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Cited by 287Metabolism, Diabetes, and CancerGenetics, Aging, and Longevity in Model OrganismsDiabetes Treatment and Management

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

Open access
Mohammed, Ibrahim, Hollenberg, Morley D., Ding, Hong, Triggle, Chris R.·2021·Frontiers in Endocrinology
DOI 10.3389/fendo.2021.718942PMC PMC8374068
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Abstract

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug. Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin. We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

Verified 2026-10-10 · 1 reference not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

This critical review concludes that metformin improves healthspan primarily indirectly through anti-hyperglycemic, insulin-sensitizing, antioxidant, and vascular-protective effects, but evidence that it extends lifespan remains controversial. It cautions that many anti-aging claims rest on preclinical studies using suprapharmacologic metformin concentrations and that human lifespan data are inconclusive.

Key findings

  • The authors conclude metformin can improve healthspan by reducing early mortality from diabetes, cardiovascular disease, cognitive decline, and cancer, but that evidence for lifespan extension is controversial; beneficial aging effects are primarily indirect via cellular metabolism, insulin sensitivity, oxidative stress reduction, and endothelial/vascular protection.
  • In *C. elegans*, 50 mM metformin enhanced survival by 27% in one study, but studies used 10–150 mM (equivalent to approximately 5 kg/day in humans); in aged worms all tested concentrations (10, 25, and 50 mM) were toxic and reduced lifespan.
  • Rodent lifespan results are dose- and age-dependent: 0.1% metformin increased male mouse lifespan by 4.15%, while 1% was toxic and reduced average lifespan by 14.4%; metformin extended lifespan by 14% when started at 1 month, by an insignificant 6% at 9 months, and was ineffective at 15 months; other studies found no lifespan extension in mice or Fischer-344 rats.
  • Human data: a retrospective UK Clinical Practice Research Datalink analysis found non-diabetics had 15% lower median survival than metformin-treated diabetics and sulfonylurea-treated diabetics had 38% lower survival than metformin-treated diabetics, suggesting healthspan but not lifespan extension; MILES (14 elderly subjects, 1700 mg/day, 6 weeks) found 647 differentially expressed genes in muscle and 146 in adipose tissue, while TAME (planned 3000 non-diabetic adults aged 65–80, 1500 mg/day for 6 years) is pending.

Methods

  • Design: critical narrative review of published literature on metformin and aging, healthspan, and lifespan across humans and other species.
  • Data: preclinical studies in *C. elegans*, rodents, and cell culture; clinical/observational studies and trials including MILES and TAME; pharmacokinetic and pharmacodynamic properties of metformin.
  • Analysis: qualitative synthesis and critical appraisal of study protocols, reproducibility, and dose/concentration relevance; no new primary data or formal meta-analysis reported.

Limitations

  • Stated: healthspan is controversial and not readily quantified; evidence that metformin increases lifespan remains controversial; many preclinical studies use metformin concentrations far above therapeutic plasma levels (in vitro x25–x1000 higher; in vivo x2–x45 therapeutic doses); lack of appropriately designed placebo-driven RCTs; effects may be age-dependent and less effective or ineffective in older organisms; MILES findings remain to be validated; TAME results are not yet available.
  • Evident from text: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or formal risk-of-bias assessment; conclusions rely on heterogeneous species, doses, and study designs, and several cited findings are preliminary or from ongoing trials.

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

Integrity signals

Registry

Crossref · 10.3389/fendo.2021.718942

Cites

272 of 274 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 353 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The use of metformin in the treatment of patients with T2DM is associated with a positive benefit on healthspan.

    “we do accept that the use of metformin in the treatment of patients with T2DM is associated with a positive benefit on healthspan.”
    Quote in the paperSubstantial claim
  • Findingnone given

    The evidence for lifespan expansion in mammalian species is not conclusive.

    “although the evidence for lifespan expansion in mammalian species is not conclusive”
    Quote in the paperNot a substantial claim
  • Interpretationcitation

    Based on evidence from both clinical and pre-clinical studies, metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium.

    “Based on evidence from both clinical and pre-clinical studies metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium (33–35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Nafisa, 2018, Endothelial Function and Dysfunction: Impact of Metformin, Pharmacol Ther source

      Not checked in the free run.

    • cites [34] Triggle, 2020, Why the Endothelium? The Endothelium as a Target to Reduce Diabetes-Related Associated Vascular Disease, Can J Physiol Pharmacol source

      Not checked in the free run.

    • cites [35] Kalyani, 2021, Glucose-Lowering Drugs to Reduce Cardiovascular Risk in Type 2 Diabetes, N Engl J Med source

      Not checked in the free run.

  • Premisecitation

    Johnson et al. reported reduced cardiovascular morbidity and mortality benefits of metformin monotherapy versus sulfonylurea monotherapy.

    “Similarly, Johnson et al. accessed the Saskatchewan Health Administrative databases for a retrospective study and also reported reduced cardiovascular morbidity and mortality benefits of metformin monotherapy versus sulfonylurea monotherapy (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Johnson, 2005, Reduced Cardiovascular Morbidity and Mortality Associated With Metformin Use in Subjects With Type 2 Diabetes, Diabetes Med source

      Not checked in the free run.

  • Premisecitation

    Metformin lowers the atherosclerotic burden in non-diabetic persons at risk of developing T2DM.

    “In addition to its benefits as an anti-hyperglycemic agent, metformin also lowers the atherosclerotic burden in non-diabetic persons at risk of developing T2DM (1, 7).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Rojas, 2013, Metformin: An Old But Still the Best Treatment for Type 2 Diabetes, Diabetol Metab Syndr source

      Not checked in the free run.

    • cites [7] 2012, Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study, Diabetes Care source

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  • May combine two claims. 127
  • Classified as probably not a substantial claim. 61
  • The quote only partly states this claim. 2

  • May combine two claims.

    Premisecitation

    Metformin has not been approved as a weight loss drug in part because its effects are highly variable and in women with PCOS despite weight loss visceral fat may not be reduced.

    “However, metformin has not been approved as a weight loss drug in part because its effects are highly variable and in women with PCOS despite weight loss visceral fat may not be reduced (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Lord, 2006, The Effect of Metformin on Fat Distribution and the Metabolic Syndrome in Women With Polycystic Ovary Syndrome–A Randomised, Double-Blind, Placebo-Controlled Trial, BJOG source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin via its insulin sensitizing actions reduces insulin and thereby should also normalize IGF-1 levels.

    “Metformin via its insulin sensitizing actions reduces insulin and thereby should also normalize IGF-1 levels (55, 56).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Dowling, 2015, Changes in Insulin Receptor Signaling Underlie Neoadjuvant Metformin Administration in Breast Cancer: A Prospective Window of Opportunity Neoadjuvant Study, Breast Cancer Res: BCR source

      Not checked in the free run.

    • cites [56] Yang, 2020, The Influence of Metformin on IGF-1 Levels in Humans: A Systematic Review and Meta-Analysis, Pharmacol Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are extra-hepatic sites of action of metformin with the gut being a major contributor to its clinical benefits as an anti-hyperglycemic drug via modulating glucagon-like peptide 1 levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota.

    “We now know there are extra-hepatic sites of action of metformin with the gut being a major contributor to its clinical benefits as an anti-hyperglycemic drug via modulating glucagon-like peptide 1 (GLP-1) levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota (25–29).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [25] Duca, 2015, Metformin Activates a Duodenal Ampk-Dependent Pathway to Lower Hepatic Glucose Production in Rats, Nat Med source

      Not checked in the free run.

    • cites [26] Buse, 2016, The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-Term Pharmacokinetic and 12-Week Dose-Ranging Studies, Diabetes Care source

      Not checked in the free run.

    • cites [27] Romero, 2017, Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [28] Glossmann, 2019, Metformin and Aging: A Review, Gerontol nd source

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    • cites [29] Vallianou, 2019, Metformin and Gut Microbiota: Their Interactions and Their Impact on Diabetes, Hormones (Athens) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from the Diabetes Prevention Program indicates that metformin is effective in preventing the development of diabetes in patients with pre-diabetes and its use following a 10-year follow up is associated with an average 2.1-kg weight loss.

    “In addition, data from the Diabetes Prevention Program (DPP) indicates that metformin is effective in preventing the development of diabetes in patients with pre-diabetes and its use following a 10-year follow up associated with an average 2.1-kg weight loss (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] 2012, Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The evidence that metformin increases lifespan remains controversial despite data in support of anti-aging benefits.

    “We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Based on a systematic review of 53 studies, Campbell et al. concluded that independent of its therapeutic efficacy as an anti-diabetic drug, the use of metformin results in a reduction of all-cause mortality associated with diseases that accelerate aging, including cancer and cardiovascular disease.

    “Based on a systematic review of 53 studies, Campbell et al. concluded that independent of its therapeutic efficacy as an anti-diabetic drug, the use of metformin results in a reduction of all-cause mortality associated with diseases that accelerate aging, including cancer and cardiovascular disease (37).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Campbell, 2017, Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-Analysis, Ageing Res Rev source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts its actions remain unclear.

    “Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts either its actions remain unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Collectively these data indicate that metformin can reduce both mortality and disease-accelerated aging of the cardiovascular system.

    “Collectively these data indicate that metformin can reduce both mortality and disease-accelerated aging of the cardiovascular system.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

    “Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Metformin can improve healthspan by reducing early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, thereby extending the period of life spent in good health.

    “However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline and cancer, metformin can improve healthspan thereby extending the period of life spent in good health.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Metformin is a synthetic biguanide, orally effective and insulin sensitizing anti-diabetic drug, which for most patients is the first line anti-hyperglycemic for the treatment of type 2 diabetes mellitus.

    “Metformin is a synthetic biguanide, orally effective and insulin sensitizing anti-diabetic drug, which for most patients is the first line anti-hyperglycemic for the treatment of type 2 diabetes mellitus (T2DM) (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Rojas, 2013, Metformin: An Old But Still the Best Treatment for Type 2 Diabetes, Diabetol Metab Syndr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Signaling via mTOR is linked to accelerated aging and dysregulation of mTOR signaling is also linked to the progression of cancer, inflammatory and neurological diseases, as well as T2DM.

    “Signaling via mTOR is linked to accelerated aging and dysregulation of mTOR signaling is also linked to the progression of cancer, inflammatory and neurological diseases, as well as T2DM (59).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Dazert, 2011, mTOR Signaling in Disease, Curr Opin Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microbiome change is an important determinant for the anti-hyperglycemic therapeutic effects, the gastrointestinal side effects and possibly the anti-aging effects of metformin.

    “This action is an important determinant for the anti-hyperglycemic therapeutic effects, the gastrointestinal side effects and possibly the anti-aging effects of metformin (88, 89).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [88] Forslund, 2015, Disentangling Type 2 Diabetes and Metformin Treatment Signatures in the Human Gut Microbiota, Nature source

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    • cites [89] Bryrup, 2019, Metformin-Induced Changes of the Gut Microbiota in Healthy Young Men: Results of a Non-Blinded, One-Armed Intervention Study, Diabetologia source

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  • May combine two claims.

    Interpretationcitation

    In C. elegans studies, very high concentrations of metformin, from 10 to 150 mM, were used, and are equivalent to a dose in humans of approximately 5 kg/day.

    “However, in these studies with C. elegans, very high concentrations of metformin, from 10 to 150 mM, were used (67, 86), and are the equivalent to a dose in humans of approximately 5 kg/day.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Cabreiro, 2013, Metformin Retards Aging in C. Elegans by Altering Microbial Folate and Methionine Metabolism, Cell source

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    • cites [86] Wu, 2016, An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. Elegans and Cancer, Cell source

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  • May combine two claims.

    Premisecitation

    In the absence of bacteria, metformin shortened lifespan, implying that it is the anti-bacterial action of metformin that explains the enhancement of lifespan in C. elegans.

    “Indeed, in the absence of bacteria, metformin shortened lifespan implying that it is the anti-bacterial action of metformin that explains the enhancement of lifespan in C. elegans (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Cabreiro, 2013, Metformin Retards Aging in C. Elegans by Altering Microbial Folate and Methionine Metabolism, Cell source

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  • May combine two claims.

    Interpretationreasoning

    Such doses in humans would be fatal and one would expect the same in C. elegans where toxicity is offset by the effects of metformin on the microbiome and inhibition of bacterial folate metabolism.

    “Such doses in humans would be fatal and one would expect the same in C. elegans where toxicity is offset by the effects of metformin on the microbiome and inhibition of bacterial folate metabolism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The addition of metformin to the diet can delay aging and increase life span in both C. elegans and rodents.

    “The addition of metformin to the diet can delay aging and increase life span in both C. elegans and rodents (66–68) (see Table 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Anisimov, 2008, Metformin Slows Down Aging and Extends Life Span of Female SHR Mice, Cell Cycle source

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    • cites [67] Cabreiro, 2013, Metformin Retards Aging in C. Elegans by Altering Microbial Folate and Methionine Metabolism, Cell source

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    • cites [68] De Haes, 2014, Metformin Promotes Lifespan Through Mitohormesis via the Peroxiredoxin PRDX-2, Proc Natl Acad Sci USA source

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  • May combine two claims.

    Premisecitation

    Sensitivity to AMPK declines with age, thus promoting the argument that activators of AMPK, such as metformin, could delay aging.

    “Worthy of note is that the sensitivity to AMPK declines with age thus promoting the argument that activators of AMPK, such as metformin, could delay aging (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Salminen, 2012, AMP-Activated Protein Kinase (AMPK) Controls the Aging Process via an Integrated Signaling Network, Ageing Res Rev source

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  • May combine two claims.

    Premisecitation

    The same pathways studied in C. elegans have also been investigated in mammals, where lifespan and healthspan were prolonged through modifying the aging pathways or through drugs, including metformin.

    “The same pathways studied in C. elegans have also been investigated in mammals, where lifespan and healthspan were prolonged through modifying the ‘aging’ pathways or through drugs, including metformin (60, 87).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Barzilai, 2016, Metformin as a Tool to Target Aging, Cell Metab source

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    • cites [87] Lamming, 2012, Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled From Longevity, Science source

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  • May combine two claims.

    Premisecitation

    In C. elegans the beneficial effects of metformin on lifespan are, at least in part, argued to be mediated through changing the microbiome and modifying microbial folate and methionine metabolism and potentially due to an anti-oxidant action via transcription factors SKN-1/Nrf2, a requirement for AMPK and the upstream serine-threonine kinase LKB1.

    “In C. elegans the beneficial effects of metformin on lifespan are, at least in part, argued to be mediated through changing the microbiome and modifying microbial folate and methionine metabolism and potentially due to an anti-oxidant action via transcription factors, SKN-1/Nrf2, a requirement for AMPK and the upstream serine-threonine kinase, liver kinase B1 (LKB1) (67, 71, 86).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Cabreiro, 2013, Metformin Retards Aging in C. Elegans by Altering Microbial Folate and Methionine Metabolism, Cell source

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    • cites [71] Onken, 2010, Metformin Induces a Dietary Restriction-Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1 and SKN-1, PloS One source

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    • cites [86] Wu, 2016, An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. Elegans and Cancer, Cell source

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  • May combine two claims.

    Premisecitation

    The lifespan and healthspan of invertebrates are extended by mutations in pathways such as DAF-2, a gene that encodes for the IGF-1 pathway in C. elegans, or the mTOR signaling pathways that are linked to accelerating the aging process.

    “The lifespan and healthspan of invertebrates are extended by mutations in pathways such as the DAF-2, a gene that encodes for the IGF-1 pathway in the nematode Caenorhabditis elegans (C. elegans), or the mTOR signaling pathways that are linked to accelerating the aging process (60, 62–65).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [60] Barzilai, 2016, Metformin as a Tool to Target Aging, Cell Metab source

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    • cites [62] Friedman, 1988, Three Mutants That Extend Both Mean and Maximum Life Span of the Nematode, Caenorhabditis Elegans, Define the Age-1 Gene, J Gerontol source

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    • cites [63] Bartke, 2001, Extending the Lifespan of Long-Lived Mice, Nature source

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    • cites [64] Blagosklonny, 2009, TOR-Driven Aging: Speeding Car Without Brakes, Cell Cycle source

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    • cites [65] Vitale, 2019, ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights From a Centenarians’ Perspective, Front Endocrinol source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Anisimov et al. concluded that metformin effects on lifespan in mice are age-dependent.

    “Conclusion: Metformin effects on lifespan in mice are age-dependent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Anisimov et al. (66) Anisimov, 2008, Metformin Slows Down Aging and Extends Life Span of Female SHR Mice, Cell Cycle source

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

    Premisecitation

    Onken and Driscoll concluded that metformin via the AMPK/LKB1/SKN-1/Nrf2 axis extends lifespan in C. elegans.

    “Conclusion: Metformin via AMPK/LB1/SKN-1/NrF2 axis extends lifespan in C. elegans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Onken and Driscoll (71) Onken, 2010, Metformin Induces a Dietary Restriction-Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1 and SKN-1, PloS One source

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

    Premisecitation

    Bannister et al. concluded that metformin extends healthspan, but not lifespan in humans.

    “Conclusion: Metformin extends healthspan, but not lifespan in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bannister et al. (69) Bannister, 2014, Can People With Type 2 Diabetes Live Longer Than Those Without? A Comparison of Mortality in People Initiated With Metformin or Sulphonylurea Monotherapy and Matched, Non-Diabetic Controls, Diabetes Obes Metab source

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

    Premisecitation

    Elevated levels of GDF15 have been linked to tumor growth and poor prognosis in cancer patients.

    “Elevated levels of GDF15 have been linked to tumor growth and poor prognosis in cancer patients raising the question as to whether GDF15 serves as a tumor suppressor or promoter and a target for the treatment of cancer (84, 85, 99).”
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    • cites [84] Modi, 2019, Growth Differentiation Factor 15 and Its Role in Carcinogenesis: An Update, Growth Factors source

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    • cites [85] Wischhusen, 2020, Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint, Front Immunol source

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    • cites [99] Welsh, 2003, Large-Scale Delineation of Secreted Protein Biomarkers Overexpressed in Cancer Tissue and Serum, Proc Natl Acad Sci source

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    Premisecitation

    Smith et al. concluded that metformin is not a calorie-restriction mimetic.

    “Conclusion: Metformin is not a calorie-restriction mimetic (CRM)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smith et al. (78) Smith, 2010, Metformin Supplementation and Life Span in Fischer-344 Rats, J Gerontol A Biol Sci Med Sci source

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  • May combine two claims.

    Interpretationreasoning

    AMPK inhibits signaling via mTOR and through this action could contribute to the reduced incidence of some cancers that has been associated with the use of metformin.

    “AMPK inhibits signaling via mTOR and through this action could contribute to the reduced incidence of some cancers that has been associated with the use of metformin: see Table 2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the ORIGIN trial, GDF15 was identified as a biomarker linked to positive cardiovascular outcomes and also elevated in those patients receiving metformin.

    “As a result of an analysis of data from the ORIGIN trial (Outcome Reduction with Initial Glargine Intervention), GDF15 was identified as a biomarker linked to positive CV outcomes and also elevated in those patients receiving metformin (80, 81).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [80] Gerstein, 2015, Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia, Circulation source

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    • cites [81] Gerstein, 2017, Growth Differentiation Factor 15 as a Novel Biomarker for Metformin, Diabetes Care source

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  • May combine two claims.

    Premisecitation

    Hepatic gluconeogenesis is inhibited by AMPK activation, which also enhances insulin sensitivity, muscle glucose absorption, and fatty acid oxidation.

    “Hepatic gluconeogenesis is inhibited by AMPK activation, which also enhances insulin sensitivity, muscle glucose absorption, and fatty acid oxidation (103, 104).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] Myers, 2017, Systemic Pan-AMPK Activator MK-8722 Improves Glucose Homeostasis But Induces Cardiac Hypertrophy, Science source

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    • cites [104] Saisho, 2015, Metformin and Inflammation: Its Potential Beyond Glucose-Lowering Effect, Endocr Metab Immune Disord Drug Targets source

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  • May combine two claims.

    Interpretationcitation

    An increase in the activity of AMPK would also explain the protective effects of metformin on endothelial function via the activation of endothelial nitric oxide synthase, thereby countering the negative effects of a diabetic milieu on cardiovascular function.

    “An increase in the activity of AMPK would also explain the protective effects of metformin on endothelial function via the activation of endothelial nitric oxide synthase (eNOS) thereby countering the negative effects of a diabetic milieu on cardiovascular function (119).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Fisslthaler, 2009, Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells, Circ Res source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Strong et al. concluded that metformin does not extend lifespan in mice.

    “Conclusion: Metformin does not extend lifespan in mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Strong et al. (77) Strong, 2016, Longer Lifespan in Male Mice Treated With a Weakly Estrogenic Agonist, an Antioxidant, an α-Glucosidase Inhibitor or a Nrf2-Inducer, Aging Cell source

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  • May combine two claims.

    Premisecitation

    AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism.

    “AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism (102, 103).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] Zhou, 2001, Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action, J Clin Invest source

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    • cites [103] Myers, 2017, Systemic Pan-AMPK Activator MK-8722 Improves Glucose Homeostasis But Induces Cardiac Hypertrophy, Science source

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

    Premisecitation

    Martin-Montalvo et al. concluded that metformin extends lifespan in mice, but dose-dependently.

    “Conclusion: Metformin extends lifespan in mice, but dose-dependent..”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Martin-Montalvo et al. (76) Martin-Montalvo, 2013, Metformin Improves Healthspan and Lifespan in Mice, Nat Commun source

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  • May combine two claims.

    Premisecitation

    Based on a proteomic analysis of plasma from 240 healthy, disease-free humans in the age range 22-93 years-old, GDF15 was identified as the protein most positively correlated with chronological age and also known to reduce appetite via an action in the hind-brain.

    “Of additional interest and based on a proteomic analysis of the plasma from 240 healthy, disease-free, humans in the age range 22-93 years-old, GDF15 was identified as the protein most positively correlated with chronological age and also known to reduce appetite via an action in the hind-brain (82, 95).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Tanaka, 2018, Plasma Proteomic Signature of Age in Healthy Humans, Aging Cell source

      Not checked in the free run.

    • cites [95] Hsu, 2017, Non-Homeostatic Body Weight Regulation Through a Brainstem-Restricted Receptor for GDF15, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin has anti-inflammatory effects but requires high concentrations.

    “Metformin has anti-inflammatory effects but requires high concentrations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hattori et al. (105) Hattori, 2006, Metformin Inhibits Cytokine-Induced Nuclear Factor kappaB Activation via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells, Hypertension source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin increased AMPK activity in rat and human hepatocytes and was associated with an increase in cellular AMP:ATP ratio.

    “Metformin increased AMPK activity in rat and human hepatocytes and was associated with an increase cellular AMP:ATP ratio.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stephenne et al. (112) Stephenne, 2011, Metformin Activates AMP-Activated Protein Kinase in Primary Human Hepatocytes by Decreasing Cellular Energy Status, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Coll et al. found that the weight loss effect of metformin was dependent on expression of the GDF15 receptor GFRAL, whereas the antihyperglycemic effect of metformin was independent of the GDF15-GRAL pathway.

    “Weight loss effect shown to be dependent on expression of the GDF15 receptor, GRAL, (glial cell-derived neurotrophic factor family receptor alpha-like) whereas the antihyperglycemic effect of metformin was independent of the GDF15-GRAL pathway.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Coll et al. (83) Coll, 2020, GDF15 Mediates the Effects of Metformin on Body Weight and Energy Balance, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gerstein et al. found that subjects taking metformin had higher GDF15 levels and lower cardiovascular outcomes.

    “Subjects taking metformin also had higher GDF15 (Growth Differentiation Factor 15) levels and lower CV outcomes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gerstein et al. (81) Gerstein, 2017, Growth Differentiation Factor 15 as a Novel Biomarker for Metformin, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mather et al. found that metformin improved endothelium-dependent vasodilation but not endothelium-independent vasodilation.

    “Metformin improved EDV but not EIDV.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mather et al. (106) Mather, 2001, Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human vascular endothelial cells, metformin caused dose- and time-dependent activation of AMPK from 1 to 10 mM and inhibition of proinflammatory and adhesion molecule genes induced by cytokines through suppression of NF-κB activity.

    “Dose- and time-dependent activation of AMPK from 1 to 10 mM metformin and inhibition of proinflammatory and adhesion molecule genes induced by cytokines through suppression of NF-kB activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hattori et al. (105) Hattori, 2006, Metformin Inhibits Cytokine-Induced Nuclear Factor kappaB Activation via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells, Hypertension source

      Not checked in the free run.

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

    Premisecitation

    Metformin inhibits activation of mTOR through down-regulation of Sp1, Sp3 and Sp4 transcription factors transcription and IGF-1R.

    “Metformin inhibits activation of mTOR through down-regulation of the Sp1, Sp3 and Sp4 transcription factors transcription and IGF-1R.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nair et al. (114) Nair, 2014, Mechanism of Metformin-Dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer: Role of Specificity Protein (Sp) Transcription Factors, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a case-control study using Tayside Scotland databases, metformin use was associated with a reduced risk of cancer and a suggestion of a dose-dependent effect.

    “Analysis indicates a reduced risk of cancer and a suggestion of a dose-dependent effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Evans et al. (113) Evans, 2005, Metformin and Reduced Risk of Cancer in Diabetic Patients, BMJ source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Metformin improved endothelium-dependent vasorelaxation in vascular tissue from diabetic db/db mice.

    “Metformin improved EDV in vascular tissue from diabetic mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ghosh et al. (111) Ghosh, 2015, Metformin Improves Endothelial Function in Aortic Tissue and Microvascular Endothelial Cells Subjected to Diabetic Hyperglycaemic Conditions, Biochem Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPKα1 was activated in human hepatocytes, whereas both AMPKα isoforms were activated in rat hepatocytes, stressing species differences.

    “AMPKα1 was activated in human hepatocytes, whereas both AMPKα isoforms were activated in rat hepatocytes stressing the importance of species differences.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stephenne et al. (112) Stephenne, 2011, Metformin Activates AMP-Activated Protein Kinase in Primary Human Hepatocytes by Decreasing Cellular Energy Status, Diabetologia source

      Not checked in the free run.

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

    Premisecitation

    Kulkarni et al. concluded that there is preliminary evidence implying metformin effects on transcription and pathways affecting healthspan and lifespan.

    “Conclusion: Preliminary evidence implying metformin effects on transcription and pathways affecting healthspan and lifespan.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kulkarni et al. (79) Kulkarni, 2018, Metformin Regulates Metabolic and Nonmetabolic Pathways in Skeletal Muscle and Subcutaneous Adipose Tissues of Older Adults, Aging Cell source

      Not checked in the free run.

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

    Premisecitation

    Hepatic AMPK activation by metformin resulted from lower cellular energy due to AMPK-independent inhibition of the mitochondrial respiratory-chain complex by metformin.

    “Hepatic AMPK activation by metformin resulted from lower cellular energy due to AMPK-independent inhibition of the mitochondrial respiratory-chain complex by metformin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stephenne et al. (112) Stephenne, 2011, Metformin Activates AMP-Activated Protein Kinase in Primary Human Hepatocytes by Decreasing Cellular Energy Status, Diabetologia source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In the Singapore Longitudinal Aging Study, metformin use for more than 6 years was linked to a decreased risk of cognitive impairment in diabetic subjects.

    “Metformin use for more than 6 years was linked to a decreased risk of cognitive impairment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ng et al. (116) Ng, 2014, Long-Term Metformin Usage and Cognitive Function Among Older Adults With Diabetes, J Alzheimers Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK is regulated by LKB1 and CaMKKβ and is positively regulated by sirtuin-1.

    “AMPK is regulated by two upstream serine threonine AMPK kinases: LKB1, and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) and is also positively regulated by the nicotinamide adenine dinucleotide (NAD+) deacetylase, sirtuin-1.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Grabowska, 2017, Sirtuins, a Promising Target in Slowing Down the Ageing Process, Biogerontology source

      Not checked in the free run.

    • cites [121] Kupis, 2016, The Role of Sirtuins in Cellular Homeostasis, J Physiol Biochem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence is a major contributor to aging and the development of cardiovascular disease.

    “Senescence is a major contributor to aging and the development of cardiovascular disease (123)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Katsuumi, 2018, Vascular Senescence in Cardiovascular and Metabolic Diseases, Front Cardiovasc Med source

      Not checked in the free run.

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

    Premisecitation

    Vascular effects mediate beneficial effects of metformin on breast cancer.

    “Vascular effects mediate beneficial effects of metformin on breast cancer.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al. (115) Wang, 2019, Metformin Inhibits Metastatic Breast Cancer Progression and Improves Chemosensitivity by Inducing Vessel Normalization via PDGF-B Downregulation, J Exp Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In endothelial cells, metformin enhances phosphorylation and increases the activity of LKB1.

    “In endothelial cells, metformin has been shown to enhance phosphorylation and increase the activity of LKB1 (122).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Xie, 2008, Phosphorylation of LKB1 at Serine 428 by Protein C-Zeta Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells, Circulation source

      Not checked in the free run.

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

    Premisecitation

    Metformin targets genes and signaling pathways important for tumor migration, invasion, proliferation and survival.

    “Metformin targets genes and signaling pathways important for tumor migration, invasion, proliferation and survival.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nair et al. (114) Nair, 2014, Mechanism of Metformin-Dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer: Role of Specificity Protein (Sp) Transcription Factors, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sirtuin-1 is the protein product of SIRT1 and targets lysine residues in proteins including histones and the tumor suppressors LKB1 and p53.

    “Sirtuin-1 is the protein product of the putative anti-aging gene SIRT1, which targets lysine residues in proteins, including histones and the tumor-suppressors, LKB1 and p53 (120, 121).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Grabowska, 2017, Sirtuins, a Promising Target in Slowing Down the Ageing Process, Biogerontology source

      Not checked in the free run.

    • cites [121] Kupis, 2016, The Role of Sirtuins in Cellular Homeostasis, J Physiol Biochem source

      Not checked in the free run.

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

    Premisecitation

    Neuronal differentiation was dependent on AMPK/atypical PKC and cyclic AMP response element-binding protein.

    “Neuronal differentiation was dependent on AMPK/atypical PKC and cyclic AMP response element-binding protein (CREB or CBP).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fatt et al. (117) Fatt, 2015, Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation, Stem Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In metastatic breast cancer mouse models, metformin decreased microvessel density, leakage, and hypoxia while increasing vascular mural cell perfusion compared to control.

    “Metformin decreased microvessel density, leakage, and hypoxia while increasing vascular mural cell perfusion as compared to a control group.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al. (115) Wang, 2019, Metformin Inhibits Metastatic Breast Cancer Progression and Improves Chemosensitivity by Inducing Vessel Normalization via PDGF-B Downregulation, J Exp Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin enhances neurogenesis, suggesting a role for metformin in neurodegenerative diseases.

    “Metformin enhances neurogenesis suggesting a role for metformin in neurodegenerative diseases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fatt et al. (117) Fatt, 2015, Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation, Stem Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expression of inflammatory cells was higher in fat-fed mice and decreased by metformin.

    “Expression of inflammatory cells was higher in fat-fed mice and decreased by metformin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ma et al. (118) Ma, 2021, Metformin Restores Hippocampal Neurogenesis and Learning and Memory via Regulating Gut Microbiota in the Obese Mouse Model, Brain Behav Immun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    1 μM metformin enhanced the self-renewal and differentiation of adult mouse neural stem cells.

    “1 μM metformin enhanced the self-renewal and differentiation of NPCs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fatt et al. (117) Fatt, 2015, Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation, Stem Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LKB1 is a tumor suppressor and mutations in LKB1 are observed in numerous cancers that reduce the inhibitory effect of the LKB1/AMPK pathway on pro-proliferative signaling via mTOR.

    “LKB1 is a tumor suppressor and that mutations in LKB1 are observed in numerous cancers that result in the reduction of the inhibitory effect of the LKB1/AMPK pathway on the pro-proliferative signaling via mTOR (125, 126).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [125] Faubert, 2014, Loss of the Tumor Suppressor LKB1 Promotes Metabolic Reprogramming of Cancer Cells via HIF-1α, PNAS source

      Not checked in the free run.

    • cites [126] Momcilovic, 2015, Targeting LKB1 in Cancer – Exposing and Exploiting Vulnerabilities, Br J Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondria play a critical role in oxidative metabolism and a link has been made in patients between obesity, insulin resistance, and defective mitochondria oxidative processes that results in a buildup of toxic intermediate metabolites.

    “Mitochondria play a critical role in oxidative metabolism and a link has been made in patients between obesity, insulin resistance, and defective mitochondria oxidative processes that results in a buildup of toxic intermediate metabolites (144).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Sergi, 2019, Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Mechanisms to the Impact of Diet, Front Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Hepa1-6 cells exposed to 75 or 1000 μM metformin, no inhibitory effects were seen on activities of complex I-IV, and subcellular distribution indicated metformin remained primarily in the cytosol with mitochondrial levels less than 70 μM.

    “even following exposure to 1000 μM, no inhibitory effects were seen on the activities of complex I-IV, and the subcellular distribution of metformin indicated that metformin remained primarily in the cytosol with levels in mitochondria less than 70 μM (139).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Wilcock, 1991, Subcellular Distribution of Metformin in Rat Liver, J Pharm Pharmacol source

      Not checked in the free run.

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

    Premisecitation

    Considerable attention has been placed on the liver and skeletal muscle as primary sites of action of metformin resulting from activation of AMPK secondary to an inhibitory action on mitochondrial complex 1.

    “Considerable attention has been placed on the liver and skeletal muscle as the primary sites of action of metformin resulting from the activation of AMPK secondary to an inhibitory action on mitochondrial complex 1.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Chien et al. argue that metformin can be trapped in intracellular organelles such as microsomes and mitochondria.

    “Chien et al. argue that metformin can be trapped in intracellular organelles such as microsomes and mitochondria (137).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Chien, 2016, Rapid Method to Determine Intracellular Drug Concentrations in Cellular Uptake Assays: Application to Metformin in Organic Cation Transporter 1-Transfected Human Embryonic Kidney 293 Cells, Drug Metab Dispos source

      Not checked in the free run.

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

    Premisecitation

    Based on thermodynamic considerations, with a mitochondrial membrane potential of -180 mV, metformin could accumulate 1000-fold, potentially providing a concentration within mitochondria that would inhibit complex 1.

    “based on thermodynamic considerations, Owen et al. (128) argue that with a mitochondrial membrane potential of – 180mV metformin could accumulate 1000 fold thus potentially providing a concentration within the mitochondria that would inhibit complex 1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Owen et al. (128) Owen, 2000, Evidence That Metformin Exerts Its Anti-Diabetic Effects Through Inhibition of Complex 1 of the Mitochondrial Respiratory Chain, Biochem J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of mitochondrial complex 1 decreases the ATP/AMP ratio, activating AMPK.

    “This inhibition would in turn decrease the ATP/AMP ratio activating AMPK (127–129).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [127] El-Mir, 2000, Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I, J Biol Chem source

      Not checked in the free run.

    • cites [128] Owen, 2000, Evidence That Metformin Exerts Its Anti-Diabetic Effects Through Inhibition of Complex 1 of the Mitochondrial Respiratory Chain, Biochem J source

      Not checked in the free run.

    • cites [129] Hardie, 2013, AMPK: A Target for Drugs and Natural With Effects on Both Diabetes and Cancer, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increase in AMP decreases adenylate cyclase activation and thereby lowers glucagon release.

    “Furthermore, an increase in AMP also decreases adenylate cyclase activation and thereby lowers glucagon release (129).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Hardie, 2013, AMPK: A Target for Drugs and Natural With Effects on Both Diabetes and Cancer, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In high-fat diet mice including AMPKα1/2 knockout mice treated with 50 mg/kg/day metformin in drinking water, complex 1 activity, mitochondria density and mitochondrial DNA were all increased via an AMPK-dependent mechanism.

    “complex 1 activity, mitochondria density and mitochondrial DNA were all increased via an AMPK-dependent mechanism (138).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Wang, 2019, Metformin Improves Mitochondrial Respiratory Activity Through Activation of AMPK, Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Collectively, data provide a link between metformin, AMPK, LKB1, sirtuin-1, and cellular mechanisms that could enhance both healthspan and lifespan by reducing cellular senescence and activation of pro-proliferative pathways.

    “Collectively these data provide a link between metformin, AMPK, LKB1, sirtuin-1, and cellular mechanisms that could enhance both healthspan and lifespan by reducing both cellular senescence and the activation of pro-proliferative pathways.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Concentrations of resveratrol present in the diet, such as in wines, are far below amounts that might have any effect on aging.

    “the concentrations of resveratrol present in the diet, e.g. in wines, are far below the amounts that might have any effect on aging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Badrick and Renehan indicated that for preclinical in vivo studies doses ranged from x2 to x45 therapeutic doses and for in vitro studies concentrations ranged from x25 to x1000 higher than those observed in patients.

    “A useful comparison of the doses of metformin used therapeutically versus pre-clinical studies was made by Badrick and Renehan, indicating that for pre-clinical studies done in vivo, the doses ranged from x2 to x45 therapeutic doses and that for studies done in vitro, concentrations ranged from x25 to x1000 higher than those observed in patients (161).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Badrick, 2014, Diabetes and Cancer: 5 Years Into the Recent Controversy, Eur J Cancer source

      Not checked in the free run.

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

    Premisecitation

    Numerous studies have reported that resveratrol has anti-aging effects in several species with its effects linked to sirtuin-1.

    “Numerous studies have also reported that resveratrol has anti-aging effects in several species with its effects, as also described for metformin, linked to the deacetylase, sirtuin-1 (153).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Morselli, 2010, Caloric Restriction and Resveratrol Promote Longevity Through the Sirtuin-1-Dependent Induction of Autophagy, Cell Death Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    If metformin can offset the decline in mitochondrial function, then this effect could contribute to enhancing both healthspan and lifespan.

    “If metformin can offset the decline in mitochondrial function, as some studies suggest, then this effect could contribute to enhancing both healthspan and lifespan (138, 149, 150).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [138] Wang, 2019, Metformin Improves Mitochondrial Respiratory Activity Through Activation of AMPK, Cell Rep source

      Not checked in the free run.

    • cites [149] Kluge, 2013, Mitochondria and Endothelial Function, Circ Res source

      Not checked in the free run.

    • cites [150] Li, 2016, Endothelial AMPK Activation Induces Mitochondrial Biogenesis and Stress Adaptation via eNOS-Dependent Mtorc1 Signaling, Nitric Oxide source

      Not checked in the free run.

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

    Premisecitation

    High expression levels of influx transporters in cells might allow much higher accumulation of metformin resulting in selective toxicity and cell death as postulated to explain anti-cancer effects.

    “A high expression levels of influx transporters in cells might allow a much higher accumulation of metformin resulting in selective toxicity and cell death as has been postulated to explain the anti-cancer effects of the drug (158).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Samuel, 2019, Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer, Biomolecules source

      Not checked in the free run.

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

    Premisecitation

    Three distinct classes of organic cation-selective transporters can be utilized by metformin: OCT1, 2 and 3; PMAT; and MATE1 and 2.

    “There are three distinct classes of organic cation-selective transporters that can be utilized by metformin: Organic Cation Transporter (OCT) 1, 2 and 3 (SLC22A1, A2, A3); Plasma membrane Monoamine Transporter (PMAT; SLC29A4); and Multidrug And Toxin Extrusion protein (MATE) 1 and 2 (SLC47A1, A2), to enter and leave cells (Figure 1) (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Gong, 2012, Metformin Pathways: Pharmacokinetics and Pharmacodynamics, Pharmacogenet Genomics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When prescribed in the usual oral dosage range of 250 to ~2550 mg/day for T2DM and in the absence of reduced renal function, peak plasma levels of metformin are unlikely to exceed 15-20 μM, with trough levels between 1-5 μM, and a plasma half-life of approximately 3 to 5 hours.

    “When prescribed in the usual oral dosage range of 250 to ~2550 mg/day for the treatment of T2DM and in the absence of reduced renal function, it is unlikely that peak plasma levels of metformin would exceed 15-20 μM, with trough levels of between 1-5 μM, and a plasma half-life of approximately 3 to 5 hours.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [34] Triggle, 2020, Why the Endothelium? The Endothelium as a Target to Reduce Diabetes-Related Associated Vascular Disease, Can J Physiol Pharmacol source

      Not checked in the free run.

    • cites [133] Fontaine, 2018, Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences, Front Endocrinol (Lausanne) source

      Not checked in the free run.

    • cites [154] Pentikäinen, 1979, Pharmacokinetics of Metformin After Intravenous and Oral Administration to Man, Eur J Clin Pharmacol source

      Not checked in the free run.

    • cites [155] Graham, 2011, Clinical Pharmacokinetics of Metformin, Clin Pharmacokinet source

      Not checked in the free run.

    • cites [156] Kinaan, 2015, Metformin: An Old Drug for the Treatment of Diabetes But a New Drug for the Protection of the Endothelium, Med Princ Pract source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Metformin is a strongly basic hydrophilic drug with a pKa of approximately 11, is not metabolized, and is excreted principally by the kidney.

    “Metformin is a strongly basic hydrophilic drug with a pKa of approximately 11 is not metabolized and is excreted principally by the kidney.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both metformin and resveratrol inhibit ROS-associated mitochondria fission.

    “Interestingly, both metformin and the anti-oxidant, resveratrol, inhibit ROS-associated mitochondria fission (152).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Li, 2016, Metformin and Resveratrol Inhibit Drp1-Mediated Mitochondrial Fission and Prevent ER Stress-Associated NLRP3 Inflammasome Activation in the Adipose Tissue of Diabetic Mice, Molec Cell Endo source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Expression levels of saturable organic cation transporters determine the rate of absorption of metformin from the gut and its subsequent cellular distribution and excretion.

    “The expression levels of the saturable organic cation transporters will determine the rate of absorption of metformin from the gut and the subsequent cellular distribution and excretion of metformin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin may play an important role in quality-control regulation of mitochondria and shift cellular dynamics to a healthy population via mitophagy and eliminate damaged mitochondria.

    “metformin may play an important role in the ‘quality-control’ regulation of mitochondria and shift the cellular dynamics to a healthy population via mitophagy and eliminate damaged mitochondria (138)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Wang, 2019, Metformin Improves Mitochondrial Respiratory Activity Through Activation of AMPK, Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial function is impaired in diabetes and additional insult of metformin-induced dysfunction would be detrimental to patients with T2DM.

    “Several studies have also provided evidence that mitochondrial function is impaired in diabetes and thus the additional insult of metformin-induced dysfunction would be detrimental to patients with T2DM (145, 146)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [145] Kelley, 2002, Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes, Diabetes source

      Not checked in the free run.

    • cites [146] Sivitz, 2010, Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities, Antioxid Redox Signaling source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial function declines with age due either to ROS and/or an accumulation of mutations in mitochondrial DNA.

    “Mitochondrial function declines with age due either to ROS and/or an accumulation of mutations in mitochondrial DNA (151).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Bratic, 2013, The Role of Mitochondria in Aging, J Clin Invest source

      Not checked in the free run.

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

    Premisecitation

    Endothelial dysfunction, defined as a reduced vasodilator response to acetylcholine, is an early prognostic indicator for the onset of cardiovascular disease.

    “endothelial dysfunction, which can be defined as a reduced vasodilator response to acetylcholine, is an early prognostic indicator for the onset of cardiovascular disease (168–171).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [168] Leung, 1993, Beneficial Effect of Cholesterol-Lowering on Coronary Endothelium-Dependent Relaxation in Hypercholsterolaemic Patients, Lancet source

      Not checked in the free run.

    • cites [169] Anderson, 1995, Close Relation of Endothelial Function in the Human Coronary and Peripheral Circulations, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [170] Landmesser, 2004, Endothelial Function: A Critical Determinant in Atherosclerosis, Circulation source

      Not checked in the free run.

    • cites [171] Lerman, 2005, Endothelial Function: Cardiac Events, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from a metabolomics analysis of T2DM patients treated with metformin indicated that levels of the amino acid citrulline were lower than controls, with comparable data from tissues from the db/db mouse model.

    “Data from a metabolomics analysis of T2DM patients treated with metformin has indicated that levels of the amino acid citrulline were lower than controls with comparable data from tissues from the db/db mouse model of T2DM and obesity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Adam, 2016, Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent systematic review concluded that metformin significantly lowered all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate chronic kidney disease.

    “a recent systematic review concluded that metformin significantly lowered all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate chronic kidney disease (163).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Hu, 2020, Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease—A Systematic Review and Meta-Analysis, Front Endocrinol source

      Not checked in the free run.

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

    Premisecitation

    Furchgott and Zawadski were first to report that an intact and undamaged endothelium was essential for acetylcholine to mediate a vasodilator response.

    “Furchgott and Zawadski were the first to report that an intact and undamaged endothelium was essential in order for acetylcholine to mediate a vasodilator response (167).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Furchgott, 1980, The Obligatory Role of Endothelial Cells in the Relaxation of Arterial Smooth Muscle by Acetylcholine, Nature source

      Not checked in the free run.

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

    Premisecitation

    The endothelium plays a critical role in regulation of cardiovascular function and as a source of nitric oxide.

    “The endothelium plays a critical role in the regulation of cardiovascular function and not least as a source of the important signaling molecule, nitric oxide (NO).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Based on critical reviews of the literature, the answer appears to be yes that metformin exerts a direct anti-aging effect on the endothelium, although clinical data could be interpreted as secondary to metformin's actions to enhance insulin sensitivity and lower blood glucose.

    “Based on critical reviews of the literature, the answer appears to be “yes”, although the clinical data could be interpreted as secondary to metformin’s actions to enhance insulin sensitivity and lower blood glucose levels (34, 106, 173).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [34] Triggle, 2020, Why the Endothelium? The Endothelium as a Target to Reduce Diabetes-Related Associated Vascular Disease, Can J Physiol Pharmacol source

      Not checked in the free run.

    • cites [106] Mather, 2001, Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [173] Salvatore, 2020, Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects, Biomedicines source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sirtuin-1 plays an essential role in regulation of angiogenesis, a protective role against oxidative stress and cardiovascular disease, and higher expression levels of sirtuin-1 are associated with reducing disease.

    “Sirtuin-1 plays an essential role in the regulation of angiogenesis, a protective role against oxidative stress and cardiovascular disease and higher expression levels of sirtuin-1 are associated with reducing disease (176–178).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [176] Alcendor, 2007, Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart, Circ Res source

      Not checked in the free run.

    • cites [177] Potente, 2007, SIRT1 Controls Endothelial Angiogenic Functions During Vascular Growth, Genes Dev source

      Not checked in the free run.

    • cites [178] Elibol, 2018, High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions, Front Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence and implicates a crucial role for the SIRT1-derived deacetylase, sirtuin-1.

    “metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence and implicates a crucial role for the SIRT1-derived deacetylase, sirtuin-1 (110, 111).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [110] Arunachalam, 2014, Metformin Modulates Hyperglycaemia-Induced Endothelial Senescence and Apoptosis Through SIRT1, Br J Pharmacol source

      Not checked in the free run.

    • cites [111] Ghosh, 2015, Metformin Improves Endothelial Function in Aortic Tissue and Microvascular Endothelial Cells Subjected to Diabetic Hyperglycaemic Conditions, Biochem Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a larger randomized placebo-controlled study with 390 patients receiving daily doses of 850 to 2550 mg metformin followed for 52 months, there were reduced levels of biomarkers of endothelial dysfunction including von Willebrand factor, soluble vascular adhesion molecule-1, tissue type plasminogen activator, plasminogen activator inhibitor-1, but not soluble E-selectin or urinary albumin.

    “The results complement the plethysmography data reported by Mather et al. (106) with reduced levels of biomarkers of endothelial dysfunction including von Willebrand factor, soluble vascular adhesion molecule-1, tissue type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), but not soluble E-selectin (sE-selectin), or urinary albumin (174).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] de Jager, 2014, Long-Term Effects of Metformin on Endothelial Function in Type 2 Diabetes: A Randomized Controlled Trial, J Internal Med source

      Not checked in the free run.

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

    Premisecitation

    Onken and Driscoll reported that the anti-aging actions of metformin in C. elegans were only seen with 50 mM metformin and not lower concentrations.

    “Onken and Driscoll (71) reported that the anti-aging actions of metformin in C. elegans were only seen with 50 mM metformin and not lower concentrations”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Onken and Driscoll (71) Onken, 2010, Metformin Induces a Dietary Restriction-Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1 and SKN-1, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a UK Clinical Practice Research Datalink study, matched non-diabetics had 15% lower median survival times versus diabetics on metformin monotherapy, and diabetics on sulfonylurea monotherapy had a 38% lower survival time compared to the metformin group.

    “The data show that matched non-diabetics had 15% lower median survival times versus diabetics on metformin monotherapy and that those diabetics on sulfonylurea monotherapy had a 38% lower survival time compared to the metformin group (37, 69).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Campbell, 2017, Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-Analysis, Ageing Res Rev source

      Not checked in the free run.

    • cites [69] Bannister, 2014, Can People With Type 2 Diabetes Live Longer Than Those Without? A Comparison of Mortality in People Initiated With Metformin or Sulphonylurea Monotherapy and Matched, Non-Diabetic Controls, Diabetes Obes Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The metabolomics data link lowering of citrulline to an increase in NO generation from arginine and improved eNOS activity, supporting that metformin protects the cardiovascular system via promoting NO generation.

    “The metabolomics data can links the lowering of citrulline to the increase in NO generation from arginine and improved eNOS activity, thus providing support to the literature that metformin protects the cardiovascular system via promoting the generation of NO (175).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] Adam, 2016, Metformin Effect on Nontargeted Metabolite Profiles in Patients With Type 2 Diabetes and in Multiple Murine Tissues, Diabetes source

      Not checked in the free run.

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

    Premisecitation

    OCT3 transporter expression in nuclear membrane facilitates metformin transport into the nucleus.

    “OCT3 transporter expression in nuclear membrane facilitates metformin transport into the nucleus (183).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Gasser, 2017, Organic Cation Transporter 3 (OCT3) Is Localized to Intracellular and Surface Membranes in Select Glial and Neuronal Cells Within the Basolateral Amygdaloid Complex of Both Rats and Mice, Brain Struct Funct source

      Not checked in the free run.

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

    Premisecitation

    In that study, metformin improved skeletal muscle insulin sensitivity by 55% and exercise by 90%.

    “The results indicated that although both metformin and exercise improved skeletal muscle insulin sensitivity by 55 and 90% respectively the combination resulted in only a 30% enhancement.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Malin, 2016, Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk, Exercise Sport Sci Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BRECs with SIRT1 knocked down showed increased sensitivity to hyperglycemic stress, whereas SIRT1 overexpression or exposure to metformin inhibited increase of mitochondrial ROS by upregulation of LKB1 and suppressed expression of NF-κB and Bax.

    “BRECs where SIRT1 was knocked down with siRNA knockdown demonstrated an increased sensitivity to hyperglycemic stress, whereas SIRT1 overexpression, or exposure to metformin, inhibited the increase of mitochondrial ROS by upregulation of LKB1, and suppressed the expression of NF-B and the apoptosis regulator protein, Bax (193).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Zheng, 2012, Sirtuin 1-Mediated Cellular Metabolic Memory of High Glucose via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Based on in vitro data, the effects of metformin are dependent on expression of sirtuin1, activation of AMPK, and nuclear orphan receptor NR4A1.

    “Based on in vitro data, the effects of metformin are dependent on the expression of the NAD+ dependent deacetylase, sirtuin1, which targets lysine residues on eNOS as reflected in the figure by removal of ac, the activation of AMPK, and the nuclear orphan receptor, NR4A1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Wang et al. reported that metformin protects complex 1 activity in hepatocytes but enhances mitochondria fission, thereby promoting healthy mitochondrial function via mitophagy.

    “Wang et al. have reported that metformin protects complex 1 activity in a cell culture protocol in hepatocytes but enhances mitochondria fission, thereby promoting healthy mitochondrial function via mitophagy (138).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Wang, 2019, Metformin Improves Mitochondrial Respiratory Activity Through Activation of AMPK, Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Based on both preclinical and clinical data, metformin elicits important protective effects on vascular function that help offset the advance of vascular-related diseases and thereby improves healthspan.

    “Thus, based on both pre-clinical and clinical data, we can conclude that metformin elicits important protective effects on vascular function that help offset the advance of vascular-related diseases and thereby improves healthspan.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Improvements in endothelial and vascular function translate into improved healthspan.

  • May combine two claims.

    Premisecitation

    In the Diabetes Prevention Program study of 3234 pre-diabetic subjects over an average of 2.8 years, both metformin and lifestyle changes were effective in reducing the risk of developing diabetes.

    “data from the Diabetes Prevention Program study of 3234 pre-diabetic subjects over an average of 2.8 years who were randomized to receive placebo, metformin (850 mg bid), or lifestyle intervention, indicated that although both metformin and lifestyle changes were effective in reducing the risk of developing diabetes, lifestyle intervention was more effective (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] 2012, Long-Term Safety, Tolerability, and Weight Loss Associated With Metformin in the Diabetes Prevention Program Outcomes Study, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Preclinical and clinical data indicate that metformin has direct effects to protect the endothelium from diabetes-induced dysfunction and treatment results in improved function of eNOS, generation of NO, and improved blood flow that facilitates glucose disposal.

    “Pre-clinical and clinical data indicates that metformin has direct effects to protect the endothelium from diabetes-induced dysfunction and treatment results in improved function of endothelial nitric oxide synthase (eNOS), the generation of nitric oxide (NO) and improved blood flow that facilitates glucose disposal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Metformin has been reported to offset the effects of aging in the elderly and in cardiovascular disease.

    “Metformin has also been reported to offset the effects of aging in the elderly and in cardiovascular disease (194, 198–200).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [194] Coppé, 2010, The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression, Annu Rev Pathol source

      Not checked in the free run.

    • cites [198] Golbidi, 2013, Exercise and Aging Endothelium, J Diabetes Res source

      Not checked in the free run.

    • cites [199] Sallam, 2016, Exercise Modulates Oxidative Stress and Inflammation in Aging and Cardiovascular Diseases, Oxid Med Cell Longev source

      Not checked in the free run.

    • cites [200] Liu, 2018, Moderate Exercise Suppresses NF-κB Signaling and Activates the SIRT1-AMPK-PGC1α Axis to Attenuate Muscle Loss in Diabetic db/db Mice, Front Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that study, systolic BP and CRP were reduced by 7 to 8% versus 20-25% respectively.

    “The results were similar for effects on systolic BP and C-Reactive Protein (CRP) that were reduced by 7 to 8% versus 20-25% respectively (201).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Malin, 2016, Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk, Exercise Sport Sci Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise activates AMPK, which enhances glucose uptake into muscle and improves insulin sensitivity, thereby offsetting negative effects of obesity, diabetes, and cardiovascular disease, reducing morbidity and improving healthspan.

    “Exercise activates AMPK, which in turn enhances glucose uptake into muscle and improves insulin sensitivity thus helping to offset the negative effects of obesity, diabetes and cardiovascular disease and thereby reducing morbidity and improving healthspan (197).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] O’Neill, 2013, AMPK and Exercise: Glucose Uptake and Insulin Sensitivity, Diabetes Metab J source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The data suggest that exercise, and not metformin, is the "ideal drug".

    “The data suggest that exercise, and not metformin, is the “ideal drug” (201).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Malin, 2016, Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk, Exercise Sport Sci Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At low micromolar concentrations used in this study, neither mitochondrial complex-I nor complex-III oxygen consumption rates were inhibited, but were when 500-μM metformin was used.

    “Furthermore, at the low micromolar concentrations used in this study, neither mitochondrial complex-I nor complex-III oxygen consumption rates were inhibited, but were when 500-μM metformin was used.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [182] Triggle, 2019, Prevention of Hyperglycaemia-Related Oxidative-Stress-Induced Endothelial Dysfunction by Metformin: Novel Involvement of Orphan Nuclear Receptor, NR4a1/Nur77, BritJPharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Wang et al. reported that treatment of streptozotocin-induced diabetic mice with metformin (300 mg/kg/day) in drinking water for 4 weeks suppressed mitochondrial fission through inhibition of dynamin-related protein (Drp1) via an AMPK-dependent process and enhanced mitochondrial fusion.

    “Wang et al., reported that treatment of streptozotocin (STZ)-induced diabetic mice with metformin (300 mg/kg/day) in their drinking water for 4 weeks suppressed mitochondrial fission through inhibition of dynamin-related protein (Drp1) via an AMPK-dependent process and enhanced mitochondrial fusion (186).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Wang, 2017, Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission, Diabetes source

      Not checked in the free run.

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

    Premisecitation

    Nur77 regulates LKB1 localization and is important for regulation of glucose uptake into C212 mouse muscle cells.

    “the orphan receptor, Nur77, regulates LKB1 localization and is also important for the regulation of glucose uptake into C212 mouse muscle cells (184, 185).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [184] Zhan, 2012, The OrphanNuclear Receptor Nur77 Regulates LKB1 Localization and Activates AMPK, Nat Chem Biol source

      Not checked in the free run.

    • cites [185] Mohankumar, 2018, Bis-Indole–Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent Glucose Metabolism and Uptake in C2C12 Cells, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several other studies using a variety of cell types have reported that metformin inhibits NF-κB activation, decreases production of inflammatory cytokines and genes that code for inflammatory response, supporting healthspan benefits of metformin.

    “Several other studies using a variety of different cell types have reported that metformin inhibits NF-κB activation, decreases the production of inflammatory cytokines and the genes that code for the inflammatory response thus supporting the healthspan benefits of metformin (105, 194–196).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [105] Hattori, 2006, Metformin Inhibits Cytokine-Induced Nuclear Factor kappaB Activation via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells, Hypertension source

      Not checked in the free run.

    • cites [194] Coppé, 2010, The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression, Annu Rev Pathol source

      Not checked in the free run.

    • cites [195] Moiseeva, 2013, Metformin Inhibits the Senescence-Associated Secretory Phenotype by Interfering With IKK/NF-κB Activation, Aging Cell source

      Not checked in the free run.

    • cites [196] Hirsch, 2013, Metformin Inhibits the Inflammatory Response Associated With Cellular Transformation and Cancer Stem Cell Growth, Proc Natl Acad Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although much evidence indicates lower levels of IGF-1 benefit enhanced lifespan, IGF-1 plays important roles in homeostasis and not just during childhood, raising concern of potential negative effects of excessive lowering of growth hormone.

    “however, although much of the evidence indicates that lower levels of IGF-1 benefit enhanced lifespan, IGF-1 does play important roles in homeostasis and not just during childhood thus raising the concern of potential negative effects of excessive lowering of the growth hormone.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Metformin inhibits the inflammatory pathway and increases AMPK activation, which inhibits mTOR, a primary target for cell aging modulation.

    “Metformin also, inhibits the inflammatory pathway and increases AMPK activation, which inhibits mTOR, a primary target for cell aging modulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and is notably less effective, or not effective, in older animals, including C. elegans.

    “For instance, as discussed in the next section, despite activating AMPK, metformin has not reproducibly been shown to enhance lifespan in rodents and notably less, or not effective in older animals, including C. elegans (66, 72, 74, 75, 77, 78).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [66] Anisimov, 2008, Metformin Slows Down Aging and Extends Life Span of Female SHR Mice, Cell Cycle source

      Not checked in the free run.

    • cites [72] Espada, 2020, Loss of Metabolic Plasticity Underlies Metformin Toxicity in Aged Caenorhabditis Elegans, Nat Metab source

      Not checked in the free run.

    • cites [74] Anisimov, 2011, If Started Early in Life, Metformin Treatment Increases Life Span and Postpones Tumors in Female SHR Mice, Aging source

      Not checked in the free run.

    • cites [75] Alfaras, 2017, Health Benefits of Late-Onset Metformin Treatment Every Other Week in Mice, NPJ Aging Mech Dis source

      Not checked in the free run.

    • cites [77] Strong, 2016, Longer Lifespan in Male Mice Treated With a Weakly Estrogenic Agonist, an Antioxidant, an α-Glucosidase Inhibitor or a Nrf2-Inducer, Aging Cell source

      Not checked in the free run.

    • cites [78] Smith, 2010, Metformin Supplementation and Life Span in Fischer-344 Rats, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    As a result of metformin moderating the cellular signaling pathways mediated by insulin, IGF-1, and cytokines, both healthspan and lifespan are increased.

    “As a result of metformin moderating the cellular signaling pathways mediated by insulin, IGF-1, and cytokines, both, healthspan and lifespan are increased.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Exercise is universally endorsed as the 'Gold Standard' for improving cardio-respiratory health, and analysis of benefits of exercise for 26 different chronic diseases reflects positively on "Exercise as Medicine".

    “Exercise is universally endorsed as the ‘Gold Standard’ for improving cardio-respiratory health and analysis of the benefits of exercise for 26 different chronic diseases reflects positively on “Exercise as Medicine” (205).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Pedersen, 2015, Exercise as Medicine - Evidence for Prescribing Exercise as Therapy in 26 Different Chronic Diseases, Scand J Med Sci Sports source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Calorie Restriction Society study, those on the calorie-restricted diet demonstrated metabolic improvements including body fat, lower blood pressure, improved insulin sensitivity, and lipid profile.

    “Those on the calorie-restricted diet demonstrated a number of metabolic improvements including body fat, lower blood pressure, and improved insulin sensitivity, and lipid profile (210–212).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [210] Fontana, 2006, Effect of Long-Term Calorie Restriction With Adequate Protein and Micronutrients on Thyroid Hormones, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [211] Fontana, 2004, Long-Term Calorie Restriction Is Highly Effective in Reducing the Risk for Atherosclerosis in Humans, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [212] Meyer, 2006, Long-Term Caloric Restriction Ameliorates the Decline in Diastolic Function in Humans, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The cellular processes that mediate the benefits of calorie restriction on lifespan in mammalian species remain controversial, and there are caveats that limit a positive correlation in mammalian species versus more convincing evidence in lower eukaryotic organisms such as C. elegans.

    “The cellular processes that mediate the benefits of calorie restriction on lifespan in mammalian species remain controversial and although it is tempting to assume an important role for AMPK as a key nutrient sensor, there are a number of caveats that limit a positive correlation in mammalian species versus more convincing evidence in lower eukaryotic organisms, such as C. elegans (219).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] Cantó, 2011, Calorie Restriction: Is AMPK a Key Sensor and Effector, Physiology source

      Not checked in the free run.

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

    Premisecitation

    Caloric restriction of 10-15% without malnutrition has been suggested to have a role in increasing lifespan in humans.

    “Caloric restriction of 10-15% without malnutrition has been suggested to have a role in increasing lifespan in humans (70) (see Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Willcox, 2014, Caloric Restriction, Caloric Restriction Mimetics, and Healthy Aging in Okinawa: Controversies and Clinical Implications, Curr Opin Clin Nutr Metab Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Applying data obtained from studies with C. elegans and rodents to intervention studies in a diverse human population raises obvious limitations.

    “In addition, applying data obtained from studies with C. elegans and rodents to intervention studies in a diverse human population raises obvious limitations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Collectively, these observations support the benefits of calorie restriction and heighten interest in pharmacologic agents, such as metformin, as calorie restriction mimetics.

    “Collectively, these observations support the benefits of calorie restriction and heighten the interest in pharmacologic agents, such as metformin, as calorie restriction mimetics;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [214] Fontana, 2007, Aging, Adiposity, and Calorie Restriction, JAMA source

      Not checked in the free run.

    • cites [215] Longo, 2015, Interventions to Slow Aging in Humans: Are We Ready, Aging Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisereasoning

    Inflammation, apoptosis, autophagy, cell survival, and protein synthesis are all affected by these mechanisms and are all linked to accelerated aging.

    “Inflammation, apoptosis, autophagy, cell survival, and protein synthesis are all affected by these mechanisms and are all linked to accelerated aging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Caloric restriction reduces the generation of growth hormone, insulin, IGF1, and other growth factors, all of which have been shown to hasten aging and increase mortality in a number of species.

    “Caloric restriction reduces the generation of growth hormone, insulin, IGF1, and other growth factors, all of which have been shown to hasten aging and increase mortality in a number of species (see Figure 3) (206).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Fontana, 2010, Extending Healthy Life Span–From Yeast to Humans, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In OVE26 diabetic mice, isolated hearts showed a substantial reduction in AMPK function and cardiomyocyte autophagy as well as mitochondria aggregations and increased apoptosis that was reversed following chronic treatment with metformin.

    “Isolated hearts, from the diabetic mice showed a substantial reduction in AMPK function and cardiomyocyte autophagy as well as mitochondria aggregations dispersed between poorly organized myofibrils and increased apoptosis that was reversed following chronic treatment with metformin (231).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Xie, 2011, Improvement of Cardiac Functions by Chronic Metformin Treatment Is Associated With Enhanced Cardiac Autophagy in Diabetic OVE26 Mice, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy is a process necessary for the removal of damaged proteins and organelles and plays an important role in the regulation of cell aging, providing a supply of nutrients to maintain cellular function during starvation, and inhibition of autophagy mimics accelerated aging.

    “Autophagy is a process necessary for the removal of damaged proteins and organelles and plays an important role in the regulation of cell aging, providing a supply of nutrients to maintain cellular function during starvation, and inhibition of autophagy mimics accelerated aging (52, 228, 229).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] de Cabo, 2014, The Search for Antiaging Interventions: From Elixirs to Fasting Regimens, Cell source

      Not checked in the free run.

    • cites [228] Levine, 2008, Autophagy in the Pathogenesis of Disease, Cell source

      Not checked in the free run.

    • cites [229] Rubinsztein, 2011, Autophagy and Aging, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Smith et al. demonstrated that calorie restriction, but not metformin (in the diet 300 mg/kg/day), extended lifespan in male Fisher-344 rats.

    “Smith et al. have demonstrated that calorie restriction, but not metformin (in the diet 300 mg/kg/day), extended lifespan in male Fisher-344 rats, leading to the conclusion that metformin is not a calorie restriction mimetic (CRM) (78) (see Table 1 for a summary).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Smith, 2010, Metformin Supplementation and Life Span in Fischer-344 Rats, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

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

    Premisenone given

    Both the innate and adaptive immune responses to inflammation play a key role in the ageing process, and differences in these responses between rodents and humans merit attention.

    “No doubt, both the innate and adaptive immune responses to inflammation play a key role in the ageing process, and differences in these responses between rodents and humans merit attention.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If we accept that metformin, despite inhibiting mTOR, is not a CRM, then metformin would not be expected to extend lifespan.

    “If we accept this argument and also accept that metformin, despite inhibiting mTOR, is not a CRM (77, 78) then metformin would not be expected to extend lifespan.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [77] Strong, 2016, Longer Lifespan in Male Mice Treated With a Weakly Estrogenic Agonist, an Antioxidant, an α-Glucosidase Inhibitor or a Nrf2-Inducer, Aging Cell source

      Not checked in the free run.

    • cites [78] Smith, 2010, Metformin Supplementation and Life Span in Fischer-344 Rats, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Embryonic fibroblasts cultured from Atg5 transgenic mice are less affected by oxidative stress-induced cell death, a tolerance reversible by an autophagy inhibitor.

    “Additionally, embryonic fibroblasts cultured from Atg5 transgenic mice are less affected by oxidative stress-induced cell death, a tolerance reversible by an autophagy inhibitor (233).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Pyo, 2013, Overexpression of Atg5 in Mice Activates Autophagy and Extends Lifespan, Nat Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Metformin may play an important role in ageing due to its potential impact on the innate immune response and the generation of ROS caused by inflammatory cytokines.

    “In this regard, metformin may play an important role, due to its potential impact on the innate immune response and the generation of ROS caused by inflammatory cytokines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Song et al. reported a link between SIRT1, AMPK, and metformin-induced autophagy, supporting a synergistic relationship between sirtuin-1 and metformin-mediated effects on aging.

    “Song et al. have reported a link between SIRT1, AMPK, and metformin-induced autophagy thereby supporting a synergistic relationship between the deacetylase, sirtuin-1, and metformin-mediated effects on aging (232).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Song, 2015, Metformin Alleviates Hepatosteatosis by Restoring SIRT1-Mediated Autophagy Induction via an AMP-Activated Protein Kinase-Independent Pathway, Autophagy source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Blagosklonny argued that the metabolic side effects of rapamycin are a consequence of it acting as a CRM and are required to mediate its positive effects on lifespan.

    “Blagosklonny argued that the metabolic side effects of rapamycin are a consequence of it acting as a CRM and are required to mediate its positive effects on lifespan (226).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] Blagosklonny, 2011, Rapamycin-Induced Glucose Intolerance: Hunger or Starvation Diabetes, Cell Cycle source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, overexpression of Atg5 boosts autophagy and induces anti-aging phenotypes including enhanced insulin sensitivity and motor control.

    “In mice, overexpression of Atg5, the protein product of the essential gene for the autophagosome, boosts autophagy and, more importantly, induces anti-aging phenotypes including enhanced insulin sensitivity and motor control (233).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Pyo, 2013, Overexpression of Atg5 in Mice Activates Autophagy and Extends Lifespan, Nat Commun source

      Not checked in the free run.

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

    Premisecitation

    Strong et al. provided the explanation that the insulin-sensitizing effect of metformin offsets the negative effects of rapamycin on glucose homeostasis.

    “Strong et al. provided the explanation that the insulin-sensitizing effect of metformin offsets the negative effects of rapamycin on glucose homeostasis (77).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Strong, 2016, Longer Lifespan in Male Mice Treated With a Weakly Estrogenic Agonist, an Antioxidant, an α-Glucosidase Inhibitor or a Nrf2-Inducer, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of metformin to inhibit autophagy were only seen following a 48-hour incubation with 2 mM metformin, and lower concentrations in the therapeutic range, including 50 μM, were ineffective.

    “The effects of metformin to inhibit autophagy were only seen following a 48-hour incubation with 2 mM metformin, and lower concentrations that are in the therapeutic range, including 50 μM, were ineffective (235).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Samuel, 2017, Metformin Represses Glucose Starvation Induced Autophagic Response in Microvascular Endothelial Cells and Promotes Cell Death, Biochem Pharmacol source

      Not checked in the free run.

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

    Premisecitation

    Calorie restriction is a strong inducer of autophagy and increases the lifespan in C. elegans.

    “Furthermore, calorie restriction is a strong inducer of autophagy and increases the lifespan in C. elegans (230).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] Jia, 2007, Autophagy Is Required for Dietary Restriction-Mediated Life Span Extension in C. elegans, Autophagy source

      Not checked in the free run.

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

    Interpretationcitation

    With the exception of the study by Martin-Montalvo et al., metformin does not extend lifespan in mammals whereas rapamycin does.

    “Collectively, these results demonstrated that the mTOR pathway has a role in lifespan extension in mammals, but raise the question as to why, with the exception of the study by Martin-Montalvo et al., metformin does not extend lifespan in mammals whereas rapamycin does (76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Martin-Montalvo, 2013, Metformin Improves Healthspan and Lifespan in Mice, Nat Commun source

      Not checked in the free run.

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

    Premisecitation

    Smith et al. concluded that metformin is not a calorie restriction mimetic (CRM).

    “Smith et al. have demonstrated that calorie restriction, but not metformin (in the diet 300 mg/kg/day), extended lifespan in male Fisher-344 rats, leading to the conclusion that metformin is not a calorie restriction mimetic (CRM) (78) (see Table 1 for a summary).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Smith, 2010, Metformin Supplementation and Life Span in Fischer-344 Rats, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A higher dose of 1% metformin w/w was toxic and decreased the average lifespan of mice by 14.4%.

    “A higher dose of 1% metformin w/w, on the other hand, was toxic and decreased the average lifespan of mice by 14.4% (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Martin-Montalvo, 2013, Metformin Improves Healthspan and Lifespan in Mice, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diabetes-associated hyperglycemia, hyperinsulinemia, elevated oxidative stress, vascular disease, and inflammation are all linked to cognitive decline.

    “Diabetes-associated hyperglycemia, hyperinsulinemia, elevated oxidative stress, vascular disease, and inflammation are all linked to cognitive decline and, as reflected by a meta-analysis, it was concluded that metformin reduces cognitive decline and dementia in T2DM subjects (255).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] Campbell, 2018, Metformin Use Associated With Reduced Risk of Dementia in Patients With Diabetes: A Systematic Review and Meta-Analysis, J Alzheimer’s Dis source

      Not checked in the free run.

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

    Premisecitation

    The retrospective study highlighted a possible link between metformin and the serine-threonine tumor suppressor LKB1 as a mechanism for the reduced risk.

    “A retrospective study published in 2005 reported that patients with diabetes who had been treated with metformin for T2DM had a lower risk of cancer and highlighted the possible link between metformin and the serine-threonine tumor suppressor, LKB1, as a mechanism for the reduced risk (113) (see Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Evans, 2005, Metformin and Reduced Risk of Cancer in Diabetic Patients, BMJ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    [14C]-Metformin uptake was 13 times higher in OCT3-BT20 cells than in BT-20 cells, and associated with increased AMPK phosphorylation and decreased pS6K phosphorylation in OCT3-BT20 cells, and these results were substantiated in mice with OCT3 overexpressing tumors.

    “[14C]-Metformin uptake was 13 times higher in OCT3-BT20 cells than in BT-20 cells, and associated with increased AMPK phosphorylation and decreased pS6K phosphorylation in OCT3-BT20 cells and these results were substantiated in mice with OCT3 overexpressing tumors (241).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241] Cai, 2016, Cation-Selective Transporters Are Critical to the AMPK-Mediated Antiproliferative Effects of Metformin in Human Breast Cancer Cells, Int J Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These metabolic pathways, rather than a direct anti-proliferative action, may be the primary target of metformin as metformin decreases hepatic gluconeogenesis, improves insulin sensitivity, reduces insulin and blood glucose levels, and these effects also reduce tumor growth.

    “These metabolic pathways, rather than a direct anti-proliferative action, may be the target as Metformin decreases hepatic gluconeogenesis, improves insulin sensitivity, reduces insulin and blood glucose levels, and these effects, which also will reduce tumor growth, rather than a direct anti-proliferative action may be the primary target of metformin (55, 248).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Dowling, 2015, Changes in Insulin Receptor Signaling Underlie Neoadjuvant Metformin Administration in Breast Cancer: A Prospective Window of Opportunity Neoadjuvant Study, Breast Cancer Res: BCR source

      Not checked in the free run.

    • cites [248] Lei, 2017, Metformin Targets Multiple Signaling Pathways in Cancer, Chin J Cancer source

      Not checked in the free run.

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

    Premisecitation

    Chandel et al. argue that higher concentrations of metformin are necessary in in vitro cell culture protocols because the abundance of growth factors and nutrients, such as glucose, reduces the sensitivity to the inhibitory effects of metformin.

    “Chandel et al. argue that higher concentrations of metformin are necessary in in vitro cell culture protocols because the abundance of growth factors and nutrients, such as glucose, reduces the sensitivity to the inhibitory effects of metformin thus reflecting the importance of glucose and the Warburg effect for cancer cell growth as well as the importance of glycemic control in diabetes (249).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Chandel, 2016, Are Metformin Doses Used in Murine Cancer Models Clinically Relevant, Cell Metab source

      Not checked in the free run.

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

    Premisecitation

    An argument to explain the selective action of metformin in some cancers but not all is that there is a differential expression of the influx and efflux transporters in tumor cells that allows for the intracellular accumulation of metformin in the cancer cell and resultant selective toxicity.

    “An argument to explain the selective action of metformin in some cancers but not all is that there is a differential expression of the influx and efflux transporters in tumor cells that allows for the intracellular accumulation of metformin in the cancer cell and resultant selective toxicity (158).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Samuel, 2019, Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer, Biomolecules source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The metabolic changes that occur as a result of diabetes (hyperinsulinemia, hyperglycemia, and dyslipidemia) potentiate signaling pathways and may increase the oncogenic nature of breast tissue through accelerating cell growth and migration, angiogenesis, increasing metastasis, and decreasing the response to chemotherapy.

    “The metabolic changes that occur as a result of diabetes (hyperinsulinemia, hyperglycemia, and dyslipidemia) potentiate signaling pathways and may increase the oncogenic nature of breast tissue through accelerating cell growth and migration, angiogenesis, increasing metastasis, and decreasing the response to chemotherapy (158, 244–247).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [158] Samuel, 2019, Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer, Biomolecules source

      Not checked in the free run.

    • cites [244] Pelton, 2014, Hypercholesterolemia Induces Angiogenesis and Accelerates Growth of Breast Tumors In Vivo, Am J Pathol source

      Not checked in the free run.

    • cites [245] Samuel, 2018, Challenges and Perspectives in the Treatment of Diabetes Associated Breast Cancer, Cancer Treat Rev source

      Not checked in the free run.

    • cites [246] Ferroni, 2015, Type 2 Diabetes and Breast Cancer: The Interplay Between Impaired Glucose Metabolism and Oxidant Stress, Oxid Med Cell Longev source

      Not checked in the free run.

    • cites [247] Mathews Samuel, 2019, Treatment With a Combination of Metformin and 2-Deoxyglucose Upregulates Thrombospondin-1 in Microvascular Endothelial Cells: Implications in Anti-Angiogenic Cancer Therapy, Cancers source

      Not checked in the free run.

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

    Premisecitation

    Concerns have been expressed about how data from observational studies are analyzed.

    “For instance, no association has been shown between the use of metformin and a lower incidence of bladder cancer and concerns have also been expressed how data from observational studies are analyzed (239, 240).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [239] Mamtani, 2014, Incidence of Bladder Cancer in Patients With Type 2 Diabetes Treated With Metformin or Sulfonylureas, Diabetes Care source

      Not checked in the free run.

    • cites [240] Suissa, 2014, Metformin and Cancer: Mounting Evidence Against an Association: Figure 1, Diabetes Care source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LnCaP prostate cancer line, very high concentrations up to 10mM of metformin were required to see significant inhibition, and a strong significant correlation between inhibition of proliferation and MATE2 expression was not seen.

    “In contrast and although LnCaP, a prostate cancer line, proved to be particularly sensitive to metformin and in a concentration range that was within that expected clinically and correlated with a high expression of mRNA for OCT3 and low expression of MATE2 for the other cell lines, very high concentrations, up to 10mM, of metformin were required to see significant inhibition, and a strong”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [254] Chowdhury, 2016, MATE2 Expression Is Associated With Cancer Cell Response to Metformin, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Triple negative breast cancer cells (TNBC) are particularly sensitive to the pro-proliferative effects of glucose, and TNBC cells are more sensitive to metformin at lower levels of glucose.

    “Studies of the effects of glucose concentration on the anti-proliferative effects of metformin on breast cancer cell growth in different human cancer lines In vitro studies reveal that triple negative breast cancer cells (TNBC) are particularly sensitive to the pro-proliferative effects of glucose, and TNBC cells are more sensitive to metformin at lower levels of glucose (250).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250] Wahdan-Alaswad, 2013, Glucose Promotes Breast Cancer Aggression and Reduces Metformin Efficacy, Cell Cycle source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Collectively, these data suggest that expression levels of the uptake and extrusion transporters are not necessarily the limiting factors determining the anti-proliferative effects of metformin and that genetically determined variations in signaling pathways are variably important as are nutrient levels in the tumor microenvironment.

    “Collectively, these data suggest that expression levels of the uptake and extrusion transporters are not necessarily the limiting factors determining the anti-proliferative effects of metformin and that genetically determined variations in signaling pathways are variably important as are nutrient levels in the tumor microenvironment (249, 254).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [249] Chandel, 2016, Are Metformin Doses Used in Murine Cancer Models Clinically Relevant, Cell Metab source

      Not checked in the free run.

    • cites [254] Chowdhury, 2016, MATE2 Expression Is Associated With Cancer Cell Response to Metformin, PloS One source

      Not checked in the free run.

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

    Premisecitation

    It has been argued that inhibition of mitochondrial complex 1 is an important contributor to the cytotoxic effects of metformin and has been observed in cancer cells and supported by data showing reduced inhibition of tumor growth in cancer cells expressing a metformin-resistant yeast complex 1, NDI1.

    “It has also been argued that the inhibition of mitochondrial complex 1 is an important contributor to the cytotoxic effects of metformin and has been observed in cancer cells and supported by data showing reduced inhibition of tumor growth in cancer cells expressing a metformin-resistant yeast complex 1, NDI1 (136, 243).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] Vial, 2019, Role of Mitochondria in the Mechanism(s) of Action of Metformin, Front Endocrinol source

      Not checked in the free run.

    • cites [243] Wheaton, 2014, Metformin Inhibits Mitochondrial Complex I of Cancer Cells to Reduce Tumorigenesis, Elife (Cambridge source

      Not checked in the free run.

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

    Premisecitation

    The link between metformin and activation of AMPK has been emphasized as the basis for the anti-proliferative effects of metformin.

    “Similarly, the link between metformin and the activation of AMPK has been emphasized as the basis for the anti-proliferative effects of metformin (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Anwar, 2014, Colorectal and Prostate Cancer Risk in Diabetes: Metformin, an Actor Behind the Scene, J Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zordoky et al. reported that metformin significantly inhibited growth in cells cultured in normoglycemic conditions, and only for the cells grown in normoglycemic conditions did metformin induce significant AMPK activation.

    “Zordoky et al. reported that metformin significantly inhibited growth in cells cultured in normoglycemic conditions, and only for the cells grown in normoglycemic conditions did metformin induce significant AMPK activation (251).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] Zordoky, 2014, The Anti-Proliferative Effect of Metformin in Triple-Negative MDA-MB-231 Breast Cancer Cells Is Highly Dependent on Glucose Concentration: Implications for Cancer Therapy and Prevention, Biochim Biophys Acta source

      Not checked in the free run.

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

    Premisecitation

    A logical target whereby metformin could mediate its putative antiproliferative effects in cancer is via inhibition of mTOR and pS6K, either via activation of AMPK or via an AMPK-independent pathway.

    “A logical target whereby metformin could mediate its putative antiproliferative effects in cancer is via inhibition of mTOR and the serine-threonine kinase, ribosomal S6K (pS6K), either via activation of AMPK or via an AMPK-independent pathway (241, 242).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [241] Cai, 2016, Cation-Selective Transporters Are Critical to the AMPK-Mediated Antiproliferative Effects of Metformin in Human Breast Cancer Cells, Int J Cancer source

      Not checked in the free run.

    • cites [242] Kalender, 2010, Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Not all of the data is supportive, and metformin, as shown in C. elegans and mice, may be less effective, or ineffective, in older humans.

    “However, not all of the data is supportive and metformin, as shown in C. elegans and mice, may be less effective, or ineffective, in older humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dysregulation of adipose tissue metabolism has been previously linked to an age-related process of ECM deposition, and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms.

    “Dysregulation of adipose tissue metabolism has been previously linked to an age‐related process of ECM deposition and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms (36, 259, 260).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Barzilai, 2012, The Critical Role of Metabolic Pathways in Aging, Diabetes source

      Not checked in the free run.

    • cites [259] Sun, 2011, Adipose Tissue Remodeling and Obesity, J Clin Invest source

      Not checked in the free run.

    • cites [260] Luo, 2016, AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The use of metformin may negate some of the positive effects of exercise and lifestyle and have less favorable effects in older subjects.

    “the use of metformin may negate some of the positive effects of exercise and lifestyle and less favorable effects in older subjects as was also emphasized by the Diabetes Prevention Program (265, 266).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [265] 2006, ]. The Influence of Age on the Effects of Lifestyle Modification and Metformin in Prevention of Diabetes, J Gerontol Ser A: Biol Sci Med Sci source

      Not checked in the free run.

    • cites [266] 2002, Reduction in the Incidence of Type 2 Diabetes With Lifestyle Intervention or Metformin, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data indicate that metformin targets monoacylglycerol lipase, an enzyme responsible for generating pro-inflammatory eicosanoids from 2-arachidonoyl glycerol, providing potential to use metformin to treat Alzheimer's.

    “The potential to use metformin to treat Alzheimer’s is also provided by data indicating that metformin targets monoacylglycerol lipase, an enzyme responsible for generating pro-inflammatory eicosanoids from 2-arachidonoyl glycerol (258).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Syal, 2020, Dysregulated Expression of Monoacylglycerol Lipase Is a Marker for Anti-Diabetic Drug Metformin-Targeted Therapy to Correct Impaired Neurogenesis and Spatial Memory in Alzheimer’s Disease, Theranostics source

      Not checked in the free run.

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

    Study design and conductcitation

    The MILES study is a double-blinded crossover study where subjects act as their own placebo control group.

    “Designed as a crossover study, the Metformin in Longevity Study (MILES) is a double-blinded study where the subjects act as their own placebo control group [(79) Table 1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Kulkarni, 2018, Metformin Regulates Metabolic and Nonmetabolic Pathways in Skeletal Muscle and Subcutaneous Adipose Tissues of Older Adults, Aging Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Metformin, via its direct protective effects on vascular function, may slow the aging process via improved blood flow and provide protection against age-related cognitive decline.

    “Metformin, via its direct protective effects on vascular function, may slow the aging process via improved blood flow and provide protection against age-related cognitive decline.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The MILES findings remain to be validated in other tissues and study designs and do not yet allow identification of the primary site of action of metformin.

    “However, it is important to note a concluding sentence from Kulkarni et al.: “These findings remain to be validated in other tissues and study designs and do not yet allow us to identify the primary site of action of metformin, which then may trigger the observed changes in gene expression” (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Kulkarni, 2018, Metformin Regulates Metabolic and Nonmetabolic Pathways in Skeletal Muscle and Subcutaneous Adipose Tissues of Older Adults, Aging Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Collectively, the attributes of metformin together with extensive literature supportive of benefits in diabetes, obesity, cardiovascular disease, and arguably cancer and dementia could justify its wider use as a prophylactic to offset the effects of aging and enhance healthspan and lifespan.

    “Collectively, these attributes together with an extensive literature supportive of benefits in the settings of diabetes, obesity, cardiovascular disease and, arguably, cancer and dementia could justify its wider use as a prophylactic to offset the effects of aging and enhance healthspan and lifespan.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Metformin is comparatively safe based on a 60-year history of use as an anti-diabetic drug for T2DM.
    • Rests on an assumption: Metformin is no longer protected by patents and is comparatively inexpensive.

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

    Premisecitation

    The apparent human lifespan limit is not likely to be improved by therapies aimed against specific chronic diseases or frailty syndrome.

    ““The proximity of the critical point revealed in this work indicates that the apparent human lifespan limit is not likely to be improved by therapies aimed against specific chronic diseases or frailty syndrome.” (263).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [263] Pyrkov, 2021, Longitudinal Analysis of Blood Markers Reveals Progressive Loss of Resilience and Predicts Human Lifespan Limit, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In adult murine neural stem cells in culture, metformin in the concentration range 500 nM to 1 μM enhanced proliferation and self-renewal dependent on Tap73, and enhanced neuronal differentiation via the AMPK-aPKC-CBP pathway.

    “A molecular basis for the effects of metformin on cognitive function is suggested by data using adult murine neural stem cells in culture that shows metformin in the concentration range 500 nM to 1 μM enhanced proliferation and self renewal dependent on the transcription factor, Tap73, and enhanced neuronal differentiation via the AMPK-atypical protein kinase C (aPKC)-CREB-binding protein (CBP)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Fatt, 2015, Metformin Acts on Two Different Molecular Pathways to Enhance Adult Neural Precursor Proliferation/Self-Renewal and Differentiation, Stem Cell Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    There are concerns about the age-dependent effects of metformin, and in older organisms including C. elegans, rodents, and humans, the effects of metformin are variable and may be detrimental.

    “However, as expressed both in this review and by others there are concerns about the age –dependent effects of metformin and in older organisms, including C.elegans, rodents and humans, the effects of metformin are variable and may be detrimental [see (202)].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Konopka, 2019, Metformin Inhibits Mitochondrial Adaptations to Aerobic Exercise Training in Older Adults, Aging Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    It is argued that TAME trial outcomes will give more insight on whether metformin decreases the risk of developing age-dependent diseases, excluding diabetes, in non-diabetic individuals, and potentially provide a tool to target aging itself.

    “It is argued that TAME trial outcomes will give more insight on whether metformin decreases the risk of developing age-dependent diseases, excluding diabetes, in non-diabetic individuals, and potentially provide a tool to target aging itself and not related diseases individually (60, 261).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Barzilai, 2016, Metformin as a Tool to Target Aging, Cell Metab source

      Not checked in the free run.

    • cites [261] Justice, 2018, Development of Clinical Trials to Extend Healthy Lifespan, Cardiovasc Endocrinol Metab source

      Not checked in the free run.

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

    Interpretationnone given

    A dependence on the use of metformin as a prophylactic to delay aging could decrease the incentive to pursue the proven benefits of lifestyle changes such as improved diet and exercise.

    “a dependence on the use of metformin as a prophylactic to delay aging could serve to decrease the incentive to pursue the proven benefits of lifestyle changes such as improved diet and exercise.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Lifestyle changes such as improved diet and exercise have proven benefits.

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

    Study design and conductcitation

    The TAME trial is a double-blinded, placebo-controlled, multicenter trial planned to involve 14 research centers in the USA and enroll 3000 ethnically diverse, non-diabetic subjects aged 65-80.

    “Targeting Aging with Metformin (TAME) trial is a double-blinded, placebo-controlled, multicenter trial that is planned to involve 14 research centers in the USA, and subject to funding and approval, will enroll 3000 ethnically diverse, non-diabetic subjects aged 65–80 (60, 261).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Barzilai, 2016, Metformin as a Tool to Target Aging, Cell Metab source

      Not checked in the free run.

    • cites [261] Justice, 2018, Development of Clinical Trials to Extend Healthy Lifespan, Cardiovasc Endocrinol Metab source

      Not checked in the free run.

166 of 166

  • The authors state this as an assumption.

    The term healthspan simply reflects a reduction in the risk of disabling disease.

    “We acknowledge that the use of the term ‘healthspan’ is considered by some to be controversial as it cannot readily be quantified and therefore is subjective; however, the term is extensively used. Therefore, to be consistent, we retain its use, accepting the limitations that the term simply reflects a reduction in the risk of disabling disease.”

  • The paper relies on this without support.

    Metformin has a bioavailability of approximately 50%, with unabsorbed drug exiting in the stool, and following a dose of up to 2550 mg/day the concentration of metformin in the gut could reach mM levels.

    “Metformin has a bioavailability of approximately 50% with the unabsorbed drug exiting in the stool and following a dose of up to 2550-mg/day; the concentration of metformin in the gut could reach mM levels.”

  • The paper relies on this without support.

    Improvements in endothelial and vascular function translate into improved healthspan.

    “thereby improves healthspan.”

  • The paper relies on this without support.

    Observational associations between metformin use and mortality reflect a causal mortality benefit of metformin.

    “Collectively, these data imply a clear mortality benefit associated with the use of metformin.”

  • The paper relies on this without support.

    Metformin is comparatively safe based on a 60-year history of use as an anti-diabetic drug for T2DM.

    “Based on a 60-year history of use as an anti-diabetic drug for the treatment of T2DM, metformin is accepted as a comparatively safe drug.”

  • The paper relies on this without support.

    Metformin is no longer protected by patents and is comparatively inexpensive.

    “Metformin is no longer protected by patents and thus is comparatively inexpensive.”

  • The paper relies on this without support.

    Lifestyle changes such as improved diet and exercise have proven benefits.

    “the proven benefits of lifestyle changes such as improved diet and exercise”

  • The paper relies on this without support.

    Long-term chronic use of metformin may cause vitamin B12 deficiency.

    “the long-term chronic use of metformin would require attention to the potential occurrence of vitamin B12 deficiency.”

  • The paper relies on this without support.

    Clinical effectiveness of metformin is associated with plasma concentrations of 20 micromolar or lower.

    “concentrations to clinical effectiveness with plasma concentrations in the range of 20 micromolar or lower.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The anti-aging benefit of calorie restriction mimetics is recognized as elongation of healthspan, like in the case of metformin.

    “the anti-aging benefit is recognized as the elongation of the period spent in good health, “healthspan”, like in the case of metformin [89].”

    From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [89]

    The Introduction defines healthspan as the period of life spent in good health, and the Conclusions accept a healthspan benefit from metformin in patients with type 2 diabetes. But the review does not establish metformin as a calorie-restriction mimetic or an anti-aging intervention that generally extends healthspan; its Calorie Restriction Mimetics section explicitly questions that classification. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Many risk indices for age-related diseases were improved after thymic regeneration in humans, and biological age was reversed.

    “For example, many risk indices for age-related diseases were improved after thymic regeneration in humans (taking three commonly used drugs: growth hormone, dehydroepiandrosterone, and metformin),365 and biological age was reversed.366”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [365]

    Citation 366 is attached to the claim that biological age was reversed. The review’s ‘Clinical Trials to Assess Effects of Metformin on Aging, Healthspan, and Lifespan’ section discusses metformin-related changes in aging pathways, but no passage found reports biological-age reversal after thymic regeneration; searches for thymic regeneration, the three-drug combination, and epigenetic-age reversal did not locate one. The preceding risk-indices clause has a separate citation (365). (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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.

  • Conflicting age ranges for the healthy GDF15 cohort

    Minor

    The table gives the 240 healthy subjects an age range of 23-93 years, while the text gives 22-93 years.

  • Conflicting starting age for the lifespan-extending mouse treatment

    Minor

    The table describes the same Anisimov et al. (74) treatment as starting at 3 months in its protocol but at 1 month in its results.

  • Conflicting diabetic-subject counts for the Singapore study

    Minor

    Table 2 says 365 diabetic subjects were monitored; the text says the study monitored 2,365 subjects with diabetes.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Cardiovascular diseases

Cited by

Sorted by citations

Related

Authors
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R.
Affiliations
  • Weill Cornell Medical College in Qatar (QA)
  • University of Calgary (CA)
Corresponding author
  • Mohammed, Ibrahim
  • Triggle, Chris R.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2021-08-05
Volume
12
Pages
718942-718942
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2021.718942
PMC
PMC8374068
OpenAlex
W3187589847
Semantic Scholar
d988eb125eb36ee919f6775d5d8420fc218b15ed
Cited by
278
References
273
Citations by year
2026: 36 · 2025: 64 · 2024: 71 · 2023: 63 · 2022: 40 · 2021: 3 · 2013: 1
FWCI
4.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Weill Cornell Medical College
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
metformin, anti-aging drugs, healthspan, lifespan extension, aging, type 2 diabetes, pharmacokinetics, pharmacodynamics, insulin sensitivity, oxidative stress, endothelial function, cellular metabolism, cardiovascular disease, cognitive decline, cancer
MeSH terms
Aging, Animals, Diabetes Mellitus, Type 2, Humans, Longevity, Metformin, Caenorhabditis elegans, Oxidative Stress, Mice

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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