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Cited by 1,287Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsMitochondrial Function and Pathology

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Open access
Wiley, Christopher D., Velarde, Michael C., Lecot, Pacome, Liu, Su, Sarnoski, Ethan A., Freund, Adam, Shirakawa, Kotaro, Lim, Hyung W. +5 more·2016·Cell Metabolism
DOI 10.1016/j.cmet.2015.11.011PMC PMC4749409
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Abstract

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.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2015.11.011

Cites

62 of 62 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

33 of 56 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The permanent growth arrest can deplete progenitor or stem cell pools, thereby compromising tissue repair and regeneration.

    “The permanent growth arrest can deplete progenitor or stem cell pools, thereby compromising tissue repair and regeneration”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Kuilman et al., 2010 source

      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)

      Experimental — accuracy not yet measured
    • cites Sousa-Victor et al., 2014 source
    • cites Velarde et al., 2015 source

      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)

      Experimental — accuracy not yet measured
  • Interpretationown data

    Absence of SIRT3 throughout embryogenesis and acute loss of SIRT3 after development can have different effects.

    “indicating that an absence of SIRT3 throughout embryogenesis and acute loss of SIRT3 after development can have different effects, as reported”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Fernandez-Marcos et al., 2012 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    p53 can suppress NF-κB.

    “p53 can suppress NF-κB (Dey et al., 2007; Murphy et al., 2011), which promotes transcription of many SASP genes (Freund et al., 2011).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Dey et al., 2007 source
    • cites Murphy et al., 2011 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    p53 limits SASP gene expression.

    “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.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Coppé et al., 2008 source

      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)

      Experimental — accuracy not yet measured
    • cites Rodier et al., 2009 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    Inducible SIRT3 knockout mice do not necessarily phenocopy germline knockout animals.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Fernandez-Marcos et al., 2012 source

      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)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 60
  • The quote only partly states this claim. 2

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

    Premisecitation

    NAD+ declines with age in several tissues, linking NAD to both senescence and aging.

    “Notably, NAD+ declines with age in several tissues”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Braidy et al., 2011 source
    • cites Gomes et al., 2013 source

      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)

      Experimental — accuracy not yet measured
    • cites Stein and Imai, 2014 source

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

    Premisecitation

    Sustained AMPK activation is a hallmark of senescence and can induce a senescence arrest.

    “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”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Moiseeva et al., 2009 source

      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)

      Experimental — accuracy not yet measured
    • cites Jiang et al., 2013b

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

    • cites Jones et al., 2005 source

  • May combine two claims.

    Premisecitation

    Dysfunctional mitochondria accumulate with age, most clearly in tissues composed mainly of post-mitotic cells.

    “Dysfunctional mitochondria accumulate with age, best documented in tissues comprised largely of post-mitotic cells”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Herbst et al., 2007 source
    • cites Lee et al., 2010 source

      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)

      Experimental — accuracy not yet measured
    • cites Safdar et al., 2010 source

      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)

      Experimental — accuracy not yet measured

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

    Findingcitation

    Ionizing radiation induced cell death after SIRT1 depletion.

    “it induced cell death after SIRT1-depletion (not shown), as reported”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Cheng et al., 2003 source
    • cites Yuan et al., 2012 source

  • May combine two claims.

    Premisecitation

    Dysfunctional mitochondria can induce cellular senescence in culture and in vivo.

    “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).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Moiseeva et al., 2009 source
    • cites Wang et al., 2003 source
    • cites Dai et al., 2010 source

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

    Premisecitation

    The SASP includes pro-inflammatory cytokines, proteases, and growth and angiogenesis factors that can disrupt tissue microenvironments and compromise tissue structure and function.

    “This senescence-associated secretory phenotype (SASP) comprises pro-inflammatory cytokines, proteases, and growth and angiogenesis factors”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Coppé et al., 2008 source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Increased ADP:ATP or AMP:ATP ratios activate AMPK.

    “Increased ADP:ATP or AMP:ATP ratios activate AMPK (Hardie et al., 2012)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Hardie et al., 2012 source

  • Classified as probably not a substantial claim.

    Premisecitation

    p53 inhibits RELA by competing for CBP binding.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Webster and Perkins, 1999 source

  • May combine two claims.

    Findingcitation

    Many SASP factors not expressed by SIRT3-depleted cells are pro-inflammatory, although the cells uniquely secreted CCL27, a pro-inflammatory cytokine that comprises the SASP of mouse but not human fibroblasts induced to senesce by IR.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Coppé et al., 2010 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IR robustly activates p53, which subsides to a low chronic level in 7-10 days as the SASP develops.

    “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).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Coppé et al., 2008 source

      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)

      Experimental — accuracy not yet measured
    • cites Rodier et al., 2009 source

      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)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    AMPK activation can induce senescence by stabilizing p16INK4a mRNA.

    “or stabilizing p16INK4a mRNA (Chang et al., 2010)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Chang et al., 2010 source

      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)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Elevated oxygen dampens the SASP in humans and mouse cells.

    “We reported that elevated oxygen dampens the SASP in humans and mouse cells (Coppé et al., 2010; Parrinello et al., 2003).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Coppé et al., 2010 source

      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)

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

      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)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Mitochondrial ROS can damage nuclear DNA, thus activating a DNA damage response that induces senescence.

    “Mitochondrial ROS can damage nuclear DNA, thus activating a DNA damage response that induces senescence (Moiseeva et al., 2009; Passos et al., 2010).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Moiseeva et al., 2009 source
    • cites Passos et al., 2010 source

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

    Premisecitation

    Cells from SIRT3 knockout mice were highly susceptible to oncogenic transformation, but this susceptibility depended on elevated ROS characteristic of sirt3−/− cells.

    “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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kim et al., 2010 source

      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)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Mitochondrial dysfunction has been linked to aging.

    “Mitochondrial dysfunction has been linked to aging (Khrapko and Vijg, 2009), but it is not clear how it drives aging, particularly in mitotic tissues.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Khrapko and Vijg, 2009 source

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

    Premisecitation

    HMGB1 is a pro-inflammatory alarmin that is a feature of senescent cells.

    “In addition, they secreted HMGB1, a pro-inflammatory alarmin that is a feature of senescent cells (Davalos et al., 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Davalos et al., 2013 source

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

    Premisecitation

    Epidermal-specific SOD2-deficient mice rapidly accumulate senescent keratinocytes, which show enhanced differentiation.

    “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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Velarde et al., 2015 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    SIRT3 depletion induced three senescence markers: reduced lamin B1 levels, decreased nuclear localization of HMGB1, and increased p21WAF1 levels.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A screen of sirtuins identified SIRT3 and, to a lesser extent, SIRT5 as suppressors of senescence and modulators of the SASP.

    “we identified the mitochondrial SIRTs SIRT3 and to a lesser extent SIRT5, as suppressors of senescence and modulators of the SASP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In proliferating human cells, multiple interventions that impair mitochondrial function trigger a senescence growth arrest accompanied by an altered SASP that is missing the IL-1-dependent inflammatory component.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These phenotypes occurred in cultured human cells and in a murine model of premature aging through mitochondrial dysfunction.

    “These phenotypes occurred in cultured human cells and a murine model of premature aging through mitochondrial dysfunction”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Despite lacking IL-1-dependent SASP factors, the MiDAS SASP suppressed adipocyte differentiation and promoted keratinocyte differentiation.

    “Despite lacking IL-1-dependent SASP factors, the MiDAS SASP suppressed adipocyte differentiation and promoted keratinocyte differentiation.”
    Quote in the paperSubstantial claim
    • 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.

  • May combine two claims.

    Findingown data

    SIRT3 or SIRT5 depletion did not increase IL-6 secretion despite induction of other senescence markers.

    “Despite the induction of other senescence markers, neither SIRT depletion increased IL-6 secretion”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SIRT3-depleted cells failed to express significant levels of SASP mRNAs encoding IL1B, CXCL1, CXCL2, IL-6, IL-8 and VEGF, but expressed high levels of AREG and IL-10, regardless of IR exposure.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IR failed to increase NF-κB activity in rho0 cells without pyruvate and reduced it below unirradiated rho0 cells with pyruvate.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SIRT3 depletion strongly suppressed IL-6 secretion by cells induced to senesce by IR, NaBu, or Bleo and moderately suppressed IL-6 secretion in response to MKK6EE or RAS.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Total NAD+ increased with MiDAS, along with a rise in NAMPT mRNA.

    “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”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    NF-κB activity was high in rho0 cells cultured with pyruvate but much lower in rho0 cells without pyruvate.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Some secreted factors were unaffected by MiDAS and insensitive to pyruvate.

    “Notably, some secreted factors were unaffected by MiDAS and were insensitive to pyruvate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In rho0 cells, lactate elicited only a small cytosolic response, suggesting that NADH was already reduced in this compartment.

    “In rho0 cells, lactate elicited only a small cytosolic response, suggesting that NADH was already reduced in this compartment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FK866 caused cell proliferation to cease after about 7 days and cells became senescent after about 21 days.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon pyruvate withdrawal, rho0 but not WT cells rapidly senesced, as measured by low EdU labeling and high SA-Bgal.

    “Upon pyruvate withdrawal, rho0, but not WT, cells rapidly senesced, as measured by low EdU labeling and high SA-Bgal”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Antioxidant EUK-134 reduced mitochondrial but not cytoplasmic ROS in SIRT3- and HSPA9-depleted cells but did not prevent the growth arrest of these or Rot-treated cells.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FK866 suppressed IR-induced IL-6 secretion and lowered total NAD levels.

    “FK866 suppressed IR-induced IL-6 secretion (Figure 3I) and lowered total NAD levels (Figure 3J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MiDAS increased p21WAF1 and p16INK4a protein levels, and this increase was prevented by pyruvate.

    “MiDAS also increased p21WAF1 and p16INK4a and decreased LMNB1 and intracellular HMGB1 protein levels, which were prevented by pyruvate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rho0 cells plus pyruvate expressed an enhanced SASP that was suppressed by IR.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MiDAS decreased LMNB1 and intracellular HMGB1 protein levels, and this decrease was prevented by pyruvate.

    “MiDAS also increased p21WAF1 and p16INK4a and decreased LMNB1 and intracellular HMGB1 protein levels, which were prevented by pyruvate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AOA-treated WT cells underwent senescence, with high SA-Bgal, low EdU labeling, and loss of nuclear HMGB1, but failed to secrete IL-6 following IR, despite slightly higher secretion by unirradiated AOA-treated cells.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Depleting mtDNA by ethidium bromide, treating with rotenone or antimycin A, or depleting HSPA9 all induced senescence as determined by reduced EdU incorporation, increased SA-Bgal activity, and loss of nuclear HMGB1 for rho0 and Rot.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rho0 and SIRT3-depleted cells showed no increase in 53BP1 foci, and EUK-134 had no effect on these foci in any senescent cell.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pyruvate lowered NADH in the cytosol while increasing NADH in mitochondria.

    “pyruvate lowered NADH in the cytosol, while increasing NADH in mitochondria”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only MiDAS cells showed marked activation of both AMPKα and p53, and this activation was blunted by pyruvate.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NMN delayed senescence by about 2 days relative to untreated rho0 cells, but both groups senesced within 7 days.

    “NMN delayed senescence by ~2 day relative to untreated cells (Figure S3I), but both groups senesced within 7 days”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All these manipulations elevated the ADP:ATP ratio, which was lowered by pyruvate.

    “All these manipulations elevated the ADP:ATP ratio (Figure 4A), which was lowered by pyruvate”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    shSIRT3 and rho0 cells cultured without pyruvate had elevated Mitosox fluorescence, but normalization to Mito-tracker showed roughly equivalent ROS levels between control and SIRT3-depleted cells.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SIRT3 shRNA induced senescence in wild-type mouse embryonic fibroblasts, but SIRT3 knockout MEFs did not senesce.

    “while SIRT3 shRNA induced senescence in wild-type (WT) mouse embryonic fibroblasts (MEFs), MEFs from SIRT3 knockout mice did not senesce”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon pyruvate withdrawal, expression of these SASP factors declined to near WT levels and the cells arrested growth.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    POLGD257A epidermis had more senescent cells in the stratum corneum (SA-Bgal positivity) and loss of HMGB1 in suprabasal epidermal nuclei compared to WT.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pyruvate, but not an antioxidant, prevented MiDAS.

    “In MiDAS, pyruvate, but not an antioxidant, prevented MiDAS, which showed no evidence of DNA damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CCL27, TNF-α, and IL-10 are examples of secreted factors unaffected by MiDAS and insensitive to pyruvate.

    “Examples include the pro-inflammatory cytokines CCL27 (Figure 1G) and TNF-α (Figure 5I) and the anti-inflammatory cytokine IL-10 (Figure 5I).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IAT from 8-month-old POLGD257A mice had more SA-Bgal positive cells and loss of nuclear HMGB1 than age-matched WT IAT, primarily in cells between mature adipocytes.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MiDAS cells secreted IL-10, CCL27, and TNF-α.

    “MiDAS cells secreted the anti-inflammatory cytokine IL-10, but also high levels of the pro-inflammatory cytokines CCL27 and TNF-α.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    SIRT3 depletion produced a stronger senescence response than SIRT5 depletion, likely because SIRT3 was more efficiently depleted.

    “SIRT3 showed a stronger response, likely because it was more efficiently depleted”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Senescent cells can build up with age and cause or contribute to aging phenotypes and pathologies.

    “there is mounting evidence that senescent cells can accumulate with age and cause or contribute to aging phenotypes and pathologies.”
    Quote in the paperSubstantial 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.

  • May combine two claims.

    Premisecitation

    Inhibiting the malate-aspartate shuttle by depleting malate dehydrogenase lowers the NAD+/NADH ratio and induces a senescence arrest.

    “Inhibition of the latter by depletion of malate dehydrogenase lowers the NAD+/NADH ratio and induces a senescence arrest”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lee et al., 2012 source

  • May combine two claims.

    Interpretationown data

    The data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

    “Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.”
    Quote in the paperSubstantial 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.

  • May combine two claims.

    Interpretationown data

    MiDAS results from a decreased NAD+/NADH ratio, activation of AMPK and subsequently p53, which limits the IL-1-mediated arm of the SASP.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Because mitochondria oxidize NADH to NAD+, mitochondrial dysfunction can lower the NAD+/NADH ratio.

    “Because mitochondria oxidize NADH to NAD+ (Lehninger et al., 2013), mitochondrial dysfunction can decrease the NAD+/NADH ratio.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lehninger et al., 2013

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

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    p53 initiates the senescence arrest and is an AMPK target.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jiang et al., 2013b

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

    • cites Jones et al., 2005 source

  • Classified as probably not a substantial claim.

    Premisecitation

    AMPK activation can induce senescence by phosphorylating p53.

    “which can induce senescence by phosphorylating p53 (Jones et al., 2005)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jones et al., 2005 source

  • May combine two claims.

    Interpretationown data

    SIRT3 depletion induced senescence with a SASP that differed from IR-induced SASP, suggesting a mitochondrial function is required for expression of a subset of SASP factors.

    “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.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    IL-1α and IL-1β initiate a positive feedback loop that drives expression of SASP factors such as IL-6 and IL-8.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Orjalo et al., 2009 source

  • May combine two claims.

    Interpretationown data

    Low NAD+/NADH ratios mediate MiDAS phenotypes, which are prevented by NADH oxidation.

    “We conclude that low NAD+/ NADH ratios mediate MiDAS phenotypes, which are prevented by NADH oxidation.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    IMR-90 human fibroblasts were mycoplasma-free.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    MiDAS elicits a SASP that lacks IL-1-dependent factors but includes others.

    “MiDAS results from an NADH-AMPK-p53-dependent pathway and elicits a SASP that lacks IL-1-dependent factors but includes others.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Data are presented either as representative examples or means of 3+ experiments.

    “Data are presented either as representative examples or means of 3+ experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Protocols were approved by the Institutional Animal Care and Use Committee.

    “Protocols were approved by the Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Mitochondrial dysfunction induces a senescence response (MiDAS), including arrested growth and a SASP that is distinct from that caused by genotoxic stress.

    “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;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    POLGD257A mice have a thicker stratum corneum and lipodystrophy compared to age-matched WT mice.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Trifunovic et al., 2004 source

  • May combine two claims.

    Premisecitation

    POLGD257A mice have a mutation in the proofreading domain of the mtDNA polymerase and rapidly accumulate mtDNA mutations and aging phenotypes.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kujoth et al., 2005 source
    • cites Trifunovic et al., 2004 source

  • May combine two claims.

    Interpretationreasoning

    AMPK most likely mediates MiDAS through p53 activation, and subsequent NF-κB inhibition.

    “Because p53 depletion was sufficient to prevent MiDAS, AMPK most likely mediates MiDAS through p53 activation, and subsequent NF-κB inhibition.”
    Quote in the paperSubstantial claim
72 of 72

  • 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.”
3 of 3

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?

  • Mitochondrial dysfunction-associated senescence has a distinct phenotype and a unique cell-non-autonomous programme potentially responsible for altered metabolism and aberrant adipocyte differentiation in aged animals.

    “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]

    The Discussion (page unavailable) describes MiDAS as a distinct senescence response with a distinct secretory phenotype. Results (‘MiDAS in POLG Mice’; page unavailable) show that conditioned medium from mitochondrially impaired cells blocked adipogenesis in cell culture, supporting a potential cell-non-autonomous effect. The paper does not establish that this programme accounts for altered metabolism or aberrant adipocyte differentiation observed in normally aged animals; its in-vivo evidence comes from progeroid mice. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Mouse models of mitochondrial dysfunction and enhanced oxidative stress show increased senescence.

    “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

    The Results section (“MiDAS in POLG Mice”; page not available) reports more senescent cells in the adipose tissue and epidermis of mice with mitochondrial dysfunction than in age-matched controls. It does not establish that those mice had enhanced oxidative stress; the paper’s cell-culture Results instead describe MiDAS phenotypes as appearing independent of ROS. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Genetic or pharmacological inhibition of the electron transport chain can induce senescence even though cells lack expression of key pro-inflammatory SASP factors such as IL-6 and IL-8.

    “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

    In Results, “Mitochondrial Dysfunction and Senescent Phenotypes” (page unavailable), rotenone and antimycin A—pharmacological ETC inhibitors—induced senescence without increased IL-6 expression or secretion. The Results also report failure to express IL-6 and IL-8 after SIRT3 depletion, but do not establish that SIRT3 depletion is genetic inhibition of the ETC or that both cytokines were absent after ETC-inhibitor treatment. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • NAD+/NADH ratios are reduced in senescent cells.

    “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

    The Results section, “Decreased NAD+/NADH Ratios Mediate MiDAS” (page not specified), reports reduced ratios in cells undergoing mitochondrial dysfunction-associated senescence (MiDAS) without pyruvate. The claim extends that finding to senescent cells generally, which this passage does not establish. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The SASP can either suppress differentiation of preadipocytes or promote differentiation of keratinocytes, resulting in lipodystrophy and skin phenotypes common in old mice.

    “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

    The Results section (“MiDAS in POLG Mice”; page unavailable) reports that conditioned medium blocked adipogenesis in preadipocytes and promoted keratinocyte differentiation. It also links these cell-culture findings to lipodystrophy and a thicker stratum corneum in progeroid POLG mice. It does not establish that the SASP causes those phenotypes in normally aged mice, as the citing sentence’s “resulting in” wording implies. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

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.

  • Cites a retracted work: 10.1371/journal.pone.0019194

    Info

    The cited work was retracted on 2024-11-13 (notice 10.1371/journal.pone.0313921), not before this paper was published (2016-02).

    Cited work 10.1371/journal.pone.0019194 · retracted 2024-11-13 · notice 10.1371/journal.pone.0313921 · this paper published 2016-02

1 of 1

Cites

1 retracted

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4 of the 66 references couldn’t be matched to a known paper.

Cited by

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Related

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)
DOI
10.1016/j.cmet.2015.11.011
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
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
  • Health Sciences › Medicine › Physiology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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