinational State
McMurray, M. A., & Gottschling, D. E. (2003) · Science · doi:10.1126/science.1087706 · Cited by 208 · see citing works
Defective DNA Repair and Increased Genomic Instability in Artemis-deficient Murine Cells
Rooney, S., Alt, F. W., Lombard, D. B., Whitlow, S. R., Eckersdorff, M., Fleming, J., Fugmann, S. D., Ferguson, D. O., Schatz, D. G., & Sekiguchi, J. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021891 · Cited by 206 · see citing works
Self-citationMutations in the <i>WRN</i> Gene in Mice Accelerate Mortality in a p53-Null Background
Lombard, D. B., Beard, C., Johnson, B., Marciniak, R. A., Dausman, J., Bronson, R., Buhlmann, J. E., Lipman, R., Curry, R., Sharpe, A., et al. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.9.3286-3291.2000 · Cited by 187 · see citing works
Self-citationSGS1 is required for telomere elongation in the absence of telomerase
Huang, P.-H., Pryde, F. E., Lester, D., Maddison, R. L., Borts, R. H., Hickson, I. D., & Louis, E. J. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00021-5 · Cited by 185 · see citing works
Sun, L.-Q., Lee, D. W., Zhang, Q., Xiao, W., Raabe, E. H., Meeker, A. K., Miao, D., Huso, D. L., & Arceci, R. J. (2004) · Genes & Development · doi:10.1101/gad.1176104 · Cited by 182 · see citing works
Expression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice.
Cao, J., Venton, L., Sakata, T., & Halloran, B. P. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.2.270 · Cited by 173 · see citing works
ATM function and telomere stability
Pandita, T. K. (2002) · Oncogene · doi:10.1038/sj.onc.1205060 · Cited by 164 · see citing works
Divide and conquer: nucleotide excision repair battles cancer and ageing
Mitchell, J. R., Hoeijmakers, J. H., & Niedernhofer, L. J. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00018-8 · Cited by 160 · see citing works
Tian, M., Shinkura, R., Shinkura, N., & Alt, F. W. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.1200-1205.2004 · Cited by 159 · see citing works
Self-citationCouëdel, C., Mills, K. D., Barchi, M., Shen, L., Olshen, A. B., Johnson, R. D., Nussenzweig, A., Essers, J., Kanaar, R., Li, G. C., et al. (2004) · Genes & Development · doi:10.1101/gad.1209204 · Cited by 159 · see citing works
Self-citationSekiguchi, J., Ferguson, D. O., Chen, H. T., Yang, E. M., Earle, J., Frank, K., Whitlow, S., Gu, Y., Xu, Y., Nussenzweig, A., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051632098 · Cited by 156 · see citing works
Self-citationRecombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase
Cohen, H. Y., & Sinclair, D. A. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061579598 · Cited by 156 · see citing works
Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice
Schubert, R. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh189 · Cited by 139 · see citing works
Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stabilityPreprint
Mills, K. D., Ferguson, D. O., Essers, J., Eckersdorff, M., Kanaar, R., & Alt, F. W. (2004) · Genes & Development · doi:10.1101/gad.1204304 · Cited by 136 · see citing works
Self-citationTRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA
Machwe, A., Xiao, L., & Orren, D. K. (2004) · Oncogene · doi:10.1038/sj.onc.1206906 · Cited by 130 · see citing works
Tahara, H., Tokutake, Y., Maeda, S., Kataoka, H., Watanabe, T., Satoh, M., Matsumoto, T., Sugawara, M., Ide, T., Goto, M., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1201377 · Cited by 130 · see citing works
Functional interaction between DNA‐PKcs and telomerase in telomere length maintenance
Espejel, S., Franco, S., Sgura, A., Gae, D., Bailey, S. M., Taccioli, G. E., & Blasco, M. A. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf593 · Cited by 128 · see citing works
Self-citationShorter telomeres, accelerated ageing and increased lymphoma in DNA‐PKcs‐deficient mice
Espejel, S., Martı́n, M., Klatt, P., Martín‐Caballero, J., Flores, J. M., & Blasco, M. A. (2004) · EMBO Reports · doi:10.1038/sj.embor.7400127 · Cited by 127 · see citing works
(1991) · PubMed · Cited by 123 · see citing works
The Werner syndrome helicase/exonuclease (WRN) disrupts and degrades D-loops in vitro
Orren, D. K., Theodore, S., & Machwe, A. (2002) · Biochemistry · doi:10.1021/bi0266986 · Cited by 112 · see citing works
Murai, M., Enokido, Y., Inamura, N., Yoshino, M., Nakatsu, Y., van der Horst, G. T. J., Hoeijmakers, J. H. J., Tanaka, K., & Hatanaka, H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.231329598 · Cited by 109 · see citing works
Trichothiodystrophy, a transcription syndrome
Bergmann, E., & Egly, J. (2001) · Trends in Genetics · doi:10.1016/s0168-9525(01)02280-6 · Cited by 105 · see citing works
Involvement of p53 and p21 in Cellular Defects and Tumorigenesis in Atm−/− Mice
Xu, Y., Yang, E. M., Brugarolas, J., Jacks, T., & Baltimore, D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.4385 · Cited by 103 · see citing works
Browne, S. E., Roberts, L. J., Dennery, P. A., Doctrow, S. R., Beal, M. F., Barlow, C., & Levine, R. L. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.01.003 · Cited by 91 · see citing works
Espejel, S., Klatt, P., Murcia, J. M., Martín‐Caballero, J., Flores, J. M., Taccioli, G. E., de MURCIA, G., & Blasco, M. A. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200407178 · Cited by 88 · see citing works
‘Accelerated aging’: a primrose path to insight?
Miller, R. A. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00081.x · Cited by 87 · see citing works
Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence?
Pelicci, P. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20750 · Cited by 85 · see citing works
Molecular Functions of BRCA1 in the DNA Damage Response
Scully, R., Xie, A., & Nagaraju, G. (2004) · Cancer Biology & Therapy · doi:10.4161/cbt.3.6.842 · Cited by 84 · see citing works
Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity
Hasty, P., & Vijg, J. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00082.x · Cited by 77 · see citing works
Karanjawala, Z. E., & Lieber, M. R. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.04.003 · Cited by 71 · see citing works
Infertility and aneuploidy in mice lacking a type IA DNA topoisomerase IIIβ
Kwan, K. Y., Møens, P. B., & Wang, J. C. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0437998100 · Cited by 71 · see citing works
The DNA double-strand break response pathway: becoming more BRCAish than ever
Ting, N. S. Y., & Lee, W. (2004) · DNA repair · doi:10.1016/j.dnarep.2004.03.026 · Cited by 66 · see citing works
Davis, T., Singhrao, S. K., Wyllie, F. S., Haughton, M. F., Smith, P. J., Wiltshire, M., Wynford-Thomas, D., Jones, C. J., Faragher, R. G. A., & Kipling, D. (2003) · Journal of Cell Science · doi:10.1242/jcs.00331 · Cited by 58 · see citing works
DNA double-strand breaks in mouse kidney cells with age
Singh, N. P., Ogburn, C. E., Wolf, N. S., van Belle, G., & Martin, G. M. (2001) · Biogerontology · doi:10.1023/a:1013262327193 · Cited by 49 · see citing works
Identification of telomere-dependent "senescence-like" arrest in mouse embryonic fibroblasts.
Espejel, S., & Blasco, M. (2002) · Experimental Cell Research · doi:10.1006/excr.2002.5533 · Cited by 47 · see citing works
RAG-Mediated V(D)J Recombination Is Not Essential for Tumorigenesis in <i>Atm</i>-Deficient Mice
Petiniot, L. K., Weaver, Z., Vacchio, M., Shen, R., Wangsa, D., Barlow, C., Eckhaus, M., Steinberg, S. M., Wynshaw-Boris, A., Ried, T., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.9.3174-3177.2002 · Cited by 40 · see citing works
Between Scylla and Charybdis: p53 links tumor suppression and aging
Campisi, J. (2002) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(02)00006-4 · Cited by 33 · see citing works
Potential misinterpretations using models of accelerated aging
Harrison, D. E. (1994) · Journal of Gerontology · doi:10.1093/geronj/49.6.b245 · Cited by 25 · see citing works
Rockwood, L. D., Nussenzweig, A., & Janz, S. (2003) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/s0027-5107(03)00108-8 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Ageing as a Risk Factor for Disease
Niccoli, T., & Partridge, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.07.024 · Cited by 1,831 · see citing works
Cellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708 · see citing works
Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.11.044 · Cited by 1,637 · see citing works
Self-citationNakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., Guarente, L. P., & Sassone-Corsi, P. (2008) · Cell · doi:10.1016/j.cell.2008.07.002 · Cited by 1,427 · see citing works
Inflammatory networks during cellular senescence: causes and consequences.
Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.003 · Cited by 1,354 · see citing works
Molecular regulation of stem cell quiescence
Cheung, T. H., & Rando, T. A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3591 · Cited by 1,148 · see citing works
Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., et al. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601758 · Cited by 1,074 · see citing works
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988 · see citing works
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972 · see citing works
Stems Cells and the Pathways to Aging and Cancer
Rossi, D. J., Jamieson, C. H. M., & Weissman, I. L. (2008) · Cell · doi:10.1016/j.cell.2008.01.036 · Cited by 895 · see citing works
SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging
Oberdoerffer, P., Michan, S., McVay, M., Mostoslavsky, R., Vann, J., Park, S.-K., Hartlerode, A., Stegmuller, J., Hafner, A., Loerch, P., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.025 · Cited by 852 · see citing works
Self-citationAging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation
Chambers, S. M., Shaw, C. A., Gatza, C. E., Fisk, C. J., Donehower, L. A., & Goodell, M. A. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050201 · Cited by 799 · see citing works
Ruzankina, Y., Pinzon‐Guzman, C., Asare, A., Ong, T., Pontano, L. L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A., & Brown, E. J. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.03.002 · Cited by 780 · see citing works
Oxidative Stress Resistance in<i>Deinococcus radiodurans</i>
Slade, D., & Radman, M. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00015-10 · Cited by 761 · see citing works
Augmented Wnt signaling in a mammalian model of accelerated aging
Liu, H., Fergusson, M. M., Castilho, R. M., Liu, J., Cao, L., Chen, J., Malide, D., Rovira, I. I., Schimel, D., Kuo, C. J., et al. (2007) · Science · doi:10.1126/science.1143578 · Cited by 755 · see citing works
Stem cells, ageing and the quest for immortality
Rando, T. A. (2006) · Nature · doi:10.1038/nature04958 · Cited by 695 · see citing works
Base excision repair of oxidative DNA damage and association with cancer and aging
Maynard, S., Schurman, S. H., Harboe, C., de Souza-Pinto, N. C., & Bohr, V. A. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn250 · Cited by 685 · see citing works
Yankner, B. A., Lu, T., & Loerch, P. (2008) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathmechdis.2.010506.092044 · Cited by 677 · see citing works
A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis
Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., et al. (2006) · Nature · doi:10.1038/nature05456 · Cited by 669 · see citing works
DNA damage and its links to neurodegeneration
Madabhushi, R., Pan, L., & Tsai, L.-H. (2014) · Neuron · doi:10.1016/j.neuron.2014.06.034 · Cited by 654 · see citing works
Molecular Mechanisms of Mammalian Global Genome Nucleotide Excision Repair
Gillet, L. C. J., & Schärer, O. D. (2006) · Chemical Reviews · doi:10.1021/cr040483f · Cited by 642 · see citing works
Senescent cells as a source of inflammatory factors for tumor progression
Davalos, A. R., Coppe, J.-P., Campisi, J., & Desprez, P.-Y. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9220-9 · Cited by 636 · see citing works
Aging of mesenchymal stem cells
Sethe, S. C., Scutt, A. M., & Stolzing, A. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.10.001 · Cited by 615 · see citing works
Mechanisms of Stem Cell Self-Renewal
He, S., Nakada, D., & Morrison, S. J. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113248 · Cited by 607 · see citing works
Hematopoietic Stem Cell Quiescence Promotes Error-Prone DNA Repair and Mutagenesis
Mohrin, M., Bourke, E., Alexander, D., Warr, M. R., Barry-Holson, K., Le Beau, M. M., Morrison, C. G., & Passegué, E. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.06.014 · Cited by 599 · see citing works
Sirtuins: critical regulators at the crossroads between cancer and aging
Saunders, L. R., & Verdin, E. M. (2007) · Oncogene · doi:10.1038/sj.onc.1210616 · Cited by 569 · see citing works
Vascular Cell Senescence: Contribution to Atherosclerosis
Minamino, T., & Komuro, I. (2007) · Circulation Research · doi:10.1161/01.res.0000256837.40544.4a · Cited by 542 · see citing works
Aging, adiposity, and calorie restriction
Fontana, L. (2007) · JAMA · doi:10.1001/jama.297.9.986 · Cited by 526 · see citing works
Alveolar Cell Senescence in Patients with Pulmonary Emphysema
Tsuji, T., Aoshiba, K., & Nagai, A. (2006) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200509-1374oc · Cited by 527 · see citing works
Haigis, M. C., & Yankner, B. A. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.002 · Cited by 525 · see citing works
Methods to Detect Biomarkers of Cellular Senescence
Itahana, K., Campisi, J., & Dimri, G. P. (2007) · Methods in molecular biology · doi:10.1007/978-1-59745-361-5_3 · Cited by 520 · see citing works
DNA damage, cellular senescence and organismal ageing: causal or correlative?
Chen, J.-H., Hales, C. N., & Ozanne, S. E. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm681 · Cited by 481 · see citing works
Bmi1 regulates mitochondrial function and the DNA damage response pathway
Liu, J., Cao, L., Chen, J., Song, S., Lee, I. H., Quijano, C., Liu, H., Keyvanfar, K., Chen, H., Cao, L.-Y., et al. (2009) · Nature · doi:10.1038/nature08040 · Cited by 474 · see citing works
The p53 network: cellular and systemic DNA damage responses in aging and Cancer
Reinhardt, H. C., & Schumacher, B. (2012) · Trends in Genetics · doi:10.1016/j.tig.2011.12.002 · Cited by 458 · see citing works
Kohl, E. A., Steinbauer, J., Landthaler, M., & Szeimies, R. (2011) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/j.1468-3083.2010.03963.x · Cited by 443 · see citing works
Choudhury, A. R., Ju, Z., Djojosubroto, M. W., Schienke, A., Lechel, A., Schaetzlein, S., Jiang, H., Stepczynska, A., Wang, C., Buer, J., et al. (2007) · Nature Genetics · doi:10.1038/ng1937 · Cited by 426 · see citing works
How does SIRT1 affect metabolism, senescence and cancer?
Brooks, C. L., & Gu, W. J. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2562 · Cited by 426 · see citing works
Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis
Matsumura, H., Mohri, Y., Binh, N. T., Morinaga, H., Fukuda, M., Ito, M., Kurata, S., Hoeijmakers, J., & Nishimura, E. K. (2016) · Science · doi:10.1126/science.aad4395 · Cited by 416 · see citing works
Biomarkers of cellular senescence and skin aging
Wang, A. S., & Dreesen, O. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00247 · Cited by 404 · see citing works
DNA damage checkpoints in stem cells, ageing and cancer
Sperka, T., Wang, J., & Rudolph, K. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3420 · Cited by 393 · see citing works
Telomere length is paternally inherited and is associated with parental lifespan
Njajou, O. T., Cawthon, R. M., Damcott, C. M., Wu, S.-H., Ott, S., Garant, M. J., Blackburn, E. H., Mitchell, B. D., Shuldiner, A. R., & Hsueh, W.-C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702703104 · Cited by 387 · see citing works
Axis of ageing: telomeres, p53 and mitochondria
Sahin, E., & DePinho, R. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3352 · Cited by 380 · see citing works
Mammalian Base Excision Repair: the Forgotten Archangel
Dianov, G. L., & Hübscher, U. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt076 · Cited by 381 · see citing works
How ageing processes influence cancer
de Magalhães, J. P. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3497 · Cited by 367 · see citing works
Theories of biological aging: Genes, proteins, and free radicals
Rattan, S. I. S. (2006) · Free Radical Research · doi:10.1080/10715760600911303 · Cited by 364 · see citing works
A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging
Murga, M., Bunting, S. F., Montaña, M. F., Soria, R., Mulero, F., Cañamero, M., Lee, Y., McKinnon, P. J., Nussenzweig, A., & Fernández-Capetillo, Ó. (2009) · Nature Genetics · doi:10.1038/ng.420 · Cited by 351 · see citing works
DNA-Damage Response in Tissue-Specific and Cancer Stem Cells
Blanpain, C., Mohrin, M., Sotiropoulou, P. A., & Passegue, E. A. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.012 · Cited by 350 · see citing works
Aging and Immune Function: Molecular Mechanisms to Interventions
Ponnappan, S., & Ponnappan, U. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3228 · Cited by 339 · see citing works
The mechanics of base excision repair, and its relationship to aging and disease
WILSONIII, D., & Bohr, V. A. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.10.017 · Cited by 343 · see citing works
Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases
Kubben, N., & Misteli, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.68 · Cited by 320 · see citing works
Repair of alkylated DNA: Recent advances
Sedgwick, B., Bates, P. A., Paik, J., JACOBS, S., & Lindahl, T. L. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.10.005 · Cited by 328 · see citing works
Molecular and biological hallmarks of ageing
Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016) · British journal of surgery · doi:10.1002/bjs.10053 · Cited by 322 · see citing works
SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair
McCord, R. A., Michishita, E., Hong, T., Berber, E., Boxer, L. D., Kusumoto, R., Guan, S., Shi, X., Gozani, O., Burlingame, A. L., et al. (2009) · Aging · doi:10.18632/aging.100011 · Cited by 313 · see citing works
Self-citationWhat has senescence got to do with cancer?
Dimri, G. P. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.025 · Cited by 313 · see citing works
The role of nuclear architecture in genomic instability and ageing.
Oberdoerffer, P., & Sinclair, D. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2238 · Cited by 305 · see citing works
Cao, L., Xu, X., Bunting, S. F., Liu, J., Wang, R.-H., Cao, L. L., Wu, J. J., Peng, T.-N., Chen, J., Nussenzweig, A., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.037 · Cited by 308 · see citing works
Yahata, T., Takanashi, T., Muguruma, Y., Ibrahim, A. A., Matsuzawa, H., Uno, T., Sheng, Y., Onizuka, M., Ito, M., Kato, S., et al. (2011) · Blood · doi:10.1182/blood-2011-01-330050 · Cited by 298 · see citing works
Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis
Larson, K., Yan, S.-J., Tsurumi, A., Liu, J., Zhou, J., Gaur, K., Guo, D., Eickbush, T. H., & Li, W. X. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002473 · Cited by 284 · see citing works
DNA damage response and metabolic disease
Shimizu, I., Yoshida, Y., Suda, M., & Minamino, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.008 · Cited by 286 · see citing works
Structural and Functional Relationships of the XPF/MUS81 Family of Proteins
Ciccia, A., McDonald, N. Q., & West, S. C. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.070306.102408 · Cited by 278 · see citing works
Neurotoxicity of substituted amphetamines: Molecular and cellular mechanisms
Cadet, J. L., Krasnova, I. N., Jayanthi, S., & Lyles, J. (2007) · Neurotoxicity Research · doi:10.1007/bf03033567 · Cited by 271 · see citing works
SIRT1 Regulates the Function of the Nijmegen Breakage Syndrome Protein
Yuan, Z., Zhang, X. M., Sengupta, N., Lane, W. S., & Seto, E. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.029 · Cited by 271 · see citing works
The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration
Azam, S., Haque, M. E., Balakrishnan, R., Kim, I., & Choi, D. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.683459 · Cited by 257 · see citing works
The placenta in fetal growth restriction: What is going wrong?
Sun, C., Groom, K. M., Oyston, C., Chamley, L. W., Clark, A. R., & James, J. L. (2020) · Placenta · doi:10.1016/j.placenta.2020.05.003 · Cited by 253 · see citing works
Age to survive: DNA damage and aging
Schumacher, B., Garinis, G. A., & Hoeijmakers, J. H. J. (2008) · Trends in Genetics · doi:10.1016/j.tig.2007.11.004 · Cited by 255 · see citing works
Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism
Kuro‐o, M. (2013) · Nature Reviews Nephrology · doi:10.1038/nrneph.2013.111 · Cited by 254 · see citing works
The hallmarks of fibroblast ageing
Tigges, J., Krutmann, J., Fritsche, E., Haendeler, J., Schaal, H., Fischer, J. W., Kalfalah, F., Reinke, H., Reifenberger, G., Stühler, K., et al. (2014) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2014.03.004 · Cited by 250 · see citing works
Tsurumi, A., & Li, W. X. (2012) · Epigenetics · doi:10.4161/epi.20540 · Cited by 248 · see citing works
A review and appraisal of the DNA damage theory of ageing
Freitas, A. A., & de Magalhães, J. P. (2011) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2011.05.001 · Cited by 242 · see citing works
HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination
Adimoolam, S., Sirisawad, M., Chen, J., Thiemann, P., Ford, J. M., & Buggy, J. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707828104 · Cited by 239 · see citing works
Progressive loss of SIRT1 with cell cycle withdrawal
Sasaki, T., Maier, B., Bartke, A., & Scrable, H. J. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00235.x · Cited by 235 · see citing works
Oxidatively generated complex DNA damage: Tandem and clustered lesions
Cadet, J., Ravanat, J.-L., TavernaPorro, M., Menoni, H., & Angelov, D. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.04.005 · Cited by 233 · see citing works
DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A
Liu, Y., Rusinol, A., Sinensky, M., Wang, Y., & Zou, Y. (2006) · Journal of Cell Science · doi:10.1242/jcs.03263 · Cited by 228 · see citing works
Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease
Shanbhag, N. M., Evans, M. D., Mao, W., Nana, A. L., Seeley, W. W., Adame, A., Rissman, R. A., Masliah, E., & Mucke, L. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0723-5 · Cited by 214 · see citing works
Ly, P., Brunner, S. F., Shoshani, O., Kim, D. H., Lan, W., Pyntikova, T., Flanagan, A. M., Behjati, S., Page, D. C., Campbell, P. J., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0360-8 · Cited by 220 · see citing works
Xu, F. L., Gao, Z., Zhang, J., Rivera, C. A., Yin, J., Weng, J., & Ye, J. (2010) · Endocrinology · doi:10.1210/en.2009-1013 · Cited by 221 · see citing works
Severino, V, Alessio, N., Farina, A., Sandomenico, A., Cipollaro, M., Peluso, G., Galderisi, U., & Chambery, A. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.445 · Cited by 214 · see citing works
Leydig cell aging and the mechanisms of reduced testosterone synthesis.
Midzak, A. S., Chen, H., Papadopoulos, V., & Zirkin, B. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.07.016 · Cited by 218 · see citing works
Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs
Kang, E., Wang, X., Tippner-Hedges, R., Ma, H., Folmes, C. D. L., Gutiérrez, N. M., Lee, Y., Dyken, C. V., Ahmed, R., Li, Y., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.02.005 · Cited by 216 · see citing works
DNA Damage and Repair: From Molecular Mechanisms to Health Implications
Fabio Altieri, F., Grillo, C., Maceroni, M., & Chichiarelli, S. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1830 · Cited by 212 · see citing works
Kraemer, S. M., Kyes, S., Aggarwal, G., Springer, A., Nelson, S. O., Christodoulou, Z., Smith, L. M., Wang, W., Levin, E., Newbold, C., et al. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-45 · Cited by 203 · see citing works
Life history correlates of oxidative damage in a free‐living mammal population
Nussey, D. H., Pemberton, J. M., Pilkington, J. G., & Blount, J. D. (2009) · Functional Ecology · doi:10.1111/j.1365-2435.2009.01555.x · Cited by 202 · see citing works
Ahmed, A. S. I., Sheng, M. H. ‐., Wasnik, S., Baylink, D. J., & Lau, K. ‐. W. (2017) · World Journal of Experimental Medicine · doi:10.5493/wjem.v7.i1.1 · Cited by 202 · see citing works
Slabicki, M. M., Theis, M., Krastev, D. B., Samsonov, S. A., Mundwiller, E., Junqueira, M., Paszkowski‐Rogacz, M., Teyra, J., Heninger, A., Poser, I., et al. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000408 · Cited by 198 · see citing works
Natural Products and Synthetic Analogs as a Source of Antitumor Drugs
Sharifi‐Rad, J., Ozleyen, A., Tumer, T. B., Adetunji, C. O., Omari, N. E., Balahbib, A., Taheri, Y., Bouyahya, A., Martorell, M., Martins, N. A., et al. (2019) · Biomolecules · doi:10.3390/biom9110679 · Cited by 198 · see citing works
Telomere biology and age-related diseases
Herrmann, M., Pusceddu, I., März, W., & Herrmann, W. (2018) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2017-0870 · Cited by 193 · see citing works
Sepúlveda, J. C., Tomé, M., Fernández‐Santos, M. E., Delgado, M., Campisi, J., Bernad, A., & Gonzalez, M. A. (2014) · Stem Cells · doi:10.1002/stem.1654 · Cited by 191 · see citing works
Molecular bases of progeroid syndromes
Navarro, C. L., Cau, P., & Lévy, N. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl214 · Cited by 189 · see citing works
Ageing and the border between health and disease
MacNee, W., Rabinovich, R., & Choudhury, G. (2014) · European Respiratory Journal · doi:10.1183/09031936.00134014 · Cited by 188 · see citing works
A conserved NAD + binding pocket that regulates protein-protein interactions during aging
Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J. Y., Rajman, L. A., Qin, B., Lou, Z., Gorbunova, V. A., et al. (2017) · Science · doi:10.1126/science.aad8242 · Cited by 188 · see citing works
Interplay between inflammation and cancer
Piotrowski, I., Kulcenty, K. I., & Suchorska, W. M. (2020) · Reports of Practical Oncology & Radiotherapy · doi:10.1016/j.rpor.2020.04.004 · Cited by 190 · see citing works
Regulation of SIRT6 protein levels by nutrient availability
Kanfi, Y., Shalman, R., Peshti, V., Pilosof, S. N., Gozlan, Y. M., Pearson, K. J., Lerrer, B., Moazed, D., Marine, J., de Cabo, R., et al. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.01.019 · Cited by 187 · see citing works
Cancer and ageing: convergent and divergent mechanisms
Serrano, M., & Blasco, M. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2242 · Cited by 182 · see citing works
Reactive Oxygen Species and Aging in Caenorhabditis elegans : Causal or Casual Relationship?
Raamsdonk, J. M. V., & Hekimi, S. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3215 · Cited by 184 · see citing works
Space Radiation Biology for “Living in Space”
Furukawa, S., Nagamatsu, A., Nenoi, M., Fujimori, A., Kakinuma, S., Katsube, T., Wang, B., Tsuruoka, C., Shirai, T., Nakamura, A., et al. (2020) · BioMed Research International · doi:10.1155/2020/4703286 · Cited by 183 · see citing works
Predictive factors for late normal tissue complications following radiotherapy for breast cancer
Lilla, C., Ambrosone, C. B., Kropp, S., Helmbold, I., Schmezer, P., von Fournier, D., Haase, W., Sautter‐Bihl, M., Wenz, F. K., & Chang-Claude, J. C. (2007) · Breast Cancer Research and Treatment · doi:10.1007/s10549-006-9480-9 · Cited by 182 · see citing works
Liang, S., Mele, J., Wu, Y., Buffenstein, R., & Hornsby, P. J. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00588.x · Cited by 177 · see citing works
The Ewing Sarcoma Protein Regulates DNA Damage-Induced Alternative Splicing
Paronetto, M. P., Miñana, B., & Valcárcel, J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.05.035 · Cited by 175 · see citing works
Early aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice
Baker, D. J., Jeganathan, K. B., Malureanu, L., Perez-Terzic, C., Terzic, A., & van Deursen, J. M. A. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507081 · Cited by 175 · see citing works
- Authors
- Lombard, D. B., Chua, K. F., Mostoslavsky, R., Franco, S., Gostissa, M., & Alt, F. W.
- Affiliations
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Alt, Frederick W.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 120
- Issue
- 4
- Pages
- 497-512
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2022572059
- Cited by
- 944
- References
- 115
- Citations by year
- 2026: 20 · 2025: 40 · 2024: 27 · 2023: 35 · 2022: 39 · 2021: 51 · 2020: 40 · 2019: 46 · 2018: 29 · 2017: 37 · 2016: 38 · 2015: 41 · 2014: 54 · 2013: 51 · 2012: 43
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- 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 › DNA Repair Mechanisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- aging, DNA repair, genome stability, DNA damage accumulation, premature aging, DNA damage response, Sir2, sirtuins, metabolism, mouse mutants
- MeSH terms
- Ku Autoantigen, Animals, DNA Damage, DNA Repair, DNA-Binding Proteins, Longevity, Tumor Suppressor Protein p53, Cellular Senescence, Reactive Oxygen Species, Antigens, Nuclear, Sirtuins, Genomic Instability, Rad51 Recombinase, Mice
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 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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
