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

Abstract

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.