The DOI matches its Crossref record; 62 of the 66 references it cites were found in a registry or an index; 33 of the 56 sources its claims cite were checked for support.
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype
Open accessAbstract
Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.
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83 Own result · 38 Own interpretation · 15 Partly supported · 11 No full text of the sources · 7 Supported · 3 Not checked yet · 3 Own method · 2 Sources not found · 1 Supported so far · accuracy not yet measured
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In the paper
“The permanent growth arrest can deplete progenitor or stem cell pools, thereby compromising tissue repair and regeneration”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Partly supportedcites Kuilman et al., 2010 sourceExperimental — accuracy not yet measured
The ‘Replicative cellular senescence’ and ‘Cell cycle arrest’ sections describe senescence as a stable, long-term loss of proliferative capacity. Our copy does not say that this arrest depletes progenitor or stem cell pools or consequently compromises tissue repair and regeneration. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites Sousa-Victor et al., 2014 source
- Partly supportedcites Velarde et al., 2015 sourceExperimental — accuracy not yet measured
The Abstract reports irreversible senescence-associated growth arrest, and the Results link epidermal stem-cell depletion in older Sod2-deficient mice to delayed wound healing. The paper does not establish that the growth arrest itself caused the depletion; it attributes the depletion to Sod2 deficiency and notes that the impaired healing appears only in older mice. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“indicating that an absence of SIRT3 throughout embryogenesis and acute loss of SIRT3 after development can have different effects, as reported”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
What the sources say
- Partly supportedcites Fernandez-Marcos et al., 2012 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says germline Sirt3 knockout is present from the beginning of embryonic development, whereas the tissue-specific deletions begin at a later developmental stage, and says this timing difference should be considered when comparing outcomes. It does not establish that those tissue-specific deletions occurred acutely after development; tissue specificity and other experimental differences also distinguish the models. (LLM, conf=0.84)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“p53 can suppress NF-κB (Dey et al., 2007; Murphy et al., 2011), which promotes transcription of many SASP genes (Freund et al., 2011).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
What the sources say
- Not checked — no full text of the sourcecites Dey et al., 2007 source
- Partly supportedcites Murphy et al., 2011 sourceExperimental — accuracy not yet measured
The Results show that loss of p53 impairs glucocorticoid receptor (GR) repression of NF-κB. The paper supports a role for p53 in suppressing NF-κB in that context, but does not establish that p53 suppresses NF-κB independently of GR and glucocorticoids. Page numbers were not available in our copy. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Because p53 also limits SASP gene expression (Coppé et al., 2008; Rodier et al., 2009), we depleted p53 in WT and rho0 cells and measured IL1A and IL1B mRNA levels.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
What the sources say
- Partly supportedcites Coppé et al., 2008 sourceExperimental — accuracy not yet measured
In “Cell-Nonautonomous Tumor-Suppressive Function of p53” (page not provided), the paper reports that p53 restrains the SASP: p53-deficient senescent cells secrete higher levels of SASP factors. Those results concern the secretory phenotype, not a demonstrated reduction in SASP gene expression or IL1A/IL1B mRNA by p53. (LLM, conf=0.84)
- Partly supportedcites Rodier et al., 2009 sourceExperimental — accuracy not yet measured
The passage describing the p53-inactivation experiments (section labelled Abstract; page unavailable) reports that loss of p53 increased secreted IL-6 in HCA2 fibroblasts, consistent with p53 limiting at least one SASP factor. It measures cytokine secretion, however, not SASP gene expression generally or the IL1A and IL1B mRNA levels mentioned in the citing sentence. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“Other reports show that inducible SIRT3 knockout mice do not necessarily phenocopy germline knockout animals (Fernandez-Marcos et al., 2012), consistent with our finding that acute SIRT3 depletion induces senescence.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Partly supportedcites Fernandez-Marcos et al., 2012 sourceExperimental — accuracy not yet measured
The Discussion reports that muscle- and liver-specific Sirt3 knockout mice did not show the metabolic phenotypes described in germline knockouts. But the Methods describe tissue-specific Cre lines, not inducible knockout mice. The paper also reports acute Sirt3 deletion in cultured hepatocytes, not in mice, so it does not establish the claim specifically for inducible mice. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Our data from POLGD257A mice indicate that MiDAS can occur in vivo, although mtDNA mutations accumulate with age at rates well below that seen in POLGD257A mice (Khrapko and Vijg, 2009).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Supportedcites Khrapko and Vijg, 2009 source
The section “Does premature aging in mtDNA mutator mice imply that mtDNA mutations cause normal aging?” (page unavailable) describes Polg mutator mice as having increased mtDNA mutation rates and reports mutation levels in homozygous whole-body mutators one to two orders of magnitude above those in normally aged mice or humans. The comparison supports the claim, although the paper reports measured mutation frequencies rather than a direct estimate of accumulation rates. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The effects of the MiDAS SASP on adipocyte and keratinocyte differentiation measured in culture are relevant to aging phenotypes in vivo.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Other mitochondrial perturbations induced a similar senescent phenotype, which we term mitochondrial dysfunction-associated senescence (MiDAS).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“depletion of SIRT3 or SIRT5, but not other SIRTs, induced senescence as judged by increased SA-Bgal activity and decreased BrdU labeling 10 days later.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 20
- It may state two separate claims as one. 60
- The quote only partly states this claim. 2
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Notably, NAD+ declines with age in several tissues”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Supportedcites Braidy et al., 2011 source
The Abstract reports a significant age-related decline in intracellular NAD+ in the heart, lung, liver, and kidney of female Wistar rats. The Discussion likewise reports declining NAD+ levels with aging in those organs. (LLM, conf=0.93)
- Partly supportedcites Gomes et al., 2013 sourceExperimental — accuracy not yet measured
In Results, under “Nuclear NAD+ Levels Regulate Mitochondrially Encoded Genes” (page unavailable), the paper reports less total NAD+ in the skeletal muscle of elderly mice and describes an overall age-related decline. It does not establish the citing sentence’s more specific claim that NAD+ declines in several tissues. (LLM, conf=0.86)
- Supportedcites Stein and Imai, 2014 source
The Introduction states that NAD+ levels decline with age in multiple peripheral tissues. The Results also report an age-related decline in mouse hippocampal NAD+ levels. No page numbers are provided in our copy. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“sustained activation of 5′AMP-activated protein kinase (AMPK), a major bioenergetic sensor, is a hallmark of senescence (Moiseeva et al., 2009) and can induce a senescence arrest”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Partly supportedcites Moiseeva et al., 2009 sourceExperimental — accuracy not yet measured
The Results (page not provided) show that AMPK was highly active in Ras-senescent cells compared with control cells, and that RISP knockdown both activated AMPK and produced senescent features. This supports an association in the studied models, but does not establish sustained AMPK activation as a hallmark of senescence generally. The citation is attached to the hallmark clause, not the subsequent claim that AMPK activation can induce arrest. (LLM, conf=0.84)
- Not matchedcites Jiang et al., 2013b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites Jones et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Dysfunctional mitochondria accumulate with age, best documented in tissues comprised largely of post-mitotic cells”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites Herbst et al., 2007 source
- Partly supportedcites Lee et al., 2010 sourceExperimental — accuracy not yet measured
The Results (page unavailable) report age-associated reductions in muscle mitochondrial function in old mice, supporting the claim's general point about aging and dysfunction. They do not establish that dysfunctional mitochondria accumulate or that the pattern is best documented in largely post-mitotic tissues; the reported mitochondrial density in soleus muscle decreased with age. (LLM, conf=0.84)
- Partly supportedcites Safdar et al., 2010 sourceExperimental — accuracy not yet measured
The Introduction reports that older adults’ skeletal muscle shows an accumulation of mitochondrial abnormalities, and the Discussion reports accumulated mtDNA mutations and deletions in older muscle. Neither passage says that accumulation is best documented in tissues composed largely of post-mitotic cells; the paper also notes that age-related changes in mitochondrial function in human muscle remain equivocal. (LLM, conf=0.84)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“it induced cell death after SIRT1-depletion (not shown), as reported”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
What the sources say
- Supportedcites Cheng et al., 2003 source
The Results section reports ionizing-radiation-induced apoptosis in SIRT1-deficient mouse thymocytes, with greater radiation sensitivity than in control thymocytes. The finding concerns thymocytes; the paper does not report the same increased sensitivity in embryonic fibroblasts. (LLM, conf=0.88)
- Supportedcites Yuan et al., 2012 source
Figure 4E (captioned under Cell viability assay; page unavailable) describes A549 cells treated with ionizing radiation and their apoptotic population measured 48 hours later. The section “DBC1 phosphorylation is important for cellular stress response” identifies the Figure 4E cells as depleted of SIRT1 and discusses their DNA damage-induced apoptosis. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Dysfunctional mitochondria can induce cellular senescence in culture (Moiseeva et al., 2009; Wang et al., 2003) and in vivo (Dai et al., 2010; Kang et al., 2013).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Supportedcites Moiseeva et al., 2009 source
Moiseeva et al. is cited for the culture portion of the sentence, not the in vivo portion. The Results report that interfering with mitochondrial function induced senescence markers, and the Discussion states that disrupting electron transport or oxidative phosphorylation was sufficient to trigger senescent cell-cycle arrest in human cells. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites Wang et al., 2003 source
- Supportedcites Dai et al., 2010 source
Dai et al. is cited for the in vivo portion of the sentence, not the culture portion. In the Results section, older mitochondrial mutator mouse hearts had approximately threefold higher expression of the senescence marker p16INK4a than wild-type hearts, and mitochondrial-targeted catalase partially reduced it. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This senescence-associated secretory phenotype (SASP) comprises pro-inflammatory cytokines, proteases, and growth and angiogenesis factors”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Partly supportedcites Coppé et al., 2008 sourceExperimental — accuracy not yet measured
The Discussion describes inflammatory cytokines and growth factors as SASP components and says chronic SASP secretion may disrupt normal tissue structure and function. The passages retrieved from our copy do not establish proteases or angiogenesis factors as SASP components, so the composition stated in the citing sentence is only partly supported. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Increased ADP:ATP or AMP:ATP ratios activate AMPK (Hardie et al., 2012)”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
What the sources say
- Supportedcites Hardie et al., 2012 source
The Introduction states that AMPK senses increases in both AMP:ATP and ADP:ATP ratios. The ‘AMPK – subunits and regulation’ section explains that AMP activates AMPK allosterically, while both AMP and ADP can promote its activation through effects on phosphorylation. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Since p53 inhibits RELA by competing for CBP binding (Webster and Perkins, 1999), p53 likely limits the IL1 arm of the SASP by reducing NF-κB activity.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
What the sources say
- Supportedcites Webster and Perkins, 1999 source
The Results report that p53 inhibits RelA-mediated transcription and that adding CBP reverses this inhibition. The Discussion states that p53 and RelA bind p300 and CBP competitively, while noting that this mechanism may only partially explain their transcriptional cross talk. The cited claim concerns RelA activity; the sentence’s subsequent inference about the SASP is not attributed to this source. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Notably, many SASP factors that were not expressed by SIRT3-depleted cells are pro-inflammatory, although the cells uniquely secreted CCL27”
- Also stated in: § Mitochondrial SIRTs Suppress Senescent Phenotypes · plain
“a pro-inflammatory cytokine that comprises the SASP of mouse, but not human, fibroblasts induced to senesce by IR”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
What the sources say
- Partly supportedcites Coppé et al., 2010 sourceExperimental — accuracy not yet measured
The Introduction and Discussion describe inflammatory cytokines as SASP factors, supporting the general characterization of many SASP factors as pro-inflammatory. The Results discuss CCL-family factors in irradiated mouse and human fibroblasts, but the passages found do not identify CCL27 as present in the mouse SASP and absent from the human SASP. The paper does not address SIRT3-depleted cells; their secretion profile is the citing authors’ own finding. (LLM, conf=0.78)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Mitochondrial SIRTs Suppress Senescent Phenotypes · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“IR robustly activates p53, which subsides to a low chronic level in 7–10 days as the SASP develops (Coppé et al., 2008; Rodier et al., 2009).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
What the sources say
- Partly supportedcites Coppé et al., 2008 sourceExperimental — accuracy not yet measured
The Results passage discussing Figure 1D and Figure S3 reports p53 stabilization and phosphorylation after irradiation, and says a robust SASP developed 4–7 days later. The passage discussing Figure 6G also gives 4–7 days for cells with wild-type p53. Neither passage says p53 subsided to a low chronic level in 7–10 days. (LLM, conf=0.86)
- Partly supportedcites Rodier et al., 2009 sourceExperimental — accuracy not yet measured
The passage labeled Abstract (page unavailable; Fig. 1a–c) reports rapid p53 activation after irradiation, and another passage reports that inflammatory cytokine secretion develops after a delay following a senescence-inducing dose. It does not establish that p53 subsides to a low chronic level at 7–10 days: the reported return toward baseline within 10 hours concerns a low dose from which cells recovered, while cytokine secretion reached senescent levels within 3–5 days. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“or stabilizing p16INK4a mRNA (Chang et al., 2010)”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
What the sources say
- Partly supportedcites Chang et al., 2010 sourceExperimental — accuracy not yet measured
The Results and Discussion (page not provided) link increased p16 mRNA stability with replicative senescence and describe HuR-mediated p16 mRNA decay. They do not show that AMPK activation stabilizes p16 mRNA or induces senescence through that mechanism. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“We reported that elevated oxygen dampens the SASP in humans and mouse cells (Coppé et al., 2010; Parrinello et al., 2003).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Partly supportedcites Coppé et al., 2010 sourceExperimental — accuracy not yet measured
The Results section on mouse fibroblast SASPs reports that 20% oxygen suppresses the SASP in mouse cells compared with 3% oxygen. It also says oxygen had only minor effects on senescent human cells, which developed robust SASPs at both concentrations. The claim is supported for mouse cells but not for human cells. (LLM, conf=0.91)
- Could not verifycites Parrinello et al., 2003 sourceExperimental — accuracy not yet measured
The paper’s Abstract (page unavailable) compares how 3% and 20% oxygen affect senescence, proliferation, and DNA damage in mouse and human fibroblasts. Searches for SASP, secretory phenotype, secretion, and cytokines found no passage addressing whether elevated oxygen dampens the SASP. (LLM, conf=0.75)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mitochondrial ROS can damage nuclear DNA, thus activating a DNA damage response that induces senescence (Moiseeva et al., 2009; Passos et al., 2010).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Supportedcites Moiseeva et al., 2009 source
The Results report oxidative DNA damage in the nuclei of Ras-expressing cells alongside mitochondrial ROS production. The Discussion says ROS-related damage to nuclear DNA could activate p53 and Rb, sustaining pathways involved in senescence. This supports the claim as a possible mechanism, rather than one the paper establishes as the sole cause of senescence. (LLM, conf=0.88)
- Supportedcites Passos et al., 2010 source
The Introduction (page unavailable) says ROS can directly damage DNA, inducing a DNA damage response and senescence. The Results and Discussion (pages unavailable) connect mitochondrial dysfunction and ROS production to renewed DNA damage foci and the maintenance of senescent growth arrest. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Our finding that loss of SIRT3 loss drives senescence appears to contradict a report in which cells from SIRT3 knockout mice were highly susceptible to oncogenic transformation; however, this susceptibility depended on the elevated ROS characteristic of sirt3−/− cells (Kim et al., 2010).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Partly supportedcites Kim et al., 2010 sourceExperimental — accuracy not yet measured
The Results sections on transformation and SOD report that SIRT3−/− mouse embryonic fibroblasts were transformed by a single oncogene and that MnSOD prevented their immortalization by Myc or Ras alone. The claim overgeneralizes the ROS dependence: MnSOD did not prevent immortalization when the cells expressed both Myc and Ras. The paper also reports normal superoxide levels in unstressed knockout cells, rather than uniformly elevated levels. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mitochondrial dysfunction has been linked to aging (Khrapko and Vijg, 2009), but it is not clear how it drives aging, particularly in mitotic tissues.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Supportedcites Khrapko and Vijg, 2009 source
The section “Mitochondria: molecular clocks of aging?” describes a proposed central role for mitochondria in aging. “Dividing tissues: mtDNA mutations in stem cells” calls mutation accumulation an attractive candidate aging mechanism while noting that its causal role remains unproven. These passages support the cited link without claiming that the mechanism is settled; page numbers were not provided. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition, they secreted HMGB1, a pro-inflammatory alarmin that is a feature of senescent cells (Davalos et al., 2013).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
What the sources say
- Supportedcites Davalos et al., 2013 source
The Introduction states that HMGB1 is an alarmin that provokes an innate immune response and that senescent cells secrete it early after a senescence-inducing stimulus. The Discussion likewise identifies HMGB1 as an alarmin and reports its active secretion by senescent cells, linking it to their inflammatory activity. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These data support the findings that epidermal-specific SOD2-deficient mice rapidly accumulate senescent keratinocytes, which show enhanced differentiation (Velarde et al., 2015) and that POLGD257A mice have a thicker stratum corneum and lipodystrophy compared to age-matched WT mice (Trifunovic et al., 2004).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > MiDAS in POLG Mice
What the sources say
- Partly supportedcites Velarde et al., 2015 sourceExperimental — accuracy not yet measured
The Results report increased senescence markers in epidermal keratinocytes after Sod2 deletion and enhanced keratinocyte differentiation at wound sites in young mice. However, senescence was assessed four months after deletion, so the paper does not establish that senescent keratinocytes accumulated rapidly; it also does not show that the senescent cells specifically were the ones with enhanced differentiation. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SIRT3 depletion induced three senescence markers: reduced lamin B1 (LMNB1) levels”
- Also stated in: § Mitochondrial SIRTs Suppress Senescent Phenotypes · plain
“decreased nuclear localization of high mobility group protein B1 (HMGB1)”
- Also stated in: § Mitochondrial SIRTs Suppress Senescent Phenotypes · plain
“increased levels of the cell-cycle inhibitor p21WAF1”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Mitochondrial SIRTs Suppress Senescent Phenotypes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we identified the mitochondrial SIRTs SIRT3 and to a lesser extent SIRT5, as suppressors of senescence and modulators of the SASP.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These phenotypes occurred in cultured human cells and a murine model of premature aging through mitochondrial dysfunction”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite lacking IL-1-dependent SASP factors, the MiDAS SASP suppressed adipocyte differentiation and promoted keratinocyte differentiation.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The effects of the MiDAS SASP on adipocyte and keratinocyte differentiation measured in culture are relevant to aging phenotypes in vivo.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite the induction of other senescence markers, neither SIRT depletion increased IL-6 secretion”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SIRT3-depleted cells failed to express significant levels of the SASP mRNAs encoding IL1B, CXCL1, CXCL2, IL-6, IL-8 and VEGF, but expressed high levels of mRNAs encoding the SASP factors AREG and IL-10, regardless of IR exposure”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IR increased NF-κB activity in WT cells, as reported (Freund et al., 2011), but failed to do so in rho0 cells without pyruvate and reduced NF-κB activity to below that of unirradiated rho0 cells cultured with pyruvate (Figure 5F).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“SIRT3 depletion strongly suppressed IL-6 secretion by cells induced to senesce by IR, NaBu, or Bleo (Figure 1H) and moderately suppressed IL-6 secretion in response to MKK6EE or RAS”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while the NAD+/NADH ratio declined with MiDAS, total NAD+ actually increased”
- Also stated in: § Decreased NAD+/NADH Ratios Mediate MiDAS · plain
“along with a rise in nicotinamide phosphoribosyltransferase (NAMPT) mRNA”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one. The quote only partly states this claim.
- Also stated in: § Decreased NAD+/NADH Ratios Mediate MiDAS · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An NF-κB reporter showed that NF-κB activity was high in rho0 cells cultured with pyruvate but much lower in rho0 cells without pyruvate (Figure 5F).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, some secreted factors were unaffected by MiDAS and were insensitive to pyruvate.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“pyruvate lowered cytosolic NADH to a much larger degree than in WT cells; it also lowered mitochondrial NADH in rho0 cells, but to a lesser extent than in the cytosol.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In rho0 cells, lactate elicited only a small cytosolic response, suggesting that NADH was already reduced in this compartment.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“when we depleted NAD+ by preventing NAD salvage using the NAMPT inhibitor FK866, cell proliferation ceased after ~7 day”
- Also stated in: § Decreased NAD+/NADH Ratios Mediate MiDAS · plain
“and cells became senescent after ~21 days”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Decreased NAD+/NADH Ratios Mediate MiDAS · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Upon pyruvate withdrawal, rho0, but not WT, cells rapidly senesced, as measured by low EdU labeling and high SA-Bgal”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial Dysfunction and Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the antioxidant EUK-134 reduced mitochondrial, but not cytoplasmic, ROS in SIRT3- and HSPA9-depleted cells”
- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
“but did not prevent the growth arrest of these or Rot-treated cells”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial Dysfunction and Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“FK866 suppressed IR-induced IL-6 secretion (Figure 3I) and lowered total NAD levels (Figure 3J).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MiDAS also increased p21WAF1 and p16INK4a and decreased LMNB1 and intracellular HMGB1 protein levels, which were prevented by pyruvate.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although IR induced a SASP in WT cells with or without pyruvate, rho0 cells plus pyruvate expressed an enhanced SASP that was suppressed by IR (Figures 5E and S5C).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MiDAS also increased p21WAF1 and p16INK4a and decreased LMNB1 and intracellular HMGB1 protein levels, which were prevented by pyruvate.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“AOA-treated WT cells underwent senescence (high SA-Bgal, low EdU labeling, loss of nuclear HMGB1; Figures 3D, 3E, S3G, and S3H) but failed to secrete IL-6 following IR, despite slightly higher secretion by unirradiated AOA-treated cells”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All treatments induced senescence as determined by reduced EdU incorporation, increased SA-Bgal activity”
- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
“and loss of nuclear HMGB1 (for rho0 and Rot”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial Dysfunction and Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“rho0 and SIRT3-depleted cells showed no increase in 53BP1 foci”
- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
“and EUK-134 had no effect on these foci in any senescent cell”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial Dysfunction and Senescent Phenotypes
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“pyruvate lowered NADH in the cytosol, while increasing NADH in mitochondria”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, only MiDAS cells showed marked activation of both AMPKα (thr-172 phosphorylation) and p53 (ser-15 phosphorylation), both of which were blunted by pyruvate (Figure 4C).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NMN delayed senescence by ~2 day relative to untreated cells (Figure S3I), but both groups senesced within 7 days”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All these manipulations elevated the ADP:ATP ratio (Figure 4A), which was lowered by pyruvate”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although shSIRT3 and rho0 cells cultured without pyruvate had elevated Mitosox fluorescence”
- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
“normalization to Mito-tracker showed roughly equivalent ROS levels between control and SIRT3-depleted cells”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial Dysfunction and Senescent Phenotypes
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while SIRT3 shRNA induced senescence in wild-type (WT) mouse embryonic fibroblasts (MEFs), MEFs from SIRT3 knockout mice did not senesce”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Upon pyruvate withdrawal, expression of these factors declined to near WT levels”
- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
“and the cells arrested growth”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial Dysfunction and Senescent Phenotypes
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Mitochondrial Dysfunction and Senescent Phenotypes · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, compared to WT, POLGD257A epidermis had more senescent cells in the stratum corneum as judged by SA-Bgal positivity (Figures S6C and S6D) and loss of HMGB1 in suprabasal epidermal nuclei (Figures S6E and S6F).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > MiDAS in POLG Mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In MiDAS, pyruvate, but not an antioxidant, prevented MiDAS, which showed no evidence of DNA damage.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Examples include the pro-inflammatory cytokines CCL27 (Figure 1G) and TNF-α (Figure 5I) and the anti-inflammatory cytokine IL-10 (Figure 5I).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Inguinal adipose tissue (IAT) from 8-month-old POLGD257A mice had more cells with SA-Bgal (Figures 6A, 6C, S6A, and S6B) and loss of nuclear HMGB1 (Figures 6B and 6D) than age-matched WT IAT, primarily in cells between mature adipocytes.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > MiDAS in POLG Mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MiDAS cells secreted the anti-inflammatory cytokine IL-10, but also high levels of the pro-inflammatory cytokines CCL27 and TNF-α.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SIRT3 showed a stronger response, likely because it was more efficiently depleted”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“there is mounting evidence that senescent cells can accumulate with age and cause or contribute to aging phenotypes and pathologies.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
plainconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Rests on an assumption: Cells that become senescent and build up over time are a cause or contributor to age-related phenotypes and disease.
In the paper
“Inhibition of the latter by depletion of malate dehydrogenase lowers the NAD+/NADH ratio and induces a senescence arrest”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites Lee et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Cells that become senescent and build up over time are a cause or contributor to age-related phenotypes and disease.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show that MiDAS results from a decreased NAD+/NADH ratio, activation of AMPK and subsequently the tumor suppressor p53, which then limits the IL-1 mediated arm of the SASP.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Because mitochondria oxidize NADH to NAD+ (Lehninger et al., 2013), mitochondrial dysfunction can decrease the NAD+/NADH ratio.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > INTRODUCTION
What the sources say
- Not matchedcites Lehninger et al., 2013
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainconditional- Asserted: passes — The authors put it forward as true.
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- Not matched
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In the paper
“Because p53 initiates the senescence arrest and is an AMPK target (Jiang et al., 2013b; Jones et al., 2005), we assessed the p53 dependence of MiDAS.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
What the sources say
- Not matchedcites Jiang et al., 2013b
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites Jones et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Not matched
In the paper
“which can induce senescence by phosphorylating p53 (Jones et al., 2005)”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Low NAD+/NADH Ratios Drive MiDAS through AMPK
What the sources say
- Not checked — no full text of the sourcecites Jones et al., 2005 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, SIRT3 depletion induced senescence but with a SASP that differed from that induced by IR, suggesting a mitochondrial function is required for expression of a subset of SASP factors.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Mitochondrial SIRTs Suppress Senescent Phenotypes
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-1α and IL-1β initiate a positive feedback loop that drives expression of SASP factors such as IL-6 and IL-8 (Orjalo et al., 2009).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > AMPK Mediates MiDAS through p53
What the sources say
- Not checked — no full text of the sourcecites Orjalo et al., 2009 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that low NAD+/ NADH ratios mediate MiDAS phenotypes, which are prevented by NADH oxidation.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > Decreased NAD+/NADH Ratios Mediate MiDAS
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“IMR-90 human fibroblasts were mycoplasma-free, cultured in 3% O2 as described (Coppé et al., 2008; Rodier et al., 2009), and used between 25 and 40 population doublings.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > EXPERIMENTAL PROCEDURES > Cell Culture
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MiDAS results from an NADH-AMPK-p53-dependent pathway and elicits a SASP that lacks IL-1-dependent factors but includes others.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Data are presented either as representative examples or means of 3+ experiments.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > EXPERIMENTAL PROCEDURES > Statistical Analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Protocols were approved by the Institutional Animal Care and Use Committee.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > EXPERIMENTAL PROCEDURES > Animals
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show that (1) mitochondrial dysfunction induces a senescence response (MiDAS), including arrested growth and a SASP that is distinct from that caused by genotoxic stress;”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These data support the findings that epidermal-specific SOD2-deficient mice rapidly accumulate senescent keratinocytes, which show enhanced differentiation (Velarde et al., 2015) and that POLGD257A mice have a thicker stratum corneum and lipodystrophy compared to age-matched WT mice (Trifunovic et al., 2004).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > MiDAS in POLG Mice
What the sources say
- Not checked — no full text of the sourcecites Trifunovic et al., 2004 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“To determine whether MiDAS occurs in vivo, we analyzed POLGD257A mice, which have a mutation in the proofreading domain of the mtDNA polymerase (PolG) and rapidly accumulate mtDNA mutations and aging phenotypes (Kujoth et al., 2005; Trifunovic et al., 2004).”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > RESULTS > MiDAS in POLG Mice
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because p53 depletion was sufficient to prevent MiDAS, AMPK most likely mediates MiDAS through p53 activation, and subsequent NF-κB inhibition.”
§ Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Cells that become senescent and build up over time are a cause or contributor to age-related phenotypes and disease.
“there is mounting evidence that senescent cells can accumulate with age and cause or contribute to aging phenotypes and pathologies.”
The paper relies on this without support.
The effects of the MiDAS SASP on adipocyte and keratinocyte differentiation measured in culture are relevant to aging phenotypes in vivo.
“which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture.”
The paper relies on this without support.
It is not clear how mitochondrial dysfunction drives aging, particularly in mitotic tissues.
“Mitochondrial dysfunction has been linked to aging (Khrapko and Vijg, 2009), but it is not clear how it drives aging, particularly in mitotic tissues.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“mitochondrial dysfunction-associated senescence (MiDAs), which is characterized by a distinct phenotype, exhibits a unique cell-non-autonomous programme that is potentially responsible for the altered metabolism and aberrant adipocyte differentiation observed in aged animals47”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [47]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mouse models of mitochondrial dysfunction and enhanced oxidative stress show increased senescence (Wiley et al., 2016), but a detailed characterization of mitochondrial function in senescent cells in vivo is lacking.”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Wiley et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Genetic or pharmacological inhibition of the ETC can induce senescence even though cells lack expression of key pro-inflammatory SASP factors, such as IL-6 and IL-8 (Wiley et al., 2016).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Wiley et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“NAD + /NADH ratios are reduced in senescent cells (Wiley et al., 2016), which could alter the activity of poly-ADP ribose polymerase (PARP) and sirtuins, both involved in activation of the SASP regulator NF-kB (Birch and Passos, 2017).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Wiley et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The SASP can either suppress differentiation (of preadipocytes) or promote it (of keratinocytes), resulting in alterations such as the lipodystrophy and skin phenotypes common in old mice (Wiley et al. 2016).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wiley et al. 2016
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Cells without a persistent DDR58, such as cells induced to senescence via mitochondrial dysfunction or enforced upregulation of the CDK4/6 inhibitors p16 and p2139,58, do not express these pro-inflammatory SASP factors.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [39]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Dysfunctional mitochondria may play an important role in senescence establishment, as depletion of mitochondrial sirtuins, a group of evolutionarily conserved proteins that regulate ageing across different species, as well as selective chemical inhibition of mitochondrial function, triggers senescence47”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [47]
The cited source says what the claim attributes to it.
In the citing paper
“For example, dysfunctional mitochondria cause a distinct senescence response, termed mitochondrial dysfunction-associated senescence (MiDAS), which lacks the IL-1-dependent proinflammatory arm of the SASP (Wiley et al. 2016).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wiley et al. 2016
The cited source says what the claim attributes to it.
In the citing paper
“mitochondrial dysfunction can be a direct inducer of senescence 51,52 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [51]
In the citing paper
“Similarly, induction of senescence by mitochondrial dysfunction presents a distinct secretory phenotype (Wiley et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Wiley et al., 2016
In the citing paper
“Another cause of senescence growth arrest, mitochondrial dysfunction, different from senescence due to genotoxic stress has recently been identified (Wiley et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Wiley et al., 2016
In the citing paper
“The key feature of miDAS is the distinct secretory phenotype, different from canonical SASP caused by genotoxic stress.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Wiley et al., 2016
In the citing paper
“This SASP lacks the canonical IL-1 mediated inflammatory components but comprises interleukin (IL)-10, tumor necrosis factor alpha (TNF-α) and chemokine (C-C motif) ligand 27 (CCL27) (Wiley et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Wiley et al., 2016
In the citing paper
“Mitochondria normally oxidize NADH to NAD+ and mitochondrial dysfunction decreases the NAD+/NADH ratio mostly in the cytosol, leading to activation of 5′ adenosine monophosphate activated protein kinase (AMPK), resulting in p53 activation and mitochondrial dysfunction associated senescence (miDAS) (Wiley et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Wiley et al., 2016
In the citing paper
“Depletion of NAD+ causes loss of efficient sirtuin activity, resulting in impaired functionality of mitochondrial SIRT3, leading to dysregulation in mitochondrial antioxidant systems, mitochondrial DNA (mtDNA) repair, and mitochondrial quality control and biogenesis (SIRT1) pathways, and may also promote senescence (70).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [70]
In the citing paper
“In primary cell culture, supplementation with NR delays cellular senescence (Wiley et al., 2016), and NR treatment also reduces the senescent state in both NSCs and other stem cell types (Zhang et al., 2016).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Wiley et al., 2016
In the citing paper
“NAD+ replenishment delays cellular senescence (including mitochondrial dysfunction-associated senescence)”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Wiley et al., 2016
In the citing paper
“Recent work shows that SIRT3 and SIRT5 attenuate the SASP, in part by preventing dysfunctional decreases in NAD+/NADH ratios ((Wiley et al. 2016)).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Wiley et al. 2016
In the citing paper
“The loss in NRF1 binding appears to account for the reduced expression of mitochondrial respiratory chain genes and defective oxidative phosphorylation that could result in poor T cell survival”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Wiley et al., 2016
In the citing paper
“neutrophils from elderly subjects show a well-preserved capability to ingest non-opsonized particles [24], but a reduced capability to uptake opsonized particles, or pathogens such as Escherichia coli [37,42]”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [24]
In the citing paper
“Senescent cells secrete a distinct suite of inflammatory cytokines and chemokines depending upon whether senescence is induced by genotoxic stress, [23] or mitochondrial dysfunction, as in the form of deficiencies in mitochondrial sirtuins or damage to mitochondrial DNA [24]”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [24]
In the citing paper
“Therefore, mitochondrial dysfunction, initiated by pathways different from DNA damage, can determine the SASP quality because local extracellular factors, such as pyruvate, can modify the SASP in senescent cells [225].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [225]
In the citing paper
“Growth arrest due to these mitochondrial perturbations was rescued by the exogenous supply of the electron acceptors pyruvate and potassium ferricyanide that artificially restore NAD+ levels.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [225]
In the citing paper
“AMPK signaling is also induced by the reduced cytosolic NAD+/NADH ratio as a result of mitochondrial defects [225].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [225]
In the citing paper
“Critically short, uncapped telomeres [9], oncogene stresses [51], and mitochondrial dysfunction [225] result in proliferative stress and senescence induction, thereby halting the proliferation of cells harboring mutations or genomic instability.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [225]
In the citing paper
“Evidence has shown that mitochondrial interventions at multiple regulation steps of the electron transport chain induce a senescent-like phenotype lacking the expression of pro-inflammatory senescence-associated secretory phenotype (SASP) elements, e.g., IL-6 and IL-8 [114,115].”
From Role of Age-Related Mitochondrial Dysfunction in Sarcopenia (2020) · cites this paper as [115]
In the citing paper
“However, we must to understand that the SASP can vary significantly in terms of the quantity and quality of secreted proteins and other factors, depending on the insult used to trigger cell senescence (Maciel‐Baron et al., 2016; Wiley et al., 2016); therefore, the composition of the SASP may be vary depending on the tissue and the insult.”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Wiley et al., 2016
In the citing paper
“Moreover, induction of senescence can occur in the absence of DNA damage, for example as a consequence of mitochondrial dysfunctions39.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [39]
Self-check
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Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
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In the paper
“Notably, NAD+ declines with age in several tissues (Braidy et al., 2011; Gomes et al., 2013; Stein and Imai, 2014; Yoshino et al., 2011), linking NAD to both senescence and aging.”
Cited work 10.1371/journal.pone.0019194 · retracted 2024-11-13 · notice 10.1371/journal.pone.0313921 · this paper published 2016-02
Citations
Cites
1 retracted
Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats
Braidy, N., Guillemin, G. J., Mansour, H., Chan-Ling, T., Poljak, A., & Grant, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019194 · Cited by 594 · cited 1×
“Notably, NAD+ declines with age in several tissues (Braidy et al., 2011; Gomes et al., 2013; Stein and Imai, 2014; Yoshino et al., 2011), linking NAD to both senescence and aging.”
BackgroundRetractedA biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · cited 3×
“Unlike the growth arrest and markers such as senescence-associated b-galactosidase (SA-Bgal) (Dimri et al., 1995), little is known about how mitochondria affect the SASP.”
BackgroundMethodInfluential(1978) · Biochemical Education · doi:10.1016/0307-4412(78)90049-3 · Cited by 5,073
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602 · cited 1×
“Increased ADP:ATP or AMP:ATP ratios activate AMPK (Hardie et al., 2012), which can induce senescence by phosphorylating p53 (Jones et al.”
BackgroundCellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
Self-citationAging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · cited 1×
“The senescence response suppresses the development of cancer (Campisi, 2003; Campisi, 2013), but there ismounting evidence that senescent cells can accumulate with age and cause or contribute to aging phenotypes and pathologies.”
BackgroundSelf-citationPremature 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
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232
Self-citationMitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging
Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., et al. (2005) · Science · doi:10.1126/science.1112125 · Cited by 2,165
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085 · cited 1×
“, 2013a) that are linked to aging (Haigis and Sinclair, 2010; Merksamer et al., 2013)—for ability to regulate senescence, we identified the mitochondrial SIRTs SIRT3, and to a lesser extent SIRT5, as suppressors of senescence and modulators of the SASP.”
Background
Cited by
Sorted by citations
Items 101–200 of 1,285
Gao, X., Yu, X., Zhang, C., Wang, Y., Sun, Y., Sun, H., Zhang, H., Shi, Y., & He, X. (2022) · Stem Cell Reviews and Reports · doi:10.1007/s12015-022-10370-8 · Cited by 180
Sex differences in inflammation, redox biology, mitochondria and autoimmunity
Di Florio, D. N., Sin, J., Coronado, M. J., Atwal, P. S., & Fairweather, D. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101482 · Cited by 185
“Interestingly, it has been observed that a lower NAD+/NADH ratio in cells can lead to a distinct SASP that lacks the IL-1 signaling arm [101].”
BackgroundHMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci
Aird, K. M., Iwasaki, O., Kossenkov, A. V., Tanizawa, H., Fatkhutdinov, N., Bitler, B. G., Le, L., Alicea, G., Yang, T.-L., Johnson, F. B., et al. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201608026 · Cited by 175
“1 F), which is consistent with previous studies of redistribution of HMGB1 from nuclei to the extracellular milieu during senescence (Davalos et al., 2013; Wiley et al., 2016).”
Context-dependent effects of cellular senescence in cancer development.
Lecot, P., Alimirah, F., Desprez, P.-Y., Campisi, J., & Wiley, C. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.115 · Cited by 183
“In culture, the MiDAS SASP inhibits adipogenesis and promotes keratinocyte differentiation (Wiley et al, 2016).”
BackgroundInfluentialSelf-citationPDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy
Dou, X., Fu, Q., Long, Q., Liu, S., Zou, Y., Fu, D., Xu, Q., Jiang, Z., Ren, X., Zhang, G., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00912-w · Cited by 200
“MiDAS is primarily driven by the accumulation of cytosolic NADH, which is usually oxidized by mitochondria to NAD + , causing a reduced NAD + /NADH ratio in cytosol and preventing the IL-1-associated SASP via AMPK-mediated p53 activation 8 .”
Self-citationTechniques to induce and quantify cellular senescence
Noren Hooten, N., & Evans, M. K. (2017) · Journal of Visualized Experiments · doi:10.3791/55533 · Cited by 178
Astrocyte senescence promotes glutamate toxicity in cortical neurons
Limbad, C., Oron, T. R., Alimirah, F., Davalos, A. R., Tracy, T. E., Gan, L., Desprez, P.-Y., & Campisi, J. (2020) · PLOS ONE · doi:10.1371/journal.pone.0227887 · Cited by 183
Self-citationRegulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions
Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.05.036 · Cited by 175
“Intriguingly, in the absence of DNA damage, mitochondrial impairment leads to modified form of senescence with a p53-mediated SAGA and a modified SASP lacking the IL-1-dependent inflammatory arm, presumably due to p53 inhibition of NFκB [89].”
BackgroundMetabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications
Xie, S., Xu, S., Deng, W., & Tang, Q. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01378-8 · Cited by 197
“NAD metabolism and sirtuin Compared with young hearts, adult and aged hearts have much lower nicotinamide adenine dinucleotide (NAD) levels and higher NADH levels, with therefore lowered cytosolic NAD/NADH ratios.(220) In addition, sirtuin and poly-ADP-ribose polymerase (PARP) is reduced in aged hearts.”
BackgroundCellular Senescence in Cardiovascular Diseases: A Systematic Review
Hu, C., Zhang, X., Teng, T., Ma, Z., & Tang, Q. (2022) · Aging and Disease · doi:10.14336/ad.2021.0927 · Cited by 184
“Additionally, other mitochondrial mechanisms, including mitochondrial calcium homeostasis, mitochondrial quality control mechanism and mitochondrial dynamics, also participate in establishing premature senescence [35,36].”
BackgroundOxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis
Wiley, C. D., Sharma, R., Davis, S. S., Lopez-Dominguez, J. A., Mitchell, K. P., Wiley, S., Alimirah, F., Kim, D. E., Payne, T., Rosko, A., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.008 · Cited by 173
Self-citationMitochondria, telomeres and cell senescence: Implications for lung ageing and disease
Birch, J., Barnes, P. J., & Passos, J. F. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.005 · Cited by 174
“(ETC) induces senescence with a distinct phenotype, termed MiDAS (mitochondrial dysfunction-associated senescence) (Wiley et al., 2016).”
BackgroundInfluentialPatil, P. R., Dong, Q. D., Wang, D., Chang, J., Wiley, C. D., Demaria, M., Lee, J., Kang, J. D., Niedernhofer, L. J., Robbins, P. D., et al. (2019) · Aging Cell · doi:10.1111/acel.12927 · Cited by 170
Self-citationSIRT3 consolidates heterochromatin and counteracts senescence
Diao, Z., Ji, Q., Wu, Z., Zhang, W., Cai, Y., Wang, Z., Hu, J., Liu, Z., Wang, Q., Bi, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab161 · Cited by 176
“Previous studies have investigated the role of SIRT3 in the regulation of cellular senescence, and most of them attribute it to the modulation of mitochondrial functions (17,67,83).”
BackgroundWhere Metabolism Meets Senescence: Focus on Endothelial Cells
Sabbatinelli, J., Prattichizzo, F., Olivieri, F., Procopio, A. D., Rippo, M. R., & Giuliani, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01523 · Cited by 173
“The forkhead box O transcription factor 1 (FOXO1) plays a major role in maintaining ECs in a quiescent state by suppressing c-myc signaling and reducing glycolysis (Wilhelm et al., 2016).”
BackgroundGruber, F., Kremslehner, C., Eckhart, L., & Tschachler, E. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2019.110780 · Cited by 166
Frasca, D., Diaz, A., Romero, M., & Blomberg, B. B. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2016.12.001 · Cited by 160
Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis
Waters, D. W., Blokland, K. E. C., Pathinayake, P. S., Burgess, J. K., Mutsaers, S. E., Prêle, C. M., Schuliga, M. J., Grainge, C., & Knight, D. A. (2018) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00037.2018 · Cited by 171
Turning back time with emerging rejuvenation strategies
Mahmoudi, S., Xu, L., & Brunet, A. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0206-0 · Cited by 171
Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
Lucas, V., Cavadas, C., & Aveleira, C. A. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000622 · Cited by 172
Zhang, B., Fu, D., Xu, Q., Cong, X., Wu, C., Zhong, X., Ma, Y., Lv, Z., Chen, F., Han, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04010-4 · Cited by 157
“0 designed for global profiling of human LncRNAs (32,586) and protein-coding transcripts (26,109) covering all entries of Refseq, UCSC known genes and Gencode was employed.”
MethodFaces of cellular senescence in skin aging
Ho, C. Y., & Dreesen, O. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111525 · Cited by 172
Liu, T., Yang, Q., Zhang, X., Qin, R., Shan, W., Zhang, H., & Chen, X. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118116 · Cited by 161
Cellular Metabolism in Lung Health and Disease
Liu, G., & Summer, R. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114640 · Cited by 157
Oxidative stress, cellular senescence and ageing
Pole, A., Dimri, M., & Dimri, G. P. (2016) · AIMS molecular science · doi:10.3934/molsci.2016.3.300 · Cited by 168
“The ROS-induced senescence proceeds via mitochondrial and non-mitochondrial pathways, which likely converge at the known molecular players of the cellular senescence such as p53, pRB, p16 and p21 [91,92] (Figure 1).”
BackgroundInfluentialImmunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases
Bleve, A., Motta, F., Durante, B., Pandolfo, C., Selmi, C., & Sica, A. (2022) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-021-08909-7 · Cited by 185
“It is, however, accepted that aged macrophages secrete more prostaglandin E2 (PGE2) than younger counterparts, as a result of increased expression of cyclooxygenase 2 (COX2) [67].”
BackgroundIdiopathic Pulmonary Fibrosis: Aging, Mitochondrial Dysfunction, and Cellular Bioenergetics
Zank, D. C., Bueno, M., Mora, A. L., & Rojas, M. M. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00010 · Cited by 152
Moon, J. S., Goeminne, L. J. E., Kim, J. T., Tian, J. W., Kim, S., Nga, H. T., Kang, S. G., Kang, B. E., Byun, J., Lee, Y., et al. (2020) · Aging Cell · doi:10.1111/acel.13195 · Cited by 141
“Given that mitochondrial damage contributes to various senescent processes with a distinct pro-inflammatory secretory phenotype (Wiley et al., 2016), the fact that the disruption of mitochondrial function is linked to age-related pathologies is not surprising (Lane, Hilsabeck, & Rea, 2015).”
BackgroundZhang, H., Xu, R., Li, B., Xin, Z., Ling, Z., Zhu, W., Li, X., Zhang, P., Fu, Y., Chen, J., et al. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00858-0 · Cited by 154
The redox requirements of proliferating mammalian cells
Hosios, A. M., & Heiden, M. G. V. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000239 · Cited by 157
“both nucleotide depletion and mitochondrial inhibition block proliferation by inducing senescence (88,89).”
BackgroundAutophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot
Yoojin, K., Kim, J. W., Jeoung, J. A., Kim, M.-S., & Kang, C. (2017) · Molecules and Cells · doi:10.14348/molcells.2017.0151 · Cited by 160
“…a distinct secretory phenotype from the SASP that lacks the IL1 dependent inflammatory arm (miDAS, mitochondrial dysfunction-associated senescence) (Wiley et al., 2016). miDAS cells have lower NAD + /NADH ratios, which cause both the growth arrest and prevent the IL1-associated SASP through…”
BackgroundSturm, G., Karan, K. R., Monzel, A. S., Santhanam, B., Taivassalo, T., Bris, C., Ware, S. A., Cross, M., Towheed, A., Higgins‐Chen, A., et al. (2023) · Communications Biology · doi:10.1038/s42003-022-04303-x · Cited by 150
“Our resource cellular lifespan data provide several novel observations that agree with previous work 79 , and that are relevant to understanding how primary mitochondrial OxPhos defects triggers core physiological and phenotypic hallmarks of aging and mitochondrial diseases.”
BackgroundResultEnvironmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence
Sachdeva, K., Do, D. C., Zhang, Y., Hu, X., Chen, J., & Gao, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02787 · Cited by 154
“Mitochondrial dysfunction has been demonstrated to be able to drive a cell into premature senescence, which affects airway diseases (151, 152).”
BackgroundWhole Chromosome Instability induces senescence and promotes SASP
Andriani, G. A., Almeida, V. P., Faggioli, F., Mauro, M., Tsai, W. L., Santambrogio, L., Maslov, A. Y., Gadina, M., Campisi, J., Vijg, J., et al. (2016) · Scientific Reports · doi:10.1038/srep35218 · Cited by 154
“Some SASP factors also showed a trend for up-regulation in the other shRNA cell lines (CCL2, CCL27, CSF2, CXCL12, IL10) however not significant compared to EV (Supplementary Table S5 and Figure S5).”
InfluentialSelf-citationRecent Insights into the Mitochondrial Role in Autophagy and Its Regulation by Oxidative Stress
Agujetas, V. R., de Dios, C., Pinilla, L. L., Marı́, M., Morales, A., & Colell, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3809308 · Cited by 153
“Furthermore, impaired mitochondria have been shown to contribute to age-related pathologies by inducing senescence [147].”
BackgroundExtracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
Oller, J., Gabandé‐Rodríguez, E., Ruiz-Rodríguez, M. J., Desdín-Micó, G., Aranda, J. F., Rodrigues‐Díez, R., Ballesteros‐Martínez, C., Blanco, E. M., Roldán-Montero, R., Acuña, P., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.051171 · Cited by 150
Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration
Wan, M., Gray-Gaillard, E. F., & Elisseeff, J. H. (2021) · Bone Research · doi:10.1038/s41413-021-00164-y · Cited by 155
Summer, R. S., Shaghaghi, H., Schriner, D., Roque, W., Sales, D., Cuevas-Mora, K., Desai, V. S., Bhushan, A., Ramirez, M. I., & Romero, F. (2019) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00244.2018 · Cited by 149
“However, it is now appreciated that increased mitochondrial function can also contribute to cellular senescence in some scenarios (5, 30, 47).”
BackgroundGut dysbiosis: Ecological causes and causative effects on human disease
Winter, S., & Bäumler, A. J. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2316579120 · Cited by 160
“For example, mito chondrial dysfunction associated with senescence is a feature of inflammageing (127), but it remains to be tested whether it trig gers a loss of epithelial hypoxia in the colon to explain the increased abundance of Gammaproteobacteria in the feces of patients (75).”
BackgroundSIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy
Lang, A., Anand, R., Altinoluk-Hambüchen, S., Ezzahoini, H., Stefanski, A., Iram, A., Bergmann, L., Urbach, J., Böhler, P., Hänsel, J., et al. (2017) · Aging · doi:10.18632/aging.101307 · Cited by 145
“Overall, the pro-aging effects of senescence and the SASP (senescence associated secretory phenotype) seem to be at least in part dependent on the presence of mitochondria [14, 15].”
Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
Alimirah, F., Pulido, T., Valdovinos, A., Alptekin, S., Chang, E., Jones, E., Diaz, D. A., Flores, J., Velarde, M. C., Demaria, M., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0108 · Cited by 128
“Among the stimuli that induce cellular senescence aremitochondrial dysfunction (2), telomere shortening (3), oncogene activation (4), epigenetic modifications (5), and genotoxic insults, including radiation and several anticancer agents (1).”
BackgroundSelf-citationChini, C., Hogan, K. A., Warner, G. M., Tarragó, M. G., Peclat, T. R., Tchkonia, T., Kirkland, J. L., & Chini, E. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.03.199 · Cited by 138
SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells
Wiley, C. D., Liu, S., Limbad, C., Zawadzka, A. M., Beck, J., Demaria, M., Artwood, R., Alimirah, F., Lopez-Dominguez, J.-A., Kuehnemann, C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.049 · Cited by 137
“Cellular senescence permanently arrests cell proliferation in response to a variety of stresses, including DNA damage, mitochondrial dysfunction, and oncogene activation (Campisi, 2013; Wiley et al., 2016).”
BackgroundMethodSelf-citationThe interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing
Liu, Y., Tan, Y., Zhang, Z., Yi, M., Zhu, L., & Peng, W. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00397-x · Cited by 156
“A previous study showed that a low intracellular NAD + /NADH ratio is involved in the mitochondrial dysfunction-related senescence, and prevents the IL-1-mediated SASP through AMPK-mediated activation of p53 [118].”
BackgroundLate-life restoration of mitochondrial function reverses cardiac dysfunction in old mice
Chiao, Y. A., Zhang, H., Sweetwyne, M. T., Whitson, J. D., Ting, Y. S., Basisty, N., Pino, L. K., Quarles, E. K., Nguyen, N.-H. T., Campbell, M. D., et al. (2020) · eLife · doi:10.7554/elife.55513 · Cited by 136
Li, Y., & Yao, H. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13518 · Cited by 141
“Indeed, a recent study has shown that mitochondrial dysfunctionassociated senescence (MiDAS) exhibits a modified SASP that lacks the IL-1-dependent inflammatory arm but shows high levels of the anti-inflammatory cytokine IL-10 (Wiley et al., 2016).”
BackgroundSenescence and the tumor-immune landscape: Implications for cancer immunotherapy
Chibaya, L., Snyder, J. T., & Ruscetti, M. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.005 · Cited by 146
Mitochondrial peptides modulate mitochondrial function during cellular senescence
Kim, S., Mehta, H. H., Wan, J., Kuehnemann, C., Chen, J., Hu, J., Hoffman, A. R., & Cohen, P. (2018) · Aging · doi:10.18632/aging.101463 · Cited by 140
“Manipulating bioenergetic status can induce senescence and a SASP, suggesting that bioenergetics play a role in the senescence phenotype [41,44,45].”
Senescent glia link mitochondrial dysfunction and lipid accumulation
Byrns, C. N., Perlegos, A. E., Miller, K. N., Jin, Z., Carranza, F. R., Manchandra, P., Beveridge, C. H., Randolph, C. E., Chaluvadi, V. S., Zhang, S., et al. (2024) · Nature · doi:10.1038/s41586-024-07516-8 · Cited by 147
“How neuron health drives glial senescence remains to be determined: aged neurons could release ROS, mtDNA 48–50 or extrude damaged mitochondria 49–51 , all of which can induce senescence in vitro 21,52–54 .”
Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing
Reiten, O. K., Wilvang, M. A., Mitchell, S. J., Hu, Z., & Fang, E. F. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111567 · Cited by 136
“NAD augmentation also ameliorates systemic and organic dysfunction and improves healthspan and/or lifespan in the preclinical models, such as roundworm Caenorhabditis elegans, fruit fly Drosophila melanogaster, and mice (Covarrubias et al., 2020b; Fang et al., 2016a, 2014; Gomes et al., 2013; Mouchiroud et al., 2013b;…”
Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging
Li, X., Wang, J., Wang, L., Gao, Y., Feng, G., Li, G., Zou, J., Yu, M., Li, Y. F., Liu, C., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00964-6 · Cited by 143
“Mitochondria are the powerhouse of the cell and play a prominent role in producing energy through respiration and regulating cellular metabolism.(38,39) Elovl2 deficiency induced a switch in metabolism from the tri-carboxylic acid cycle to glycolysis, an effect which produces more reactive oxidative species (ROS), cau…”
BackgroundHodes, R. J., Sierra, F., Austad, S. N., Epel, E., Neigh, G. N., Erlandson, K. M., Schafer, M. J., LeBrasseur, N. K., Wiley, C., Campisi, J., et al. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13299 · Cited by 132
Self-citationThe Fountain of Youth by Targeting Senescent Cells?
de Keizer, P. L. J. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.11.006 · Cited by 127
Putting the brakes on the cell cycle: mechanisms of cellular growth arrest
Pack, L. R., Daigh, L. H., & Meyer, T. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.05.005 · Cited by 139
“However, metabolic profiling and functional studies of senescent cells indicate that senescent cell metabolism differs significantly from proliferating cells [45,72,73].”
BackgroundSecretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis
Wiley, C. D., Brumwell, A. N., Davis, S. S., Jackson, J., Valdovinos, A., Calhoun, C., Alimirah, F., Castellanos, C. A., Ruan, R., Wei, Y., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.130056 · Cited by 136
“Oncogene-induced senescence was induced using lentiviral-mediated overexpression of HRASV12, as described (31).”
BackgroundMethodSelf-citationNAD metabolism: Role in senescence regulation and aging
Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023) · Aging Cell · doi:10.1111/acel.13920 · Cited by 148
“This metabolic shift leads to decreased NAD + /NADH ratios, increased AMP/ATP and ADP/ATP ratios, AMPK activation, and p53-mediated growth arrest (Sabbatinelli et al., 2019; Wiley et al., 2016).”
BackgroundLiu, H., Xu, Q., Wufuer, H., Li, Z., Sun, R., Jiang, Z., Dou, X., Fu, Q., Campisi, J., & Sun, Y. (2023) · Aging Cell · doi:10.1111/acel.13921 · Cited by 138
Self-citationNeuroinflammation: The central enabler of postoperative cognitive dysfunction
Liu, Y., Yang, W., Xue, J., Chen, J., Liu, S., Zhang, S., Zhang, X., Gu, X., Dong, Y., & Qiu, P. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115582 · Cited by 139
Self-citationCellular Interactions in the Tumor Microenvironment: The Role of Secretome
da Cunha, B. R., Domingos, C., Stefanini, A. C. B., Henrique, T., Polachini, G. M., Castelo‐Branco, P., & Tajara, E. H. (2019) · Journal of Cancer · doi:10.7150/jca.21780 · Cited by 133
“This mechanism is a response to stress, which blocks cell proliferation and is often associated with expression of the tumor suppressor protein p16INK4a and accompanied by a secretory phenotype (senescence-associated secretory phenotype - SASP) with stress-type–dependent profile [62-64].”
BackgroundEpigenetic Regulation of Cellular Senescence
Crouch, J. D., Shvedova, M., Thanapaul, R. J. R. S., Botchkarev, V. A., & Roh, D. S. (2022) · Cells · doi:10.3390/cells11040672 · Cited by 139
“Mitochondrial dysfunction, driven by mitochondrial DNA depletion, electron transport chain inhibition, or mitochondrial chaperone depletion also drives cellular senescence [15].”
BackgroundSenotherapeutics: targeting senescence in idiopathic pulmonary fibrosis
Merkt, W., Bueno, M., Mora, A. L., & Lagares, D. (2020) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.12.008 · Cited by 119
“Of note, senescent cells are metabolically active and secrete a particular set of proinflammatory cytokines (e.g. IL1-beta and IL-6), chemokines (e.g. IL8), growth factors, and proteases, known as the senescenceassociated secretory phenotypes (SASP) [54,55].”
BackgroundInfluentialMouse Models to Disentangle the Hallmarks of Human Aging
Folgueras, A. R., Freitas-Rodríguez, S., Velasco, G., & López-Otín, C. (2018) · Circulation Research · doi:10.1161/circresaha.118.312204 · Cited by 113
“Finally, a recent study has demonstrated that mitochondrial dysfunction can also induce senescence with a distinctive secretory profile, which has been named mitochondrial dysfunction-associated senescence.(171) This type of senescence has been found in vivo in mtDNA mutator mice, adding another level of complexity to…”
BackgroundCellular Senescence: Pathogenic Mechanisms in Lung Fibrosis
Parimon, T., Hohmann, M. S., & Yao, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126214 · Cited by 123
“Cellular senescence and mitochondrial dysfunction are closely linked: cell senescence, more specifically persistent DDR signaling, directly contributes to senescence-associated mitochondrial dysfunction [101], while mitochondrial dysfunction drives and maintains cell senescence [71].”
BackgroundKang, C. (2019) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2019.0298 · Cited by 129
“Precision senostatics have not been seriously considered yet mainly because the composition of the SASP highly varies, depending on the cell type, the stage of senescence (early versus late senescence), and the type of senescence-inducing stimuli (De Cecco et al., 2019; Hernandez-Segura et al., 2017; Hoare et al., 201…”
BackgroundCellular senescence and cardiovascular diseases: moving to the “heart” of the problem
Evangelou, K., Vasileiou, P. V. S., Papaspyropoulos, A., Hazapis, O. G., Petty, R., Demaria, M., & Gorgoulis, V. G. (2022) · Physiological Reviews · doi:10.1152/physrev.00007.2022 · Cited by 127
The Role of Oxidative Stress in Tumorigenesis and Progression
Li, K., Deng, Z., Lei, C., Ding, X., Li, J., & Wang, C. (2024) · Cells · doi:10.3390/cells13050441 · Cited by 142
“MiDAS) [226].”
BackgroundAstaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants
Nishida, Y., Nawaz, A., Hecht, K. A., & Tobe, K. (2021) · Nutrients · doi:10.3390/nu14010107 · Cited by 128
Local H2 release remodels senescence microenvironment for improved repair of injured bone
Chen, S., Yu, Y., Xie, S., Liang, D., Shi, W. K., Chen, S., Li, G., Tang, W., Liu, C., & He, Q. (2023) · Nature Communications · doi:10.1038/s41467-023-43618-z · Cited by 130
Pharmacological CDK4/6 inhibition reveals a p53‐dependent senescent state with restricted toxicity
Wang, B., Varela‐Eirin, M., Brandenburg, S. M., Hernandez‐Segura, A., van Vliet, T., Jongbloed, E. M., Wilting, S. M., Ohtani, N., Jager, A., & Demaria, M. (2022) · The EMBO Journal · doi:10.15252/embj.2021108946 · Cited by 113
“However, recent reports have highlighted those differences in SASP expression might not be only quantitative but also qualitative (Hoare et al , 2016; Wiley et al , 2016).”
Peng, X., Wu, Y., Brouwer, U., van Vliet, T., Wang, B., Demaria, M., Barazzuol, L., & Coppes, R. P. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03074-9 · Cited by 126
Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells
Mikuła‐Pietrasik, J., Niklas, A. A., Uruski, P., Tykarski, A., & Książek, K. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03261-8 · Cited by 131
“, increased mass [16]) and function [17].”
A common signature of cellular senescence; does it exist?
Sikora, E., Bielak-Żmijewska, A., & Mosieniak, G. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101458 · Cited by 124
Aging: Molecular Pathways and Implications on the Cardiovascular System
de Almeida, A. J. P. O., Ribeiro, T. P., & de Medeiros, I. A. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/7941563 · Cited by 120
“route that leads to senescence is the mitochondrial dysfunction, a process that decreases cellular energy supply, leading the cell to decrease its metabolic activity [25, 26].”
BackgroundCellular senescence: a promising strategy for cancer therapy
Lee, S., & Lee, J. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.1.294 · Cited by 117
“Transcriptional factors involved in SASP regulation are NF-B, mitochondrial dysfunction-associated senescence (MiDAS), GATA4, and CCAAT/enhancer-binding protein- (C/EBP) (24-27).”
BackgroundCellular senescence: Neither irreversible nor reversible
Reimann, M., Lee, S., & Schmitt, C. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232136 · Cited by 125
“A key driver of post-mitotic senescence is mitochondrial dysfunction, which promotes pro-senescent metabolic changes and the generation of reactive oxygen species (ROS) in these non-dividing cells (Wiley et al., 2016).”
BackgroundExtracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis
Kadota, T., Yoshioka, Y., Fujita, Y., Araya, J., Minagawa, S., Hara, H., Miyamoto, A., Suzuki, S., Fujimori, S., Kohno, T., et al. (2020) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0002oc · Cited by 125
The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age
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“An important role for mitochondria is supported by the causal link between mitochondrial dysfunction and age-related senescence.(14,15) Intentional mitochondrial damage to human cells induces senescence, and mice with accelerated rates of mitochondrial DNA damage also exhibit senescent cell accumulation and increased…”
Adult mesenchymal stem cell ageing interplays with depressed mitochondrial Ndufs6
Zhang, Y., Guo, L., Han, S., Chen, L., Li, C., Zhang, Z., Hong, Y., Zhang, X., Zhou, X., Jiang, D., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03289-w · Cited by 112
Adipose tissue inflammation in aging
Mau, T., & Yung, R. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2017.10.014 · Cited by 110
“While sources of inflammaging remain under investigation, some prominent conversations include immunosenescence 6,11 , self-debris 12 , senescent cells 13 , mitochondria dysfunction 14,15 , microbiome 16 , and adipose tissue 17–20 .”
BackgroundIncreased immunosuppression impairs tissue homeostasis with aging and age-related diseases
Salminen, A. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01988-7 · Cited by 111
Expansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence
Ogrodnik, M., Salmonowicz, H., Jurk, D., & Passos, J. F. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.06.011 · Cited by 104
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Evidence and perspectives of cell senescence in neurodegenerative diseases
Si, Z., Sun, L., & Wang, X. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111327 · Cited by 105
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Cellular Senescence and Ageing: Mechanisms and Interventions
Mylonas, A., & O’Loghlen, A. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.866718 · Cited by 114
Mitophagy plays a central role in mitochondrial ageing
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“Low levels of heteroplasmic mtDNA mutants may be present in symptom-free maternal relatives.”
BackgroundRole of cellular senescence in inflammation and regeneration
Saito, Y., Yamamoto, S., & Chikenji, T. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00342-5 · Cited by 127
“MiDAS is mitochondrial damage that triggers senescence with a distinct secretory phenotype that lacks IL-1-de-pendent inflammation [37].”
BackgroundTargeting senescent cells for a healthier longevity: the roadmap for an era of global aging
Sun, Y., Li, Q., & Kirkland, J. L. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac030 · Cited by 105
Regulation of senescence and the SASP by the transcription factor C/EBPβ
Salotti, J., & Johnson, P. F. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110752 · Cited by 103
Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan?
Sanz, A. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.03.018 · Cited by 111
Fibroblast Senescence in Idiopathic Pulmonary Fibrosis
Lin, Y., & Xu, Z. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.593283 · Cited by 109
Caloric restriction and cellular senescence
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Mitochondrial Dysfunction in Pulmonary Fibrosis
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Mahoney, S. A., Venkatasubramanian, R., Darrah, M. A., Ludwig, K. R., VanDongen, N. S., Greenberg, N., Longtine, A. G., Hutton, D. A., Brunt, V. E., Campisi, J., et al. (2023) · Aging Cell · doi:10.1111/acel.14060 · Cited by 111
“Further, mitochondrial dysfunction, including increased ROS production, is a key feature of senescent cells (Wiley et al., 2016 ).”
BackgroundSelf-citationTammaro, A., Kers, J., Scantlebery, A. M. L., & Florquin, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01346 · Cited by 105
“In addition to the common components of the SASP, senescent cells produce exacerbated levels of mitochondrialderived ROS and might also release mtDNA, which can act as a DAMP, further fueling PRR activation (101, 112).”
BackgroundThe role of myeloid-derived suppressor cells (MDSC) in the inflammaging process
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Mitochondrial dysfunction and its association with age-related disorders
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“Cells undergoing MiDAS are characterized by lower NAD+/NADH ratios, leading to cell growth arrest and IL-1-associated senescence-associated secretory phenotype (SASP) (Wiley et al., 2016).”
BackgroundHorváth, E., Sólyom, Á., Székely, J., Nagy, E. E., & Popoviciu, H. V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242216468 · Cited by 111
“In adipocytes and keratinocytes, mitochondrial dysfunction-associated senescence (MiDAS) is induced, characterized by low NAD+/NADH ratios and an altered SASP pattern controlled by the NAD+/AMPK/p53 pathway, with CCL-27, TNF-α and IL-10 secretion without the involvement of NF-kB and IL-1 β [92,93].”
BackgroundPrinciples of the Molecular and Cellular Mechanisms of Aging
da Silva, P. F. L., & Schumacher, B. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.11.018 · Cited by 106
Impact of COVID-19 on Mitochondrial-Based Immunity in Aging and Age-Related Diseases
Ganji, R., & Reddy, P. H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.614650 · Cited by 96
Metadata
- Authors
- Wiley, C. D., Velarde, M. C., Lecot, P., Liu, S., Sarnoski, E. A., Freund, A., Shirakawa, K., Lim, H. W., Davis, S. S., Ramanathan, A., Gerencser, A. A., Verdin, E., & Campisi, J.
- Affiliations
- Buck Institute for Research on Aging (US)
- Gladstone Institutes (US)
- Corresponding author
- Campisi, Judith
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 23
- Issue
- 2
- Pages
- 303-314
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4749409
- OpenAlex
- W2191745121
- Cited by
- 1,275
- References
- 66
- Citations by year
- 2026: 162 · 2025: 161 · 2024: 169 · 2023: 148 · 2022: 128 · 2021: 139 · 2020: 115 · 2019: 95 · 2018: 71 · 2017: 51 · 2016: 35
- FWCI
- 38.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R37AG009909, K99AG041221, T32AG000266)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK085610, P30DK063720, P30DK026743)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitochondrial dysfunction, cellular senescence, senescence-associated secretory phenotype, NAD+/NADH ratio, AMPK, p53 activation, progeroid mice, mitochondrial DNA mutations, adipogenesis, keratinocyte differentiation, aging, growth arrest
- MeSH terms
- DNA Polymerase gamma, Adenylate Kinase, Animals, DNA-Directed DNA Polymerase, Enzyme Activation, Mitochondria, NAD, Phenotype, Tumor Suppressor Protein p53, Cellular Senescence, Sirtuins, Mice
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