A summary of the article “A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan”
Background
In this review article by Mohammed et al (2021), published in Frontiers in Endocrinology in August 2021, the authors critically evaluate the data supporting metformin’s potential beyond its established role as a treatment for type 2 diabetes mellitus (T2DM). Metformin is a synthetic biguanide, widely used as the first-line oral anti-hyperglycemic drug for T2DM. With over 60 years of clinical use and being off-patent and inexpensive, its beneficial health outcomes in diabetic patients have prompted investigations into its potential as an anti-aging drug.
Scope
The article defines an “anti-aging action” as preventing and treating age-related diseases, which positively affects healthspan; the period of life spent in good health and free of disabling diseases. This is distinct from extending lifespan (longevity), which is the total length of time an organism lives. While it is controversial whether metformin extends lifespan, evidence suggests that by reducing early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline, and cancer, metformin can improve healthspan.
Results
The potential anti-aging effects of metformin are linked to several cellular mechanisms. A key mechanism involves AMP-activated kinase (AMPK) activation. AMPK is a crucial energy sensor that regulates metabolic pathways linked to healthspan and lifespan, similar to the effects of calorie restriction. Metformin’s insulin-sensitising actions can reduce insulin and potentially normalise IGF-1 levels, which signals via pathways involving mTOR; metformin activates AMPK and inhibits mTOR signaling. Dysregulation of mTOR signaling is linked to accelerated aging and various diseases. Metformin is also thought to influence the gut microbiome and enhance the release of glucagon-like peptide-1 (GLP-1), which contributes significantly to its anti-hyperglycemic effects and may play a role in its broader benefits. Furthermore, some studies suggest metformin can improve mitochondrial function, potentially offsetting age-related decline. Protection of endothelial function, crucial for cardiovascular health, is another proposed benefit, potentially mediated via AMPK and sirtuin-1 (SIRT1), which is associated with anti-aging pathways.
Data from multiple studies indicate that T2DM patients treated with metformin have improved survival rates compared to non-diabetic controls and those treated with sulfonylureas, implying a mortality benefit associated with its use in this population. Metformin has also shown potential benefits in reducing cardiovascular morbidity and mortality in patients with T2DM. Interest has extended to repurposing metformin for conditions like polycystic ovary syndrome (PCOS), preeclampsia, cancer, rheumatoid arthritis, and potential antiviral actions. Metformin has been associated with a reduced risk of certain cancers and cognitive decline in diabetic patients.
Despite supportive data, the evidence that metformin directly increases lifespan, especially in non-diabetic individuals or older organisms, remains controversial. Some studies in animals have shown variable or even detrimental effects in older subjects. A significant caution raised is the relevance of high metformin concentrations used in many in vitro studies compared to the much lower concentrations typically achieved in plasma clinically, which questions the translatability of some reported mechanisms, particularly regarding anti-proliferative effects.
Several clinical trials are underway, such as MILES and TAME, specifically designed to assess metformin’s effects on aging, healthspan, and lifespan in non-diabetic elderly subjects. These trials aim to provide more definitive answers regarding metformin’s potential to target aging itself rather than just age-related diseases.
Conclusion
In conclusion, while metformin’s benefits in improving healthspan, particularly in the context of T2DM and associated diseases, are well-supported, largely due to its positive effects on cellular metabolism and reduction of disease burden, the evidence for its ability to extend lifespan directly is not yet conclusive and remains controversial. The authors caution against viewing metformin as a panacea for aging and emphasise the continued importance of lifestyle interventions like diet and exercise. Further prospective studies, especially in healthy individuals of different age groups, are needed to clarify metformin’s potential benefits beyond treating pre-existing diseases.
References
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021). A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Frontiers in Endocrinology, 12, 718942. https://doi.org/10.3389/fendo.2021.718942
