NF‐κB as the mediator of metformin's effect on ageing and ageing‐related diseases

Abstract

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 lipids. 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 mediators 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 cancer. 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, metformin has become a potential candidate drug, improving in the context of ageing and ageing‐related diseases. An inappropriate NF‐kB activation is associated with diseases and pathologic conditions which can impair the activity of genes involved in cell senescence, apoptosis, immunity, and inflammation. Metformin, inhibiting the expression of NF‐kB gene, eliminates the susceptibility to common diseases. This review underlines the pleiotropic effects of metformin in ageing and different ageing‐related diseases and attributes its effects to the modulation of NF‐kB.

Metformin inhibits chronic kidney disease‐induced DNA damage and senescence of mesenchymal stem cells

“…Using bioinformatic analysis of oncogene‐expressing senescence cells, Moiseeva et al reported that NF‐κB pathway is the most relevant transcription factor altered during senescence and inhibited by metformin treatment (Moiseeva et al, 2013). In agreement, Sultuybek et al revealed NF‐κB signaling as the target of the anti‐aging effect of metformin in dermal fibroblasts (Kanigur Sultuybek et al, 2019). In line with these observations, our data indicate that CKD MSCs had higher NF‐κB activity, and this effect was rescued by metformin treatment, resulting in a decrease in SASP.…”

Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults

“…Our findings can also have potential therapeutic implications. For example, metformin is a drug that is commonly used for the treatment of type 2 diabetes and can have anti-senescence effects by modulating key intracellular pathways related to SASP (e.g., NFκB and p53) and reducing circulating SASP 53–55 . Metformin can also lead to weight loss in overweight and obese diabetic and non-diabetic patients 56 .…”

Extra Virgin Olive Oil Polyphenols: Modulation of Cellular Pathways Related to Oxidant Species and Inflammation in Aging

“…Its activation is associated with diverse upstream signaling pathways related to immune attacks, growth factors, and internal and external danger signals [78,79]. It regulates expression of hundreds of genes [80] that are mainly implicated in inflammatory responses and immune signaling, as those encoding cytokines and chemokines (tumor necrosis factor alfa-TNF-α and interleukins), growth factors and their receptors, pro-inflammatory enzymes (inducible nitric oxide synthase-iNOS and cyclooxygenase-2-COX-2 above all), other transcription factors, but also genes that regulate apoptosis and cell-cycle progression [81,82]. The increase of NF-κB pathway activity is associated with a whole-body persistent, low-level inflammation that characterizes the aging process [83,84].…”