Metformin
Metformin is an approved medication used to treat type 2 diabetes.[1] It has been proposed as a potential longevity drug based on its healthspan extending effects in various animals, as well as human studies suggesting that diabetic patients on metformin live longer than non-diabetic people. For these reasons, it is currently being studied in the first large-scale phase 3 human longevity trial - the TAME trial.[2]
Use in Medicine
Metformin is a common, inexpensive drug that has been used to treat and prevent type 2 diabetes for over 60 years. It is known to reduce the amount of sugar the liver releases into the blood and helps the body respond better to insulin.[3] Metformin is also used to treat metabolic syndrome, which is a combination of obesity, high blood pressure, high cholesterol, and insulin resistance, and is sometimes used for polycystic ovary syndrome (PCOS).[1]
Life extension effects
Life extension in model organisms
In animal trials, metformin has been found to extend the lifespan of roundworms, silkworms, mice, and rats.[4][5]
Life extension in humans
Research undertaken since metformin was approved by the FDA in 1994 has found that people with type 2 diabetes who take metformin tend to be healthier than those who take another diabetes-related drug.[6] They appear to live longer, have fewer cardiovascular issues, get cancer less often, and tend to outlive other people with both diabetes and cancer on different medications. Notably, this finding is based on observational studies that cannot account for confounding and other biases. Currently, there is no clinical evidence that metformin is beneficial for human aging.
In a retrospective observational study of 90,400 subjects with diabetes who took metformin, compared to those taking another diabetes drug, and a matched control group of subjects without diabetes, it was found that metformin patients not only outlived the other subjects with diabetes but also lived longer than the subjects in the control group.[7] While there are various criticisms of the methodology of this paper, this has led scientists at the forefront of longevity to consider metformin as a drug with the potential to extend healthy lifespans – which could help people to not just live longer, but live more healthily for longer.
Mechanism
Metformin appears to mimic the processes involved with dietary restriction (DR) without the person having to restrict their diet.[8] The exact mechanism of action of metformin remains unknown; it is often regarded as a 'dirty drug' because it targets a wide range of molecular pathways, and therefore exhibits many different effects. Some examples of its beneficial effects on human physiology in type 2 diabetes include its ability to reduce blood sugar levels, prevent accumulation of fat, and prevent hardening of the arteries.[9][10] However, the caloric restriction (CR) mechanism of metformin has been called into question. One study has demonstrated that metformin-treated mice have impaired vision and spatial memory, in contrast with the known data for central nervous system benefits from CR.[11]
Both type 1 and type 2 diabetes are regarded by aging biology researchers as diseases of accelerated aging. They lead to premature morbidity and mortality due to frailty, cancer, stroke, heart disease, dementia, kidney disease, diabetic retinopathy, peripheral neuropathy, and many other age-related diseases.
As metformin is known to inhibit complex I of the mitochondria to activate AMPK and reduce mTOR signaling, which are molecular pathways associated with aging, there is some biological rationale for repurposing this drug to promote healthy aging in people without diabetes.[12] However, there is no clinical evidence that metformin can slow aging in healthy adult humans.
The TAME Trial
Animal studies have shown that metformin can delay aging and prevent various age-related diseases, which allows for the possibliity that this may extend to humans as well. The Targeting Aging with Metformin (TAME) trial is being conducted across 14 leading research institutions in the United States. Researchers aim to determine whether metformin can delay the development or progression of age-related diseases (cardiovascular diseases, dementia, cancer) and reduce mortality in 3,000 older adults aged 65-79 over six years.[2]
Side effects
Common side effects (which affect 1 in 100 people) include feeling or being sick, stomach ache, diarrhea, loss of appetite and/or a metallic taste in the mouth.
Serious side effects are very rare and affect less than 1 in 10,000 people. These can include severe tiredness, a slow heart rate, liver problems, or a rash. One controversial adverse effect is related to lactic acidosis; a cochrane review of randomized trials published in 2010 showed that metformin is not associated with an increased risk for lactic acidosis, when prescribed under specified study conditions.[13] It is also possible to have a serious allergic reaction (anaphylaxis) to metformin if one is allergic to its active ingredients.
References
- ↑ 1.0 1.1 Metformin: Medicine to treat type 2 diabetes. (2019, February 25). NHS. https://www.nhs.uk/medicines/metformin/
- ↑ 2.0 2.1 TAME – Targeting Aging with Metformin. (n.d.). American Federation for Aging Research. https://www.afar.org/tame-trial
- ↑ Metformin: Medicine to treat type 2 diabetes. (2019, February 25). NHS.https://www.nhs.uk/medicines/metformin/#:~:text=Metformin%20works%20by%20reducing%20the,to%20reduce%20the%20side%20effects.
- ↑ Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Pharmacologic means of extending lifespan. Journal of Clinical & Experimental Pathology, Suppl 4. https://doi.org/10.4172/2161-0681.S4-002
- ↑ Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. Aging (Albany NY), 11(1), 240.
- ↑ Saraei, P., Asadi, I., Kakar, M. A., & Moradi-Kor, N. (2019). The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances. Cancer Management and Research, 11, 3295–3313. https://doi.org/10.2147/CMAR.S200059
- ↑ Bannister, C. A., Holden, S. E., Jenkins-Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., Mukherjee, J., & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obesity and Metabolism, 16(11), 1165–1173. https://doi.org/https://doi.org/10.1111/dom.12354
- ↑ Lee, S.-H., & Min, K.-J. (2013). Caloric restriction and its mimetics. BMB Reports, 46(4), 181–187. https://doi.org/10.5483/BMBRep.2013.46.4.033
- ↑ Wang, C., Liu, F., Yuan, Y., Wu, J., Wang, H., Zhang, L., ... & Ye, J. (2014). Metformin suppresses lipid accumulation in skeletal muscle by promoting fatty acid oxidation. Clin Lab, 60(6), 887-896.
- ↑ Rena, G., Hardie, D. G., & Pearson, E. R. (2017). The mechanisms of action of metformin. Diabetologia, 60(9), 1577-1585.
- ↑ Thangthaeng, N., Rutledge, M., Wong, J. M., Vann, P. H., Forster, M. J., & Sumien, N. (2017). Metformin impairs spatial memory and visual acuity in old male mice. Aging and disease, 8(1), 17.
- ↑ Vial, G., Detaille, D., & Guigas, B. (2019). Role of mitochondria in the mechanism(s) of action of metformin. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00294
- ↑ Salpeter, S. R., Greyber, E., Pasternak, G. A., & Salpeter, E. E. (2010). Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane database of systematic reviews, (4).
