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Cited by 94Mitochondrial Function and PathologyAutophagy in Disease and TherapyGenetics, Aging, and Longevity in Model Organisms

The mitochondrial permeability transition: Nexus of aging, disease and longevity

Open access
Rottenberg, Hagai, Hoek, Jan B.·2021·Cells
DOI 10.3390/cells10010079PMC PMC7825081

Published version of a preprint

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Abstract

The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the mitochondrial permeability transition pore (mPTP) is a central nexus linking aging, degenerative disease, and longevity, with full/long mPTP opening releasing damaging reactive oxygen species, Ca2+, and NAD+. It proposes that autophagy/mitophagy protect against aging only when mPTP is inhibited, while mPTP overactivation turns these processes destructive and drives diseases such as Parkinson’s disease.

Key findings

  • mPTP is a mitochondrial inner-membrane mega-channel with conductance up to 1.5 nS; full opening allows passage of solutes with MW up to 1.5 KDa, collapses the protonmotive force, inhibits oxidative phosphorylation, and can cause necrosis or apoptosis.
  • mPTP activity is enhanced in aging and aging-driven degenerative diseases; full, extended opening releases large amounts of mROS and NAD+, damages proteins, lipids, and DNA, and accelerates aging, whereas partial, short openings can serve beneficial signaling.
  • Autophagy/mitophagy antiaging effects depend on mPTP inhibition: mTORC2/SGK1 phosphorylation of VDAC1 tags it for degradation and inhibits mPTP; VDAC1 accumulation activates mPTP in an ANT1-dependent manner, shortens lifespan in C. elegans, and abrogates autophagy-dependent life extension.
  • Mitophagy is inhibited in aging, and failure to remove mitochondria with activated mPTP contributes to Parkinson’s disease; familial Parkinson’s forms often involve mutations in mitophagy/autophagy proteins, and α-synuclein can activate mPTP, apparently via ATP synthase.

Methods

  • Narrative review synthesizing published literature on mPTP, aging, autophagy/mitophagy, degenerative disease, and lifespan/healthspan interventions.
  • No primary experimental data, sample, or formal quantitative analysis are reported; evidence is drawn from model organisms, isolated mitochondria, and cited mechanistic studies.
  • Main analysis is conceptual integration of pathways that activate or inhibit mPTP and their proposed roles in aging and disease.

Limitations

  • The paper states that the exact composition of mPTP is still not fully resolved, that the nature of a composite ATP synthase/ANT channel remains elusive, and that contributions of several other proteins are unresolved.
  • It also states that what determines whether mPTP opens briefly or for long durations is not entirely clear, and that mechanisms of inhibition by melatonin and metformin are unclear.
  • Evident from the text: this is a narrative review without systematic search or meta-analysis, and the paper notes that efforts to identify clinically useful mPTP inhibitors have not been successful to date.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/cells10010079

Cites

299 of 299 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 191 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Autophagy protects the cell against aging and disease.

    “Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [128] Abdellatif, 2018, Autophagy in Cardiovascular Aging, Circ. Res. source

      Not checked in the free run.

    • cites [129] Nakamura, 2018, Autophagy and Longevity, Mol. Cells

      Not checked in the free run.

    • cites [130] Hansen, 2018, Autophagy as a promoter of longevity: Insights from model organisms, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

  • Premisecitation

    Autophagy is inhibited in aging cells.

    “Autophagy is inhibited in aging cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [131] Bareja, 2019, Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy, Front. Cell Dev. Biol. source

      Not checked in the free run.

    • cites [137] Leidal, 2018, Autophagy and the cell biology of age-related disease, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [138] Liang, 2020, Aging is associated with a decline in Atg9b-mediated autophagosome formation and appearance of enlarged mitochondria in the heart, Aging Cell source

      Not checked in the free run.

  • Interpretationcitation

    Mitophagy retards aging by removing mitochondrial fragments with activated mPTP.

    “Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Markaki, 2018, Novel Insights into the Anti-Aging Role of Mitophagy, Int. Rev. Cell. Mol. Biol. source

      Not checked in the free run.

  • Interpretationnone given

    mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+.

    “mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The protective effect of autophagy depends on mTORC2/SGK1 inhibition of mPTP.

    “However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

  • May combine two claims. 48
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Interpretationreasoning

    Pathways that control mPTP activity can either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan.

    “The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    mPTP is a mitochondrial inner membrane multicomponent mega-channel with variable conductance up to 1.5 nS, activated by calcium, oxidative stress and membrane depolarization.

    “The mitochondrial permeability transition pore (mPTP) is a mitochondrial inner membrane multicomponent mega-channel, with variable conductance (up to 1.5 nS) that is activated by calcium, oxidative stress and membrane depolarization [1,2].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Carraro, 2020, Molecular nature and regulation of the mitochondrial permeability transition pore(s), drug target(s) in cardioprotection, J. Mol. Cell Cardiol. source

      Not checked in the free run.

    • cites [2] Bernardi, 2006, The mitochondrial permeability transition from in vitro artifact to disease target, FEBS J. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inhibition of mitophagy in aging leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.

    “this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [158] Martin, 2014, Mitochondrial permeability transition regulates Parkinson’s disease development in mutant α-synuclein transgenic mice, Neurobiol. Aging source

      Not checked in the free run.

    • cites [159] Arrázola, M.S., Ramos-Fernández, E., Cisternas, P., Ordenes, D., and Inestrosa, N.C. (2017). Wnt Signaling Prevents the Aβ Oligomer-Induced Mitochondria l Permeability Transition Pore Opening Preserving Mitochondrial Structure in Hippocampal Neurons. PLoS ONE, 12. source

      Not checked in the free run.

    • cites [160] Fivenson, 2017, Mitophagy in neurodegeneration and aging, Neurochem. Int. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP.

    “Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [241] Lamming, 2016, Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island, J. Gerontol. A Biol. Sci. Med. Sci. source

      Not checked in the free run.

    • cites [245] Petrosillo, 2009, Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening, Am. J. Physiol. Heart Circ. Physiol. source

      Not checked in the free run.

    • cites [252] Piskovatska, 2019, Metformin as a geroprotector: Experimental and clinical evidence, Biogerontology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The activity of the mitochondrial permeability transition pore (mPTP) is enhanced in aging and in aging-driven degenerative diseases.

    “The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.

    “elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Opening of mPTP can be reversed readily if the pore is only partially open because Ca2+ is lost quickly, proton flow lowers pH which inhibits the channel, and membrane potential is restored to close the pore.

    “The opening of mPTP can be reversed readily if the pore is only partially open since Ca2+, which is required to keep the pore open, is lost quickly; in addition, proton flow into the matrix lowers the pH, which inhibits the channel [2], and membrane potential is restored to close the pore.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Bernardi, 2006, The mitochondrial permeability transition from in vitro artifact to disease target, FEBS J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extensive and prolonged activation of mPTP may lead to cell death by necrosis, and rupture of the mitochondrial outer membrane releases proapoptotic proteins, inducing apoptosis or similar processes.

    “The inhibition of oxidative phosphorylation depletes cellular ATP and therefore extensive and prolonged activation of mPTP may lead to cell death by necrosis; in addition, the rupture of the mitochondrial outer membrane releases proapoptotic proteins, including cytochrome c, AIF and endonuclease, thereby inducing cell death by apoptosis or similar processes”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Canton, 2001, Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart, J. Biol. Chem. source

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    • cites [4] Petronilli, 2001, The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ, J. Biol. Chem. source

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    • cites [5] Vaseva, 2012, Moll UM. p53 opens the mitochondrial permeability transition pore to trigger necrosis, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Release of mROS by mPTP opening activates PARP1, which further depletes cellular NAD+.

    “In addition, the release of mROS by mPTP opening activates PARP1 which further depletes cellular NAD+ [85,86].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Schriewer, 2013, ROS-mediated PARP activity undermines mitochondrial function after permeability transition pore opening during myocardial ischemia-reperfusion, J. Am. Heart Assoc. source

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    • cites [86] Kahraman, 2015, Permeability transition pore-dependent and PARP-mediated depletion of neuronal pyridine nucleotides during anoxia and glucose deprivation, J. Bioenerg. Biomembr. source

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  • May combine two claims.

    Premisecitation

    VDAC locks ANT in the C conformation, which is known to activate mPTP.

    “Moreover, VDAC was shown to lock ANT in the C conformation [30], which is known to activate mPTP [2,31].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Vyssokikh, 2003, The function of complexes between the outer mitochondrial membrane pore (VDAC) and the adenine nucleotide translocase in regulation of energy metabolism and apoptosis, Acta Biochim. Pol. source

      Not checked in the free run.

    • cites [2] Bernardi, 2006, The mitochondrial permeability transition from in vitro artifact to disease target, FEBS J. source

      Not checked in the free run.

    • cites [31] Hunter, 1979, The Ca2+-induced membrane transition in mitochondria. I.The protective mechanisms, Arch. Biochem. Biophys. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Oxidative damage to mitochondrial and cellular proteins, lipids and DNA done by extended production of mROS cannot be fully erased, and cell aging will progress.

    “However, the oxidative damage to mitochondrial and cellular proteins, lipids and DNA, that was done by the extended production of mROS, cannot be fully erased, and cell aging will progress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NAD+ that exits the matrix into the outer compartment is hydrolyzed by CD38, depleting the cellular pool of NAD+ and inhibiting cytoplasmic sirtuins.

    “Moreover, the NAD+ that exits the matrix into the outer compartment is hydrolyzed by CD38, depleting the cellular pool of NAD+ [3,84], thus also inhibiting cytoplasmic sirtuins (e.g., sirt1).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Canton, 2001, Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart, J. Biol. Chem. source

      Not checked in the free run.

    • cites [84] Chini, 2016, D38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A full and longer lasting opening of mPTP can generate a large excess of superoxide and H2O2 release that can overpower mitochondrial and cellular antioxidant systems and cause damage to membrane phospholipids, enzymes, transporters and DNA.

    “However, a full and longer lasting opening of the pore can generate a large excess of superoxide and H2O2 release that can overpower the mitochondrial and cellular antioxidant systems and cause damage to membrane phospholipids, enzymes, transporters and most importantly DNA [72].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Guidarelli, 2017, Arsenite induces DNA damage via mitochondrial ROS and induction of mitochondrial permeability transition, Biofactors source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Removal of mitochondria with activated mPTP by mitophagy protects the cell from progression to apoptosis, reduces oxidative damage and retards aging.

    “Another critical mechanism that can stop the propagation of mPTP opening in the cell is the removal of mitochondria with activated mPTP by mitophagy, a process that protects the cell from progression to apoptosis, reduces oxidative damage and retards aging (see below).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Markaki, 2018, Novel Insights into the Anti-Aging Role of Mitophagy, Int. Rev. Cell. Mol. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of NAD+ from the mitochondrial matrix inhibits mitochondrial sirtuins (sirt3, sirt4, sirt5), resulting in increased mROS generation and enhanced activity of mPTP because CypD is inhibited by deacetylation by sirt3.

    “The loss of NAD+ from the mitochondrial matrix inhibits the mitochondrial sirtuins (sirt3, sirt4, sirt5), resulting in increased mROS generation [80], and also enhanced activity of mPTP because CypD is inhibited by deacetylation by sirt3 [81,82].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [80] Ansari, 2017, Function of the SIRT3 mitochondrial deacetylase in cellular physiology.; cancer.; and neurodegenerative disease, Aging Cell source

      Not checked in the free run.

    • cites [81] Hafner, 2010, Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy, Aging source

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    • cites [82] Bochaton, 2015, Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D, J. Mol. Cell Cardiol. source

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  • May combine two claims.

    Interpretationcitation

    The effects of VDAC1 accumulation on mPTP activation, autophagy and lifespan are dependent on ANT1, suggesting that activation of mPTP by VDAC1 is mediated by the VDAC/ANT complex.

    “Furthermore, the effects of VDAC1 accumulation on mPTP activation, autophagy and lifespan were dependent on ANT1 [27], suggesting that the activation of mPTP by VDAC1 is mediated by the VDAC/ANT complex.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Moderate activation of mPTP may be insufficient to cause cell death but may damage mitochondrial and cellular proteins, lipids and DNA and thus accelerate cell aging.

    “Moderate activation of mPTP may be insufficient to cause cell death but may result in damage to both mitochondrial and cellular proteins, lipids and DNA and thus accelerate cell aging [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Rottenberg, 2017, The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When mPTP is activated, protons flow into the matrix, calcium, superoxide, hydrogen peroxide and other ions flow out, and the mitochondrial protonmotive force collapses, inhibiting oxidative phosphorylation.

    “When activated, protons flow into the matrix, while calcium, superoxide, hydrogen peroxide and other ions flow out of the matrix and the mitochondrial protonmotive force (∆Ѱ + ∆pH) collapses, thus inhibiting oxidative phosphorylation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Carraro, 2020, Molecular nature and regulation of the mitochondrial permeability transition pore(s), drug target(s) in cardioprotection, J. Mol. Cell Cardiol. source

      Not checked in the free run.

    • cites [2] Bernardi, 2006, The mitochondrial permeability transition from in vitro artifact to disease target, FEBS J. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    When mPTP is fully activated and this activation is propagated throughout the cell, the inevitable outcome is cell death unless the process can be stopped or reversed before cell death processes progress.

    “When mPTP is fully activated, and this activation is propagated throughout the cell, the inevitable outcome is cell death, as described above, unless the process can be stopped or reversed before the cell death processes progress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    VDAC interacts with ANT to form a channel, and reconstitution of a complex of ANT/VDAC/CypD exhibits mPTP-like activities.

    “It was previously shown that VDAC interacts with ANT to form a channel [28] and that the reconstitution of a complex of ANT/VDAC/CypD exhibits mPTP-like activities [29].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Beutner, 1996, Complexes between kinases.; mitochondrial porin and adenylate translocator in rat brain resemble the permeability transition pore, FEBS Lett. source

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    • cites [29] Crompton, 1998, Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore, Eur. J. Biochem. source

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  • May combine two claims.

    Premisecitation

    Mitochondrial dysfunction in aging is often manifested as excess production of mROS, calcium overloading, and membrane depolarization.

    “Mitochondrial dysfunction in aging is often manifested as the excess production of mROS, calcium overloading, and membrane depolarization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Bernardi, 2006, The mitochondrial permeability transition from in vitro artifact to disease target, FEBS J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondria are the major source of ROS in the cell, and oxidative damage to phospholipids, proteins, mtDNA and nuclear DNA in aging results from excess production of mROS.

    “It has been recognized for a long time that mitochondria are the major source of ROS in the cell and that oxidative damage to phospholipids, proteins, mtDNA and nuclear DNA in aging results from the excess production of mROS [47,48,49,50,51,52].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [47] Harman, 1972, The biologic clock: The mitochondria?, J. Am. Geriatr. Soc. source

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    • cites [48] Sohal, 1985, Relationship between metabolic rate, free radicals, differentiation and aging: A unified theory, Basic Life Sci.

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    • cites [49] Beckman, 1998, The free radical theory of aging matures, Physiol. Rev. source

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    Premisecitation

    AMPK is the major activator of autophagy, is activated by AMP and is very sensitive to any modulation of the AMP/ADP ratio.

    “AMPK, the major activator of autophagy, is activated by AMP and is very sensitive to any modulation of the AMP/ADP ratio [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Herzig, 2018, AMPK: Guardian of metabolism and mitochondrial homeostasis, Nat. Rev. Mol. Cell Biol. source

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

    Premisecitation

    Autophagy catabolizes damaged cellular components to protect cells against stress and maintain homeostasis.

    “Autophagy catabolizes damaged cellular components to protect cells against stress and maintain homeostasis [126,127].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [126] Stead, 2019, Agephagy—Adapting Autophagy for Health During Aging, Front. Cell Dev. Biol. source

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    • cites [127] Gross, 2020, Mechanisms of Autophagy in Metabolic Stress Response, J. Mol. Biol. source

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    Premisecitation

    The mTOR pathway controls autophagy and thus lifespan.

    “Another nutrient-sensing pathway that controls autophagy and thus lifespan is the mTOR pathway [148,149,150,151,152].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [148] Sabatini, 2017, Twenty-five years of mTOR: Uncovering the link from nutrients to growth, Proc. Natl. Acad. Sci. USA source

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    • cites [149] Lushchak, 2017, The role of the TOR pathway in mediating the link between nutrition and longevity, Mech. Ageing Dev. source

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    • cites [150] Weichhart, 2018, mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review, Gerontology source

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    Premisecitation

    mTORC1 regulates cell growth and metabolism and negatively regulates autophagy.

    “mTORC1 regulates cell growth and metabolism and negatively regulates autophagy.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [148] Sabatini, 2017, Twenty-five years of mTOR: Uncovering the link from nutrients to growth, Proc. Natl. Acad. Sci. USA source

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    • cites [149] Lushchak, 2017, The role of the TOR pathway in mediating the link between nutrition and longevity, Mech. Ageing Dev. source

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    • cites [150] Weichhart, 2018, mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review, Gerontology source

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  • May combine two claims.

    Premisecitation

    Mitophagy specifically removes damaged mitochondria and thus protects the cell from deleterious effects of dysfunctional mitochondria, and specifically mitochondria with activated mPTP.

    “A selective form of macroauthophagy is mitophagy, which specifically removes damaged mitochondria and thus protects the cell from the deleterious effects of dysfunctional mitochondria, and specifically mitochondria with activated mPTP (see below).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [167] Rodger, 2018, Mammalian mitophagy—from in vitro molecules to in vivo models, FEBS J. source

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    • cites [168] Pickles, 2018, Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance, Curr. Biol. source

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  • May combine two claims.

    Premisecitation

    In C. elegans cells, genetic interference with this process results in the accumulation of VDAC1 on the outer mitochondrial membrane, and in the ANT1-dependent activation of mPTP, leading to mitochondrial fragmentation, and a shorter lifespan.

    “In C. elegans cells, genetic interference with this process results in the accumulation of VDAC1 on the outer mitochondrial membrane, and in the ANT1-dependent activation of mPTP, leading to mitochondrial fragmentation, and a shorter lifespan.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of specific autophagy genes leads to life extension, while loss of function of autophagy genes is often associated with age-dependent degenerative diseases.

    “The overexpression of specific autophagy genes leads to life extension, while the loss of function of autophagy genes is often associated with age-dependent degenerative diseases [131,137,138,139].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [131] Bareja, 2019, Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy, Front. Cell Dev. Biol. source

      Not checked in the free run.

    • cites [137] Leidal, 2018, Autophagy and the cell biology of age-related disease, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [138] Liang, 2020, Aging is associated with a decline in Atg9b-mediated autophagosome formation and appearance of enlarged mitochondria in the heart, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    What determines whether autophagy is a cell protective mechanism or a cell destructive mechanism is the activation state of mPTP: when mPTP is inhibited, autophagy is protective, while overactivation of mPTP turns autophagy into a destructive process.

    “It has been shown recently that what determines whether autophagy is a cell protective mechanism or a cell destructive mechanism is the activation state of mPTP: when mPTP is inhibited, autophagy is protective, while overactivation of mPTP turns autophagy into a destructive process [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

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    Premisecitation

    mROS initiate signals that activate several pathways that protect mitochondria from oxidative stress; these pathways slow aging, inhibit cell death and may result in lifespan extension.

    “In addition to inducing protection of nuclear DNA from oxidative damage, mROS initiate signals that activate several pathways that protect mitochondria from oxidative stress. These pathways slow aging, inhibit cell death and may result in lifespan extension [67,108,109].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [67] Sun, 2016, The Mitochondrial Basis of Aging, Mol. Cell source

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    • cites [108] Gross, 2017, Non-apoptotic functions of BCL-2 family proteins, Cell Death Differ. source

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    • cites [109] Ou, 2018, DNA damage responses and p53 in the aging process, Blood source

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    Premisecitation

    In SGK1-knockout mouse hepatocytes, the VDAC1 level was elevated, mPTP activity was increased, I/R susceptibility was increased, and this effect was reversed by cyclosporin A.

    “In SGK1-knockout mouse hepatocytes, the VDAC1 level was elevated, mPTP activity was increased, I/R susceptibility was increased and this effect was reversed by cyclosporin A.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD38 expression increases with age, which further enhances the destructive effects of mPTP opening in aging.

    “CD38 expression increases with age, which further enhances the destructive effects of mPTP opening in aging [93].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Guerreiro, S., Privat, A.L., Bressac, L., and Toulorge, D. (2020). CD38 in Neurodegeneration and Neuroinflammation. Cells, 9. source

      Not checked in the free run.

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

    Premisecitation

    Mitophagy is a specialized form of autophagy in which damaged mitochondria are tagged for removal by autophagy.

    “Mitophagy is a specialized form of autophagy in which damaged mitochondria are tagged for removal by autophagy [167,168].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Rodger, 2018, Mammalian mitophagy—from in vitro molecules to in vivo models, FEBS J. source

      Not checked in the free run.

    • cites [168] Pickles, 2018, Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance, Curr. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These results strongly suggest that all the antiaging effects of autophagy are contingent on the inhibition of mPTP activity, supporting the hypothesis that mPTP activity is critical for the progression of aging.

    “These results strongly suggest that all the antiaging effects of autophagy are contingent on the inhibition of mPTP activity, supporting the hypothesis that mPTP activity is critical for the progression of aging [14].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Rottenberg, 2017, The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore, Aging Cell source

      Not checked in the free run.

    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

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

    Premisecitation

    mTORC2 controls cell proliferation and survival by the phosphorylation of several protein kinases, including AKT and SGK1.

    “mTORC2 controls cell proliferation and survival by the phosphorylation of several protein kinases, including AKT and SGK1.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [148] Sabatini, 2017, Twenty-five years of mTOR: Uncovering the link from nutrients to growth, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [149] Lushchak, 2017, The role of the TOR pathway in mediating the link between nutrition and longevity, Mech. Ageing Dev. source

      Not checked in the free run.

    • cites [150] Weichhart, 2018, mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review, Gerontology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivation of mTORC2 and SGK1 in C. elegans enhanced autophagic degradation of mitochondria (mitophagy), led to developmental and reproductive defects, and was associated with increased release of mitochondria-derived ROS.

    “The results of Zhou et al. [27] were corroborated by recent studies [156,157] that similarly showed that the inactivation of mTORC2 and SGK1 in C. elegans enhanced autophagic degradation of mitochondria (mitophagy), which led to developmental and reproductive defects, and was associated with increased release of mitochondria-derived ROS”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Aspernig, 2019, Mitochondrial Perturbations Couple mTORC2 to Autophagy in C. elegans, Cell Rep. source

      Not checked in the free run.

    • cites [157] Heimbucher, 2020, TORC2-SGK-1 signaling integrates external signals to regulate autophagic turnover of mitochondria via mtROS, Autophagy source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under normal conditions, mTORC2 phosphorylates SGK1, SGK1 phosphorylates VDAC1 at a specific site, and that phosphorylation tags VDAC1 for ubiquitination and proteasomal degradation, thereby inhibiting mPTP.

    “Under normal conditions, when mTORC2 phosphorylates SGK1, SGK1 phosphorylates VDAC1 at a specific site, and that phosphorylation tags VDAC1 for ubiquitination and proteasomal degradation, thereby inhibiting mPTP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Zhou, 2019, Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In model animals, as well as humans, the expression and activity of autophagy genes is reduced with age in various tissues, resulting in accumulation of intermediates of the process, indicating defective autophagy.

    “In model animals, as well as humans, the expression and activity of autophagy genes is reduced with age in various tissues, resulting in the accumulation of intermediates of the process, indicating defective autophagy.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [131] Bareja, 2019, Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy, Front. Cell Dev. Biol. source

      Not checked in the free run.

    • cites [137] Leidal, 2018, Autophagy and the cell biology of age-related disease, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [138] Liang, 2020, Aging is associated with a decline in Atg9b-mediated autophagosome formation and appearance of enlarged mitochondria in the heart, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol activates sirt3, which inhibits mPTP.

    “Resveratrol activation of sirt3 (which inhibits mPTP) was also demonstrated in several studies [271,272,273].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [271] Fu, 2017, Resveratrol rescues cadmium-induced mitochondrial injury by enhancing transcriptional regulation of PGC-1α and SOD2 via the Sirt3/FoxO3a pathway in TCMK-1 cells, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

    • cites [272] Zhou, 2014, Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells, Cell Death Dis. source

      Not checked in the free run.

    • cites [273] Sun, Q., Kang, R.R., Chen, K.G., Liu, K., Ma, Z., Liu, C., Deng, Y., Liu, W., and Xu, B. Sirtuin 3 is required for the protective effect of Resveratrol on Manganese-induced disruption of mitochondrial biogenesis in primary cultured neurons. J. Neurochem., 2020. source

      Not checked in the free run.

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

    Premisecitation

    NIX can mediate mitophagy independent of the PINK1/PARKIN pathway.

    “Additionally, Nip3-like protein X (NIX) can mediate mitophagy independent of the PINK1/PARKIN pathway [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Koentjoro, 2017, Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson’s disease, Sci Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise retards aging and increases human healthspan.

    “Exercise is a well-established lifestyle modification that retards aging and increases human healthspan [283].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [283] Andrade, 2018, Aging Hallmarks: The Benefits of Physical Exercise, Front. Endocrinol. (Lausanne) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol enhances autophagy and mitophagy.

    “Resveratrol was shown to enhance autophagy and mitophagy [263,264]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [263] Morselli, 2009, Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol, Aging source

      Not checked in the free run.

    • cites [264] Li, 2020, Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction, Front. Cell Dev. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise enhances mitophagy and autophagy.

    “Exercise enhances mitophagy and autophagy [284,285]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [284] He, 2020, Exercise enhances mitochondrial fission and mitophagy to improve myopathy following critical limb ischemia in elderly mice via the PGC1a/FNDC5/irisin pathway, Skelet Muscle source

      Not checked in the free run.

    • cites [285] Andreotti, 2020, Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies, Front. Nutr. source

      Not checked in the free run.

    • Rests on an assumption: Autophagy and mitophagy are associated with inhibition of mPTP.

  • May combine two claims.

    Premisecitation

    Damaged mitochondrial fragments are tagged for autophagy mostly by the PINK1/PARKIN pathway, while undamaged fragments, as well as newly synthesized mitochondria, are fused into elongated tubular filaments.

    “However, damaged mitochondrial fragments are tagged for autophagy, mostly by the PINK1/PARKIN pathway [186], while the undamaged fragments, as well as newly synthesized mitochondria, are fused into elongated tubular filaments.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Imai, 2020, PINK1-Parkin signaling in Parkinson’s disease: Lessons from Drosophila, Neurosci. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spermidine provides cardioprotection and extends life in mice through activation of autophagy and mitophagy.

    “It was shown to provide cardioprotection and to extend life in mice through the activation of autophagy and mitophagy [276].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [276] Eisenberg, 2016, Cardioprotection and lifespan extension by the natural polyamine spermidine, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent evidence suggests that the fission process is accelerated by aging, while fusion is inhibited, thereby increasing mitochondrial fragmentation in aging.

    “Recent evidence suggests that the fission process is accelerated by aging [187], while fusion is inhibited [188], thereby increasing mitochondrial fragmentation in aging.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [187] Amartuvshin, O., Lin, C.H., Hsu, S.C., Kao, S.H., Chen, A., Tang, W.C., Chou, H.L., Chang, D.L., Hsu, Y.Y., and Hsiao, B.S. (2020). Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss. Aging Cell, e13191. source

      Not checked in the free run.

    • cites [188] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol protects against neurodegeneration by activating sirt1, which activates PGC1a, accelerating mitochondrial biogenesis.

    “Resveratrol was also shown to protect against neurodegeneration by activating sirt1 which activates PGC1a that accelerates mitochondrial biogenesis (which replaces mPTP-damaged mitochondria with newly minted mitochondria) [270,271].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [270] Smith, 2009, Resveratrol and neurodegenerative diseases: Activation of SIRT1 as the potential pathway towards neuroprotection, Curr. Neurovasc. Res. source

      Not checked in the free run.

    • cites [271] Fu, 2017, Resveratrol rescues cadmium-induced mitochondrial injury by enhancing transcriptional regulation of PGC-1α and SOD2 via the Sirt3/FoxO3a pathway in TCMK-1 cells, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ubiquitination in mitophagy is not limited to outer mitochondrial membrane proteins; the inner membrane protein prohibitin 2 is also ubiquitinated and this process is critical for mitophagy.

    “The ubiquitination is not limited to OMM proteins, as the inner membrane protein prohibitin 2 is also ubiquitinated and this process is critical for mitophagy [179].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Wei, 2017, Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the PINK1/PARKIN pathway, PINK1 accumulates on the mitochondrial outer membrane surface of depolarized and oxidatively stressed mitochondria, recruits PARKIN to the outer membrane, where it participates in ubiquitination of mitochondrial proteins, marking the mitochondria for delivery to autophagosomes.

    “In this pathway, PTEN-induced kinase 1 (PINK1), a serin/threonine kinase, accumulates on the mitochondrial outer membrane (MOM) surface of depolarized and oxidatively stressed mitochondria [177,178]. It recruits the E3 ubiquitin protein ligase PARKIN to MOM, where it participates in the ubiquitination of mitochondrial proteins, marking the mitochondria for delivery to autophagosomes that are taken”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [177] Bowling, J.L., Skolfield, M.C., Riley, W.A., Nolin, A.P., Wolf, L.C., and Nelson, D.E. (2019). Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway. BMC Mol. Cell Biol., 20. source

      Not checked in the free run.

    • cites [178] Gao, F., Zhang, Y., Hou, X., Tao, Z., Ren, H., and Wang, G. (2020). Dependence of PINK1 accumulation on mitochondrial redox system. Aging Cell, e13211. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary restriction prevents mPTP opening in liver and brain mitochondria but not in skeletal muscle or heart.

    “Several studies demonstrated that dietary restriction prevents mPTP opening in liver and brain mitochondria [293,294,295], but not in the skeletal muscle or heart [296].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [293] Kristal, 1998, Dietary restriction augments protection against induction of the mitochondrial permeability transition, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [294] Amigo, 2017, Caloric restriction protects livers from ischemia/reperfusion damage by preventing Ca(2+)-induced mitochondrial permeability transition, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [295] Amigo, 2017, Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity, Aging Cell source

      Not checked in the free run.

    • cites [296] Serna, 2020, Functional changes induced by caloric restriction in cardiac and skeletal muscle mitochondria, J. Bioenerg. Biomembr. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The complex control of mPTP activity plays a critical role in both the mechanisms that protect the cell from aging and disease and in the mechanisms that accelerate aging and drive aging-dependent degenerative diseases.

    “Recent studies show how the complex control of mPTP activity can play a critical role in both the mechanisms that protect the cell from aging and disease, and in the mechanisms that accelerate aging and drive the aging-dependent degenerative diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oxidative stress is both a major cause of enhanced mPTP activity and an outcome of enhanced mPTP activation.

    “since oxidative stress is both a major cause of enhanced mPTP activity, and an outcome of enhanced mPTP activation [14]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Rottenberg, 2017, The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore, Aging Cell source

      Not checked in the free run.

53 of 53

  • The paper relies on this without support.

    Autophagy and mitophagy are associated with inhibition of mPTP.

    “which are associated with the inhibition of mPTP”

  • The paper relies on this without support.

    mPTP activity is enhanced in aging.

    “two decades ago, it was first shown that mPTP activity is enhanced in aging.”

  • The paper relies on this without support.

    Findings from animal models about dietary restriction and mPTP apply to humans.

    “it is likely that mPTP activity is reduced in ageing humans subjected to dietary restrictions.”
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?

  • Testosterone may protect the respiratory chain of mitochondria from oxidative damage and maintain a normal OXPHOS function.

    “Moreover, testosterone may protect the respiratory chain of mitochondria from oxidative damage and maintain a normal OXPHOS function (149).”

    From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [149]

Cites

1 retracted

Flagged first, then by citations

21 of the 320 references couldn’t be matched to a known paper.

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Related

Authors
Rottenberg, H., & Hoek, J. B.
Affiliations
  • New Hope Biomedical R&D, 23 W. Bridge street, New Hope, PA 18938, USA
  • Thomas Jefferson University (US)
Corresponding author
Rottenberg, Hagai
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2021-01-06
Volume
10
Issue
1
Pages
79
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells10010079
PMC
PMC7825081
OpenAlex
W3110227391
Semantic Scholar
2003de76ddb1a15f86aaf8b6118049a15dbdccc9
Cited by
94
References
320
Citations by year
2026: 17 · 2025: 16 · 2024: 13 · 2023: 19 · 2022: 15 · 2021: 14
FWCI
1.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • Preprints.org (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Medicine Forum (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (AA018873, EB023224)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
mitochondrial permeability transition pore, aging, degenerative diseases, autophagy, mitophagy, mTORC2, reactive oxygen species, calcium release, healthspan, lifespan, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, cellular aging
MeSH terms
Mitochondrial Permeability Transition Pore, Animals, Autophagy, Disease, Humans, Longevity, Models, Biological, Mitophagy

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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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