Metformin inhibits the senescence‐associated secretory phenotype by interfering with IKK/NF‐κ B activation
Open accessAbstract
Summary: We show that the antidiabetic drug metformin inhibits the expression of genes coding for multiple inflammatory cytokines seen during cellular senescence. Conditioned medium (CM) from senescent cells stimulates the growth of prostate cancer cells but treatment of senescent cells with metformin inhibited this effect. Bioinformatic analysis of genes downregulated by metformin suggests that the drug blocks the activity of the transcription factor NF‐κ B. In agreement, metformin prevented the translocation of NF‐κ B to the nucleus and inhibited the phosphorylation of I κ B and IKK α/β, events required for activation of the NF‐κ B pathway. These effects were not dependent on AMPK activation or on the context of cellular senescence, as metformin inhibited the NF‐κ B pathway stimulated by lipopolysaccharide (LPS) in ampk null fibroblasts and in macrophages. Taken together, our results provide a novel mechanism for the antiaging and antineoplastic effects of metformin reported in animal models and in diabetic patients taking this drug.
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SASP inhibitors can directly or indirectly attenuate the SASP by inhibiting NF-κB, JAK-STAT, mTOR, mitochondrial complex-1-related or 4-related targets, or other pathways involved in SASP induction and maintenance.
“SASP inhibitors (senomorphics) can directly or indirectly attenuate the SASP of senescent cells by inhibiting transcription factor nuclear factor (NF)-κB, the JAK-STAT signal transduction pathway, the serine/threonine protein kinase mTOR, mitochondrial complex-1-related or 4-related targets, or other pathways involved in the induction and maintenance of the SASP103–106.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [106]
The Discussion reports that metformin reduces inflammatory cytokine production in senescent cells by interfering with NF-κB, and the Effects of metformin on the NF-κB pathway section reports inhibition of IKK activation. The paper does not establish SASP attenuation through JAK-STAT, mTOR, or mitochondrial complex-1- or complex-4-related targets, so it supports only part of the cited list. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe pro-inflammatory cytokine network is one potential anti-aging target, using anti-inflammation drugs such as metformin, aspirin, rapamycin, and ibuprofen.
“Recent studies have demonstrated that the pro-inflammatory cytokine network is one potential anti-aging target, using anti-inflammation drugs such as metformin, aspirin, rapamycin, and ibuprofen.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [337]
The Discussion reports that metformin reduces pro-inflammatory cytokine production in senescent cells through NF-κB inhibition, supporting the cytokine network as a potential anti-aging target. The paper does not establish aspirin, rapamycin, or ibuprofen as drugs acting on that target, so it supports only the metformin example. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMetformin can reduce chronic inflammation and improve healthy mid-life aging by acting on targets such as IKK/NF-κB in patients with Type 2 diabetes, as well as GPX7/NRF2 and PEN2.
“For example, metformin can reduce chronic inflammation and improve healthy mid-life aging by acting on possible targets such as IKK/NF-κB in patients with Type 2 diabetes,337 as well as GPX7/NRF2338 and a recently found target, PEN2.339”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [337]
The Abstract and Discussion report that metformin suppresses inflammatory cytokines by interfering with IKK/NF-κB signaling. The experiments described are in cells; the Discussion cites reduced cytokines in patients with impaired fasting glucose, but does not establish this mechanism or improved healthy mid-life aging in patients with Type 2 diabetes. GPX7/NRF2 and PEN2 have separate citations in the citing sentence and are not judged here. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMetformin prevents nuclear translocation of NF-κB pathway components and their subsequent transactivation at target gene promoters, thereby reducing expression of various SASP factors and potentially explaining, at least in part, the anti-ageing and antitumour effects of metformin in both mouse models and patients with diabetes.
“Metformin, to some extent, prevents nuclear translocation of NF-κB pathway components and their subsequent transactivation at target gene promoters, thereby reducing expression of various SASP factors and potentially explaining, at least in part, the anti-ageing and antitumour effects of metformin in both mouse models and patients with diabetes 219 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [219]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCompounds that modulate NF-κB signalling, such as metformin, apigenin, kaempferol, and BAY 11-7082, have been shown to reduce SASP production.
“Compounds that modulate NF-κB signalling, including metformin137,235–237, apigenin238, kaempferol238 and BAY 11–7082 (REF.118), have also been shown to decrease SASP production.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [235]
Experimental — accuracy not yet measured
Metformin alleviates a number of age-related conditions in experimental animal models and humans and inhibits multiple proinflammatory SASP factors by blocking NF-κB nuclear translocation.
“The antidiabetic drug metformin alleviates a number of age-related conditions in experimental animal models and humans and inhibits multiple proinflammatory SASP factors by blocking NF-κB nuclear translocation (Moiseeva et al. 2013).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Moiseeva et al. 2013
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”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Moiseeva et al. 2013
Metformin's senotherapeutic role is mediated by an anti-inflammatory effect preventing NF-κB translocation into the nucleus, thereby inhibiting the NF-κB pathway.
“Metformin’s senotherapeutic role is also mediated by its anti-inflammatory effect by preventing NF-κB translocation into the nucleus thereby not phosphorylating IκB and its kinase and inhibiting NF-κB pathway altogether (Moiseeva et al. 2013).”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Moiseeva et al. 2013
Metformin's anticancer effect has been attributed to suppression of the senescence-associated secretory phenotype through interference with proinflammatory NF-kappaB signalling.
“A recent study linked this antineoplastic activity of metformin to inhibition of the SASP by interfering with proinflammatory nuclear factor-κB signaling (91).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [91]
Metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells.
“the diabetic drug, metformin has senostatic properties and reduces the stimulatory effect of SASP intermediates on prostate cancer cells [123]”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [123]
Several other studies using a variety of cell types have reported that metformin inhibits NF-κB activation, decreases production of inflammatory cytokines and genes that code for inflammatory response, supporting healthspan benefits of metformin.
“Several other studies using a variety of different cell types have reported that metformin inhibits NF-κB activation, decreases the production of inflammatory cytokines and the genes that code for the inflammatory response thus supporting the healthspan benefits of metformin (105, 194–196).”
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 [195]
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- Authors
- Moiseeva, O., Deschênes‐Simard, X., St‐Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G.
- Affiliations
- Université de Montréal (CA)
- Département de Biochimie Université de Montréal Pavillon Roger‐Gaudry 2900 boul. Édouard Montpetit Montréal QC H3C 3J7 Canada
- Division of Experimental Medicine McGill University and Segal Cancer Centre of Jewish General Hospital 3755 Côte Ste Catherine Montréal QC H3T 1E2 Canada
- Corresponding author
- Ferbeyre, Gerardo
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2013-04-23
- Volume
- 12
- Issue
- 3
- Pages
- 489-498
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- OpenAlex
- W2109838416
- Semantic Scholar
- b1adae8e6571aff95a96f6cc0fce9248417d24cc
- Cited by
- 654
- References
- 45
- Citations by year
- 2026: 76 · 2025: 77 · 2024: 83 · 2023: 71 · 2022: 80 · 2021: 73 · 2020: 56 · 2019: 42 · 2018: 27 · 2017: 21 · 2016: 23 · 2015: 11 · 2014: 9 · 2013: 4
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Prostate Cancer Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- metformin, cellular senescence, senescence-associated secretory phenotype, NF-κB signaling, IκB phosphorylation, IKKα/β, inflammatory cytokines, prostate cancer, anti-aging, antineoplastic effects, AMPK-independent mechanism, lipopolysaccharide, macrophages, fibroblasts
- MeSH terms
- Animals, Enzyme Activation, Fibroblasts, Gene Expression Regulation, Humans, Hypoglycemic Agents, Inflammation, Lipopolysaccharides, Macrophages, Male, Metformin, Phosphorylation, Prostatic Neoplasms, Signal Transduction, Gene Expression, Cytokines, NF-kappa B, Cellular Senescence, Culture Media, Conditioned, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, p38 Mitogen-Activated Protein Kinases, Cell Proliferation, Mice, I-kappa B Kinase, Transcription Factor RelA
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