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Cited by 766Metabolism, Diabetes, and CancerGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

Benefits of Metformin in Attenuating the Hallmarks of Aging

Open access
Kulkarni, Ameya S., Gubbi, Sriram, Barzilai, Nir·2020·Cell Metabolism
DOI 10.1016/j.cmet.2020.04.001PMC PMC7347426
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Abstract

Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (targeting aging by metformin). This review focuses on metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.

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Crossref · 10.1016/j.cmet.2020.04.001

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  • Findingcitation

    In older human adults, the authors previously demonstrated metformin targets multiple age-associated metabolic and non-metabolic pathways and reverts derangements, using cardiometabolic and transcriptomic outcomes.

    “Moreover, in older human adults, we recently demonstrated metformin’s efficacy in targeting multiple age-associated metabolic and non-metabolic pathways and reverting derangements, using cardiometabolic and transcriptomic outcomes”
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    • cites Kulkarni et al. 2018 source

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  • Findingcitation

    Short-term metformin treatment in older adults induced BRCA-mediated DNA damage response and DNA repair in skeletal muscle.

    “we have previously shown that short-term metformin treatment in older adults induced BRCA-mediated DNA damage response and DNA repair in skeletal muscle”
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    • cites Kulkarni et al. 2018 source

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  • Premisecitation

    Metformin's antihyperglycemic action is attributed to suppression of hepatic gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase, modifying hepatocellular redox state to reduce glucose formation from lactate and glycerol.

    “Metformin’s antihyperglycemic role is attributed to its action on glucose metabolism, specifically as a suppressor of hepatic gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase, thereby modifying the hepatocellular redox state to reduce glucose formation from lactate and glycerol”
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    • cites Madiraju et al. 2014 source

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  • Premisecitation

    Hepatic, intestinal, and adipocytic uptake of metformin is primarily mediated by OCT1.

    “The hepatic, intestinal and adipocytic uptake of metformin is primarily mediated through the OCT1”
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    • cites Wang et al. 2002 source

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    • cites Moreno-Navarrete et al. 2011 source

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  • Premisenone given

    Metformin modulates gut microbiota and branched-chain amino acid availability to gut microbiota, attributable to its effect on nutrient-sensing and aging.

    “A novel role of metformin was elucidated in modulating the gut microbiota and the availability of branched-chain amino acids to the gut microbiota, which is directly attributable to its effect on nutrient-sensing and aging.”
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    Premisecitation

    Biological aging is driven by conserved molecular mechanisms that can be targeted and are summarized as the hallmarks of aging.

    “Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging.”
    • Also stated in: § Introduction · plain
      “To systematically dissect the biological aging process, Lopez-Otin et al characterized nine major hallmarks of aging, widely accepted by the geroscience research community”
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    • cites López-Otín et al. 2013 source

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    • Rests on an assumption: Aging is malleable and can be targeted therapeutically.

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    Premisecitation

    Aging and age-related diseases upregulate mTORC1, while AMPK and sirtuins act in the opposite direction to mTOR signaling.

    “aging and age-related diseases upregulate mTORC1, while AMPK and sirtuins act in the opposite direction to mTOR signaling”
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    • cites López-Otín et al. 2013 source

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    Premisecitation

    Metformin directly inhibits mTORC1 via Rag-GTPase inhibition and indirectly via REDD1 upregulation promoting TSC2 activity and AMPK-mediated phosphorylation of S6K1 and 4E-BP1, decreasing translation.

    “Metformin is shown to directly inhibit mTORC1 via Rag-GTPase inhibition and indirectly via REDD1 upregulation promoting TSC2 activity and AMPK activation-mediated phosphorylation of S6K1 and 4E-BP1- mTORC1 substrates decreasing its translation”
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    Premisecitation

    Metformin reduces age-related disorders and improves healthspan.

    “Metformin- a biguanide that combats age-related disorders and improves healthspan”
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    • cites Barzilai et al. 2016 source

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    Premisecitation

    With aging, cells decline in ability to maintain metabolic homeostasis, contributing to organismal aging.

    “with aging, there is a decline in the ability of the cell to maintain metabolic homeostasis, further contributing to the organismal aging phenotype”
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    • cites Bettedi and Foukas 2017

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    Premisecitation

    Metformin's AMPK-independent mechanisms directly activate SIRT1, directly inhibit mTORC1 via Rag-GTPases, suppress adipogenesis through p70S6K inhibition, activate DNA damage-like response via ATM/Chk2, and activate Nrf2, resulting in downregulation of inflammatory responses.

    “Metformin’s AMPK-independent mechanisms also contribute to the direct activation of SIRT1, direct inhibition of mTORC1 via Rag-GTPases, suppression of adipogenesis through inhibition of p70S6K pathway, activation of DNA damage-like response via the activation of ATM/Chk2 pathway, and activation of Nuclear factor erythroid 2-Related Factor 2 (Nrf2), all of which result in downregulation of”
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    • cites Chen et al. 2017

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    Premisecitation

    Association studies suggest metformin decreases the incidence of most age-related cancers and Alzheimer's disease, and clinical studies support reduced cognitive decline and mortality in diabetics taking metformin compared with non-diabetics.

    “Association studies suggest a decrease in the incidence of most age-related cancers, Alzheimer’s Disease while clinical studies support metformin’s role in a decrease in cognitive decline and reduced mortality in diabetics taking metformin compared to non-diabetics”
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    • cites Barzilai et al. 2016 source

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    Premisecitation

    Human studies suggest attenuation of the GH/IGF-1 axis may protect from age-related conditions, despite inconsistencies in directionality.

    “a number of human studies suggest that its attenuation may protect from age-related conditions”
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    • cites Milman et al. 2016 source

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    Premisecitation

    Metformin reduces hepatic glucose production by improving hepatic insulin sensitivity, thereby lowering fasting plasma glucose, without causing hypoglycemia per se.

    “metformin does not cause hypoglycemia per se but rather reduces hepatic glucose production through improved hepatic insulin sensitivity, which results in the reduction of fasting plasma glucose levels”
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    • cites Jackson et al. 1987 source

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    • cites DeFronzo et al. 1991 source

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    Premisecitation

    In mice and C. elegans, metformin extends lifespan and improves several healthspan indicators.

    “In mice and C. elegans, metformin extends lifespan and improves several indicators of healthspan”
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    • cites Anisimov et al. 2008 source

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    • cites Martin-Montalvo et al. 2013 source

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    • cites De Haes et al. 2014 source

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    Premisecitation

    Metformin activates AMPK via an LKB1-dependent mechanism, mediating lifespan and healthspan extension in mice and C. elegans.

    “metformin activates AMPK via LKB1-dependent mechanism, mediating its effect on lifespan and healthspan extension in mice and C. elegans”
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    • cites Onken and Driscoll 2010

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    • cites Martin-Montalvo et al. 2013 source

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    Premisecitation

    Clinical studies including the Diabetes Prevention Program and the U.K. Prospective Diabetes Study support metformin as effective against diabetes and cardiovascular disease.

    “Clinical studies including the Diabetes Prevention Program (DPP) in non-diabetics and U.K. Prospective Diabetes Study (UKPDS) in diabetics, support metformin’s role as an effective intervention against diabetes and cardiovascular disease.”
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    Metformin decreases insulin and IGF-1 levels and downregulates insulin/IGF-1 signaling in cancer cells.

    “Metformin is shown to decrease insulin and IGF-1 levels and downregulate IIS in cancer cells”
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    Premisecitation

    Very high metformin concentrations are needed to directly inhibit complex I in isolated mitochondria, whereas micromolar concentrations produce weak, reversible, selective, dose- and time-dependent complex I inhibition.

    “Although, very high concentrations of metformin are needed to directly inhibit complex I activity in isolated mitochondria, micromolar concentrations of the drug are effective in achieving a dose- and time-dependent weak, reversible and selective complex I inhibition”
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    • cites Vial et al. 2019 source

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    Premisecitation

    Metformin monotherapy is the preferred first-line pharmacological treatment for type-2 diabetes because of its glucose-lowering effects, as recommended by the American Diabetes Association.

    “As recommended by the American Diabetes Association, due to its glucose-lowering effects, metformin monotherapy is the preferred first-line pharmacological action against type-2 diabetes (2019).”
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    • cites [2019]

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    Premisecitation

    Epidemiological studies show metformin lowers the incidence of multiple age-related diseases and all-cause mortality in both diabetics and non-diabetics.

    “Epidemiological studies have revealed metformin’s gerotherapeutic effect in lowering the incidence of multiple age-related diseases as well as all-cause mortality, in both diabetics and non-diabetics”
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    • cites Campbell et al. 2017 source

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    Premisecitation

    AMPK activation by metformin suppresses advanced glycation end products, mitigating inflammatory cytokine expression.

    “AMPK-activation by metformin is also indicative of its suppressive effect on advanced glycation end products (AGEs), thereby mitigating the expression of inflammatory cytokines”
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    • cites Chung et al. 2017 source

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    Premisecitation

    In humans, metformin has been used clinically for over 60 years, is extensively studied, has a high safety profile, and is positioned to affect pathways of aging and age-related diseases.

    “In humans, metformin has been in clinical use for over 60 years, studied extensively, has a high safety profile and is uniquely positioned to intervene several crucial pathways responsible for aging and age-related diseases”
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    • cites Barzilai et al. 2016 source

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    Premisecitation

    Metformin's metabolic actions include reducing intestinal glucose absorption, restoring insulin secretion in pancreatic beta-cells, and increasing insulin-mediated glucose uptake in muscle and adipose.

    “metformin’s metabolic action includes a reduction in glucose absorption in the intestine (Wu et al. 2017), restoring insulin secretion in pancreatic beta-cells (Patane et al. 2000) and to a lesser extent increasing insulin-mediated glucose uptake in the peripheral tissues of muscle and adipose (Galuska et al. 1991).”
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    • cites Galuska et al. 1991

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    Premisecitation

    Direct activation of AMPK and inhibition of mTORC1 by metformin results from its action on the lysosomal pathway requiring v-ATP-ase-AXIN/LKB1, proposed to increase C. elegans lifespan.

    “The direct activation of AMPK and inhibition of mTORC1 is a result of metformin’s action on the lysosomal pathway, requiring v-ATP-ase-AXIN/LKB1, proposed to be a mechanism to increase the lifespan of C. elegans”
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    Premisecitation

    Inhibition of mitochondrial complex I increases cytoplasmic AMP:ATP and ADP:ATP ratios, which leads to phosphorylation and activation of AMPK.

    “The downstream effect of mitochondrial complex I inhibition is directly evident from the increase in cytoplasmic AMP:ATP and ADP:ATP ratios, which in turn leads to phosphorylation and activation of AMPK”
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    • cites Foretz et al. 2014 source

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    Premisecitation

    Genomic instability is a pivotal hallmark of biological aging, evidenced by increased DNA repair deficits in accelerated aging mouse models and human progeroid syndromes and increased nuclear and mitochondrial DNA damage.

    “as evidenced by increased DNA repair deficits in mouse models of accelerated aging and human progeroid syndromes as well as increased nuclear and mitochondrial DNA damage, genomic instability is a pivotal hallmark of biological aging”
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    Premisecitation

    Genomic instability often accompanies biological aging, and its artificial induction can lead to accelerated aging.

    “genomic instability often accompanies biological aging, while its artificial induction can often lead to an accelerated aging phenotype”
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    • cites Niedernhofer et al. 2018 source

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    Premisecitation

    Metformin delays aging and increases lifespan in C. elegans by modulating microbial folate and inducing methionine restriction.

    “Early evidence of metformin’s role in delaying aging and increasing lifespan, via modulating the microbial folate and inducing methionine restriction was demonstrated in C. elegans”
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    Interpretationcitation

    Metformin lowers body weight and improves insulin metabolism and sensitivity, indirectly lowering systemic inflammation.

    “metformin’s action in lowering body weight and improving insulin metabolism and sensitivity has indirect implications on lowering systemic inflammation as well”
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    Premisecitation

    A highly regulated network of over 2000 proteins comprising molecular chaperones, proteolytic systems, and regulators is crucial to maintain proteostasis.

    “A highly regulated network of > 2000 proteins comprising of molecular chaperones, proteolytic systems and regulators, is crucial to maintain a stable proteome or protein homeostasis (proteostasis)”
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    Premisecitation

    In Clk1 mutant Parkinson's disease mouse models with increased MPP activity, metformin reversed behavioral impairments, reduced alpha-synuclein accumulation, and enhanced LC3-II-mediated autophagy in dopaminergic neurons and midbrain via an AMPK-dependent mechanism.

    “In a Clk1 mutant Parkinson’s Disease mouse models, with increased activity of neurotoxin MPP, metformin treatment reversed behavioral impairments, reduced α-synuclein accumulation and enhanced LC3-II-mediated autophagy in dopaminergic neurons and midbrain, in an AMPK-dependent mechanism”
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    • cites Yan et al. 2017 source

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    Premisecitation

    Age-associated microbial dysbiosis promotes inflammation, gut permeability, and proinflammatory cytokine release.

    “Age-associated microbial dysbiosis (alterations in gut microbiota) is shown to promote inflammation, gut permeability and proinflammatory cytokine release”
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    • cites Thevaranjan et al. 2017 source

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    Metformin induces enhanced autophagic responses in delta-sarcoglycan deficiency-induced dilated cardiomyopathic mouse hearts and enhanced mitophagy in ob/ob mice.

    “metformin induces enhanced autophagic responses in δ-Sarcoglycan deficiency-induced dilated cardiomyopathic mouse hearts and enhanced mitophagy in ob/ob mice”
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    Premisecitation

    In rats, 10-fold lower metformin levels are needed to scavenge mitochondrial ROS than to inhibit mitochondrial complex I, without directly impacting respiratory capacity.

    “it takes 10-fold lower levels of metformin to scavenge mitochondrial ROS than required to inhibit mitochondrial complex I, without directly impacting respiratory capacity as evidenced in rats”
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    Premisecitation

    Metformin extends Drosophila lifespan in a dose-dependent manner only in control OP50 E. coli-colonized strains, not germ-free strains, indicating microbiota mediate metformin-induced lifespan extension across species.

    “recent evidence suggests that metformin extends Drosophila lifespan in a dose-dependent manner, only in control OP50 E.coli colonized strains, and not germ-free strains, indicating the role of microbiota in mediating metformin-induced lifespan extension across species”
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    • cites Pryor et al. 2019 source

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    Premisenone given

    Model organism studies show lifespan extension through alterations in pathways enhancing proteostasis, including insulin/IGF-1 signaling, mitochondrial ETC, enhanced autophagy, and nutrient-sensing.

    “Model organism studies have revealed lifespan extensions through alterations within pathways enhancing proteostasis, including Insulin/IGF-1 signaling, mitochondrial ETC, enhanced autophagy, and nutrient-sensing.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Studies show metformin's genome protective effects via reduction of oxidative stress, DNA damage and DNA damage response, regulation of ATM protein kinase and epigenetic effects, but there is no consensus on the underlying mechanism.

    “Studies have shown metformin’s genome protective effects via reduction of oxidative stress, DNA damage and DNA damage response, regulation of Ataxia Telangiectasia Mutated (ATM) protein kinase and epigenetic effects, however, there is no consensus regarding the underlying mechanism”
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    • cites Najafi et al. 2018 source

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    Premisecitation

    Metformin upregulates autophagy-related proteins LAMP-1 and Beclin-1, which attenuate hyperglycemia-induced apoptosis in cardiomyocytes.

    “Autophagy-related proteins LAMP-1 and Beclin-1 are upregulated by metformin treatment, which have been shown to attenuate hyperglycemia-induced apoptosis in cardiomyocytes”
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    • cites Wang et al. 2017 source

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    Premisecitation

    In older diabetic individuals, metformin monotherapy lowered circulating pro-inflammatory cytokines and associated mortality risk in a five-year follow-up study.

    “In older diabetic individuals, metformin monotherapy lowered the levels of circulating pro-inflammatory cytokines and the associated mortality risk in a recent five-year follow-up study”
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    • cites Tizazu et al. 2019 source

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    Premisecitation

    In animals, metformin's glucoregulatory role results from increased Lactobacilli abundance in the upper small intestine, while its anti-inflammatory role is associated with increased Akkermansia, Bacteroides, Butyricimonas, and Parabacteroides genera.

    “animal studies revealed that metformin’s glucoregulatory role was an effect of increased Lactobacilli abundance in the upper small intestine, while its anti-inflammatory role was associated with increased abundance of Akkermansia, Bacteroides, Butyricimonas, and Parabacteroides genera”
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    Premisecitation

    A key consequence of disrupted intercellular communication is inflammaging, accompanied by increased pro-inflammatory cytokines (TNF, IL-6, IL-1beta), NF-kB and interferon signaling, senescent cell burden and secretome, and altered autophagy.

    “A key consequence of this dysregulation is age-associated chronic, sterile, low-grade inflammatory state called inflammaging, that is usually accompanied by a consistent increase in pro-inflammatory cytokine secretion (TNF, IL-6, and IL-1β), activation of NF-κB and interferon signaling, increased burden of senescent cells and their secretome as well as altered autophagic response”
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    Premisecitation

    Metformin inhibits IKK/NF-kB activation, suppressing proinflammatory cytokine markers and SASP.

    “This suppression of proinflammatory cytokine markers along with senescence-associated secretory phenotype (SASP) is also evident through metformin’s inhibition of IKK/NF-κB activation”
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    • cites Moiseeva et al. 2013 source

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    Premisecitation

    In a dose-dependent manner, metformin prevents activation of ATM protein kinase, lowering ROS and gammaH2AX.

    “in a dose-dependent manner, metformin prevents activation of ATM-protein kinase, thereby lowering ROS and γH2AX-a sensitive marker of DNA-double stranded breaks and genomic instability”
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    Premisecitation

    Metformin reversed age-associated dysregulation of the rejuvenating and differentiating capacity of oligodendrocyte progenitor cells, improving remyelination.

    “Interestingly, metformin also reversed age-associated dysregulation of rejuvenating and differentiating capacity of oligodendrocyte progenitor cells, further improving remyelination (Neumann et al. 2019).”
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    • cites Neumann et al. 2019 source

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    Premisecitation

    Metformin's cardioprotective role in human arterial appendage tissue is through dose-dependent mild inhibition of complexes I, IV, and V, with reduced superoxide production and attenuation of mitochondrial permeability transition pore.

    “metformin’s cardioprotective role in human arterial appendage tissue was elucidated through its dose-dependent mild inhibitory effect on the activity of complexes I, IV and V with a reduced superoxide production and attenuation of mitochondrial permeability transition pore”
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    • cites Emelyanova et al. 2019 source

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    Premisecitation

    Complex I inhibition by metformin reduces ROS-mediated IL-6 release in alveolar macrophages, preventing arterial thrombosis in mice.

    “complex I inhibition by metformin also reduces ROS mediated IL-6 release in alveolar macrophages, thereby preventing arterial thrombosis in mice”
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    • cites Soberanes et al. 2019 source

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    Premisenone given

    There is no consensus on the association between changes in stem cell number of various tissue subtypes and aging.

    “Currently, there is no consensus regarding the association between the change in stem cell number of various tissue sub-types and aging.”
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    Premisecitation

    Loss of histones, imbalance in histone modifications, changes in chromatin architecture, breakdown of the nuclear lamina, and DNA and histone methylation changes characterize biological aging.

    “Loss of histones, imbalance in histone modifications, changes in chromatin architecture, breakdown of the nuclear lamina, as well as DNA and histone methylation changes are characteristics of biological aging (Sen et al. 2016).”
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    • cites Sen et al. 2016 source

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    Premisecitation

    Metformin's activation of Gpx7 through Nrf2 delays cellular attrition and premature aging, extending the lifespan of human mesenchymal stem cells.

    “The previously mentioned gerotherapeutic effect of metformin in activating Gpx7 via Nrf2 is shown to delay cellular attrition and prevent premature aging thereby increasing the lifespan of human mesenchymal stem cells (Fang et al. 2018).”
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    • cites Fang et al. 2018 source

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    Premisecitation

    In non-diabetic HER2-positive breast cancer patients and human breast cancer xenografts in nude mice, metformin augmented global H3K27me3 levels and directly targeted demethylase KDM6A/UTX.

    “In non-diabetic HER2-positive breast cancer patients as well as human breast cancer xenografts injected into nude mice, the drug augmented global H3K27me3 levels, directly targeted demethylase KDM6A/UTX”
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    • cites Cuyàs et al. 2017

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    Premisecitation

    Metformin's AMPK-dependent and independent mechanisms influence histone modifications through phosphorylation of HATs, inhibition of Class II HDACs, and activation of SIRT1.

    “Metformin’s AMPK-dependent and independent mechanisms have been observed to influence histone modifications through phosphorylation of histone acetyltransferases (HATs), inhibition of Class II histone deacetylases (HDACs) and activation of SIRT1 (Bridgeman et al. 2018).”
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    • cites Bridgeman et al. 2018 source

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    Premisecitation

    Metformin induces mitochondrial biogenesis and delays cellular senescence by acting through SIRT3 upregulation, linking histone methylation and sirtuin activation.

    “metformin was also shown to induce mitochondrial biogenesis and delay cellular senescence by acting through SIRT3 upregulation”
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    • cites Karnewar et al. 2018 source

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    Interpretationcitation

    In several instances, metformin has been effective in targeting stem cell exhaustion, delaying stem cell aging and maintaining stem cell function.

    “In several instances, metformin has been effective in targeting stem cell exhaustion, delaying stem cell aging and maintaining stem cell function.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Metformin inhibits complex I of the mitochondrial ETC, directly impacting mitochondria-induced oxidative stress by lowering ROS or indirect scavenging.

    “Metformin inhibits complex I (NADH:ubiquinone oxidoreductase) of the mitochondrial ETC, thereby directly impacting mitochondria-induced oxidative stress via lowering ROS or by indirect scavenging mechanism”
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    • cites Kelly et al. 2015 source

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    Premisecitation

    Metformin treatment delays satellite cell activation and maintains a quiescent, low metabolic state, thereby maintaining stem cell numbers.

    “Metformin treatment is shown to delay satellite cell activation and maintain a quiescent, low metabolic state thereby maintaining stem cell numbers (Pavlidou et al. 2019).”
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    • cites Pavlidou et al. 2019 source

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    • Rests on an assumption: Aged muscle satellite cells fail to maintain quiescence and the capacity to self-renew once activated.

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    Premisecitation

    Metformin increases expression and protein activity of hepatic and skeletal muscle PGC-1alpha, inducing mitochondrial biogenesis.

    “Metformin increases the expression and protein activity of hepatic and skeletal muscle associated PGC-1α, a co-transcriptional regulator that induces mitochondrial biogenesis”
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    • cites Suwa et al. 2006 source

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    • cites Aatsinki et al. 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin promoted neurogenesis and cognitive recovery in both sexes.

    “while still promoting neurogenesis and cognitive recovery in both sexes (Ruddy et al. 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ruddy et al. 2019 source

      Not checked in the free run.

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

    Premisecitation

    Some studies show hematopoietic and intestinal stem cells increase with age in humans and animal models (mice, Drosophila).

    “some studies have demonstrated that hematopoietic and intestinal stem cells increase with age in humans as well as animal models (mice, Drosophila spp.)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schultz and Sinclair 2016

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Maintaining stem cell number and function can combat age-associated loss of rejuvenation potential and promote tissue repair.

    “Maintenance of stem cell number and function can help combat age-associated loss of rejuvenation potential and thereby promote tissue repair.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Ubiquitination, sumoylation, O-GlcNAcylation, and ADP-ribosylation can have varying influences on transcriptional dysregulation.

    “while post-translational modifications like ubiquitination, sumoylation, O-GlcNAcylation, and ADP-ribosylation, can have varying influences on transcriptional dysregulation (Pal and Tyler 2016, Peleg et al. 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pal and Tyler 2016 source

      Not checked in the free run.

    • cites Peleg et al. 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Histone acetylation and phosphorylation can lead to active transcription, loss of cellular homeostasis and age-associated metabolic decline.

    “Histone modifications such as acetylation and phosphorylation can lead to active transcription, loss of cellular homeostasis and age-associated metabolic decline”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pal and Tyler 2016 source

      Not checked in the free run.

    • cites Peleg et al. 2016 source

      Not checked in the free run.

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

    Premisecitation

    The exact mechanism for decreased stem and progenitor cell rejuvenation capacity is unknown, but common mechanisms of stem cell aging include telomere attrition, molecular damage, epigenetic drift, and deregulation of developmental pathways.

    “The exact mechanism for decreased stem and progenitor cell capacity to rejuvenate is not known, but the common mechanisms of stem cell aging can be explained by some cell-intrinsic and extrinsic factors including telomere attrition, molecular damage, epigenetic drift and deregulation of developmental pathways”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ermolaeva et al. 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Metformin attenuates the increased burden of senescent cells and upregulation of SASP with aging.

    “It is evident that metformin attenuates the increased burden of senescent cells and upregulation of SASP with aging.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Metformin's effects on mitochondrial function and cellular senescence may induce protective feedback on telomere maintenance.

    “Additionally, metformin’s effect on mitochondrial function and cellular senescence may induce protective feedback mechanisms on telomere maintenance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Unexpected positive side effects of metformin include increased healthspan and decreased mortality.

    “Clearly, the unexpected positive side effects of metformin include increased healthspan and decreased mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Metformin's effect on cellular senescence and SASP is context-dependent, being anti-cancer by inducing apoptosis and anti-aging by inhibiting inflammation.

    “Thus, metformin’s effect on cellular senescence and SASP is context-dependent (anti-cancer by inducing apoptosis and anti-aging by inhibiting inflammation)”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    There is inherent variability in metformin's transcriptional and epigenetic regulation via histone and DNA modifications and its effects on miRNA.

    “There is inherent variability in metformin’s transcriptional and epigenetic regulation via histone and DNA modifications and its effects on miRNA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Metformin, although not senolytic, effectively suppresses cellular senescence and SASP in multiple age-associated dysfunctions.

    “Metformin- although not exhibiting senolytic properties, has been effective in suppressing cellular senescence and SASP in multiple age-associated dysfunctions.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Telomeres are conserved ribonucleoprotein complexes at eukaryotic chromosome ends that protect against degradation from incomplete DNA replication.

    “Telomeres are highly conserved ribonucleoprotein complexes on the termini of eukaryotic chromosomes that play a crucial role in protecting chromosomal ends from degradation caused by an incomplete DNA replication (Casagrande and Hau 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Casagrande and Hau 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With aging and stress, telomeres deteriorate, and because adult cells have insufficient telomerase, they progressively shorten with cell proliferation.

    “With aging and stress exposure, these regions are particularly vulnerable to deterioration, and due to insufficient telomerase in adult cells to replenish this loss, they undergo progressive attrition with cell proliferation (Blackburn et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Blackburn et al. 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular senescence is a major driver of aging, with age-associated accumulation of senescent cells.

    “Seminal discoveries, first by Hayflick and Moorehead, and lately by Baker et al., concretized cellular senescence as a major driver of aging with the age-associated accumulation of senescent cells”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hayflick and Moorhead 1961 source

      Not checked in the free run.

    • cites Baker et al. 2011 source

      Not checked in the free run.

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

    Premisecitation

    Senescent cells can adopt a SASP phenotype that can paradoxically cause tumor growth.

    “recent evidence suggests that senescent cells can morph their phenotype to SASP, which can paradoxically cause tumor growth (Coppé et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Coppé et al. 2010 source

      Not checked in the free run.

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

    Premisecitation

    Senolytics, drugs that selectively induce apoptosis in senescent cells, have shown potential and clinical utility to alleviate aging and age-related phenotypes.

    “More recently, senolytics- drugs that selectively induce apoptosis in senescent cells have shown tremendous potential and clinical utility to alleviate aging and age-related phenotypes (Kirkland et al. 2017, Xu et al. 2018, Justice et al. 2019).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kirkland et al. 2017 source

      Not checked in the free run.

    • cites Xu et al. 2018

      Not checked in the free run.

    • cites Justice et al. 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin upregulates DICER1 and downstream miRNAs, several of which are reduced with cellular senescence.

    “Apart from its effect on DNA and histone methylation, metformin also upregulates DICER1 and downstream miRNAs, several of which are reduced with cellular senescence”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Noren Hooten et al. 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    As evidence links metformin to all hallmarks of aging, metformin's impact on any hallmark has direct consequences on systemic attenuation across several other hallmarks.

    “But as the accumulation of evidence links metformin to all hallmarks of aging, it is very important to remember that metformin’s impact on any of these hallmarks has direct consequences on systemic attenuation across several other hallmarks of aging (Figure 2).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    An important limitation to studying metformin's action on aging is its tissue-specificity, dose-dependency, and the role of mitochondrial inhibition in contributing to its effects.

    “An important limitation to studying metformin’s action on aging is its tissue-specificity, dose-dependency and the role of mitochondrial inhibition in contributing to any of its effects.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Most minor side effects include gastrointestinal discomfort such as abdominal or stomach pain, early satiety, decreased appetite, and diarrhea, which usually subside after one or two weeks.

    “Most of these minor side effects include gastrointestinal discomfort such as abdominal or stomach pain, early satiety, decreased appetite, and diarrhea, which usually subside after one or two weeks of use (McCreight et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McCreight et al. 2016 source

      Not checked in the free run.

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

    Interpretationcitation

    Microbiome changes may be secondary to reduced vitamin B12 levels with chronic metformin use.

    “Microbiome changes may also be secondary to reduced vitamin B12 levels with chronic metformin use, although the mechanism is still unclear”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aroda et al. 2016 source

      Not checked in the free run.

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

    Interpretationnone given

    Patients with severe side effects including MALA may be more sensitive to mitochondrial complex-1 inhibition due to genetic mechanisms.

    “but it is possible that those with severe side effects including MALA subjects may be more sensitive to the inhibition of mitochondrial complex-1, attributable to genetic mechanisms.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Targeting aging at any primary or secondary level will ultimately make cells, tissues, and systems more youthful, with a direct effect on systemic biology of aging.

    “With this line of thought, we suggest that targeting aging at any of the primary or secondary levels, will ultimately make the cells, tissues, and systems more youthful, with a direct effect on the systemic biology of aging (Figure 2).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Several clinical trials are currently underway to assess metformin as monotherapy and with lifestyle interventions on clinical and molecular outcomes of aging hallmarks.

    “Several clinical trials are currently underway to assess the response of metformin as a monotherapy and in combination with lifestyle interventions like exercise, on clinical and molecular outcomes of individual hallmarks of aging.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites NCT03451006

      Not checked in the free run.

    • cites NCT03309007

      Not checked in the free run.

    • cites NCT03107884

      Not checked in the free run.

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

    Premisecitation

    Minor side effects occur with metformin.

    “As in most drugs, minor side effects occur with metformin, but it is important to understand whether they reveal anything about the mechanism of action of this drug.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McCreight et al. 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Metformin's metabolic effects are mainly through activation of AMPK and inhibition of mitochondrial complex I.

    “The metabolic effects of metformin are mainly through its metabolic arm via activation of AMPK and oxidative arm through inhibition of complex I of the mitochondrial ETC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Metformin-induced attenuation of major hallmarks of biological aging and their interconnectivity, along with its known safety profile and long-term human use, makes it an attractive candidate against aging.

    “In addition to its known safety profile and long-term use in humans, metformin-induced attenuation of the major hallmarks of biological aging and their interconnectivity makes it a very attractive candidate against aging”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Few patients need vitamin B12 replacement.

    “and few patients need vitamin B12 replacement (Aroda et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aroda et al. 2016 source

      Not checked in the free run.

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

    Interpretationcitation

    These side effects could result from an acute change in the gut microbiome, as evidenced in nematodes and other smaller organisms.

    “These side effects could be the result of an acute change in the gut microbiome, as evidenced in nematodes and other smaller organisms (Cabreiro et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cabreiro et al. 2013 source

      Not checked in the free run.

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

    Premisenone given

    Metformin has additional direct effects on mTORC1, PGC1-α, Insulin-IGF1 signaling, SIRT1, NF-κB signaling, and pro-inflammatory cytokines.

    “There are additional direct effects on mTORC1, PGC1-α, Insulin-IGF1 signaling, SIRT1, NF-κB signaling, and pro-inflammatory cytokines”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Since metformin is not a hypoglycemic agent, it is not likely to cause hypoglycemia unless used with other glucose-lowering drugs in diabetic individuals.

    “It is also important to understand that, consistent with its biological effects since metformin is not a hypoglycemic agent it is not likely to cause hypoglycemia unless used in combination with other glucose-lowering drugs in diabetic individuals.”
    Quote in the paperNot a substantial claim
84 of 84

  • The paper relies on this without support.

    Effects of metformin on aging hallmarks observed in cell lines and model organisms can be translated to human aging.

    “These characteristics make metformin an attractive gerotherapeutic to translate to human trials.”
    “here we attempt to link its mode of action by highlighting its role on individual hallmarks of biological aging as evidenced in cell lines and model organisms”

  • The paper relies on this without support.

    Aging is malleable and can be targeted therapeutically.

    “Aging is accompanied by an inherent biological mechanism that is malleable and can be targeted using therapeutic interventions.”

  • The paper relies on this without support.

    The hallmarks of aging and their interconnectivity can serve as an evaluation tool to assess and prioritize interventions effective in targeting aging.

    “The hallmarks and their interconnectivity can serve as an evaluation tool to assess and prioritize interventions that can be deemed effective in targeting aging.”

  • The paper relies on this without support.

    Aged muscle satellite cells fail to maintain quiescence and the capacity to self-renew once activated.

    “In muscle, aged satellite cells fail to maintain quiescence and the capacity to self-renew once activated.”
4 of 4

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?

  • Metformin inhibits the SASP and alleviates several age-related conditions and chronic diseases.

    “The antidiabetic drug metformin, which, among other activities, inhibits the SASP, alleviates several age-related conditions and chronic diseases110–114.”

    From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [113]

    The section on cellular senescence reports that metformin suppresses SASP in several age-associated settings, but also says its effect is context-dependent and can increase SASP-related expression in some cancer settings. The Introduction reports clinical benefits for diabetes and cardiovascular disease, while evidence for several other age-related diseases is described largely as associations with lower incidence; the unqualified claim that metformin alleviates them overstates that evidence. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Metformin has been shown to improve cardiovascular function and prolong life span in diabetic patients, prompting investigation into its ability to delay aging in nondiabetic individuals.

    “Metformin has been shown to improve cardiovascular function and prolong life span in diabetic patients, prompting investigation into the ability of metformin to delay aging in nondiabetic individuals (Targeting Aging with Metformin; TAME study) (Kulkarni et al. 2020).”

    From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Kulkarni et al. 2020

    The Introduction (page unavailable) reports evidence for reduced cardiovascular disease and mortality associated with metformin, and identifies TAME as a study of its potential to target human aging. It does not establish that metformin has been shown to improve cardiovascular function or prolong lifespan specifically in diabetic patients; its human evidence concerns disease outcomes and mortality, while the explicit lifespan-extension finding concerns mice and C. elegans. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Dysfunctional mitochondria, persistent DNA damage response, C/EBPβ and NF-κB, mTOR, and other factors are involved in regulating SASP.

    “Furthermore, dysfunctional mitochondria,195 persistent DNA damage response,196 CCAAT/enhancer-binding protein β (C/EBPβ) and NF-κB,197 mTOR, and other factors are involved in regulating SASP.194”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [197]

    The section “Metformin downregulates SASP and lowers senescent cell burden” (page unavailable) identifies NF-κB inhibition as a way metformin modulates SASP. The paper also discusses mTORC1, mitochondrial function, and DNA-damage responses, but the passages found do not establish them—or C/EBPβ—as regulators of SASP. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Metformin improves hallmarks of ageing, such as DNA repair and imbalanced protein homeostasis.

    “Metformin, an effective drug, has been shown to improve hallmarks of ageing, such as DNA repair and imbalanced protein homoeostasis.405”

    From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [405]

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.

  • Metformin is described as both activating and inhibiting sirtuins

    Minor

    The paper repeatedly describes metformin as activating SIRT1, but later says that it directly inhibits sirtuins. The direction of the claimed effect is inconsistent.

1 of 1

The citation lists haven’t been fetched yet

References 184 · Cited by 766

Authors
Kulkarni, A. S., Gubbi, S., & Barzilai, N.
Affiliations
  • Albert Einstein College of Medicine (US)
  • National Institutes of Health (US)
Corresponding author
  • Kulkarni, Ameya S.
  • Barzilai, Nir
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2020-07
Volume
32
Issue
1
Pages
15-30
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2020.04.001
PMC
PMC7347426
OpenAlex
W3019800544
Cited by
766
References
184
Citations by year
2026: 127 · 2025: 135 · 2024: 134 · 2023: 144 · 2022: 118 · 2021: 78 · 2020: 30
FWCI
8.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
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 › Physiology › Telomeres, Telomerase, and Senescence
Keywords
metformin, hallmarks of aging, nutrient sensing, autophagy, intercellular communication, macromolecular damage, stem cell aging, mitochondrial function, transcriptional regulation, telomere shortening, cellular senescence, healthspan
MeSH terms
Aging, Animals, Autophagy, Cell Communication, Humans, Hypoglycemic Agents, Metformin, Mitochondria, Cellular Senescence

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 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

Statistics and arithmetic are recomputed, not judged.

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

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