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Cited by 990Mitochondrial Function and PathologyGenetics, Aging, and Longevity in Model OrganismsAutophagy in Disease and Therapy

Mitochondrial and metabolic dysfunction in ageing and age-related diseases

Open access
Amorim, João A., Coppotelli, Giuseppe, Rolo, Anabela P., Palmeira, Carlos M., Ross, Jaime M., Sinclair, David A.·2022·Nature Reviews Endocrinology
DOI 10.1038/s41574-021-00626-7PMC PMC9059418
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Abstract

Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches. This Review discusses the role of mitochondria in metabolism and how mitochondria contribute to age-related metabolic diseases. This knowledge might guide us in designing therapies targeting metabolic disorders to extend human health span and lifespan. The rate of ageing is coordinated, at least in part, by conserved genetic and biochemical pathways. A complex network of interactions between longevity pathways reveals an intricate regulation of mitochondrial physiology during ageing. Cellular metabolism interconnects the nine hallmarks of ageing, and deregulation of energy metabolism by environmental variations is an essential process leading to mitochondrial dysfunction during ageing. A better understanding of mitochondrial dysfunction during ageing and age-related metabolic diseases will provide fundamental knowledge to develop therapies to combat late-life morbidities. Human longitudinal studies will be essential to understand individuals’ risk of diseases much earlier in life, and will inform health choices and medical care options. The rate of ageing is coordinated, at least in part, by conserved genetic and biochemical pathways. A complex network of interactions between longevity pathways reveals an intricate regulation of mitochondrial physiology during ageing. Cellular metabolism interconnects the nine hallmarks of ageing, and deregulation of energy metabolism by environmental variations is an essential process leading to mitochondrial dysfunction during ageing. A better understanding of mitochondrial dysfunction during ageing and age-related metabolic diseases will provide fundamental knowledge to develop therapies to combat late-life morbidities. Human longitudinal studies will be essential to understand individuals’ risk of diseases much earlier in life, and will inform health choices and medical care options.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that mitochondria are central to ageing and age-related metabolic diseases through energy supply–demand imbalance, ROS, mtDNA mutations, senescence, inflammation, and crosstalk with conserved longevity pathways. It surveys lifestyle, pharmacological, NAD⁺-boosting, mitochondrial uncoupler, and mitochondria-targeted antioxidant interventions, while noting that many mechanisms and clinical translations remain unresolved.

Key findings

  • Mitochondrial dysfunction is linked to metabolic syndrome, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease, vascular disease, and chronic inflammation. In islets from patients with T2DM, PGC1α expression was reduced by 90%, and PGC1α silencing in healthy human islets reduced insulin secretion.
  • mtDNA variation and copy number are associated with metabolic disease: the 16189T>C substitution in the D-loop is associated with obesity and T2DM in European and Asian populations; haplogroup N9A is likely protective against metabolic syndrome in Japanese women and against T2DM in Japanese and Korean populations; patients with metabolic syndrome show reduced mtDNA copies in peripheral blood and adipose tissue.
  • Interventions targeting mitochondrial physiology show mixed evidence: resveratrol improves mitochondrial function, reduces inflammation, and decreases lipid levels in patients with obesity; nicotinamide riboside at 2,000 mg per day was safe but did not improve insulin sensitivity or whole-body glucose metabolism in patients with obesity and insulin resistance; MitoQ improves vascular ageing in middle-aged and older adults aged 60–79 years; elamipretide reverses mitochondrial dysfunction in ageing human muscle.
  • The mtDNA mutator mouse accumulates mtDNA mutations and recapitulates premature ageing signs, including reduced lifespan, reduced fertility, anaemia, sarcopenia, osteoporosis, hair greying, hair loss, hearing loss, and elevated lactate; however, the role of mtDNA mutations as a primary ageing driver remains debated because mutation levels in normal aged tissues may be below the threshold needed to affect mitochondrial function.

Methods

  • Narrative review; no primary data are generated. It synthesizes mechanistic, preclinical, and clinical literature on mitochondrial and metabolic dysfunction in ageing and age-related diseases.
  • Covers conserved longevity pathways (IIS, mTOR, AMPK, sirtuins), mitochondrial dysfunction mechanisms (mtDNA mutations, genomic instability, cellular senescence, epigenetic alterations), age-related metabolic disorders, and therapeutic approaches.
  • Main analysis is qualitative synthesis, with figures and a table summarizing approaches targeting mitochondria and their clinical stage.

Limitations

  • Stated: how important mitochondria are to the ageing process remains under debate; the role of mtDNA mutations as a primary driver is still debated; mechanisms behind calorie restriction-driven longevity extension are poorly understood; further elucidation is needed for senescence, p66Shc, mTOR inhibition, and mtDNA epigenetics.
  • Stated: preclinical challenges include adequate disease modelling when considering biological age; clinical challenges include focusing on specific pathologies because of multi-organ functional decay during ageing.
  • Evident: as a narrative review, it does not report a systematic search, risk-of-bias assessment, or quantitative synthesis, so conclusions rely on selected cited studies.

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

Integrity signals

Registry

Crossref · 10.1038/s41574-021-00626-7

Cites

311 of 311 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 309 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Regulation of energy metabolism by environmental variation and excessive ROS may be associated with age-related metabolic diseases through constitutive changes in OXPHOS that lead to mitochondrial dysfunction.

    “Hence, regulation of energy metabolism by environmental variations and excessive levels of the by-product reactive oxygen species (ROS) might be associated with age-related metabolic diseases through constitutive changes in mitochondrial oxidative phosphorylation (OXPHOS), that ultimately lead to mitochondrial dysfunction.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Mitochondrial physiology is involved in the beneficial effects of calorie restriction in budding yeast, C. elegans, and mammals.

    “Although the mechanisms behind calorie restriction-driven longevity extension are still poorly understood, mitochondrial physiology is involved in the beneficial effects of calorie restriction in budding yeast11 and Caenorhabditis elegans12, as well as in mammals13.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Lin, S. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). source

      Not checked in the free run.

    • cites [12] Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007). source

      Not checked in the free run.

    • cites [13] Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005). source

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  • Interpretationnone given

    Mitochondria have an essential role in the development of ageing-associated diseases such as neurodegenerative and cardiovascular diseases.

    “Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Ageing and age-related diseases are tightly related to an imbalance between energy supply and demand.

    “Ageing and age-related diseases are tightly related to an imbalance in energy supply and demand.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Mitochondrial dysfunction can severely impair cellular energy conversion, especially in tissues that depend heavily on mitochondrial chemical energy throughout life.

    “Mitochondrial dysfunction can lead to severe impairment of cellular energy conversion, especially in tissues that rely heavily on chemical energy generated by mitochondria throughout life9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Chinnery, P. F. Mitochondrial disease in adults: what’s old and what’s new? EMBO Mol. Med. 7, 1503–1512 (2015). source

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  • May combine two claims. 129
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Premisecitation

    Calorie restriction moves the ETC away from a reduced state, lowers ROS production, induces OXPHOS and antioxidant defences, prevents age-related diseases, and increases lifespan.

    “By reducing the excess of ingested calories, calorie restriction interventions move the ETC away from a reduced state, lower ROS production, induce OXPHOS and antioxidant defences, prevent age-related diseases and increase lifespan14.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Excess calories favour ROS production, mtDNA mutagenesis, and premature cell death.

    “This environment favours ROS production, mitochondrial DNA (mtDNA) mutagenesis and, consequently, premature cell death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    When carbohydrates and calories are in excess, OXPHOS and antioxidant defences are downregulated and the ETC remains chronically reduced.

    “When carbohydrates and, consequently, calories are in excess, OXPHOS and antioxidant defences are downregulated, and the electron transport chain (ETC) remains in a chronically reduced state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In DAF-2 mutants, age-related changes in mitochondrial morphology and density are mitigated, and mitochondrial trafficking is maintained at normal levels in adulthood.

    “In DAF-2 mutants, age-related changes in mitochondrial morphology and density are mitigated, and mitochondrial trafficking is maintained at under normal levels in adulthood21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Morsci, N. S., Hall, D. H., Driscoll, M. & Sheng, Z. H. Age-related phasic patterns of mitochondrial maintenance in adult Caenorhabditis elegans neurons. J. Neurosci. 36, 1373–1385 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Rapamycin inhibits mTORC1 by binding to FKBP12.

    “which was discovered after it was shown that rapamycin is able to inhibit mTORC1 via binding to the protein FKBP12 (REFS31,32).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Loewith, R. et al. Two TOR complexes only one of which is rapamycin sensitive have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002). source

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    • cites [32] Bai, X. et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318, 977–980 (2007). source

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

    Premisecitation

    mTOR is a ubiquitously expressed serine-threonine protein kinase of the PI3K family that regulates cytoplasmic nutritional and growth factor status, cellular energy levels, and overall cellular function.

    “Mammalian TOR (mTOR) is a ubiquitously expressed serine–threonine protein kinase, belonging to the PI3K family, that has a vital role in regulating cytoplasmic nutritional and growth factor status, as well as cellular energy levels and overall cellular function30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017). source

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    Premisecitation

    Activated AMPK phosphorylates PGC1α, which induces mitochondrial gene expression.

    “Subsequent studies also elucidated this signalling pathway and indicated that activated AMPK phosphorylates PGC1α, which consequently induces mitochondrial gene expression41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Jäger, S., Handschin, C., St-Pierre, J. & Spiegelman, B. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007). source

      Not checked in the free run.

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    Premisecitation

    Suppression of IIS dramatically extends lifespan in multiple organisms, suggesting an evolutionarily conserved mechanism.

    “Suppression of the insulin–insulin-like growth factor 1 (IGF1) signalling (IIS) pathway dramatically extends lifespan in multiple organisms, which suggests that it is an evolutionarily conserved mechanism16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Fontana, L., Partridge, L. & Longo, V. Extending healthy life span–from yeast to humans. Science 328, 321–326 (2010). source

      Not checked in the free run.

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

    Premisecitation

    AMPK is the primary sensor of cellular AMP to ATP and ADP to ATP ratios and a key regulator of cellular energy homeostasis and metabolism.

    “AMPK is considered the primary sensor of cellular AMP to ATP and ADP to ATP ratios and a key regulator of cellular energy homeostasis and metabolism39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTOR exists in two complexes, mTORC1 with raptor and mTORC2 with rictor, which account for the diversity, specificity, and selectivity of rapamycin-mediated TOR inhibition.

    “mTOR is present in two complexes, mTORC1 (associated with ‘raptor’) and mTORC2 (associated with ‘rictor’), accounting for the diversity, specificity and selectivity of rapamycin-mediated inhibition of TOR signalling”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Loewith, R. et al. Two TOR complexes only one of which is rapamycin sensitive have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002). source

      Not checked in the free run.

    • cites [32] Bai, X. et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318, 977–980 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mitochondria might be the critical mediator for the effects of mTOR inhibition on longevity and might be a notable therapeutic target in ageing and age-related diseases.

    “Therefore, mitochondria might be the critical mediator for the effects of mTOR inhibition on longevity, and might represent a notable therapeutic target in ageing and age-related diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    C. elegans DAF-2 mutants and long-lived mitochondrial mutants show extensive overlap in gene expression, and DAF-2 mutants have decreased mitochondrial protein turnover.

    “Extensive overlap in gene expression has been found between the C. elegans insulin receptor DAF-2 mutant and long-lived mitochondrial mutant strains17, with the DAF-2 mutant showing an overall decrease in mitochondrial protein turnover18.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Senchuk, M. M. et al. Activation of DAF-16/FOXO by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans. PLoS Genet. 14, e1007268 (2018). source

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    • cites [18] Dhondt, I. et al. FOXO/DAF-16 activation slows down turnover of the majority of proteins in C. elegans. Cell Rep. 16, 3028–3040 (2016). source

      Not checked in the free run.

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    Premisecitation

    Increased ROS levels induced antioxidant enzyme expression, followed by a decrease in ROS levels.

    “In addition, increased ROS levels induced expression of antioxidant enzymes, followed by a decrease in ROS levels20.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Zarse, K. et al. Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab. 15, 451–465 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DAF-2 mutants have increased OXPHOS protein abundance, respiratory capacity, and membrane potential.

    “Moreover, DAF-2 mutants have increased abundance of proteins involved in OXPHOS, increased respiratory capacity and increased membrane potential19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Brys, K., Castelein, N., Matthijssens, F., Vanfleteren, J. R. & Braeckman, B. P. Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing Caenorhabditis elegans. BMC Biol. 8, 91 (2010). source

      Not checked in the free run.

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    Premisecitation

    FIRKO mice have increased lifespan compared with wild-type mice despite a leaner phenotype from 3 months of age and normal food intake throughout life.

    “Likewise, fat-specific insulin receptor knockout (FIRKO) mice have increased lifespan compared with wild-type mice despite having a leaner phenotype from a young age (3 months of age) and normal food intake throughout life27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Blüher, M., Kahn, B. & Kahn, C. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003). source

      Not checked in the free run.

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    Premisecitation

    Deletion of the mTORC1 component raptor in mouse skeletal muscle affects PGC1α expression, reduces oxidative capacity, and induces premature ageing.

    “Deletion of the mTORC1 component raptor in mouse skeletal muscle affects PGC1α expression, reducing oxidative capacity36, and consequently inducing premature ageing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inhibition of IIS improves mitochondrial bioenergetics together with a ROS-mediated adaptive response, contributing to lifespan extension in C. elegans.

    “Thus, these results suggest that inhibition of IIS improves mitochondrial bioenergetics together with a ROS-mediated adaptive response, contributing to the lifespan extension effects observed in C. elegans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a mouse model of Leigh syndrome, rapamycin inhibition of mTOR improves mitochondrial function and alleviates symptoms.

    “In the context of mitochondrial diseases, inhibition of mTOR using rapamycin improves mitochondrial function and alleviates symptoms of Leigh syndrome37, a disease caused by mtDNA deletions, in a mouse model of the syndrome.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Johnson, S. et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342, 1524–1529 (2013). source

      Not checked in the free run.

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    Premisecitation

    Increased expression of the mitochondrial biogenesis transcription driver HAP4 extends lifespan under normal caloric conditions in Saccharomyces cerevisiae, and calorie restriction fails to further extend this longevity benefit.

    “Interestingly, increased expression of mitochondrial biogenesis transcription driver HAP4 resulted in lifespan extension under normal caloric conditions in yeast (Saccharomyces cerevisiae), with calorie restriction failing to further extend this longevity benefit11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Lin, S. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT4 interacts with adenine nucleotide translocator, possibly regulating the ADP to ATP ratio and mitochondrial physiology.

    “SIRT4 interacts with adenine nucleotide translocator, possibly regulating the ADP to ATP ratio and mitochondrial physiology54.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Ahuja, N. et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583–33592 (2007). source

      Not checked in the free run.

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

    Interpretationreasoning

    ROS production might not be the leading cause of phenotypes correlated with ageing, and other factors might contribute.

    “These findings have helped guide the field to hypothesize that ROS production might not be the leading cause of the phenotypes correlated with ageing and that other factors might contribute.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The mtDNA mutator mouse has a proofreading-defective nuclear-encoded POLGγ and builds up many mtDNA mutations and deletions.

    “Evidence for a contribution of mtDNA mutations to the mammalian ageing phenotypes has come from the mtDNA mutator mouse, which carries a mutated, proofreading-deficient form of the nuclear-encoded mtDNA polymerase (POLGγ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mtDNA mutator mice and in mice carrying maternally inherited mtDNA mutations with an otherwise wild-type nuclear genome, lifespan and ageing features such as spinal curvature, lower body weight, and hair loss can be affected by mutation burden.

    “Moreover, it has been demonstrated that ageing phenotypes (such as spine curvature, reduced body weight and hair loss) and lifespan can be influenced by mtDNA mutation levels in mtDNA mutator mice69 and surprisingly also in mice with maternally-inherited mtDNA mutations but an otherwise wild-type nuclear genome70.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013). source

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    • cites [70] Ross, J. M., Coppotelli, G., Hoffer, B. J. & Olson, L. Maternally transmitted mitochondrial DNA mutations can reduce lifespan. Sci. Rep. 4, 6569 (2014). source

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    Premisecitation

    SIRT3 regulates ATP levels in multiple tissues and AMPK activation.

    “Notably, SIRT3 regulates ATP levels in multiple tissues52, as well as AMPK activation53.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008). source

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    • cites [53] Palacios, O. M. et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1α in skeletal muscle. Aging 1, 771–783 (2009). source

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  • May combine two claims.

    Premisecitation

    The number of mtDNA mutations increases with age and is closely linked to mitochondrial ROS production.

    “Closely linked to mitochondrial ROS production, the number of mtDNA mutations is known to increase with age63.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927–6933 (1990). source

      Not checked in the free run.

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

    Premisecitation

    Harman expanded the free radical theory of ageing with the mitochondrial theory of ageing, which included the possibility that mtDNA mutations are drivers of mitochondrial dysfunction during ageing.

    “In 1972, Harman expanded the free radical theory of ageing with the ‘mitochondrial theory of ageing’, which included the possibility that mtDNA mutations might in fact be the drivers behind the mitochondrial dysfunction observed during ageing61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Harman, D. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145–147 (1972). source

      Not checked in the free run.

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    Premisecitation

    The mtDNA mutator mouse recapitulates several signs of premature ageing, including shortened lifespan, lower fertility, anaemia, muscle loss, bone loss, grey hair, hair loss, hearing impairment, and raised lactate.

    “The mtDNA mutator mouse was shown to accumulate considerable levels of mtDNA mutations and deletions and to recapitulate several signs of premature ageing, such as reduced lifespan, reduced fertility, anaemia, sarcopenia, osteoporosis, hair greying, hair loss66, hearing loss67 and elevated lactate levels68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004). source

      Not checked in the free run.

    • cites [67] Niu, X., Trifunovic, A., Larsson, N. G. & Canlon, B. Somatic mtDNA mutations cause progressive hearing loss in the mouse. Exp. Cell Res. 313, 3924–3934 (2007). source

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    • cites [68] Ross, J. M. et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc. Natl Acad. Sci. USA 107, 20087–20092 (2010). source

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

    Premisecitation

    Some reports favour the idea that mitochondrial mutations contribute to ageing and age-related diseases, while others question this hypothesis because of the level of mutations observed.

    “However, while some reports favour the idea that mitochondrial mutations contribute to ageing and age-related diseases64, others have questioned this hypothesis due to the level of mutations observed65.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Linnane, A. W., Ozawa, T., Marzuki, S. & Tanaka, M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1, 642–645 (1989). source

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    • cites [65] Khrapko, K. & Vijg, J. Mitochondrial DNA mutations and aging: devils in the details? Trends Genet. 25, 91–98 (2009). source

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    Premisecitation

    The resulting NAD+ availability increases SIR2 activity, which boosts mitochondrial respiration and suppresses recombinant DNA recombination, a known cause of ageing in yeast.

    “The resulting availability of NAD+ increases SIR2 activity, which boosts mitochondrial respiration and suppresses recombinant DNA recombination11,46, a known cause of ageing in yeast47.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Lin, S. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002). source

      Not checked in the free run.

    • cites [46] Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and Pnc1 govern lifespan extension by calorie restriction and stress. Nature 423, 181–185 (2003). source

      Not checked in the free run.

    • cites [47] Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles–a cause of aging in yeast. Cell 91, 1033–1042 (1997). source

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

    Premisecitation

    Accumulation of mitochondrial oxidative damage, the basis for Harman's free radical theory of ageing, has been suggested as a driver of mitochondrial dysfunction and age-related decline in organ function.

    “The accumulation of mitochondrial oxidative damage, which is the basis for Harman’s ‘free radical theory of ageing’56, has been suggested as a driver of mitochondrial dysfunction and the observed age-related decline in organ function during ageing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Failure to regulate energy homeostasis by longevity pathways is highly linked with mitochondrial dysfunction, which ultimately leads to age-related metabolic diseases.

    “Failure to regulate energy homeostasis by these pathways is highly linked with mitochondrial dysfunction, which ultimately leads to age-related metabolic diseases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some studies support the free radical theory of ageing, while others show that increased ROS production does not always shorten lifespan.

    “However, while several studies have supported the free radical theory of ageing57,58, others have shown that increased ROS production does not always shorten lifespan59.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [57] Melov, S. et al. Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics. J. Neurosci. 21, 8348–8353 (2001). source

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    • cites [58] Kirby, K., Hu, J., Hilliker, A. J. & Phillips, J. P. RNA interference-mediated silencing of Sod2 in Drosophila leads to early adult-onset mortality and elevated endogenous oxidative stress. Proc. Natl Acad. Sci. USA 99, 16162–16167 (2002). source

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    • cites [59] Van Raamsdonk, J. M. & Hekimi, S. Superoxide dismutase is dispensable for normal animal lifespan. Proc. Natl Acad. Sci. USA 109, 5785–5790 (2012). source

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    Premisecitation

    An ATM mouse model displayed mitochondrial dysfunction, higher ROS, and build-up of damaged mitochondria.

    “Analysis of an ATM mouse model showed dysfunctional mitochondria with increased ROS levels and the accumulation of damaged mitochondria87.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Valentin-vega, Y. A. et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119, 1490–1500 (2012). source

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    Premisecitation

    Mice lacking Parp1 have higher NAD+ levels, greater SIRT1 activity, and more mitochondrial biogenesis.

    “Indeed, deletion of the Parp1 gene in mice increases NAD+ levels, SIRT1 activity and mitochondrial biogenesis83.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011). source

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    Premisecitation

    Nuclear DNA encodes most mitochondrial proteins, and mutations in these nuclear genes are usually linked to mitochondrial disease.

    “Moreover, most of the mitochondrial proteins are encoded by nuclear DNA, and mutations on those genes are typically associated with mitochondrial diseases78.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Wilkins, H. M. et al. in The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms 369–414 (Elsevier, 2018). source

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    Premisecitation

    Cellular senescence is marked by permanent cell-cycle arrest, altered gene expression, activation of tumour suppression, chromatin changes, apoptosis resistance, and higher protein synthesis.

    “Cellular senescence is characterized by an irreversible cell cycle arrest, changes in gene expression, tumour suppression activation, altered chromatin, resistance to apoptosis and increased protein synthesis89.”
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    • cites [89] Tchkonia, T., Zhu, Y., Deursen, J. V., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source

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    Premisecitation

    Genomic instability caused by single- or double-strand breaks that activate the DNA damage response is an ageing hallmark and can originate from external or internal sources.

    “Genomic instability induced by single-strand breaks or double-strand breaks triggering the DNA damage response (DDR) is a hallmark of ageing2, and can arise from both exogenous and endogenous sources79.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). source

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    • cites [79] Hoeijmakers, J. H. J. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009). source

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    Premisecitation

    Atm−/− mice show mitochondrial defects, and NAD+ supplementation lessens their health deterioration.

    “Similarly, Atm−/− mice also have mitochondrial defects and interventions based on NAD+ supplementation88 attenuate their health decline.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Fang, E. F. et al. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566–581 (2016). source

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    Premisecitation

    Senescence lowers mitochondrial membrane potential, raises proton leak and ROS output, and thereby increases DNA damage and the DNA damage response.

    “Cellular senescence leads to decreased mitochondrial membrane potential, increased proton leakage and increased ROS production94, thus enhancing DNA damage and DDR95.”
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    • cites [94] Passos, J. F. et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 5, e110 (2007). source

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    • cites [95] Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010). source

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    Premisecitation

    Whether mtDNA mutations primarily drive ageing remains contested, partly because normal aged tissues seem to have mutation loads below the level needed to impair mitochondrial function.

    “However, the role of mtDNA mutations as a primary driver of the ageing process is still debated, in part because the number of mutations observed in normal aged tissues is seemingly below the threshold required to affect mitochondrial function71.”
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    • cites [71] Vermulst, M. et al. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat. Genet. 39, 540–543 (2007). source

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    Premisecitation

    In these models, supplying NAD+ pharmacologically or blocking PARP1 restores SIRT1 activity and mitochondrial homeostasis.

    “Pharmacological NAD+ supplementation or inhibition of PARP1 was able to re-establish SIRT1 activity and recover mitochondrial homeostasis85,86.”
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    • cites [85] Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882–896 (2014). source

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    • cites [86] Scheibye-Knudsen, M. et al. A high-fat diet and NAD+ activate sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab. 20, 840–855 (2014). source

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    Premisecitation

    Senescent cells show disturbed mitochondrial metabolite balance and reduced fatty acid oxidation, causing lipids to accumulate.

    “Moreover, cells undergoing senescence display altered mitochondrial metabolite homeostasis96, as well as decreased fatty acid oxidation, leading to accumulation of lipids97.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [96] Correia-Melo, C. & Passos, J. F. Mitochondria: are they causal players in cellular senescence? Biochim. Biophys. Acta 1847, 1373–1379 (2015). source

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    • cites [97] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source

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    Premisecitation

    Once activated, PARP1 uses NAD+ and produces PAR by PARylation.

    “Activated PARP1 will consume NAD+, generating PAR through a process called PARylation82.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411–424 (2012). source

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  • May combine two claims.

    Premisecitation

    People with HIV show premature ageing features and early cardiovascular disease, along with mitochondrial mutations and OXPHOS impairment, which may result from anti-retroviral drugs that block POLGγ.

    “That said, patients with HIV, who also present with phenotypes of premature ageing72 and premature age-associated cardiovascular disease73, have mitochondrial mutations and OXPHOS dysfunction74, possibly caused by anti-retroviral drugs that inhibit POLGγ75.”
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    • cites [72] Desquilbet, L. et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J. Gerontol. A Biol. Sci. Med. Sci. 62, 1279–1286 (2007). source

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    • cites [73] Guaraldi, G. et al. Coronary aging in HIV-infected patients. Clin. Infect. Dis. 49, 1756–1762 (2009). source

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    • cites [74] Payne, B. A. I. et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat. Genet. 43, 806–810 (2011). source

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    Premisecitation

    Repairing nuclear DNA requires substantial energy, and unrepaired DNA damage can cause mitochondrial dysfunction and metabolic deficits.

    “Nuclear DNA repair is energy-demanding80, and persistent DNA damage can lead to mitochondrial dysfunction and metabolic deficits76.”
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    • cites [76] Fang, E. F. et al. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 17, 308–321 (2016). source

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    • cites [80] Chaudhuri, A. R. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18, 610–621 (2017). source

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  • May combine two claims.

    Premisecitation

    No universal senescent-cell marker exists, but common features include cell-cycle arrest, DNA damage response, β-galactosidase activity, and the pro-inflammatory senescence-associated secretory phenotype.

    “No universal marker has been discovered for senescent cells but cell cycle arrest, DDR, β-galactosidase activity and the pro-inflammatory senescence-associated secretory phenotype are common features of cells undergoing senescence90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Campisi, J. & D’Adda Di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007). source

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  • May combine two claims.

    Premisecitation

    Pharmacological PARP1 inhibition in nematodes boosts mitochondrial biogenesis and prolongs lifespan.

    “In nematodes, pharmacological inhibition of PARP1 increases mitochondrial biogenesis and extends lifespan84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013). source

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

    Premisecitation

    In prediabetic individuals, dyslipidaemia has been linked to oxidized LDL.

    “Indeed, an association between dyslipidaemia and oxidized LDL has been observed in individuals with prediabetes122.”
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    • cites [122] Kopprasch, S. et al. In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance. Diabetes 51, 3102–3106 (2002). source

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  • May combine two claims.

    Premisecitation

    Senescence increases mitochondrial biogenesis, producing an unhealthy mitochondrial network.

    “During senescence, mitochondrial biogenesis is upregulated, leading to an unhealthy mitochondrial network.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Passos, J. F. et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 6, 347 (2010). source

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    • cites [98] Mai, S., Klinkenberg, M., Auburger, G., Bereiter-Hahn, J. & Jendrach, M. Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J. Cell Sci. 123, 917–926 (2010). source

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  • May combine two claims.

    Premisecitation

    Greater total body mass, particularly visceral fat, correlates with higher morbidity and with metabolic inflexibility-an inability to switch between fat and glucose use.

    “An excess in total body mass, especially visceral adipose tissue, is associated with increased morbidity119 as well as metabolic inflexibility120, a phenomenon caused by the inability to transition between fatty acid and glucose metabolism.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [119] Matsumoto, A. M. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J. Gerontol. A. Biol. Sci. Med. Sci. 57, M76–M99 (2002). source

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    • cites [120] Griffin, T. M., Humphries, K. M., Kinter, M., Lim, H. Y. & Szweda, L. I. Nutrient sensing and utilization: getting to the heart of metabolic flexibility. Biochimie 124, 74–83 (2015). source

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  • May combine two claims.

    Premisecitation

    mtDNA contains both 5-mC and 5-hmC, and also DNMT3A and DNMT3B methyltransferases.

    “Both 5-mC and 5-hmC have been found in mtDNA, as well as DNMT3A and B DNA methyltransferases101–103.”
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    • cites [101] Chestnut, B. A. et al. Epigenetic regulation of motor neuron cell death through DNA methylation. J. Neurosci. 31, 16619–16636 (2011). source

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    • cites [102] Bellizzi, D. et al. The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern. DNA Res. 20, 537–547 (2013). source

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    • cites [103] Wong, M. et al. Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front. Cell Neurosci. 7, 279 (2013).

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  • May combine two claims.

    Premisecitation

    Metabolic syndrome becomes more common with age and is linked to obesity, high blood glucose, dyslipidaemia, insulin resistance, and cardiovascular disease.

    “The metabolic syndrome, which occurs increasingly with age, is associated with obesity, hyperglycaemia, dyslipidaemia, insulin resistance and cardiovascular diseases117,118.”
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    • cites [117] Haslam, D. W. & James, W. P. T. Obesity. Lancet 366, 1197–1209 (2005). source

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    • cites [118] Bhatti, G. K., Bhadada, S. K., Vijayvergiya, R., Mastana, S. S. & Bhatti, J. S. Metabolic syndrome and risk of major coronary events among the urban diabetic patients: North Indian Diabetes and Cardiovascular Disease Study–NIDCVD-2. J. Diabetes Complicat. 30, 72–78 (2016). source

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  • May combine two claims.

    Premisecitation

    Haplogroup N9A in mtDNA appears protective against metabolic syndrome among Japanese women and against type 2 diabetes in Japanese and Korean groups.

    “Additionally, mtDNA analysis showed that the haplogroup N9A is likely to be protective against the metabolic syndrome in Japanese women128, as well as being protective against T2DM in Japanese and Korean populations129.”
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    • cites [128] Tanaka, M. et al. Women with mitochondrial haplogroup N9a are protected against metabolic syndrome. Diabetes 56, 518–521 (2007). source

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    • cites [129] Fuku, N. et al. Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am. J. Hum. Genet. 80, 407–415 (2007). source

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  • May combine two claims.

    Premisecitation

    In islets from people with type 2 diabetes, ATP content and the glucose-stimulated ATP-to-ADP ratio are lower than in control islets.

    “In islets from patients with T2DM, the ATP content, and the increase in the ATP to ADP ratio stimulated by glucose, was lower than in islets from control individuals143.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

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  • May combine two claims.

    Premisecitation

    Hyperglycaemia-induced reactive oxygen species activate UCP2, causing proton leak across the mitochondrial inner membrane, reduced ATP synthesis, oxidative membrane damage, cytochrome c release, and apoptosis.

    “Increased ROS levels due to hyperglycaemia activate UCP2, resulting in proton leak across the mitochondrial inner membrane, which leads to reduced ATP synthesis and oxidative damage to the membrane, cytochrome c release and the induction of apoptosis149.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Butler, A. et al. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 102, 1295–1297 (2003).

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  • May combine two claims.

    Premisecitation

    People with metabolic syndrome have fewer mtDNA copies in peripheral blood and adipose tissue, a change usually seen before type 2 diabetes develops.

    “Apart from variations in mtDNA, patients with the metabolic syndrome show a reduced number of mtDNA copies in peripheral blood and adipose tissue132, a physiological change typically observed before the development of T2DM133.”
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    • cites [132] Mozhey, O. I. et al. Evaluating the number of mitochondrial DNA copies in leukocytes and adipocytes from metabolic syndrome patients: pilot study. Mol. Biol. 48, 590–593 (2014). source

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    • cites [133] Lee, H. K. et al. Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res. Clin. Pract. 42, 161–167 (1998). source

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  • May combine two claims.

    Interpretationreasoning

    Mitochondrial dysfunction is increasingly viewed as a central contributor to β-cell failure in type 2 diabetes, with metabolic-stress-induced reactive oxygen species as a key event.

    “Mitochondrial dysfunction is increasingly thought to be a central contributor to β-cell failure in the evolution of T2DM, with ROS production induced by metabolic stress as a key event leading to β-cell failure.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In one white family, the T4291C mtDNA mutation was linked to metabolic syndrome, while the T16189C variant was linked to body-mass abnormalities, insulin resistance, cardiomyopathy, and higher metabolic syndrome risk.

    “Furthermore, in a white family, the T4291C mtDNA mutation has been associated with the metabolic syndrome, and the T16189C mtDNA variant has been reported to be associated with abnormalities in body mass, insulin resistance and increased cardiomyopathy, as well as increased risk of the metabolic syndrome130.”
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    • cites [130] Palmieri, V. O. et al. T16189C mitochondrial DNA variant is associated with metabolic syndrome in Caucasian subjects. Nutrition 27, 773–777 (2011). source

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  • May combine two claims.

    Premisecitation

    Mitochondrial dynamics are important in type 2 diabetes and its vascular complications because mitochondria are central to ATP production, insulin secretion, and reactive oxygen species formation.

    “Mitochondrial dynamics are crucial to T2DM and related vascular complications, given the central role of mitochondria in ATP production, insulin secretion and ROS formation134.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Kytövuori, L. et al. A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism. J. Neurol. 263, 2188–2195 (2016). source

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  • May combine two claims.

    Premisecitation

    Islets from people with type 2 diabetes have increased expression of UCP2, complex I, and ATP synthase.

    “Moreover, increased expression of uncoupling protein 2 (UCP2), complex I and ATP synthase have been observed in islets from patients with T2DM143.”
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    • cites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

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    Premisecitation

    In white adipose tissue, uncoupling of oxidative phosphorylation decreases fatty acid synthesis, increases energy expenditure, and reduces lipogenesis, providing energy through fatty acid oxidation.

    “In white adipose tissue, the uncoupling of OXPHOS has been shown to decrease fatty acid synthesis156, leading to increased energy expenditure and reduced lipogenesis, which provides an important energy source to cells through oxidation of fatty acids157.”
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    • cites [156] Rossmeisl, M. et al. Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue. FASEB J. 14, 1793–1800 (2000). source

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    • cites [157] Serra, D., Mera, P., Malandrino, M. I., Mir, J. F. & Herrero, L. Mitochondrial fatty acid oxidation in obesity. Antioxid. Redox Signal. 19, 269–284 (2013). source

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  • May combine two claims.

    Premisecitation

    People with non-alcoholic steatohepatitis and fatty liver rat models show decreased ATP content, impaired mitochondrial bioenergetics, and increased reactive oxygen species generation.

    “Decreased ATP content, impaired mitochondrial bioenergetics and increased ROS generation have all been found in patients with non-alcoholic steatohepatitis, and in fatty liver models in the rat161–163.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [161] Cortez-Pinto, H. et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282, 1659–1664 (1999). source

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    • cites [162] Teodoro, J., Rolo, A. P., Oliveira, P. J. & Palmeira, C. M. Decreased ANT content in Zucker fatty rats: relevance for altered hepatic mitochondrial bioenergetics in steatosis. FEBS Lett. 580, 2153–2157 (2006). source

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    • cites [163] Teodoro, J. S., Rolo, A. P., Duarte, F. V., Simões, A. M. & Palmeira, C. M. Differential alterations in mitochondrial function induced by a choline-deficient diet: understanding fatty liver disease progression. Mitochondrion 8, 367–376 (2008). source

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  • May combine two claims.

    Premisecitation

    Islets from people with type 2 diabetes have higher mitochondrial density volume than islets from people without type 2 diabetes, along with morphological and functional abnormalities not seen in control β-cells.

    “While there is no evidence for mitochondrial depletion in β-cells from patients with T2DM, the mitochondrial density volume is considerably higher in islets from patients with T2DM than in islets from those without T2DM, with both morphological and functional abnormalities that have not been observed in β-cells from control individuals143.”
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    • cites [143] Anello, M. et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 48, 282–289 (2005). source

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  • May combine two claims.

    Premisecitation

    β-cell desensitization and depletion are reversible, but persistent hyperglycaemia can lead to irreversible loss of insulin production and β-cell death.

    “Both desensitization and depletion of β-cells are reversible states; however, if the hyperglycaemic situation persists, it can lead to the irreversible loss of insulin production and, ultimately, the death of β-cells142.”
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    • cites [142] DeFronzo, R. A. & Abdul-Ghani, M. A. Preservation of β-cell function: the key to diabetes prevention. J. Clin. Endocrinol. Metab. 96, 2354–2366 (2011). source

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    Premisecitation

    NAFLD has been described as a hepatic example of metabolic syndrome, in which insulin resistance is a key pathological feature.

    “Age-associated liver diseases, such as NAFLD, have been described as hepatic examples of the metabolic syndrome152, where insulin resistance is also a key pathological feature.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Paschos, P. & Paletas, K. Non-alcoholic fatty liver disease and the metabolic syndrome. Hippokratia 13, 9–19 (2009).

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  • May combine two claims.

    Premisecitation

    Skeletal muscle from people with obesity and insulin resistance shows lower mitochondrial oxidative capacity and content, defective lipid metabolism, and greater lipid peroxidation than muscle from healthy lean people.

    “Decreased mitochondrial oxidative capacity and mitochondrial content, reduced oxidative capacity, defective lipid metabolism and increased lipid peroxidation are also seen in skeletal muscle from patients with obesity and insulin resistance compared with healthy and lean individuals136,137.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [136] Kelley, D. E., He, J., Menshikova, E. V. & Ritov, V. B. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950 (2002). source

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    • cites [137] Schrauwen, P., Schrauwen-Hinderling, V., Hoeks, J. & Hesselink, M. K. C. Mitochondrial dysfunction and lipotoxicity. Biochim. Biophys. Acta Biophys. Acta 1801, 266–271 (2010). source

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  • May combine two claims.

    Premisecitation

    In obese rats and the OLETF obese hyperphagic rat model, reduced hepatic mitochondrial content and function precede NAFLD and insulin resistance, supporting a crucial role for mitochondria in NAFLD pathophysiology.

    “Studies of obesity in rats and a T2DM model known as the OLETF obese hyperphagic rat showed that reduced hepatic mitochondrial content and function precede the development of NAFLD and insulin resistance, supporting a crucial role for mitochondria in the pathophysiology of NAFLD160.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Rector, R. S. et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J. Hepatol. 52, 727–736 (2010). source

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

    Premisenone given

    The innate immune response is rapid, under 90 hours, and non-specific, activated by a broad range of molecules including viruses and bacteria.

    “Unlike the adaptive immune response, the innate immune response is rapid (<90 h) and non-specific, being activated by a broad range of molecules that comprise viruses and bacteria.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    p66Shc activation is involved in adipogenesis, insulin resistance, and cardiovascular complications associated with diabetes mellitus.

    “Additional work has revealed that p66Shc activation is involved in adipogenesis, insulin resistance and cardiovascular complications associated with diabetes mellitus187–189.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [187] Camici, G. G. et al. Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc. Natl Acad. Sci. USA 104, 5217–5222 (2007). source

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    • cites [188] Berniakovich, I. et al. p66Shc-generated oxidative signal promotes fat accumulation. J. Biol. Chem. 283, 34283–34293 (2008). source

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    • cites [189] Paneni, F., Costantino, S. & Cosentino, F. p66Shc-induced redox changes drive endothelial insulin resistance. Atherosclerosis 236, 426–429 (2014). source

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

    Premisecitation

    Innate immunity has a central role in inflammation and coordinates its initiation, propagation, and resolution.

    “Innate immunity has a central role in the inflammatory process and coordinates the three stages of inflammation: initiation, propagation and resolution195.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Sugimoto, M. A., Sousa, L. P., Pinho, V., Perretti, M. & Teixeira, M. M. Resolution of inflammation: what controls its onset? Front. Immunol. 7, 160 (2016). source

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  • May combine two claims.

    Premisecitation

    mtDNA released by stressed mitochondria is a strong alarmin and a strong activator of innate immunity, particularly interferon signalling.

    “One of the strongest alarmins released by stressed mitochondria is mtDNA, which has emerged as a strong activator of innate immunity, particularly of the interferon signalling pathway201.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] West, A. P. & Shadel, G. S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17, 363–375 (2017). source

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    Premisecitation

    Elevated reactive oxygen species lead to endothelial dysfunction, an early event in atherosclerosis pathogenesis that occurs mainly during atherosclerotic lesion formation.

    “Indeed, elevated ROS levels lead to endothelial dysfunction171, an early event in atherosclerosis pathogenesis that occurs mainly in atherosclerotic lesion formation172,173.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [171] Thomas, S. R., Witting, P. K. & Drummond, G. R. Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 10, 1713–1765 (2008). source

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    • cites [172] Abe, J. & Berk, B. C. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc. Med. 8, 59–64 (1998). source

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    • cites [173] Grootaert, M. O. J., Roth, L., Schrijvers, D. M., De Meyer, G. R. Y. & Martinet, W. Defective autophagy in atherosclerosis: to die or to senesce? Oxid. Med. Cell. Longev. 2018, 7687083 (2018). source

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  • May combine two claims.

    Interpretationcitation

    Under an imbalanced redox state, increased mitochondrial reactive oxygen species production may modify arterial walls and be followed by an inflammatory environment.

    “Under conditions of an imbalanced redox state, increased mitochondrial ROS production might lead to modifications of the arterial walls180, followed by an inflammatory environment181.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [180] Naik, E. & Dixit, V. M. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J. Exp. Med. 208, 417–420 (2011). source

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    • cites [181] Davies, J. M. S. et al. The Oxygen Paradox, the French Paradox, and age-related diseases. GeroScience 39, 499–550 (2017). source

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    Premisecitation

    mtDNA mutations are associated with atherosclerosis, hypertension, type 2 diabetes, cardiovascular disease, and obesity.

    “Moreover, mtDNA mutations have been associated with the development of chronic human diseases, such as atherosclerosis, hypertension, T2DM, cardiovascular disease and obesity175–178.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [175] Nomiyama, T. et al. Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients. Ann. N. Y. Acad. Sci. 1011, 193–204 (2004). source

      Not checked in the free run.

    • cites [176] Bhopal, R. S. & Rafnsson, S. B. Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in South Asian populations? Int. J. Epidemiol. 38, 1072–1081 (2009). source

      Not checked in the free run.

    • cites [177] Corral-Debrinski, M. et al. Hypoxemia is associated with mitochondrial DNA damage and gene induction: implications for cardiac disease. JAMA 266, 1812–1816 (1991). source

      Not checked in the free run.

    • cites [178] Ding, Y., Xia, B., Yu, J., Leng, J. & Huang, J. Mitochondrial DNA mutations and essential hypertension (review). Int. J. Mol. Med. 32, 768–774 (2013). source

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    Premisecitation

    PKCβ-induced Ser26 phosphorylation of p66Shc triggers its transport from cytosol to mitochondria, where it promotes reactive oxygen species accumulation by oxidizing cytochrome c and leads to apoptosis.

    “Induction of Ser26 phosphorylation of p66Shc by protein kinase C-β (PKCβ) triggers the transport of p66Shc from the cytosol to mitochondria, where it promotes ROS accumulation by oxidizing cytochrome c184, ultimately leading to apoptosis.”
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    • cites [184] Giorgio, M. et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122, 221–233 (2005). source

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    Premisecitation

    In one study, 16-month-old MnSOD+/− mice showed elevated reactive oxygen species production and mtDNA damage followed by endothelial dysfunction.

    “In one study, 16-month-old MnSOD+/− mice consistently showed elevated ROS production and mtDNA damage, followed by the development of dramatic endothelial dysfunction182.”
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    • cites [182] Wenzel, P. et al. Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction. Cardiovasc. Res. 80, 280–289 (2008). source

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    Premisecitation

    p66Shc−/− mice are resistant to oxidative stress and have increased lifespan.

    “Mutant p66Shc−/− mice have been reported to be resistant to oxidative stress and to have an increased lifespan185, as well as reduced age-dependent endothelial dysfunction186.”
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    • cites [185] Migliaccio, E. et al. The p66Shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999). source

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    Premisecitation

    Alarmins bind to and activate pattern recognition receptors, triggering an immune response and propagating inflammation.

    “Alarmins bind to and activate PRRs, thus triggering an immune response and propagating the inflammation199.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020). source

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    Premisecitation

    Vascular p66Shc levels are increased in animal models of obesity and contribute to endothelial insulin resistance, an effect reversed by silencing p66Shc in vivo.

    “Moreover, vascular levels of p66Shc were increased in animal models of obesity and had a role in endothelial insulin resistance189, an effect restored when p66Shc was silenced in vivo189.”
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    • cites [189] Paneni, F., Costantino, S. & Cosentino, F. p66Shc-induced redox changes drive endothelial insulin resistance. Atherosclerosis 236, 426–429 (2014). source

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    Premisecitation

    Oxidative stress is characteristic of type 2 diabetes, hypertension, and atherosclerosis and is also the dominant feature of vascular ageing.

    “Oxidative stress, a characteristic of T2DM, hypertension and atherosclerosis, is also the dominant feature of vascular ageing170.”
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    • cites [170] Ding, Y. N., Tang, X., Chen, H. Z. & Liu, D. P. Epigenetic regulation of vascular aging and age-related vascular diseases. Adv. Exp. Med. Biol. 1086, 55–75 (2018). source

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    Interpretationreasoning

    Uncoupling of oxidative phosphorylation and increased reactive oxygen species, with oxidative damage to electron transport chain complexes and mtDNA, further compromise mitochondrial function and perpetuate reactive oxygen species formation, destabilizing cellular redox.

    “Thus, uncoupling of OXPHOS and increased ROS generation, with oxidative damage to ETC complexes and mtDNA, further compromise mitochondrial function and perpetuate ROS formation, thus destabilizing the redox environment of the cell.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Pathogen-associated molecular patterns share conserved features among microbes that are not present in mammalian cells.

    “Pathogen-associated molecular patterns (PAMPs) share conserved features among microbes not present in mammalian cells196.”
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    • cites [196] Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006). source

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

    Premisecitation

    Recognition of pathogen-associated molecular patterns by pattern recognition receptors activates and escalates an immune response, inducing inflammation and cytokine release to recruit the adaptive immune system.

    “Once these PAMPs are recognized by specific receptors belonging to the pattern recognition receptor (PRR) family, an immune response is activated and escalates to induce inflammation and the release of numerous cytokines for recruitment of the more specific adaptive immune system197.”
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    • cites [197] Jain, A. & Pasare, C. Innate control of adaptive immunity: beyond the three-signal paradigm. J. Immunol. 198, 3791–3800 (2017). source

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    Premisecitation

    Reduced p66Shc levels can protect against obesity but do not prevent obesity-associated metabolic dysfunction.

    “In one study using animal models and human samples from patients with obesity undergoing elective surgery, it was demonstrated that reduced p66Shc levels could protect from obesity but failed to prevent obesity-associated metabolic dysfunction192, highlighting the need for further studies to dissect the role of p66Shc in metabolism.”
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    • cites [192] Ciciliot, S. et al. p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans. Diabetologia 58, 2352–2360 (2015). source

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    Premisecitation

    Genetic ablation of mitochondrial GPX1 in mice caused vascular dysfunction with increased oxidative stress and impaired nitric oxide metabolism.

    “Similarly, genetic ablation of mitochondrial GPX1 in mice triggered noticeable vascular dysfunction, coinciding with increased oxidative stress and impaired nitric oxide metabolism183, thus linking perturbations in redox status to vascular ageing.”
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    • cites [183] Oelze, M. et al. Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 63, 390–396 (2014). source

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    Premisecitation

    NAFLD patients have ultrastructural changes including enlarged mitochondria, loss of cristae organization, and crystalline inclusion bodies in the matrix.

    “Ultrastructural changes include the presence of enlarged mitochondria, loss of cristae organization and crystalline inclusion bodies in the matrix in patients with NAFLD164.”
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    • cites [164] Shami, G. J. et al. Three-dimensional ultrastructure of giant mitochondria in human non-alcoholic fatty liver disease. Sci. Rep. 11, 3319 (2021). source

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    Premisecitation

    p66Shc−/− mice are protected against streptozotocin-induced diabetic cardiomyopathy and diabetes-induced vascular endothelial dysfunction and oxidative stress.

    “Consequently, work has shown that p66Shc−/− mice are protected against streptozotocin-induced diabetic cardiomyopathy191, diabetes mellitus-induced vascular endothelial dysfunction and oxidative stress187.”
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    • cites [187] Camici, G. G. et al. Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc. Natl Acad. Sci. USA 104, 5217–5222 (2007). source

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    • cites [191] Rota, M. et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ. Res. 99, 42–52 (2006). source

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    Premisecitation

    Several alarmins are mitochondrial molecules, and their ability to activate pattern recognition receptors depends on similarity to bacterial components, supporting the prokaryotic origin of mitochondria.

    “Several alarmins consist of mitochondrial molecules, and the ability of these molecules to activate PRRs is dependent on their similarity to bacterial components, reaffirming once again the prokaryotic origin of mitochondria200.”
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    • cites [200] Roger, A. J., Muñoz-Gómez, S. A. & Kamikawa, R. The origin and diversification of mitochondria. Curr. Biol. 27, R1177–R1192 (2017). source

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    Premisecitation

    Vascular ageing is a major risk factor for vascular disease and health status in older populations, contributing to age-dependent hypertension and atherosclerosis and being characteristic of cardiovascular risk factors.

    “Vascular ageing is the major risk factor for vascular diseases and health status in the aged population168, contributing to the age-dependent increased risk of pathological conditions of vascular dysfunction, such as hypertension and atherosclerosis, and are also characteristic of cardiovascular risk factors, such as obesity, smoking and a sedentary lifestyle169.”
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    • cites [168] El Assar, M., Angulo, J. & Rodríguez-Mañas, L. Oxidative stress and vascular inflammation in aging. Free Radic. Biol. Med. 65, 380–401 (2013). source

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    • cites [169] Jani, B. & Rajkumar, C. Ageing and vascular ageing. Postgrad. Med. J. 82, 357–362 (2006). source

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    Premisecitation

    Imeglimin decreases reactive oxygen species production and prevents hyperglycaemia-induced cell death via complex I by inhibiting reverse electron transfer-mediated reactive oxygen species in preclinical studies.

    “Interestingly, a newly reported molecule, imeglimin, a tetrahydrotriazine-containing oral glucose-lowering agent, decreased ROS production and prevented hyperglycaemia-induced cell death via complex l by inhibiting reverse electron transfer-mediated ROS production in preclinical studies240, and its efficacy and favourable safety and tolerability profile have been confirmed in patients with T2DM241”
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    • cites [240] Detaille, D. et al. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov. 2, 15072 (2016). source

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    Premisecitation

    TFAM is a DNA-binding protein in the same family as high mobility group box 1 protein and is an important alarmin in inflammation and autoimmune disorders.

    “TFAM is a DNA-binding protein belonging to the same family as high mobility group box 1 protein and is a very important alarmin involved in inflammation and autoimmune disorders209.”
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    • cites [209] Harris, H. E., Andersson, U. & Pisetsky, D. S. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat. Rev. Rheumatol. 8, 195–202 (2012). source

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    Premisecitation

    Metformin activates AMPK, improves mitochondrial function, decreases age-associated inflammation, and improves hyperglycaemia in people with obesity and prediabetes and in high-fat-diet-fed mice.

    “Additionally, metformin, which is widely used to treat T2DM, activates AMPK, improves mitochondrial function, decreases age-associated inflammation and improves hyperglycaemia in people with obesity and prediabetes, as well as in HFD-fed mice238,239.”
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    • cites [238] Bharath, L. P. et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 32, 44–55 (2020). source

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    • cites [239] Wang, Y. et al. Metformin improves mitochondrial respiratory activity through activation of AMPK. Cell Rep. 29, 1511–1523 (2019). source

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    Premisecitation

    SRT2104 did not improve glucose homeostasis or insulin sensitivity in patients with type 2 diabetes.

    “Notably, SRT2104, another non-naturally occurring sirtuin-activating compound, has been tested in the clinic but did not improve glucose homeostasis and insulin sensitivity in patients with T2DM232.”
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    • cites [232] Baksi, A. et al. A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes. Br. J. Clin. Pharmacol. 78, 69–77 (2014). source

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    Premisecitation

    SRT1720 enhances insulin sensitivity and oxidative metabolism in animal models of obesity, partly by improving mitochondrial oxidative capacity.

    “Additionally, the non-naturally occurring sirtuin-activating compound, SRT1720, has enhanced insulin sensitivity and oxidative metabolism in animal models of obesity, in part, by improving mitochondrial oxidative capacity231.”
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    • cites [231] Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007). source

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    Premisecitation

    Chronic moderate inhibition of cytochrome c oxidase by TPP-thiazole improves mitochondrial bioenergetics and glucose homeostasis and reduces visceral adipose tissue in 14-18-month-old mice, limiting age-associated obesity and glucose irregularities.

    “Similarly, chronic moderate inhibition of cytochrome c oxidase by TPP–thiazole improves mitochondrial bioenergetics and glucose homeostasis and reduces visceral adipose tissue in 14–18-month-old mice, limiting age-associated obesity and glucose irregularities242.”
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    • cites [242] Tavallaie, M. et al. Moderation of mitochondrial respiration mitigates metabolic syndrome of aging. Proc. Natl Acad. Sci. USA 117, 9840–9850 (2020). source

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    Premisecitation

    Rapamycin inhibits mTOR, extends lifespan in model organisms, and prevents age-related diseases, and is being tested in multiple clinical trials.

    “In addition, inhibition of mTOR by rapamycin, which also extends the lifespan of model organisms (for example, yeast, nematodes, fruit flies and mice) and prevents age-related diseases, is also currently being tested in multiple clinical trials243.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] Garay, R. P. Investigational drugs and nutrients for human longevity. Recent clinical trials registered in ClinicalTrials.gov and clinicaltrialsregister.eu. Expert Opin. Investig. Drugs 30, 749–758 (2021). source

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    Premisecitation

    TLR9 binds mtDNA and activates NF-κB signalling, inducing release of pro-inflammatory cytokines.

    “For example, TLR9 binds to mtDNA and activates the NF-κB signalling pathway, inducing the release of pro-inflammatory cytokines202.”
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    • cites [202] Garcia-Martinez, I. et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Invest. 126, 859–864 (2016). source

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  • May combine two claims.

    Premisecitation

    Mitochondrial protein translation starts with N-formylated methionine, and leakage of N-formylated peptides activates formyl peptide receptors, which are potent innate immune inducers.

    “Similar to bacteria, mitochondrial protein translation initiates with an N-formylated methionine instead of a regular methionine as in eukaryotic cells. Thus, the leakage of N-formylated peptides outside the mitochondria activates a specific family of PRRs, the formyl peptide receptors, which are potent inducers of the innate immune system203.”
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    • cites [203] Bufe, B. et al. Recognition of bacterial signal peptides by mammalian formyl peptide receptors: a new mechanism for sensing pathogens. J. Biol. Chem. 290, 7369–7387 (2015). source

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    Premisecitation

    In patients with type 2 diabetes, walking and ergometer cycling increase mitochondrial muscle respiration, mitochondrial content and density, and oxidative enzyme activity.

    “In patients with T2DM, walking and ergometer cycling exercise increased mitochondrial muscle respiration and mitochondrial content and density, as well as the activity of oxidative enzymes214,215.”
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    • cites [214] Toledo, F. G. S. et al. Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 56, 2142–2147 (2007). source

      Not checked in the free run.

    • cites [215] Phielix, E., Meex, R., Moonen-Kornips, E., Hesselink, M. K. C. & Schrauwen, P. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53, 1714–1721 (2010). source

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  • May combine two claims.

    Premisecitation

    Calorie restriction induces oxidative phosphorylation, antioxidant defences, and mitochondrial biogenesis.

    “Under calorie restriction, OXPHOS and antioxidant defences14, as well as mitochondrial biogenesis, are induced218.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005). source

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    • cites [218] Civitarese, A. E. et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 4, e76 (2007). source

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    Premisecitation

    Imeglimin efficacy and safety have been confirmed in patients with type 2 diabetes.

    “Interestingly, a newly reported molecule, imeglimin, a tetrahydrotriazine-containing oral glucose-lowering agent, decreased ROS production and prevented hyperglycaemia-induced cell death via complex l by inhibiting reverse electron transfer-mediated ROS production in preclinical studies240, and its efficacy and favourable safety and tolerability profile have been confirmed in patients with T2DM241”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241] Hallakou-Bozec, S. et al. Mechanism of action of imeglimin: a novel therapeutic agent for type 2 diabetes. Diabetes Obes. Metab. 23, 664–673 (2021). source

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    Premisecitation

    In humans, resveratrol improves mitochondrial function, reduces inflammation, and decreases lipid levels in patients with obesity.

    “In humans, resveratrol improves mitochondrial function, reduces inflammation and decreases lipid levels in patients with obesity228.”
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    • cites [228] Timmers, S. et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14, 612–622 (2011). source

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    Premisecitation

    Exercise prevents metabolic disorders such as obesity and type 2 diabetes, while reduced physical activity and a sedentary lifestyle are key contributing factors.

    “Exercise is a well-known lifestyle intervention that prevents metabolic disorders, such as obesity and T2DM, whereas reduced physical activity and a sedentary lifestyle are key contributing factors213.”
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    • cites [213] Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002). source

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    Premisecitation

    Cardiolipin is a mitochondrial alarmin, a phospholipid abundant in prokaryotic membranes and a constituent of the mitochondrial inner membrane.

    “Another alarmin of mitochondrial origin is cardiolipin, a unique phospholipid abundant in prokaryotic membranes and a constituent of the mitochondrial inner membrane204.”
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    • cites [204] Oemer, G. et al. Molecular structural diversity of mitochondrial cardiolipins. Proc. Natl Acad. Sci. USA 115, 4158–4163 (2018). source

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    Premisecitation

    Hydrogen peroxide crosses mitochondrial membranes into the cytoplasm, activating the inflammasome and redox-sensitive transcription factors HIF1α and NF-κB.

    “Hydrogen peroxide, a reaction product of superoxide radical (O2•−) conversion by MnSOD, crosses the mitochondrial membranes into the cytoplasm, activating the inflammasome and redox-sensitive transcription factors, such as HIF1α and NF-κB210–212.”
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    • cites [210] Wang, D., Malo, D. & Hekimi, S. Elevated mitochondrial reactive oxygen species generation affects the immune response via hypoxia-inducible factor-1α in long-lived Mclk1+/− mouse mutants. J. Immunol. 184, 582–590 (2010). source

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    • cites [211] Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P. & Malik, A. B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126–1167 (2014). source

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    • cites [212] Chandel, N. S., Trzyna, W. C., McClintock, D. S. & Schumacker, P. T. Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin. J. Immunol. 165, 1013–1021 (2000). source

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    Premisecitation

    Extracellular ATP binds purinergic P2 receptors on several cell types including macrophages and promotes chemotaxis and phagocytosis.

    “Extracellular ATP binds to purinergic P2 receptors that are present on several cell types, including macrophages, and promotes chemotaxis and phagocytosis206.”
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    • cites [206] Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009). source

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    Premisecitation

    The AMPK agonist 5-aminoimidazole-4-carboxamide rescues mitochondrial dysfunction and improves exercise performance in Cox-deficient mice.

    “The AMPK agonist 5-aminoimidazole-4-carboxamide rescues mitochondrial dysfunction and improves exercise performance capacity in Cox-deficient mice237.”
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    • cites [237] Viscomi, C. et al. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. Cell Metab. 14, 80–90 (2011). source

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    Premisecitation

    Succinate stabilizes HIF1α by inhibiting prolyl hydroxylase domain enzyme activity in macrophages, promoting secretion of pro-inflammatory chemokines such as IL-1β.

    “One of succinate’s actions is the stabilization of HIF1α by inhibiting the prolyl hydroxylase domain enzyme activity in macrophages. This action promotes the secretion of pro-inflammatory chemokines, such as IL-1β208.”
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    • cites [208] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source

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    Premisecitation

    BAM15 improves insulin sensitivity and decreases oxidative stress, body adipose tissue mass, hepatic triglyceride accumulation, and inflammatory lipids in diet-induced obese mice.

    “Alexopoulus and colleagues273 found that the orally available BAM15, a pH-dependent self-limiting uncoupler, improved insulin sensitivity and decreased oxidative stress, body adipose tissue mass, hepatic triglyceride accumulation and inflammatory lipids in diet-induced obese mice.”
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    • cites [273] Alexopoulos, S. J. et al. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice. Nat. Commun. 11, 2397 (2020). source

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    Premisecitation

    In a 2021 phase I trial, mitochondrial uncoupler HU6 was well tolerated without serious adverse effects and produced improvements in resting energy expenditure and dose-dependent weight loss.

    “In 2021, positive results from a phase I clinical trial testing mitochondrial uncoupler HU6 were presented. HU6 was well tolerated without serious adverse effects, and provided additional improvements in resting energy expenditure and dose-dependent weight loss277, supporting the potential for the development of mitochondrial uncouplers for the treatment of metabolic dysfunction in humans.”
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    • cites [277] Rivus Pharmaceuticals. Rivus Pharmaceuticals announces positive results from phase 1 trial of lead candidate HU6, demonstrating safety, efficacy in key targets for multiple cardio-metabolic diseases. https://www.rivuspharma.com. (2021).

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    Premisecitation

    OPC-163493 decreases hepatic steatosis, lowers fasting glucose and HbA1c, increases nitric oxide bioavailability, and reduces vascular oxidative stress in multiple rodent models of metabolic syndrome.

    “Kanemoto and colleagues272 described a liver-localized mitochondrial uncoupler, OPC-163493, which was shown to have various benefits in multiple rodent models of the metabolic syndrome, such as decreasing hepatic steatosis and lowering fasting levels of glucose and HbA1c, as well as increasing nitric oxide bioavailability and reducing oxidative stress in blood vessels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [272] Kanemoto, N. et al. Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler. Nat. Commun. 10, 2172 (2019). source

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    Premisecitation

    CZ5 reduces body weight, total adipose tissue mass, fasting glucose levels, and insulin levels.

    “CZ5, an orally bioavailable mitochondrial uncoupler271, also reduces body weight, total adipose tissue mass, fasting glucose levels and insulin levels271.”
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    • cites [271] Fu, Y. Y. et al. A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake. Diabetologia 56, 2297–2307 (2013). source

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    Premisecitation

    Human studies of nicotinamide riboside at 2,000 mg per day show it is safe but does not improve insulin sensitivity or whole-body glucose metabolism in patients with obesity and insulin resistance.

    “However, results from human studies testing nicotinamide riboside supplementation at 2,000 mg per day showed that although safe, nicotinamide riboside does not improve insulin sensitivity and whole-body glucose metabolism in patients with obesity and insulin resistance259.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Dollerup, O. L. et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am. J. Clin. Nutr. 108, 343–353 (2018). source

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    Premisecitation

    Traditional exogenous antioxidants and compounds with antioxidant properties reduce oxidative stress but have limited cellular uptake and do not accumulate where needed.

    “Traditional exogenous antioxidants (for example, vitamins E, C and D), as well as chemical compounds with described antioxidants properties (for example, coenzyme Q, α-lipoic acid and N-acetylcysteine), have been used to reduce oxidative stress279,280, but their cellular uptake is limited and they do not accumulate where needed281.”
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    • cites [279] Safarpour, P. et al. Vitamin D supplementation improves SIRT1, irisin, and glucose indices in overweight or obese type 2 diabetic patients: a double-blind randomized placebo-controlled clinical trial. BMC Fam. Pract. 21, 26 (2020). source

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    • cites [280] Yi, X. & Maeda, N. α-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E-deficient mice fed high-fat/low-cholesterol diet. Diabetes 55, 2238–2244 (2006). source

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    • cites [281] Eskurza, I., Monahan, K. D., Robinson, J. A. & Seals, D. R. Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing. J. Physiol. 556, 315–324 (2004). source

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    Premisecitation

    Upregulation of the NAD salvage pathway extends lifespan and mimics caloric restriction in yeast cells.

    “The upregulation of the NAD salvage pathway, which recycles NAD+ from nicotinamide, was first shown to extend lifespan and mimic caloric restriction in yeast cells46.”
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    • cites [46] Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and Pnc1 govern lifespan extension by calorie restriction and stress. Nature 423, 181–185 (2003). source

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    Premisecitation

    PARP inhibition in mice with NAFLD restores NAD+ levels, improving mitochondrial function and insulin sensitivity and decreasing hepatic lipid accumulation.

    “Indeed, PARP inhibition in mice with NAFLD restores NAD+ levels, thereby improving mitochondrial function and insulin sensitivity, and decreasing hepatic lipid accumulation261.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Gariani, K. et al. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease. J. Hepatol. 66, 132–141 (2017). source

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    Premisecitation

    Nicotinamide mononucleotide and nicotinamide riboside increase mitochondrial function and improve glucose homeostasis in obese mice.

    “Moreover, NMN252 and nicotinamide riboside255, another NAD+ precursor, increased mitochondrial function and improved glucose homeostasis in obese mice.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [252] Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011). source

      Not checked in the free run.

    • cites [255] Canto, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MitoQ protects against oxidative stress and offers neuroprotection in preclinical studies.

    “MitoQ, one of the best-characterized mitochondrially-targeted antioxidants, has been shown to protect against oxidative stress284 and offers neuroprotection285 in preclinical studies.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [284] James, A. M. et al. Interaction of the mitochondria-targeted antioxidant MitoQ with phospholipid bilayers and ubiquinone oxidoreductases. J. Biol. Chem. 282, 14708–14718 (2007). source

      Not checked in the free run.

    • cites [285] Zhou, J. et al. Mitochondrial-targeted antioxidant MitoQ provides neuroprotection and reduces neuronal apoptosis in experimental traumatic brain injury possibly via the Nrf2-ARE pathway. Am. J. Transl. Res. 10, 1887–1899 (2018).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In two nonhuman primate models of metabolic syndrome, CRMP reduces hepatic steatosis and insulin resistance and increases β-oxidation rates.

    “Importantly, in two different nonhuman primate models of the metabolic syndrome, high-fat, fructose-fed cynomolgus macaques and spontaneously obese dysmetabolic rhesus macaques, CRMP was shown to reduce hepatic steatosis and insulin resistance and increase the rates of β-oxidation268.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [268] Goedeke, L. et al. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Sci. Transl. Med. 11, eaay0284 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In diabetic mice, compound 6j improves insulin sensitivity, glucose homeostasis, and liver steatosis.

    “Studies performed in diabetic mice have shown that compound 6j is able to improve insulin sensitivity, glucose homeostasis and liver steatosis276.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [276] Jiang, H. et al. Mitochondrial uncoupling coordinated with PDH activation safely ameliorates hyperglycemia via promoting glucose oxidation. Diabetes 68, 2197–2209 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Derivatives 10b and 12i are efficacious in the STAM mouse model of non-alcoholic steatohepatitis by decreasing hepatic triglycerides, improving serum alanine transaminase, and improving NAFLD activity score.

    “In an attempt to optimize BAM15 limitations, such as tissue distribution and uncoupling effects, 10b and 12i (SHS4121705) derivatives are being tested and are being shown to be efficacious in the STAM mouse model of non-alcoholic steatohepatitis, by decreasing hepatic levels of triglycerides, improving serum levels of alanine transaminase and improving NAFLD activity score274,275.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [274] Childress, E. S. et al. [1,2,5]Oxadiazolo[3,4-b]pyrazine-5,6-diamine derivatives as mitochondrial uncouplers for the potential treatment of nonalcoholic steatohepatitis. J. Med. Chem. 63, 2511–2526 (2020). source

      Not checked in the free run.

    • cites [275] Salamoun, J. M. et al. 6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol derivatives as efficacious mitochondrial uncouplers in STAM mouse model of nonalcoholic steatohepatitis. J. Med. Chem. 63, 6203–6224 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Niclosamide ethanolamine reverses hyperglycaemia, hyperinsulinaemia, and hepatic steatosis in high-fat-diet-fed mice and delays hyperglycaemia in db/db mice.

    “Niclosamide ethanolamine reversed hyperglycaemia, hyperinsulinaemia and hepatic steatosis in mice fed a high-fat diet and delayed hyperglycaemia in db/db mice269.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [269] Tao, H., Zhang, Y., Zeng, X., Shulman, G. I. & Jin, S. Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat. Med. 20, 1263–1269 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hyperglycaemic mice, nicotinamide riboside improves liver steatosis and glucose tolerance and reduces weight gain.

    “In hyperglycaemic mice, nicotinamide riboside administration improved liver steatosis and glucose tolerance, and reduced weight gain257.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [257] Trammell, S. A. J. et al. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Sci. Rep. 6, 26933 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S6K1 knockout mice mimic the lean phenotype of Raptorad−/− mice and are protected against diet-induced obesity.

    “Interestingly, the phenotype of mice with knockout of a downstream target of mTOR, S6K1, mimics the lean phenotype of Raptorad−/− mice, and the mice are protected against diet-induced obesity245.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [245] Binsch, C. et al. Absence of the kinase S6k1 mimics the effect of chronic endurance exercise on glucose tolerance and muscle oxidative stress. Mol. Metab. 6, 1443–1453 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In db/db mice, rapamycin improves whole-body insulin sensitivity and increases markers of fatty acid oxidation and mitochondrial biogenesis in white adipose tissue.

    “In db/db mice, rapamycin exhibits anti-obesity properties by improving whole-body insulin sensitivity and increasing markers of fatty acid oxidation and mitochondrial biogenesis in white adipose tissue246.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [246] Deepaa, S. S. et al. Rapamycin modulates markers of mitochondrial biogenesis and fatty acid oxidation in the adipose tissue of db/db mice. J. Biochem. Pharmacol. Res. 1, 114–123 (2013).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNPME and CRMP decrease liver triglyceride accumulation and improve insulin sensitivity in rat models of type 2 diabetes and NAFLD.

    “Both DNPME and CRMP decreased triglyceride accumulation in liver and improved insulin sensitivity in rat models of T2DM and NAFLD266,267.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [266] Perry, R. J., Zhang, D., Zhang, X. M., Boyer, J. L. & Shulman, G. I. Controlled-release mitochondrial protonophore reverses diabetes and protonophore reverses diabetes and steatohepatitis in rats. Science 347, 1253–1256 (2015). source

      Not checked in the free run.

    • cites [267] Perry, R. J. et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18, 740–748 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Leucine increases NAD+ levels, mitochondrial biogenesis, insulin sensitivity, and lipid disposal in obese mice.

    “Finally, leucine, which is sensed by mTOR247, increases NAD+ levels, mitochondrial biogenesis, insulin sensitivity and lipid disposal when given to obese mice248.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [247] Gran, P. & Cameron-Smith, D. The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC Physiol. 11, 10 (2011). source

      Not checked in the free run.

    • cites [248] Li, H., Xu, M., Lee, J., He, C. & Xie, Z. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am. J. Physiol. Endocrinol. Metab. 303, E1234–E1244 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In high-fat-diet-fed mice, 2,4-dinitrophenol improves metabolic parameters including reduced body weight, improved glucose homeostasis, decreased serum insulin, and decreased liver triglycerides.

    “Mice fed a high-fat diet have improved metabolic parameters, such as reduced body weight, improved glucose homeostasis, decreased serum levels of insulin and decreased liver levels of triglycerides264,265.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [264] Caldeira Da Silva, C. C., Cerqueira, F. M., Barbosa, L. F., Medeiros, M. H. G. & Kowaltowski, A. J. Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7, 552–560 (2008). source

      Not checked in the free run.

    • cites [265] Goldgof, M. et al. The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality. J. Biol. Chem. 289, 19341–19350 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 22-month-old mice, nicotinamide mononucleotide restores NAD+ levels and markers of mitochondrial decline during ageing, reduces age-associated body weight gain, and increases energy metabolism and physical activity.

    “In 22-month-old mice, NMN restored NAD+ levels and markers of mitochondrial decline during ageing48, while reducing age-associated body weight gain and increasing energy metabolism and physical activity254.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Gomes, A. et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013). source

      Not checked in the free run.

    • cites [254] Mills, K. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of obese rats with nicotinamide induces mitochondrial biogenesis and improves insulin sensitivity in a SIRT1-dependent manner.

    “Interestingly, treatment of obese rats with nicotinamide induces mitochondrial biogenesis and improves insulin sensitivity in a SIRT1-dependent manner260.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [260] Yang, S. J. et al. Nicotinamide improves glucose metabolism and affects the hepatic NAD–sirtuin pathway in a rodent model of obesity and type 2 diabetes. J. Nutr. Biochem. 25, 66–72 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1,3-bis(dichlorophenyl)urea reduces body weight gain and adipose tissue mass, improves insulin sensitivity and glucose homeostasis, and decreases hepatic lipid content.

    “Another promising candidate is 1,3-bis(dichlorophenyl)urea, which reduces body weight gain and body adipose tissue mass, improving insulin sensitivity and glucose homeostasis, and decreasing hepatic lipid content270.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [270] Figarola, J. L. et al. COH-SR4 reduces body weight, improves glycemic control and prevents hepatic steatosis in high fat diet-induced obese mice. PLoS ONE 8, e83801 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nicotinamide mononucleotide supplementation restores β-cell glucose-stimulated insulin secretion and hepatic and skeletal muscle insulin sensitivity in mouse models with impaired glucose homeostasis.

    “Supplementation of the precursor nicotinamide mononucleotide (NMN) re-established β-cell glucose-stimulated insulin secretion as well as hepatic and skeletal muscle insulin sensitivity in mouse models with impaired glucose homeostasis252,253.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [252] Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011). source

      Not checked in the free run.

    • cites [253] Stromsdorfer, K. L. et al. NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep. 16, 1851–1860 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This difficulty is partly explained by the widespread presence of mitochondria and the varied clinical presentations linked to multi-organ involvement in age-associated metabolic diseases.

    “this can be explained by the ubiquitous nature of mitochondria and the heterogeneous clinical presentations associated with multi-organ involvement in age-associated metabolic diseases”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    In preclinical ageing research, adequate disease modelling that accounts for biological age is a major challenge.

    “one of the main challenges in the field of ageing is adequate disease modelling when considering biological age”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Maintaining healthy mitochondria and metabolic regulation is essential for long-term health.

    “the maintenance of healthy mitochondria and metabolic regulation are key to long-term health”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MitoQ alleviates Alzheimer disease-like pathology in the 3×Tg-AD mouse model by improving cognition, decreasing oxidative stress, and increasing survival.

    “Interestingly, MitoQ also alleviated Alzheimer disease-like pathology in the 3×Tg-AD mouse model287 by improving cognition, decreasing oxidative stress and increasing survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [287] Young, M. L. & Franklin, J. L. The mitochondria-targeted antioxidant MitoQ inhibits memory loss, neuropathology, and extends lifespan in aged 3xTg-AD mice. Mol. Cell. Neurosci. 101, 103409 (2019). source

      Not checked in the free run.

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

    Interpretationnone given

    Among all processes that affect ageing, those controlled by mitochondria respond most to environmental variations.

    “of all the processes that affect ageing, those controlled by mitochondria are the most responsive to environmental variations”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MitoVitE decreases hepatic oxidative stress and inhibits hepatic lipid deposition in mice.

    “MitoVitE decreases hepatic oxidative stress and inhibits hepatic lipid deposition in mice282.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282] Mao, G. et al. A mitochondria-targeted vitamin E derivative decreases hepatic oxidative stress and inhibits fat deposition in mice. J. Nutr. 140, 1425–1431 (2010). source

      Not checked in the free run.

138 of 138

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?

  • Excessive mutations in ROS-producing mtDNA result in mitochondrial abnormalities, influencing mitophagy, mitochondrial biogenesis, and dynamics, and inducing sarcopenia and alleviated physical activity or exercise training.

    “Excessive mutations in ROS-producing mtDNA result in mitochondrial abnormalities, influencing aspects such as mitophagy, mitochondrial biogenesis, and dynamics, and inducing sarcopenia and alleviated physical activity or exercise training [32].”

    From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [32]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Oxygen is described as both produced and reduced during respiration

    Minor

    The respiratory quotient definition says oxygen is produced during respiration, but the paper's description of the electron transport chain says oxygen is reduced to water.

  • Conflicting Diabetes journal volumes for 2003

    Minor

    Two references assign different volumes of the same journal to 2003: volume 102 and volume 52.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Wallace, D. C. The human mitochondrion and pathophysiology of aging and age-related diseases. in Molecular Biology of Aging 1st edn (eds. Guarente, L., Partridge, L. & Wallace, D. C.) 1–38 (Cold Spring Harbor Laboratory Press, 2008).
  2. Litvinova, L. S., Kirienkova, E. V., Mazunin, I. O., Vasilenko, M. A. & Fattakhov, N. S. Pathogenesis of insulin resistance in metabolic obesity. Biochem. Suppl. B Biomed. Chem. 8, 192–202 (2014).

Cited by

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Related

Authors
Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A.
Affiliations
  • Harvard University (US)
  • Centro de Neurociências e Biologia Celular (PT)
Corresponding author
Sinclair, David A.
ORCID
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2022-02-10
Volume
18
Issue
4
Pages
243-258
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
DOI
10.1038/s41574-021-00626-7
PMC
PMC9059418
OpenAlex
W4211154726
Semantic Scholar
71bb301316680bd24c63e75b2b9b8b48c533b656
Cited by
990
References
309
Citations by year
2026: 225 · 2025: 302 · 2024: 252 · 2023: 159 · 2022: 52
FWCI
19.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Journal of Media Literacy Education (submittedVersion, cc-by)
Funders
  • National Institute on Aging (R01AG028730, R00AG055683)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100263)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial dysfunction, metabolic dysfunction, aging, age-related diseases, energy homeostasis, caloric restriction, physical activity, longevity pathways, neurodegenerative diseases, cardiovascular disease, metabolic disorders
MeSH terms
Aging, Energy Metabolism, Humans, Metabolic Diseases, Mitochondria, Caloric Restriction

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.

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