Metformin: Addressing the Challenges of Ageing through Cellular Mechanisms

Metformin, a well-established drug used to treat type 2 diabetes, has increasingly been recognised for its potential in mitigating the effects of ageing and reducing the burden of age-related diseases. By targeting several of the biological hallmarks associated with ageing, metformin offers significant promise for improving healthspan. This article discusses the mechanisms through which metformin works to address age-related decline, based on the findings of Cheng et al. (2022).

Mechanisms of Action

Ageing is characterised by several fundamental biological changes, often referred to as hallmarks of ageing. These include genomic instability, mitochondrial dysfunction, altered nutrient sensing, chronic inflammation, and cellular senescence. Metformin’s ability to influence these processes highlights its potential as a therapeutic agent for addressing ageing.

Activation of AMPK

One of the central mechanisms through which metformin exerts its effects is the activation of AMP-activated protein kinase (AMPK), a master regulator of energy balance at the cellular level. AMPK plays a critical role in promoting cellular maintenance and repair. Metformin’s activation of AMPK enhances energy efficiency, reduces inflammation by downregulating pro-inflammatory pathways, and inhibits growth-promoting signals such as the mTOR (mechanistic target of rapamycin) pathway. By modulating these processes, metformin contributes to improved cellular resilience and metabolic health.

Reducing Mitochondrial Dysfunction

Mitochondria, the energy-producing structures within cells, are central to the ageing process. Dysfunction in mitochondria leads to increased production of reactive oxygen species (ROS), which cause oxidative damage to cellular components. Metformin reduces the generation of mitochondrial ROS, limiting oxidative stress and preserving mitochondrial health. This action helps protect cells from age-related damage and supports overall cellular function.

Inhibition of the mTOR Pathway

The mTOR pathway, which regulates cell growth and metabolism, is closely associated with ageing. Overactivation of mTOR with age contributes to reduced autophagy (the process by which cells clear out damaged components) and an accumulation of cellular debris. Metformin inhibits mTOR, which encourages autophagy, prevents the build-up of senescent cells, and reduces the inflammation associated with ageing.

Anti-Inflammatory Effects

Chronic low-grade inflammation, often referred to as inflammaging, is a key driver of many age-related conditions, including cardiovascular disease, cancer, and neurodegeneration. Metformin reduces systemic inflammation by lowering the production of pro-inflammatory cytokines and modulating immune cell activity. This anti-inflammatory effect supports tissue health and resilience against the challenges of ageing.

Evidence Supporting Metformin’s Role

Preclinical Studies

Extensive research in laboratory and animal models supports metformin’s role in addressing age-related mechanisms. Cellular studies show that metformin can reduce DNA damage and improve cellular stress responses. In animal models, metformin has been shown to extend lifespan and delay the onset of age-related conditions, including cancer and metabolic dysfunction, through its effects on mitochondrial health and inflammation.

Clinical Observations

Although most clinical research on metformin has focused on its role in diabetes management, observational studies suggest wider benefits. People with type 2 diabetes who are treated with metformin exhibit lower rates of cardiovascular disease and certain cancers compared to those treated with other drugs. Moreover, some evidence suggests that metformin users may live longer than non-diabetic individuals, although further controlled trials are necessary to confirm these findings.

Implications for Research and Therapeutics

Metformin’s ability to target multiple hallmarks of ageing makes it a compelling candidate for therapeutic interventions aimed at improving healthspan. Its established safety profile and affordability make it an attractive option for translational research. The ongoing Targeting Ageing with Metformin (TAME) trial aims to evaluate whether metformin can delay the onset of age-related diseases in non-diabetic populations. If successful, this research could lead to wider applications of metformin in preventative healthcare strategies.

Conclusion

Metformin offers a promising approach to addressing the challenges of ageing. By targeting fundamental mechanisms such as mitochondrial dysfunction, chronic inflammation, and impaired nutrient sensing, metformin has the potential to improve quality of life in older populations. As further research clarifies its role in promoting healthy ageing, metformin may become a cornerstone of therapeutic strategies to combat age-related decline.

Reference

Cheng, F. F., Liu, Y. L., Du, J., & Lin, J. T. (2022). Metformin’s Mechanisms in Attenuating Hallmarks of Aging and Age-Related Disease. Aging and Disease, 13(4), 970–986. https://doi.org/10.14336/AD.2021.1213