The DOI matches its Crossref record; 82 of the 83 references it cites were found in a registry or an index; 50 of the 74 sources its claims cite were checked for support.
Metformin as a Tool to Target Aging
Open accessAbstract
Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This perspective argues that metformin engages multiple aging-related mechanisms and reviews evidence from model organisms and human studies to support testing it as an aging-targeted intervention. It describes the planned TAME trial, which would test metformin in older adults using a composite outcome of age-related diseases.
Key findings
- Metformin affects several pathways linked to aging, including reduced insulin/IGF-1 signaling, mTOR inhibition, mitochondrial complex I inhibition, AMPK activation, lower reactive oxygen species and DNA damage, and effects on inflammation, autophagy, and senescence. In C. elegans it extends lifespan partly by altering microbial folate and methionine metabolism, though the paper notes no human evidence for that mechanism.
- Animal lifespan results are mixed. Metformin increased mean lifespan by about 40% in female outbred mice, by 14% when started early (with weaker effects when started later), by 8% in a breast cancer model, by about 20% in a Huntington’s disease model only in males, and by 4%–6% across different mouse breeds; healthspan indices improved by about 30%. Some studies found no lifespan extension, including Drosophila at 1 mM and rats at a dose roughly 15 times the human dose, which the paper suggests may reflect toxicity.
- Human evidence includes a 31% reduction in type 2 diabetes incidence versus placebo over about 3 years in the Diabetes Prevention Program; in UKPDS, about 20% lower cardiovascular risk (p = 0.032) and 42% lower diabetes-related death (p = 0.017); in HOME, a 40% reduction in a cardiovascular composite over 4 years; a meta-analysis reporting 31% lower cancer incidence and 34% lower cancer mortality; a 51% lower risk of cognitive impairment in the Singapore Longitudinal Aging Study; and a 36% reduction in all-cause mortality in UKPDS long-term follow-up (p = 0.011). Negative trials included GIPS III and CAMERA.
- The proposed TAME trial would enroll 3,000 subjects aged 65–79 at about 14 U.S. centers and measure time to a composite outcome including cardiovascular events, cancer, dementia, and mortality, along with functional and geriatric endpoints.
Methods
- This is a narrative review/perspective that synthesizes evidence from model organisms, randomized clinical trials, and observational studies to justify metformin as an initial aging-targeted drug.
- It describes the design of the planned TAME randomized controlled trial: 3,000 participants, ages 65–79, approximately 14 centers, and a composite outcome of cardiovascular events, cancer, dementia, and mortality plus functional and geriatric endpoints.
- No primary data analysis, systematic search strategy, or meta-analytic method is reported in the paper.
Limitations
- The paper states that it remains unclear whether metformin acts through multiple pathways or whether its effects are downstream of a single primary mechanism; that not all animal studies show lifespan extension, with high doses possibly toxic; that human observational data cannot exclude residual bias and confounding; that no definitive trials have tested cognition; and that TAME has not yet been conducted.
- Evident from the text: as a review/perspective, the evidence is selected rather than systematically appraised, and the TAME design description lacks details on dosing, follow-up duration, and statistical analysis. Human benefits are drawn largely from diabetic or high-risk populations, which limits generalization to broader aging populations.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
50 of 74 cited sources checked · 39 supported · 1 flagged · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“inhibition of mitochondrial complex 1 in the electron transport chain and reduction of endogenous production of reactive oxygen species (ROS) (Batandier et al., 2006; Bridges et al., 2014; Zheng et al., 2012)”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Not checked — no full text of the sourcecites Batandier et al., 2006 source
- Disputedcites Bridges et al., 2014 sourceExperimental — accuracy not yet measured
The Results section (“Biguanide effects on the flavin site and H2O2 production”) says metformin increases ‘native’ H2O2 production, rather than reducing it. It distinguishes that effect from a decrease in paraquat-stimulated H2O2 production. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Supportedcites Zheng et al., 2012 source
The Results section reports that metformin decreased ROS generation in cells exposed to high glucose. It also reports that metformin reduced the increase in retinal ROS in diabetic rats, supporting the attributed reduction in ROS production. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“When rapamycin is administered late in life, it extends lifespan (Harrison et al., 2009; Miller et al., 2011), slows aging in a dose-dependent manner, shows differential effects by sex (Wilkinson et al., 2012), and is synergistic with metformin.”
§ Metformin as a Tool to Target Aging > Introduction > Interventions to Prolong Lifespan
What the sources say
- Partly supportedcites Wilkinson et al., 2012 sourceExperimental — accuracy not yet measured
The Liver degeneration Results report a dose-dependent decline in an age-related liver lesion in male mice, and the Adrenal tumors Results report a significant trend across doses. The Discussion concludes more broadly that rapamycin slows aspects of aging in mice, but does not establish that its overall effect on aging is dose-dependent. (LLM, conf=0.88)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“activation of AMP-activated kinase (AMPK) (Cho et al., 2015; Duca et al., 2015; Foretz et al., 2010; Lien et al., 2014; Lu et al., 2015; Zheng et al., 2012)”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Supportedcites Cho et al., 2015 source
The Results passage reports that metformin induced AMPK activation in rat pituitary adenoma cells, measured by phosphorylation. This directly supports the attributed claim. (LLM, conf=0.94)
- Supportedcites Duca et al., 2015 source
In the passage labeled Abstract (Fig. 1f), the paper reports that intraduodenal metformin increased phosphorylated AMPK relative to total AMPK in rat duodenal mucosa. It also describes this as activation of duodenal AMPK. (LLM, conf=0.94)
- Supportedcites Foretz et al., 2010 source
The Introduction states that metformin treatment activates AMPK and reports that this has been observed in human and rodent tissues. The Discussion further suggests that metformin indirectly stimulates AMPK by lowering ATP levels; its finding that gluconeogenesis inhibition is AMPK-independent does not contradict the activation claim. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Metformin favorably influences metabolic and cellular processes closely associated with the development of age-related conditions, such as inflammation (Saisho, 2015), autophagy (Song et al., 2015; Xie et al., 2011), and cellular senescence (Jadhav et al., 2013; Moiseeva et al., 2013).”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Not checked — no full text of the sourcecites Saisho, 2015 source
- Supportedcites Song et al., 2015 source
Song et al. is cited for the autophagy portion of the sentence, not for inflammation or cellular senescence. The Results section reports increased autophagic flux after metformin treatment in hepatocytes, and the Discussion reports induced liver autophagic flux in ob/ob mice. The Discussion also notes that autophagy function can decline with age; it does not establish a benefit for age-related conditions in humans. (LLM, conf=0.92)
- Supportedcites Xie et al., 2011 source
The Discussion reports that chronic metformin treatment enhanced cardiac autophagy in diabetic mice. Xie et al. is cited for the autophagy portion of the sentence, not for its separate claims about inflammation or cellular senescence. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery source the paper cites for this claim was checked and supports it.
In the paper
“More importantly, these pathways have been evaluated in mammalian models, in which health span and lifespan have been extended by genetic manipulation or drugs (Johnson et al., 2013).”
§ Metformin as a Tool to Target Aging > Introduction > Targeting Health Span
What the sources say
- Supportedcites Johnson et al., 2013 source
The “mTOR in mammalian ageing and healthspan” section reports that rapamycin extends lifespan in mice and delays several age-related changes. It also reports increased lifespan after S6K1 gene knockout in female mice. The paper thus supports the claim about drug and genetic interventions in mammalian models, though the knockout lifespan benefit was sex-specific. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In C. elegans metformin extends lifespan by several possible mechanisms including the alteration of the microbiome, specifically by changing microbial folate and methionine metabolism (Cabreiro et al., 2013).”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Supportedcites Cabreiro et al., 2013 source
The Introduction states that metformin’s lifespan-extending effects in C. elegans are mediated by cocultured E. coli, in which it inhibits folate and methionine metabolism. The Discussion adds that the lifespan effect depends on the bacterial strain; the citing sentence presents this as one possible mechanism, not a universal effect. (LLM, conf=0.94)
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Studies have demonstrated that genetic pathways modulate healthy lifespan in diverse species across great evolutionary distance and established that aging-related pathways constitute a target for intervention (Barzilai et al., 2012; Longo et al., 2015).”
§ Metformin as a Tool to Target Aging > Introduction
What the sources say
- Supportedcites Barzilai et al., 2012 source
The section on attenuated mTOR signaling describes a highly conserved pathway whose genetic inhibition extends lifespan in yeast, nematodes and fruit flies. The section on exceptional human survival links FOXO3A to longevity and healthy aging, supporting the cross-species paraphrase. Page numbers are not available in our copy. (LLM, conf=0.88)
- Supportedcites Longo et al., 2015 source
In “Inhibitors of the TOR pathway,” the paper links mTOR signaling to lifespan and healthspan in several model species and reports that genetic or pharmacological reduction extends lifespan in yeast, worms, flies, and mice. It also identifies mTOR signaling as a candidate for targeted intervention. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“inhibition of mitochondrial complex 1 in the electron transport chain and reduction of endogenous production of reactive oxygen species (ROS) (Batandier et al., 2006; Bridges et al., 2014; Zheng et al., 2012)”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Not checked — no full text of the sourcecites Batandier et al., 2006 source
- Supportedcites Bridges et al., 2014 source
The Results section (‘Metformin and related compounds inhibit catalysis by isolated complex I’) reports that metformin inhibits complex I catalysis, although weakly and reversibly. This supports the attributed claim about complex I inhibition; the claim does not attribute the sentence’s separate ROS-reduction point to this source alone. (LLM, conf=0.94)
- Partly supportedcites Zheng et al., 2012 sourceExperimental — accuracy not yet measured
The Results section reports that metformin decreased ROS generation in retinal endothelial cells under high-glucose stress. The Discussion links this effect to the SIRT1/LKB1/AMPK pathway, but the paper does not say that metformin inhibits mitochondrial complex I of the electron transport chain. No page number is available in our copy. (LLM, conf=0.86)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A more recent study (Martin-Montalvo et al., 2013) demonstrated that metformin increased lifespan by 4%–6% in different mouse breeds.”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Partly supportedcites Martin-Montalvo et al., 2013 sourceExperimental — accuracy not yet measured
The Results (‘Metformin increases healthspan and longevity of mice’) report mean lifespan extensions of 5.83% in C57BL/6 mice and 4.15% in B6C3F1 mice at the 0.1% dose. The B6C3F1 result was not statistically significant, so saying the study ‘demonstrated’ an increase in both strains overstates the evidence. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Studies have demonstrated that genetic pathways modulate healthy lifespan in diverse species across great evolutionary distance and established that aging-related pathways constitute a target for intervention (Barzilai et al., 2012; Longo et al., 2015).”
§ Metformin as a Tool to Target Aging > Introduction
What the sources say
- Supportedcites Barzilai et al., 2012 source
The Conclusions and Future Directions section identifies metabolic signaling pathways as potential therapeutic targets for delaying aging and reports that rapamycin can extend mammalian life span. The section on attenuated mTOR signaling also describes genetic and pharmacological interventions in that aging-related pathway that extend life span in model organisms. (LLM, conf=0.93)
- Supportedcites Longo et al., 2015 source
The ‘Inhibitors of the TOR pathway’ section reports lifespan extension through genetic or pharmacological intervention in yeast, worms, flies, and mice, and identifies mTOR signaling as a target. The Conclusions likewise identify aging-related pathways and interventions to target them. Page numbers were not provided in our copy. (LLM, conf=0.93)
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
- It may state two separate claims as one. 20
- Probably not a substantial claim. 7
Every source the paper cites for this claim was checked and supports it.
In the paper
“When started early in life, mean lifespan was increased by 14%, but with initiation at older ages, this effect declined (Anisimov et al., 2011).”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Supportedcites Anisimov et al., 2011 source
The Abstract reports a 14% increase in mean lifespan when metformin treatment began at 3 months in female SHR mice, compared with 6% when it began at 9 months and no increase at 15 months. The Results (Survival and longevity of female SHR mice) give the corresponding figures as 14.1% and 6.1% and note p>0.05. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Metformin delays the onset of carcinoma and extends lifespan by a mean of 8% in a breast cancer model (Anisimov et al., 2010)”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Supportedcites Anisimov et al., 2010 source
The Introduction reports that metformin increased mean lifespan by 8% and delayed mammary adenocarcinoma onset in HER-2/neu mice. The Discussion likewise says it slowed mammary tumor development in this breast-cancer model. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Beyond these cellular processes, there is a growing body of evidence that metformin can delay aging and increase healthy lifespan in vivo, specifically in nematodes and several rodent strains by adding metformin to the diet (Anisimov et al., 2008, 2011; Cabreiro et al., 2013; De Haes et al., 2014).”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Partly supportedcites Anisimov et al., 2008 sourceExperimental — accuracy not yet measured
The Abstract reports that metformin extended lifespan and slowed age-related loss of estrous function in female SHR mice; the Introduction also describes findings in another mouse strain. This paper does not report metformin extending lifespan in nematodes, and its own experiment administered metformin in drinking water, not in the diet. (LLM, conf=0.88)
- Partly supportedcites Anisimov et al., 2011 sourceExperimental — accuracy not yet measured
The Discussion reports increased lifespan, delayed tumors, and signs of delayed cellular senescence in female SHR mice treated with metformin, supporting the rodent portion of the claim. But Materials and Methods (Experimental design; page unavailable) specifies metformin was given in drinking water, not added to the diet. This paper does not provide the nematode evidence, which the citing sentence also attributes to other citations. (LLM, conf=0.89)
- Supportedcites Cabreiro et al., 2013 source
The Results section reports that metformin increased C. elegans lifespan and slowed its age-related rise in mortality. The Experimental Procedures describe metformin-supplemented culture medium. The Introduction also reports delayed aging in rodents as background, while the sentence provides separate citations for the rodent evidence. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“When rapamycin is administered late in life, it extends lifespan (Harrison et al., 2009; Miller et al., 2011), slows aging in a dose-dependent manner, shows differential effects by sex (Wilkinson et al., 2012), and is synergistic with metformin.”
§ Metformin as a Tool to Target Aging > Introduction > Interventions to Prolong Lifespan
What the sources say
- Supportedcites Wilkinson et al., 2012 source
The Discussion reports that rapamycin diminished the age-dependent decline in spontaneous activity, but the effective dose differed between males and females. The Results also describe age-related lesions affected by rapamycin in males, females, or both sexes. (LLM, conf=0.92)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Surprisingly, metformin-treated diabetic patients had survival rates similar to (and, among those age > 70, even better than) their matched non-diabetic control group, despite the fact that the diabetic patients were more obese and had greater co-morbidities at baseline.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Association of Metformin with Decreased Mortality
What the sources say
- Partly supportedcites Bannister et al., 2014 sourceExperimental — accuracy not yet measured
The Metformin monotherapy compared with matched control group section reports higher BMI and greater baseline morbidity in the metformin group. The Unadjusted survival patterns section reports little overall survival difference and better survival with metformin among patients aged 71–75, but it does not establish that result for everyone over 70. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Feeding metformin to Drosophila resulted in a robust activation of AMPK and reduced lipid stores, but did not increase lifespan (Slack et al., 2012).”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Supportedcites Slack et al., 2012 source
The Abstract states that feeding metformin to adult Drosophila robustly activated AMPK, reduced lipid stores, and did not increase lifespan in either sex. The Results section, “Metformin Treatment does not Extend Lifespan in Drosophila,” likewise reports no survival benefit across the tested concentrations. (LLM, conf=0.95)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“One study suggested that T2DM patients treated with metformin had increased risk for poor cognitive performance (Moore et al., 2013); however, it had a number of methodological flaws (Alagiakrishnan et al., 2013) and has not been replicated.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Association of Metformin with Better Cognitive Function
What the sources say
- Supportedcites Moore et al., 2013 source
The Results section reports worse cognitive performance among participants with diabetes who were taking metformin (adjusted OR 2.23, 95% CI 1.05–4.75), and the Conclusions describe the finding as an association. The methodological-flaws clause cites a different source, while the replication statement is not attributed to Moore et al.; neither is part of this verdict. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites Alagiakrishnan et al., 2013
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In non-diabetic subjects, the GIPS III study (Lexis et al., 2014) failed to demonstrate the benefit of short-term metformin treatment (4 months) on left ventricular ejection fraction, major adverse cardiovascular events, and mortality in post-myocardial infarction patients”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Clinical Trials
What the sources say
- Supportedcites Lexis et al., 2014 source
The Abstract reports that four months of metformin did not improve left ventricular ejection fraction compared with placebo in patients without diabetes after STEMI. Major adverse cardiac events were not significantly different between groups (P = .16), and all patients were alive at four months, so the trial demonstrated no benefit on mortality during that period. (LLM, conf=0.94)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“a more thorough analysis that included more data and accounted for heterogeneous comparators showed that overall cancer incidence was reduced by 31% and cancer mortality by 34% (Gandini et al., 2014).”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Observational Studies Suggest Metformin Decreases Cancer Incidence
What the sources say
- Supportedcites Gandini et al., 2014 source
The Results section, “Overall Cancer Incidence and Mortality – Effects of BMI and Study Type,” reports 31% lower overall cancer incidence and 34% lower cancer mortality among metformin users compared with users of other anti-diabetic compounds. These are the paper’s pooled estimates; the paper also cautions that the associations may not be causal and become smaller or nonsignificant in some bias-adjusted analyses. (LLM, conf=0.94)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“As expected in these studies, metformin also increased AMPK activity and increased antioxidant protection, resulting in reductions in both chronic inflammation and accumulation of oxidative damage (Martin-Montalvo et al., 2013)”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
What the sources say
- Supportedcites Martin-Montalvo et al., 2013 source
The Results section (page unavailable) reports increased phosphoactive AMPK in metformin-treated mice and increased antioxidant and stress-response proteins that contributed to reduced hepatic oxidative damage. It also reports reduced inflammatory signaling and increased expression of anti-inflammatory genes in their livers. (LLM, conf=0.88)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“After a single 1.5 g dose, the peak plasma concentration of 18 mM occurs in 3 hr, with a mean plasma half-life of about 20 hr (Foretz et al., 2014).”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Considerations in Designing Human Metformin Trials
What the sources say
- Partly supportedcites Foretz et al., 2014 sourceExperimental — accuracy not yet measured
The Pharmacokinetics of metformin section reports a peak at 3 hours after a 1.5 g dose and a mean plasma half-life of about 20 hours. It gives the peak concentration as about 18 µM, not 18 mM; the citing sentence overstates it by a factor of 1,000. (LLM, conf=0.95)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While one meta-analysis (Stevens et al., 2012) did not show that metformin prevents cancer”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Observational Studies Suggest Metformin Decreases Cancer Incidence
What the sources say
- Supportedcites Stevens et al., 2012 source
The Discussion reports that the meta-analysis found no statistically significant beneficial effect of metformin on cancer outcomes. It also cautions that the broad confidence intervals do not rule out a smaller protective effect, which is consistent with saying the analysis did not show prevention rather than that it disproved it. (LLM, conf=0.94)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“To date, there is no evidence for such effects in humans.”
§ Metformin as a Tool to Target Aging > Metformin Modulates the Biology of Aging and Health Span in Model Organisms
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Lifespan has been verifiably modulated by genetic, pharmacologic, and dietary interventions in multiple model systems.”
§ Metformin as a Tool to Target Aging > Introduction
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“In the Singapore Longitudinal Aging Study, metformin use was associated with a 51% reduced risk of cognitive impairment (defined by modified Mini-Mental Status Exam score % 23), which remained robust to adjustment for vascular and non-vascular risk factors.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Association of Metformin with Better Cognitive Function
What the sources say
- Not matchedcites Ng et al., 2014
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Data from several randomized clinical trials and multiple observational studies provide evidence for such an effect, which would not be expected from glucose lowering alone.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
In the paper
“Further, the risk of lactic acidosis appears to be related to renal function, not age per se, and is currently considered to be very low (Aroda et al., 2016).”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Considerations in Designing Human Metformin Trials
What the sources say
- Not checked — no full text of the sourcecites Aroda et al., 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The majority of observational data support metformin benefit in CVD, but residual bias and confounding cannot be ruled out”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Observational Studies
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Vitamin B12 deficiency occurred in ~7% of metformin group versus 5% in placebo group after 13 years; risk of B12 deficiency increases with duration of use but was not greater in older compared with younger subjects in DPPOS (Lalau et al., 1990).”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Considerations in Designing Human Metformin Trials
What the sources say
- Not checked — no full text of the sourcecites Lalau et al., 1990
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If metformin can target and delay aging, its administration should be associated with fewer age-related diseases in general, rather than merely the decreased incidence of a single disease.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Studies on biodistribution of metformin in mice showed accumulation mainly in the gastrointestinal tract, kidney, and liver.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Considerations in Designing Human Metformin Trials
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“Patients with T2DM allocated to metformin compared with conventional treatment had risk reduction of ~20% (p = 0.032) for CVD and 42% (p = 0.017) for diabetes-related death (UKPDS Group, 1998).”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Clinical Trials
What the sources say
- Not matchedcites UKPDS Group, 1998
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The mechanisms proposed relate to reduced insulin levels, improved insulin action, decreased IGF-1 signaling, and activation of AMPK.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Observational Studies Suggest Metformin Decreases Cancer Incidence
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“While metformin can beprescribed at dosages of up to 2,250 mg/day, no further effects of decreasing glucose are noted after 1,600–1,700 mg/day.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Considerations in Designing Human Metformin Trials
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear? Based: unclearIt may state two separate claims as one.
In the paper
“the safety of met-formin use in DPP/DPPOS was reported on in 2012, when over 18,000 patients-years of follow-up had accrued, and by which time ~20% of the cohort was age 70 or older (mean age ~64). There were no cases of lactic acidosis or significant hypoglycemia (Diabetes Prevention Program Research Group, 2012).”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Considerations in Designing Human Metformin Trials
What the sources say
- Not matchedcites Diabetes Prevention Program Research Group, 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
In the paper
“In one small clinical trial, T2DM patients with depression (n = 58) were treated with metformin or placebo for 24 weeks (Guo et al., 2014). The metformin group showed improved cognitive performance and reduced depressive symptoms, concurrent with improved glycemic control.”
§ Metformin as a Tool to Target Aging > Human Studies of Metformin that Target Age-Related Diseases > Association of Metformin with Better Cognitive Function
What the sources say
- Not checked — no full text of the sourcecites Guo et al., 2014 source
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Metformin's aging-related mechanisms observed in model organisms are conserved in humans.
“Metformin is a drug approved to treat diabetes but appears to target a number of aging-related mechanisms.”
The paper relies on this without support.
A composite outcome of cardiovascular events, cancer, dementia, and mortality can serve as a measure of aging per se in TAME.
“Rather than study the effects of metformin on each separate condition, we will measure time to a new occurrence of a composite outcome that includes cardiovascular events, cancer, dementia, and mortality.”
The paper relies on this without support.
Age-related diseases share a common aging process such that a single drug can delay them together.
“If metformin can target and delay aging, its administration should be associated with fewer age-related diseases in general, rather than merely the decreased incidence of a single disease.”
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 cited source says what the claim attributes to it.
In the citing paper
“Metformin is a powerful calorie restriction mimetic in aging mice (Dhahbi, Mote, Fahy, & Spindler, 2005) and has been proposed as a candidate for slowing aging in humans (Barzilai, Crandall, Kritchevsky, & Espeland, 2016).”
From Reversal of epigenetic aging and immunosenescent trends in humans. (2019) · cites this paper as Barzilai, Crandall, Kritchevsky, & Espeland, 2016
In the citing paper
“Metformin- a biguanide that combats age-related disorders and improves healthspan”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Barzilai et al. 2016
In the citing paper
“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”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Barzilai et al. 2016
In the citing paper
“One of the main actions of metformin is the inhibition of mitochondrial complex I (NADH:ubiquinone oxidoreductase), that leads to multiple downstream effects both on metabolic and non-metabolic pathways responsible in the aging process”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Barzilai et al. 2016
In the citing paper
“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”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Barzilai et al. 2016
In the citing paper
“Metformin, a widely prescribed antidiabetic drug, has been shown to alleviate aging in preclinical studies [177].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [177]
In the citing paper
“New insights may also come from the use of caloric restriction mimetics, such as metformin, an activator of 5′ AMP-activated protein kinase (AMPK).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [94]
In the citing paper
“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).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [60]
In the citing paper
“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).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [60]
In the citing paper
“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).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [60]
In the citing paper
“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).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [60]
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.
Trial described as unpublished despite a published citation
MinorThe text calls the Luchsinger et al. trial unpublished, but its reference lists results of a randomized clinical trial published in the Journal of Alzheimer's Disease in 2016.
“In an unpublished trial, non-diabetic subjects (n = 80) with mild cognitive impairment showed significant improvements in some cognitive domains after 12 months of metformin treatment (Luchsinger et al., 2016).”
“51. Luchsinger JA Perez T Chang H Mehta P Steffener J Pradabhan G Ichise M Manly J Devanand DP Bagiella E 2016 Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial J Alzheimers Dis 51 501 514”
Citations
Cites
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Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
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mTOR is a key modulator of ageing and age-related disease
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Metformin improves healthspan and lifespan in mice
Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M.-J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3192 · Cited by 1,445
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Flagged first, then by citations
1 of the 83 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 501–600 of 1,150
Gao, F., Wen, H., Feng, S., Li, M., Zhu, L., Zhang, Y., Xi, Y., & Xiang, X.-L. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.164747 · Cited by 21
Mitochondrial Dysfunction as a Key Event during Aging: From Synaptic Failure to Memory Loss
Jara, C., Torres, A. K., Olesen, M. A., & Tapia‐Rojas, C. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.88445 · Cited by 20
Rad, A. N., Shams, G., Safdarian, M., Khorsandi, L., Grillari, J., & Makhmalzadeh, B. S. (2020) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2020.119603 · Cited by 20
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The development and benefits of metformin in various diseases
Dong, Y., Qi, Y., Jiang, H., Tian, M., Zhang, Y., Peng, C. S., Li, W.-C., Zhang, Y., Zhou, Y., Zang, Y., et al. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-0998-6 · Cited by 21
Ma, M., Pan, Y., Zhang, Y., Yang, M., Xi, Y., Lin, B., Hao, W., Liu, J., Wu, L., Liu, Y., et al. (2023) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-023-00781-8 · Cited by 20
“Metformin is widely used for diabetes treatment (Aroda et al. 2017; Barzilai et al. 2016).”
BackgroundThe autophagy-senescence axis as a threshold model of aging and therapeutic targeting
Bahar, M. E., Hwang, J. S., Lai, T. H., Akter, K.-M., Maulidi, R. F., & Kim, D. R. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104079 · Cited by 20
“[75]”
Richardson, A. G. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa208 · Cited by 20
Biological resilience in health and disease
Weavers, H. (2024) · Disease Models & Mechanisms · doi:10.1242/dmm.050799 · Cited by 20
“…drug metformin, which mimics the effects of dietary restriction and prolongs lifespan in animal models by activating numerous stress responses (Barzilai et al., 2016), as well as rapamycin, a potent inhibitor of the mTOR protein kinase that regulates cellular metabolism, growth and survival…”
Suzuki, H., Hasegawa, S., Fushimi, S., Tagami, K., Nishikawa, M., Kondo, Y., & Yasuda, H. (2025) · Scientific Reports · doi:10.1038/s41598-025-93647-5 · Cited by 20
Corley, M. J., Pang, A. P. S., Shikuma, C. M., & Ndhlovu, L. C. (2023) · Aging Cell · doi:10.1111/acel.13926 · Cited by 19
Gedawy, A., Al‐Salami, H., & Dass, C. R. (2020) · Therapeutic Delivery · doi:10.4155/tde-2020-0102 · Cited by 19
Lin, H., Shi, F., Jiang, S., Wang, Y., Zou, J., Ying, Y., Huang, D., Luo, L., Yan, X., & Luo, Z. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16076 · Cited by 19
New tricks from old dogs join the fight against ageing
Savage, N. J. (2017) · Nature · doi:10.1038/d41586-017-08387-y · Cited by 19
Repurposing digoxin for geroprotection in patients with frailty and multimorbidity
Lee, H., Wilson, D. V., Bunting, K. V., Kotecha, D., & Jackson, T. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101860 · Cited by 19
“multi-centre randomised controlled trial which will assess the effect of metformin on ageing more holistically (Barzilai et al., 2016; Justice et al., 2018).”
BackgroundRehman, A., Satyam, S. M., El‐Tanani, M., Prabhakar, S., KUMARI, R. R., Shetty, P., Mohammed, S. S. N., Nafees, Z., & Alomar, B. (2025) · Cancers · doi:10.3390/cancers17152466 · Cited by 20
“The ongoing TAME (Targeting Aging with Metformin) trial represents a paradigm shift, evaluating metformin as a gerotherapeutic agent to delay multimorbidity in aging populations, offering a unique opportunity to test aging biology in a clinical context [116].”
Kumari, S., Bubak, M. P., Schoenberg, H. M., Davidyan, A., Elliehausen, C. J., Kuhn, K. G., VanWagoner, T. M., Karaman, R., Scofield, R. H., Miller, B. F., et al. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab358 · Cited by 20
A Critical Assessment of Fasting to Promote Metabolic Health and Longevity
Fazeli, P. K., & Steinhauser, M. L. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf021 · Cited by 19
“AMP kinase is induced by fasting, is 1 of the pathways targeted by the diabetes drug metformin, and therefore metformin is being repurposed as a potential antiaging therapy (266). mTor is another nutrient sensing regulatory node.”
Martinović, A., Mantovani, M., Trpchevska, N., Novak, E., Milev, N. B., Bode, L., Ewald, C. Y., Bischof, E. Y., Reichmuth, T., Lapides, R. A., et al. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1495029 · Cited by 19
Targeting mitochondrial autophagy for anti-aging
Shan, W., Liu, Y., Tang, R., Li, L., Yang, H., & Lin, L. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02913-y · Cited by 19
“Metformin is a drug approved for treating diabetes, but it has been found to regulate aging by inhibiting in fl ammatory pathways and modulating oxidative stress, autophagy, and protein synthesis [104].”
Pharmacological interventions in human aging
Petr, M. A., Matiyevskaya, F., Osborne, B., Berglind, M., Reves, S., Zhang, B., Ezra, M. B., Carmona-Marin, L. M., Syadzha, M. F., Mediavilla, M. C., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102213 · Cited by 20
Kidney-Targeted Drug Delivery System Based on Metformin-Grafted Chitosan for Renal Fibrosis Therapy
Sun, H., Shi, K., Zuo, B., Zhang, X., Liu, Y., Sun, D., & Wang, F. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00827 · Cited by 19
Metformin protects red blood cells against rotenone induced oxidative stress and cytotoxicity
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“FRAP, being a marker of antioxidant capacity of plasma, is a reliable and primary measure for the evaluation of oxidative damage (Benzie and Strain 1996).”
BackgroundMethodKoppula, S., Akther, M., Haque, M. E., & Kopalli, S. R. (2021) · Nutrients · doi:10.3390/nu13114058 · Cited by 18
Is anti-ageing drug discovery becoming a reality?
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Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging
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Metformin: a metabolic modulator
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“[4] Previous reports have shown that phenformin retains the ability to reduce passive transport through NPC and to inhibit mTORC1 in a manner that depends on Rag GTPase (RAG) heterodimers.[1], [7] Wu and colleagues hypothesized that phenformin limits mTORC1 activation by restraining the nucleo-cytosolic transit of RAGs”
BackgroundEvaluation of the pharmacokinetics of metformin and acarbose in the common marmoset
Fernández, E., Ross, C. N., Liang, H., Javors, M. A., Tardif, S. D., & Salmon, A. B. (2019) · Pathobiology of Aging & Age-related Diseases · doi:10.1080/20010001.2019.1657756 · Cited by 18
“However, there is strong support for testing the effects of metformin on human aging due in part to its relative safety and widespread use [7,8].”
BackgroundTargeting the Electron Transport System for Enhanced Longevity
Radovic, M., Gartzke, L. P., Wink, S. E., van der Kleij, J. A., Politiek, F. A., & Krenning, G. (2025) · Biomolecules · doi:10.3390/biom15050614 · Cited by 17
“More recently, and still ongoing, the ‘Targeting Aging with Metformin’ (TAME) trial [64,65] is focusing on the effect that metformin has on delaying age-related chronic diseases and its effects on healthspan by tracking multiple aging biomarkers in non-diabetic adults.”
Acer Truncatum Seed Oil Alleviates Learning and Memory Impairments of Aging Mice
Xiao, L., Li, T., Hong, X., Liu, J., Yang, X. F., & Liu, G. P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.680386 · Cited by 18
“Metformin targeted several molecular mechanisms of aging, and also reduced the incidence of cancer and neurodegenerative disease (Barzilai et al., 2016).”
BackgroundModulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs
Thomas, C., Wurzer, L., Malle, E., Ristow, M., & Madreiter‐Sokolowski, C. T. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.905261 · Cited by 18
“, 2010) the regulation of autophagy (Semancik and Vanderwoude, 1976; Suwa et al., 2006; Salminen and Kaarniranta, 2012; Aatsinki et al., 2014; Barzilai et al., 2016; Zhou et al., 2016; Herzig and Shaw, 2018).”
BackgroundInfluentialChhunchha, B., Kubo, E., Krueger, R. R., & Singh, D. P. (2023) · Antioxidants · doi:10.3390/antiox12010140 · Cited by 18
Şeylan, C., & Tarhan, Ç. (2023) · FEMS Yeast Research · doi:10.1093/femsyr/foad018 · Cited by 18
“…it is not certain whether this multifaceted effect of metformin in the cell is associated with triggering a single mechanism related to aging and sequential cellular events, or whether it occurs because it can affect many targets in different pathways at the same time (Barzilai et al. 2016).”
BackgroundDrugs that target aging: how do we discover them?
Myers, A., & Lithgow, G. J. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1597049 · Cited by 18
“Interested readers may wish to follow the progress of the proposed metformin TAME trial, which would be a novel long-range clinical study aimed at monitoring metformin’s potential to delay onset of multiple agingrelated comorbidities [48].”
BackgroundMetformin treatment of juvenile mice alters aging-related developmental and metabolic phenotypes
Zhu, Y. X., Fang, Y., Medina, D., Bartke, A., & Yuan, R. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111597 · Cited by 18
Phillips, P. C. A., Branco, M. S. L. A., Cliff, C. L., Ward, J. K., Squires, P. E., & Hills, C. E. (2024) · Diabetic Medicine · doi:10.1111/dme.15408 · Cited by 18
Zhang, J., Brown, R., Hogan, M. V., Onishi, K., & Wang, J. H. (2022) · Journal of Orthopaedic Research® · doi:10.1002/jor.25470 · Cited by 18
Cellular senescence in the tumor with a bone niche microenvironment: friend or foe?
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Wu, H., Zhang, Q., Zhu, J., Wu, L., Xiao, Y., & Yang, X. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.09.002 · Cited by 18
“In parallel, pioneering studies such as the Targeting Aging with Met-formin trial are establishing crucial precedents for geroscience-based regulatory endpoints [309,310].”
Targeting Aging with Metformin (TAME)
Padki, M. M., & Stambler, I. (2021) · Springer eBooks · doi:10.1007/978-3-030-22009-9_400 · Cited by 18
Ketone body metabolism declines with age in mice in a sex-dependent mannerPreprint
Eap, B., Nomura, M., Panda, O., Garcia, T. Y., King, C. D., Rose, J., Leone, T. C., Kelly, D. P., Schilling, B., & Newman, J. C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.05.511032 · Cited by 18
McKenzie, A. I., Mahmassani, Z. S., Petrocelli, J. J., de Hart, N. M. M. P., Fix, D. K., Ferrara, P. J., LaStayo, P. C., Marcus, R. L., Rondina, M. T., Summers, S. A., et al. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111804 · Cited by 18
Reitz, K. M., Seymour, C. W., Vates, J., Quintana, M., Viele, K., Detry, M. A., Morowitz, M. J., Morris, A., Methé, B. A., Kennedy, J. N., et al. (2020) · BMJ Open · doi:10.1136/bmjopen-2020-037690 · Cited by 17
Murillo-Cancho, A. F., Lozano‐Paniagua, D., & Soriano, B. J. N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199643 · Cited by 17
“Metformin, widely used in the treatment of type 2 diabetes, has been associated with cognitive improvements, reductions in inflammatory biomarkers (IL-6, TNF-α ), and activation of autophagic processes, even in non-diabetic individuals [46,55].”
Liu, W., Weng, S., Chen, Y., Cao, C., & Peng, D. (2024) · Aging Clinical and Experimental Research · doi:10.1007/s40520-023-02660-z · Cited by 17
“Retrospective observational studies associate metformin with increased human life span and fewer age-related diseases by suppressing adipocyte proinflammatory responses [64].”
BackgroundAre GLP-1s the first longevity drugs?
(2025) · Nature Biotechnology · doi:10.1038/s41587-025-02932-1 · Cited by 17
Longevity Science and Women’s Health and Wellbeing
Farrelly, C. (2023) · Journal of Population Ageing · doi:10.1007/s12062-023-09411-y · Cited by 17
“TAME (Targeting Aging with Meformin) is a clinical trial to test the drug metformin as a safe and effective intervention against several age-related diseases (Barzilai et al., 2016; Kulkarni et al., 2022).”
Combinatorial interventions in aging
Parkhitko, A. A., Filine, E., & Tatar, M. (2023) · Nature Aging · doi:10.1038/s43587-023-00489-9 · Cited by 17
“Yet, because metformin has protective age-associated effects in diabetics, trials are envisioned to measure its potential to delay normal human aging 84 .”
BackgroundKeys, M. T., Thinggaard, M., Larsen, L. A., Pedersen, D. A., Hallas, J., & Christensen, K. (2022) · International Journal of Epidemiology · doi:10.1093/ije/dyac200 · Cited by 16
Mai, X., Zhou, F., Lin, P., Lin, S., Gao, J., Ma, Y., Fan, R., Ting, W., Huang, C., Yin, D., et al. (2020) · Environmental Toxicology · doi:10.1002/tox.22982 · Cited by 16
“Food and Drug Administration (FDA) for clinical trials as the first antiaging drug.(45) Although the underlying mechanisms of action are not completely clear, a large number of studies at the animal and cellular levels have shown that the AMPK, mammalian target of rapamycin, and insulin-like growth factor-1 signaling…”
BackgroundIs metformin a geroprotector? A peek into the current clinical and experimental data
Zajda, A., Huttunen, K. M., Sikora, J., Podsiedlik, M., & Markowicz-Piasecka, M. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111350 · Cited by 16
Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis
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Cesari, M., Azzolino, D., LeBrasseur, N. K., Whitson, H. E., Rooks, D., Sourdet, S., Angioni, D., Fielding, R. A., Vellas, B. J., Rolland, Y., et al. (2022) · The Journal of Frailty & Aging · doi:10.14283/jfa.2022.62 · Cited by 16
“The Targeting Aging with Metformin (TAME) study, a proof-of-concept clinical trial designed to look at the effect of metformin on the incidence of age-related diseases, is an example of how to describe the effects of an intervention on health trajectories before the occurrence of overt diseases (41, 42).”
Function Begets Function and Resilience in Old Age: Is Precision Gerontology Possible?
Kuchel, G. A. (2017) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14901 · Cited by 16
Justice, J. N., Pajewski, N. M., Espeland, M. A., Brubaker, P. H., Houston, D. K., Marcovina, S. M., Nicklas, B. J., Kritchevsky, S. B., & Kitzman, D. W. (2022) · GeroScience · doi:10.1007/s11357-021-00509-9 · Cited by 16
“The committee then applied selection criteria to refine this set emphasizing: [1] measurement reliability and feasibility; [2] relevance to aging; [3] robust and consistent ability to predict both functional and a range of clinical outcomes; [4] demonstrated responsiveness to intervention; and [5] a preference for com…”
BackgroundMethodInfluentialSelf-citationEnhanced cellular longevity arising from environmental fluctuations
Liu, Y., Zhou, Z., Su, H., Wu, S., Ni, G., Zhang, A., Tsimring, L. S., Hasty, J., & Hao, N. (2024) · Cell Systems · doi:10.1016/j.cels.2024.07.007 · Cited by 16
Bridging expectations and science: a roadmap for the future of longevity interventions
Yu, D., Zeng, X., Barzilai, D. A., Thor, D., & Lyu, Y.-X. (2025) · Biogerontology · doi:10.1007/s10522-025-10278-z · Cited by 16
“At the more affordable end of the spectrum are drugs like rapamycin and metformin, which have demonstrated promising results in preclinical models and exhibit a relatively safe profile in human populations (Moel et al. 2025; Barzilai et al. 2016).”
The impacts of different dietary restriction regimens on aging and longevity: from yeast to humans
Ching, T., & Hsu, A. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01188-w · Cited by 17
“Those observations have led to the TAME (Targeting Aging with Metformin) study, which aims to demonstrate metformin’s potential as a geroprotective agent in non-diabetic populations [181].”
The goal of geroscience is life extension
Blagosklonny, M. V. (2021) · Oncotarget · doi:10.18632/oncotarget.27882 · Cited by 16
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Advancing Geroscience Research – A Scoping Review of Regulatory Environments for Gerotherapeutics
Muscedere, J., Shorey, C., Duque, G., Kim, P., Lorbergs, A. L., McGlory, C., Merchant, R. A., Newman, J. C., Rolland, Y., & Vellas, B. J. (2025) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2025.100637 · Cited by 15
“As a result, securing funding for large-scale trials often requires alternative strategies, including public funding mechanisms or intellectual property protections for reformulated versions of older drugs [27].”
InfluentialCao, Y., Wang, Z., Zhang, C., Bian, Y., Zhang, X., Liu, X., Chen, W., & Zhao, Y. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1028510 · Cited by 15
“The diabetes drug metformin has been shown to delay aging in several experimental models (Martin-Montalvo et al., 2013; Barzilai et al., 2016; Fang et al., 2018) and to reduce oxidative stress and germ cell loss (Ghasemnejad-Berenji et al.”
BackgroundMarra, P. S., Yamanashi, T., Crutchley, K. J., Wahba, N. E., Anderson, Z. M., Modukuri, M., Chang, G., Tran, T., Iwata, M., Cho, H. R., et al. (2023) · Aging · doi:10.18632/aging.204498 · Cited by 15
Bang, E., Lee, B., Park, J.-O., Jang, Y., Kim, A., Kim, S., & Shin, H. (2018) · Experimental Neurobiology · doi:10.5607/en.2018.27.1.45 · Cited by 15
“However, no definitive trials have been conducted to evaluate the efficacy of metformin in cognitive dysfunction in the elderly [17].”
BackgroundInfluentialWu, Z., Zhan, Y., Wang, L., Tong, J., Zhang, L., Lin, M. M., Jin, X., Jiang, L., Lou, Y., & Qiu, Y. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110556 · Cited by 15
Rodent diet aids and the fallacy of caloric restriction
Wolf, A. M. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111584 · Cited by 15
“Polyphenolic pancreatic lipase inhibitors contained in tea also reduce body weight and body weight gain in mice fed a high fat diet by decreasing fat uptake (Basu and Lucas, 2007; Chan et al., 1999; Grove et al., 2012; Yang et al., 2016).”
BackgroundWahdan-Alaswad, R. S., & Thor, A. D. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.91183 · Cited by 15
Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases
Parkhitko, A. A., & Cracan, V. (2025) · Science Advances · doi:10.1126/sciadv.adu1710 · Cited by 15
“Metformin demonstrated protective effects against several age-related diseases in humans and is now in the Targeting Aging with Metformin (TAME) trial, which is aimed at delaying aging in humans ( 130 ).”
Translating cellular senescence research into clinical practice for metabolic disease
Chaib, S., Palmer, A. K., Wyles, S. P., Musi, N., Kirkland, J. L., & Tchkonia, T. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01187-9 · Cited by 17
“It is through these mechanisms that metformin might exhibit gerotherapeutic effects on multiple age-related diseases 105,106 .”
Yusuf, J. A., Akanbi, S. T., Ijibadejo, M. S., Sulaiman, S. E., Olorunlowu, D. R., Akinola, A. O., Abe, A. P., Opoola, E. K., Adejobi, E. O., Adigun, T. D., et al. (2025) · Discover Neuroscience · doi:10.1186/s13064-025-00223-8 · Cited by 15
“Resveratrol activates SIRT1 and boosts PGC-1α transcriptional activity [84, 88], while metformin stimulates PGC-1α via AMPK activation and decreases reactive oxygen species production [12, 66].”
Radak, M., & Fallahi, H. (2023) · Biogerontology · doi:10.1007/s10522-023-10039-w · Cited by 15
Senotherapy, cancer, and aging
Balducci, L., Falandry, C., & Monfardini, S. (2023) · Journal of Geriatric Oncology · doi:10.1016/j.jgo.2023.101671 · Cited by 16
Li, W., Chen, S., Lang, J., Luo, J., Chen, J., Zhang, L., Sun, Z., & Dong, D. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.03.031 · Cited by 15
“Metformin, an AMPK activator, has been as a tool to target aging 23 .”
Oral Azelaic Acid Ester Decreases Markers of Insulin Resistance in Overweight Human Male Subjects
Streeper, R. T., Louden, C., & Izbicka, E. (2020) · In Vivo · doi:10.21873/invivo.11890 · Cited by 15
Dadashpour, M., Mahmoudi, H., Rahimi, Z., Poodeh, R. J., Mousazadeh, H., Firouzi‐Amandi, A., Yazdani, Y., Asl, A. N., & Akbarzadeh, A. (2023) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2023.104769 · Cited by 15
Senotherapeutic repurposing of metformin for age-related diseases and their signaling pathways
Turgut, Ş., Atasever, E., Cebe, T., Andican, G., & Çakatay, U. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10524-0 · Cited by 15
“Therefore, because it is an AMP activator, metformin has drawn attention as a possible senotherapeutic medication and its potential function in promoting anti-aging [1–3].”
New Directions in Research on Aging
Bartke, A. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10305-9 · Cited by 15
“A search for potential health benefits of metformin in individuals who do not have diabetes was spearheaded by Barzilai and his colleagues and a study termed “TAME” (Targeting Aging with Metformin) is ongoing [43].”
BackgroundGuilbaud, A., Mailliez, A., & Boulanger, É. (2020) · médecine/sciences · doi:10.1051/medsci/2020224 · Cited by 15
Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks
Mallikarjun, V., & Swift, J. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.11.020 · Cited by 14
50 years of the “war on cancer”: lessons for public health and geroscience
Farrelly, C. (2021) · GeroScience · doi:10.1007/s11357-021-00366-6 · Cited by 14
“TAME (Targeting Ageing withMetformin) is a clinical trial to test the drug metformin as a safe and effective intervention against several age-related diseases [24].”
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Metabolic reprogramming in inflammaging and aging in T cells
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Discovering Biological Mechanisms of Exceptional Human Health Span and Life SpanPreprint
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Impact of covid-19 on mental health and aging
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Hypoglycemic agents and incidence of pancreatic cancer in diabetic patients: a meta-analysis
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“In recent years, some clinical studies have found that in addition to lowering blood glucose levels, metformin also has certain effects on alleviating fatty liver, protecting the cardiovascular system, inhibiting tumor growth, and relieving symptoms of neurodegenerative diseases (Morales and Morris, 2015; Barzilai et…”
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“Indeed, exciting trials designed to address metformin as a human anti-aging intervention loom (see the TAME project (Targeting Aging with Metformin) [66].”
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“Recently, metformin, an antidiabetic drug for type 2 diabetes mellitus, has emerged as a successful and consistent pharmacological drug that exerts a protective effect against the age-associated deterioration of biological functions in addition to improving the lifespan [11].”
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Applying C. elegans to the Industrial Drug Discovery Process to Slow Aging
Weinkove, D., & Zavagno, G. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.740582 · Cited by 13
“Many are looking to the Targeting Aging with Metformin trial (TAME), approved by the FDA (Barzilai et al., 2016).”
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Senotherapeutics: An emerging approach to the treatment of viral infectious diseases in the elderly
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“It could also decrease age-related chronic inflammation and the risk of cardiovascular diseases, cancer, neurodegenerative diseases and cognitive dysfunction, ultimately exerting a constructive effect on improving the overall health status and prolonging the lifespan of aged persons (Barzilai et al., 2016; Campbell et…”
BackgroundCimicifuga racemosa Extract Ze 450 Re-Balances Energy Metabolism and Promotes Longevity
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“This study may deepen the knowledge about other therapeutic indications beyond its impact on diabetes mellitus type II [55].”
Background
Metadata
- Authors
- Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Barzilai, Nir
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 23
- Issue
- 6
- Pages
- 1060-1065
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5943638
- OpenAlex
- W2422981416
- Cited by
- 1,096
- References
- 83
- Citations by year
- 2026: 129 · 2025: 117 · 2024: 101 · 2023: 108 · 2022: 105 · 2021: 131 · 2020: 127 · 2019: 110 · 2018: 97 · 2017: 59 · 2016: 11
- FWCI
- 8.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG021654, R24AG044396, P01AG027734, P30AG038072, R37AG018381, R01AG046949, P30AG021332)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048349)
- 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, aging, lifespan extension, healthspan, age-related diseases, anti-aging drugs, drug repurposing
- MeSH terms
- Aging, Animals, Clinical Trials as Topic, Humans, Longevity, Metformin, Models, Biological, Models, Animal
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