Metformin inhibits the senescence‐associated secretory phenotype by interfering with IKK/NF‐κB activation

Abstract

SummaryWe 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-jB. In agreement, metformin prevented the translocation of NF-jB to the nucleus and inhibited the phosphorylation of IjB and IKKa/b, events required for activation of the NF-jB pathway. These effects were not dependent on AMPK activation or on the context of cellular senescence, as metformin inhibited the NF-jB 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.

The effects of metformin on gut microbiota and the immune system as research frontiers

“…We have observed strong experimental evidence that metformin can act to suppress inflammation associated with senescence [40], and there is also convincing evidence from in vivo and in vitro models that the drug suppresses cancer-related inflammation [41]. In both cases, NF-κB activation is reduced, with concomitant reductions in secretion of inflammatory cytokines.…”

“…Although no detailed clinical studies examining influences of metformin on more subtle aspects of immune function have been carried out, laboratory studies [34][35][36][37][38][39][40][41][42][43][44][45] have provided considerable evidence for a variety of immunomodulatory effects.…”

“…While the notion that metformin may influence immune function as a consequence of altering energy metabolism in the many cell lineages that comprise the immune system is straightforward, it is unclear what subpopulations of immune cells are most affected by the drug, and therefore what the net effect on immune function would be in different clinical contexts. Recent results in tumour immunology provide examples of enhanced immune function as a consequence of metformin exposure [36][37][38], while studies in other contexts, including tuberculosis and multiple sclerosis, suggest anti-inflammatory actions [40][41][42][43][44][45].…”

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

“…Therefore, partial suppression of the SASP seems to be a reasonable option, particularly when short-term alleviation of agerelated dysfunction might be indicated. Several drugs, including glucocorticoids (57), metformin (58), and rapamycin (59), have been found to inhibit the SASP. Inhibition of the JAK/STAT pathway appears to be a viable option for the following reasons.…”

MLL1 is essential for the senescence-associated secretory phenotype

“…Hence, approaches to separate the beneficial tumor-suppressive growth arrest of senescence from the deleterious secretion of the SASP would be of significant clinical value (Coppe et al 2010;Munoz-Espin and Serrano 2014;van Deursen 2014). Indeed, recent studies have shown that the mechanism of the anti-aging and anti-cancer effects of the diabetes medication metformin may be through SASP inhibition (Algire et al 2012;Moiseeva et al 2013).…”