Metformin and ageing: improving ageing outcomes beyond glycaemic control

Abstract

In a world where the population is ageing, there is growing interest and demand for research evaluating strategies that address the ageing process. After 60 years of successful use of metformin in our pharmaceutical armamentarium, we are learning that, beyond improving glycaemic control, metformin may have additional mechanisms and pathways of action that need further study. Although, metformin's effect on clinical ageing outcomes may still be considered speculative, the findings from studies into cellular and animal models and from observational and pilot human studies support the existence of beneficial effects on ageing. At present, progress for human research, using randomised clinical trials to evaluate metformin's clinical impact, has just started. Here, we present a review on the ageing process and the mechanisms involved, and the role that metformin may have to counter these. We go on to discuss the upcoming large randomised clinical trials that may provide insight on the use of metformin for ageing outcomes beyond glycaemic control.

Keywords: Ageing; Mechanisms of ageing; Metformin; Older adults; Review.

Fig. 1

Anti-ageing mechanisms of metformin. Metformin impacts on mechanisms of ageing, preventing DNA damage and inflammation; it activates the AMP-activated protein kinase (AMPK) signalling pathway, blocking inflammatory-cytokine mediated DNA translation. It also prevents DNA damage from excess production of superoxide by directly decreasing ROS synthesis via reverse electron flux, and by inhibiting mTOR signalling pathways that result in superoxide production. IRAK4, IL-1 receptor-associated kinase 4; JAK, Janus kinase signalling pathway; ${\mathrm{O}}_2^{-}$, superoxide; PIKK, phosphatidylinositol 3-kinase

Fig. 2

Potential clinical targets for metformin, beyond glycaemic control. In the ageing individuals, metformin may provide many benefits other than glycaemic control. These benefits may improve physical function (e.g. mobility, muscle strength and endurance), clinical outcomes (e.g. blood pressure, weight and cardiovascular health), and psychological health (e.g. cognition, depression and quality of life)