Clin Exp Pharmacol Physiol. 2019;46:413–422. wileyonlinelibrary.com/journal/cep © 2019 John Wiley & Sons Australia, Ltd
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4131 | INTRODUCTION
The process of ageing and ageing‐related disorders is associated with a variety of imbalance in homeostasis, eg, oxidative stress, genotoxic stress and an abundance of accumulating proteotoxic waste products. Many types of cellular damages including DNA damage, mitochondrial damage, telomere attrition and accumulation of macromolecular waste may promote ageing by driving cellular se‐ nescence, apoptosis, or dysfunction. The damage of cellular macro‐ molecules and organelles is thought to be the triggering force behind ageing and ageing‐related diseases.1‐3
It is not surprising that the NF‐kB system is activated during ageing and ageing‐related diseases since most of the pro‐ageing sig‐ nals and conditions eg, immune defence, oxidative stress, and DNA damage are well‐known inducers of NF‐kB. The mammalian Rel/NF‐ kB family includes three Rel proteins, RelA/p65, c‐Rel, and RelB, as well as two NF‐kB components, p50 and p52. These components form dimeric complexes with each other, which are trapped into the cytoplasm when they become bound to several inhibitory proteins (IkB).4‐7
The NF‐kB signalling pathway has a critical role in inflamma‐ tion and cancer development. The mechanism of action consists
Received: 20 September 2018
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Revised: 5 February 2019|
Accepted: 7 February 2019 DOI: 10.1111/1440‐1681.13073R E V I E W A R T I C L E
NF‐κB as the mediator of metformin's effect on ageing and
ageing‐related diseases
Gönül Kanigur Sultuybek
1| Tugba Soydas
1,2| Guven Yenmis
3,41Medical Faculty, Department of Medical Biology and Genetics, Istanbul Aydin University, Istanbul, Turkey 2Cerrahpasa Faculty of
Medicine, Department of Medical Biology, Istanbul University, Istanbul, Turkey 3Acıbadem Healthcare Services, Labgen Genetic Diagnosis Center, Istanbul, Turkey 4Department of Child
Development, Institute of Health Sciences, Istanbul Bilgi University, Istanbul, Turkey
Correspondence
Gönül Kanigur Sultuybek, Medical Faculty, Department of Medical Biology and Genetics, Istanbul Aydin University, Istanbul, Turkey.
Email: kanigur@istanbul.edu.tr
Summary
Ageing can be defined as the progressive failure of repair and maintenance systems with a consequent accumulation of cellular damage in nucleic acids, proteins, and li‐ pids. These various types of damage promote ageing by driving cellular senescence and apoptosis. The nuclear factor‐kappa B (NF‐kB) pathway is one of the key media‐ tors of ageing and this pathway is activated by genotoxic, oxidative and inflammatory stress, and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell‐cycle progression, and inflammation. Therefore, NF‐kB is increased in a variety of tissues with ageing, thus the inhibition of NF‐kB leads to delayed onset of ageing‐related symptoms and pathologies such as diabetes, atherosclerosis, and can‐ cer. Metformin is often used as an anti‐diabetic medication in type 2 diabetes throughout the world and appears to be a potential anti‐ageing agent. Owing to its antioxidant, anticancer, cardio‐protective and anti‐inflammatory properties, met‐ formin has become a potential candidate drug, improving in the context of ageing and ageing‐related diseases. An inappropriate NF‐kB activation is associated with dis‐ eases and pathologic conditions which can impair the activity of genes involved in cell senescence, apoptosis, immunity, and inflammation. Metformin, inhibiting the ex‐ pression of NF‐kB gene, eliminates the susceptibility to common diseases. This re‐ view underlines the pleiotropic effects of metformin in ageing and different ageing‐related diseases and attributes its effects to the modulation of NF‐kB.
K E Y W O R D S
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KANIGUR SULTUYBEK ETAL. of two different pathways, namely canonical and noncanonical.The canonical pathway involves a variety of steps, including the phosphorylation, ubiquitination, and degradation of the IκBα, which enables the nuclear translocation of the p50‐ p65 subunits of NF‐κB followed by p65 methylation, DNA binding, phosphory‐ lation, acetylation, and gene transcription. I kappa B kinase (IKK) phosphorylates inhibitor of NF‐kB, inducing its ubiquitination and proteasomal degradation, which then facilitates the nuclear trans‐ location of NF‐kB complexes predominantly p50/c‐ReI and p50/ ReIA dimers. The p50/ReIA activation induces the transcription of several pro‐inflammatory genes so plays a prominent role in inflam‐ mation. The noncanonical pathway, which leads to the activation of the p52/RelB dimer, includes different signalling molecules.8‐10
NF‐kB triggers several of these cellular alterations and has been reported to be permanently activated in some types of cancer cells, and abnormalities in the NF‐kB regulation are related to the pathogenesis of inflammatory diseases and cancer. With much controversy as to its role in tumour formation, the dual ability of p50 dimer to both repress and activate gene transcription prompts a complex relationship between this NF‐kB subunit and cancer. A large and growing body of literature has highlighted the ageing‐re‐ lated constitutive activation of the NF‐kB system and the role of oxidative stress in the sustained activation of the NF‐kB system during ageing and inflammatory diseases. Interestingly, they have not detected any “ageing‐related changes” in the expression levels of NF‐kB or IkB component mRNAs.4‐7 However, Forman et al11
demonstrated the decrease of NF‐kB p50, p52, p65 from cytosol to nuclei in the hearts from senescence‐accelerated prone mice (SAMP8) together with a decreased of IkB. It is also crucial to note that the lungs of old SAMP8 mice showed a remarkable increase in their pro‐inflammatory, pro‐apoptotic and pro‐oxidant status, in contrast with senescence‐accelerated resistant mice.12 Strikingly,
many of the longevity factors are inhibitors of NF‐kB signalling, either directly or indirectly.
An inhibitor of NF‐kB, metformin is often used as an anti‐dia‐ betic medication in type 2 diabetes mellitus (T2DM), throughout the world and appears to be a potential anti‐ageing agent. It has become a potential therapeutic candidate in the improvement of ageing and ageing‐related diseases, including T2DM, cancer, obesity, and cardiovascular diseases (Figure 1). The protective effects against diabetic complications have been observed with metformin mono‐ therapy.13 Metformin suppresses hyperglycaemia‐induced reactive
oxygen species (ROS) generation and oxidative stress in endothelial, and smooth muscle cells.14,15 We have previously demonstrated that
metformin causes amelioration of antioxidant activities in various tissues and limits lipid peroxidation both in vivo and in vitro.16,17
2 | FREE R ADICAL/OXIDATIVE STRESS
THEORIES OF AGEING
The free radical/oxidative theory is a well‐known ageing theory.18
Free radicals can react with DNA, proteins, and lipids, and produce toxic constituents.19,20 The antioxidant systems are unable to coun‐
terbalance all the free radicals continuously generated during the life of the cell. This results in oxidative damage in the cell and thus in the tissues.3,21 Aged animals have shown a higher index of oxidation
than young ones, and indeed various cellular compounds such as oxi‐ dized proteins, DNA forms, and lipids are accumulated. This damage can be attributed to an increased rate of free radical production in aged organisms. The elevated levels of ROS are involved in oxida‐ tive stress associated with the age.22,23 We previously reported that
the intact erythrocytes of aged subjects are equally capable of with‐ standing the oxidative stress induced by cumene hydroperoxide, al‐ though there is a decrease in membrane defence with ageing.24
Oxidative stress is undoubtedly one of the reasons for ageing due to the progressive increase of protein glycation. Protein gly‐ cation products are called advanced glycation end products (AGE)
F I G U R E 1 Metformin shows its
potential effects of the action on a variety of diseases
and oxidative stress and hyperglycaemia can modify the formation of these AGE products.13 It seems that AGE, with the induction
of elevated levels of ROS, enhances the NF‐kB signalling via the classical pathway, involving the deposition of IKKs (Figure 2). The NF‐kB signalling, in turn, combats against apoptosis by inducing the expression of several anti‐apoptotic genes such as FLIP, Bcl‐ XI, XIAP. It seems that ageing‐related oxidative stress activates the anti‐apoptotic NF‐kB pathway system to defend cells against apoptotic cells death. The oxidative stress may have a crucial role in the maintenance of this pro‐apoptotic and pro‐inflammatory phenotype during ageing.25,26
The oxidation–inflammation theory of ageing has demonstrated that the ageing process is also associated with the inflammatory changes. It is now widely accepted that not only oxidative stress but also chronic inflammation represent major risk factors for the ageing process. There are clear tissue‐specific differences in the level of the inflammatory profile of the ageing process. This inflammatory pro‐ file provokes and aggravates ageing‐related diseases such as neuro‐ degenerative diseases and atherosclerosis. A chronic inflammatory response has several harmful effects on tissues, eg, it increases oxi‐ dative stress and lipid peroxidation as well as evoking the secretion of matrix metalloproteinases (MMPs) which can cause extracellular matrix degeneration. Furthermore, inflammation can regulate the activation of the NF‐kB family members which can trigger the tis‐ sue‐specific ageing‐related degenerative process.27‐29 Recent stud‐
ies showed an increase in inflammatory status and NF‐kB protein expression in old mice together with anti‐apoptotic and antioxidant enzyme activity in pancreas, lung tissue of senescence‐accelerated mice.11,30
Mitochondrial free radical theory of ageing (MFRTA) is generat‐ ing considerable interest in terms of ageing, however, what we know about MFRTA lacks consistent evidence which has led to disagree‐ ment and rejection of this idea. Mitochondria, due to their produc‐ tion of ROS, are recognized to perform a key role in DNA damage which ultimately leads to cellular failure. MFRTA should not be easily discarded since there is an agreement in that ROS is not simply a critical toxic metabolic by‐product, but also an irreplaceable signal‐ ling switch that is vital for cellular fitness. Remarkably, the traditional terminology of “mitochondrial function” has changed from apoptosis and bioenergetics to other key biological processes such as immu‐ nity/inflammation, intracellular and endocrine signalling, and com‐ plex metabolic processes.31
3 | GENOTOXIC STRESS THEORY OF
AGEING
Genomic instability seems to be a major stochastic mechanism of ageing.32‐34 This hypothesis is supported by much experimen‐
tal evidence, among which, the human progeroid syndromes and transgenic animal models are the most convincing. DNA lesions ap‐ pear during ageing in both the nuclear and the mitochondrial DNA. Several studies have indicated that free radicals and oxidative stress probably are the most important source of ageing‐related DNA mu‐ tations. The major signalling pathways induced by genotoxic stress are p53, NF‐kB and PARP‐1.35‐37 Recently, it was demonstrated that
the activation of NF‐kB signalling is one of the cellular hallmarks evoked by DNA damage.38,39 Surveys such as that conducted by F I G U R E 2 Metformin has an indirect
effect on survival, proliferation, apoptosis, and inflammation via modulating NF‐kB pathway efficiency
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KANIGUR SULTUYBEK ETAL. Rodier et al40 showed that the persistent DNA damage in senescentcells can trigger the secretion of inflammatory cytokines, such as IL‐1α/β, IL‐2, 3, 6, 12, and TNFα, ie, it activates the innate immunity defence. Indeed, transcriptional control of cytokine expression by NF‐kB is likely one of the most important factors when evaluating the role of NF‐kB in pathologic states. NF‐kB also regulates the ex‐ pression of chemokines and adhesion molecules that allow for the attachment of immune cells to sites of inflammation. Moreover, NF‐ kB upregulates the expression of receptors such as CD80/81, TLR‐2, and proteins involved in antigen presentation on immune cells, al‐ lowing for immune responses.41
4 | EFFECTS OF METFORMIN ON AGEING
Human ageing and ageing‐related diseases are becoming one of the greatest challenges.1‐3 Evidence from in vitro studies and ani‐
mal models also suggests that metformin may influence metabolic and cellular processes associated with the development of chronic conditions of older age.42 Among these conditions, there are inflam‐
mation, oxidative damage, and increased glycation of proteins, cell senescence, diminished autophagy, and apoptosis. It is clear that metformin can block or diminish many of the fundamental factors that accelerate ageing,43‐47 however, it is actually unknown whether
metformin's observed effects reflect downstream consequences of a single action on a unique mechanism of ageing, or metformin, itself, has different effects on several pathways as reviewed by Barzilai et al.42 A longitudinal study of metformin by Bonnefont et al48 re‐
ports that metformin also directly scavenges ROS or indirectly acts by modulating the intracellular production of superoxide anion free radicals. ROS cause DNA damage and induce a variety of lesions in DNA such as DNA strand breaks and the formation of cross‐links be‐ tween DNA and proteins. Moreover, elevated concentrations of ROS can result in a significant amount of single and double strand breaks in DNA. Metformin has been shown to facilitate DNA repair, which is critical for ageing and ageing‐related disorders such as cancer and T2DM. In our previously published data, we suggest that the in vitro short‐term effect of metformin in the pharmacologic concentration has a protective effect against pro‐oxidant stimulus‐induced DNA damage in lymphocytes of elderly subjects.17,49
Although the mechanism of metformin is still unclear at the molecular level, fortunately, a wealth of recent studies have deter‐ mined that metformin provides a glucose‐lowering effect inhibiting hepatic gluconeogenesis, via activating 5′ AMP‐activated protein ki‐ nase (AMPK)‐ one of the prominent metabolic sensors of the cell.50
AMPK also mediates the downregulation of the fatty acid synthesis pathway, the mechanistic target of rapamycin (mTOR) and acetyl‐ CoA‐carboxylase partially.51 Metformin exposure induces mTOR
signalling, downregulation of insulin‐like growth factor 1 and hy‐ perinsulinaemia, thereby influencing proliferation, autophagy, and cell growth.52 Along with downregulation pro‐inflammatory NF‐kB
signalling, enhanced insulin sensitivity in parallel with reduced hy‐ perglycaemia results in minimized formation of ROS and AGE. More
recent evidence reveals that metformin inhibits NF‐kB, therefore can suppress the inflammatory responses in both AMPK‐dependent and independent pathways.53 In addition, metformin also prevents
DNA damage by interacting with the ataxia telangiectasia mutated serine/threonine kinase/checkpoint kinase pathways and mitochon‐ drial complex I. Moreover, metformin mediates histone modifica‐ tion and epigenetic regulation via reducing the activities of DNA acetyltransferases and methylases.52 Metformin also plays a major
role in the prevention of ageing and ageing‐related disorders such as cancer, cardiovascular diseases, osteoporosis, and neurocogni‐ tive diseases.54,55 Studies have shown that metformin specifically
influences the lifespan by activating AMPK, as an inhibitor of NF‐ kB. Similarly, Moiseeva et al56 assert that metformin prevented the
translocation of NF‐kB to the nucleus and inhibited the phosphory‐ lation of IkB and IKKα/β in senescent cells. NF‐kB is a common pleio‐ tropic transcription factor which dominates the gene expression of some cytokines, growth factors, chemokines, and cell adhesion mol‐ ecules in the mammalian cell.57,58 In many cell types, NF‐kB plays
a major role in numerous physiological and pathological processes like an immune response, differentiation, proliferation, cell adhesion, and apoptosis.59
According to bioinformatic analysis from several aged tissues, NF‐kB was indicated to be the most associated transcription factor altered in gene expression during the ageing,60 and reducing NF‐kB
activity is reported to attenuate the accelerated ageing of a mouse model of progeria.61 NF‐kB activation leads to the NF‐kB‐dependent
transcription of genes coding for survival signals, inflammatory cyto‐ kines, cell‐cycle modulators, and angiogenic and growth factors, all are key drivers in a tumour‐promoting environment.
We have indicated previously that metformin has a protective ef‐ fect on an in vitro model of ageing 3T3 fibroblasts under high glucose conditions in case of cell proliferation, collagen I and III production, escaping apoptosis and reducing NF‐kB (p65) activity.62 Metformin
was recently found to have a protective effect against skin ageing. Protein glycation contributes to skin ageing as it deteriorates the existing collagens by cross‐linking. The progressive increase in AGE during ageing not only causes oxidative damage to cellular macro‐ molecules but also modulates the activation of NF‐kB. NF‐kB also regulates skin ageing by regulating the expression level of collage‐ nase, namely MMP‐1, in dermal fibroblasts,63,64 which then exerts
degradation of the dermal type I collagen.66 Moreover, several re‐
ports have revealed that inhibition of NF‐kB activation suppresses MMP‐1 expression in several cells including dermal fibroblasts.65,66
Metformin may restore collagen production by decreasing the NF‐ kB activity. Meanwhile, collagen production and cell proliferation may be regulated by NF‐kB activity (Figure 3). For example, the ex‐ perimental data presented in our previous publication confirm that high glucose condition accelerates ageing‐related alterations of the collagen production and NF‐kB (p65) DNA‐binding activity while metformin may ameliorate these effects as an anti‐diabetic agent and supports the interest of these biomarkers of ageing. In addition, we claimed that metformin not only significantly decreased RELA/ p65 expression but also had a possible direct anti‐ageing effect on
a primary culture of dermal fibroblasts from the aged human skin at different glucose concentrations which could be partially medi‐ ated via promotions of COL1A1 and COL3A1 expression.67 Taken
together, these findings can provide a possible mechanism for the anti‐ageing and potential inhibitory effects of metformin on NF‐kB, observed in vitro models of human cells in severe hyperglycaemic conditions.
5 | EFFECTS OF METFORMIN ON AGEING‐
REL ATED DISEASES
Ageing in humans is a well‐known primary risk factor for many dis‐ eases and conditions, among them are diabetes, cardiovascular dis‐ eases, neurodegenerative diseases, and cancer. Indeed, the risk of death due to these conditions is dramatically elevated in older ages. For this reason, there is a need for the development of new attempts to improve and maintain health in the older subject.68 Therefore, re‐
searchers have identified effective mechanisms involved in ageing, the prevention of ageing and the delay of ageing‐related diseases. Thus, the possibility of a commonly used versatile drug, metformin, has been examined to reverse relevant aspects of the process of ageing and ageing‐related diseases. Metformin has been shown to
have pleiotropic effects on ageing‐related conditions, making met‐ formin a potential candidate for the treatment of ageing‐associated disorders like T2DM, cancer, obesity, neurodegenerative and cardio‐ vascular diseases.69
6 | T YPE II DIABETES AND METFORMIN
Type 2 diabetes mellitus is defined by insulin resistance and is often accompanied by numerous sequela or co‐morbidities including dys‐ lipidemia, hypertension, atherosclerosis, and obesity.70 NF‐kB has
been implicated in insulin resistance and glucose metabolism by both pharmacologic and genetic suppression approaches.71 Upregulation
of NF‐kB signalling in hepatocytes results in a T2DM phenotype.72
It is further hypothesized that innate immune activation and inflam‐ matory response underlie T2DM and its associated features.73 Thus,
aberrant NF‐kB activation in numerous tissues including adipose, pancreas, and liver contributes to disease pathology observed in pa‐ tients with T2DM.
Clinical trials state that the anti‐hyperglycaemic action of met‐ formin is multifactorial and has been attributed to a diminished in‐ testinal absorption of carbohydrates, reduced gluconeogenesis and oxidative stress, and increased glucose uptake. One of the major
F I G U R E 3 The aging process of 3T3 fibroblasts is a combination of decreased cell proliferation and collagen production and increased
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KANIGUR SULTUYBEK ETAL. mechanisms postulated to explain the hyperglycaemic action ofbiguanides is the enhancement of peripheral glucose uptake.73,74
This improvement in peripheral glucose disposal has been explained by an increase in insulin binding to membrane receptors,75 and by
activation of post‐receptor events.73,76 Recently, we suggested that
metformin increased the insulin receptor numbers in liver tissue in alloxan and streptozotocin‐induced diabetic rats.15 Furthermore,
impaired glucose tolerance (IGT) sites are associated with increased and varying risk of developing T2DM. IGT has been associated with an increased risk of cardiovascular events and increased mortality.77
We have concluded that metformin increases glucose transport in non‐insulin target tissue like erythrocytes and platelets in IGT and T2DM.78
A disorder in lipid metabolism is a common finding in diabetes. An effect of metformin on lipid metabolism has also been advocated that biguanides have a beneficial effect on lipid metabolism. It is also known that biguanides may reduce the oxidation of free fatty acids.77,78 Previous in vitro and in vivo studies have demonstrated
that metformin improves antioxidant activities in various tissues and acts to limit lipid peroxidation.15,49 The putative mechanism of lipid
peroxidation in metformin action is still unknown in ageing‐related diseases.
7 | CARDIOVASCUL AR DISEASE AND
METFORMIN
Many clinical studies have reported that metformin has cardiovas‐ cular protective effects and reduces the incidence and mortality of cardiovascular events via the mechanisms which are still unclear. Metformin treatment is reported to reduce effectively the risk of myocardial infarction and death compared to sulphonylurea and insulin treatment.79‐81 Similarly, in their cohort study of metformin
treatment, Roumie et al82 identified that metformin treatment is as‐
sociated with a decreased hazard of cardiovascular disease events or death in T2DM. Metformin also has anti‐atherosclerotic proper‐ ties, such as increasing tyrosine kinase activity and decreasing the intracellular calcium concentration. It may exert beneficial effects to prevent cardiovascular disease through improving lipo‐metabolism and reducing the level of LDL cholesterol by activation of AMPK.83
Metformin treatment of rat aortas is reported to reverse the hy‐ peroxia‐induced abolishment of the vascular relaxation in response to acetylcholine.84 Moreover, metformin can reduce inflammatory
response, as well as improving the endothelial cell function.85,86
Accumulating evidence suggests that inflammatory processes par‐ ticipate in T2DM and its atherothrombotic manifestations. In ath‐ erosclerosis as an inflammatory disorder, NF‐kB plays a central role in mediating cytokines, growth factors, receptor signalling proteins, cell adhesion molecules, and other proteins of immunity in cell types resident to the plaque microenvironment, ie, endothelial cells, SMCs, and macrophages.87,88 Activation of NF‐kB transcriptionally
activates multiple pro‐inflammatory genes, including those that en‐ code the pro‐atherogenic cytokines IL‐6 and IL‐8. As noted by Isoda
et al,85 metformin can exert a direct vascular anti‐inflammatory ef‐
fect by inhibiting NF‐kB through blockade of the PI3K–Akt pathway.
8 | CANCER AND METFORMIN
Metformin is used as an anti‐diabetic medication in T2DM through‐ out the world and has started to become a common anticancer agent.89 One of the emerging questions in cancer biology is: “How
is inflammation and metformin usage linked to cancer?” In a cohort study with T2DM patients, in new metformin users, a significant de‐ cline in cancer prevalence is found among metformin users (7.3%) compared to the controls (11.6%).90 So far, several epidemiologic
studies have reported the antitumour effect of metformin in sev‐ eral tumours, of prostate,91 colorectal92 and breast tissue origin.93,94
Metformin significantly reduces the proliferation of cancer cell and tumorigenesis although its mechanism has not been well understood.
Epidemiological studies indicate that women with T2DM are more likely to develop breast cancer. Along similar lines, a meta‐ analysis study argues that T2DM is related to a higher risk of breast cancer by 23%, particularly in postmenopausal women.95 In an ob‐
servational study including women with T2DM, the type 2 diabetics’ who used metformin in the long‐term have been found to have lower risk of cancers, especially breast cancer.96 On the basis of the cur‐
rently available epidemiologic evidence, it seems fair to suggest that the reduced risk of cancer in patients with diabetes through met‐ formin uptake becomes widespread in the field of oncology.
Recent studies have exhibited that metformin, both directly and indirectly, shows its anti‐proliferative effects on the breast cancer cells by developing insulin sensitivity, and therefore re‐ ducing hyperinsulinaemia.97,98 Mainly, these effects of metformin
have been shown due to AMPK. Metformin also inhibits the cellular energy cascade via repressing the AMPK‐independent pathway by activating the hexokinase‐II enzyme in the glycol‐ ysis pathway and disrupting glucose uptake.99 Tumour invasion
and metastasis are generally in charge of many complex biologi‐ cal processes in cancer. Cell–extracellular matrix (ECM) connec‐ tions, degradation of intercellular adhesion molecules and ECM invasion via lymph and blood vessels are crucial processes for the cancer invasion and metastasis.100 Several proteolytic en‐
zymes act a part and play a critical role in the degradation of the microenvironment in cancer, including the ECM and basal membrane.101 Underlining the role of MMPs in tumour invasion
and metastasis is crucial as they block tumour cells’ spread.102
MMPs are a family of structural and functional zinc‐dependent endopeptidases and participate in the proteolysis of several ECM components, such as collagen, and fibronectin.101 The activity of
these proteins is accurately regulated to inhibit tissue degrada‐ tion under physiological conditions. The balance of these condi‐ tions may be likely to be broken down in tumour cells which are able to invade other tissues.103 Until now, most of the research‐
ers have unveiled the expression profiles of MMP‐2 and MMP‐9, which are capable of degrading type IV collagen.104 Degradation
of the basal membrane, which separates the stromal tissue from epithelial cells, is an obligatory step required for tumour inva‐ sion, resulting in increased expression levels and activities of MMP‐2 and ‐9.105 As in transcription factors, there are many ac‐
tivator proteins such as AP‐1 (activator protein‐1) and NF‐kB in the expression of MMP‐2 and ‐9 in the transcription processes. The balance between NF‐kB activation and control is lost during pathological conditions such as chronic inflammation and cancer, but the overarching role played by the NFKB1 gene in carcino‐ genesis still remains incompletely understood.
In one of our previous studies, we pointed out that metformin acts as a potential agent against breast cancer in a dose‐dependent manner according to the outcomes of our in vitro study. We ob‐ served that metformin inhibited NF‐kB by its inhibition of nuclear translocation as well as decreased expression of proteins involved in the invasion pathway of breast cancer, such as MMP‐2 and MMP‐9 (Figure 4).106 These results support the observation that metformin
may have a protective effect against breast cancer via modulating NF‐kB.
9 | CONCLUSION
NF‐kB, one of the prominent inflammation marker transcription factors, can be modulated by metformin in anti‐ageing process. Therefore, this review highlights the relationship between the activ‐ ity and expression of NF‐kB in the presence of metformin and the risk of ageing and different ageing‐related disorders. More research is required to better delineate the specific role of NF‐kB activation in ageing, ageing‐related diseases, and cancer, which may also take us one step closer to the development of powerful anti‐ageing, anti‐ cancer, and anti‐inflammatory therapies in the future.
CONFLIC T OF INTEREST
On behalf of all authors, I declare no conflict of interest.
ORCID
Gönül Kanigur Sultuybek https://orcid.org/0000‐0001‐9029‐1910
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How to cite this article: Kanigur Sultuybek G, Soydas T, Yenmis
G. NF‐κB as the mediator of metformin's effect on ageing and ageing‐related diseases. Clin Exp Pharmacol Physiol.
