Metformin: our fountain of youth?

By Nick Bitterlich

The myth of eternal youth was popularised by an array of pop-culture movies. Nevertheless, some aspects of this are more fact than fiction as mankind is edging ever closer to the prospect of achieving sustainable longevity. One of the biggest contenders that may accelerate our progress is metformin. This oral drug was indented to treat type 2 diabetes in overweight individuals in addition to treating polycystic ovary syndrome. Nowadays metformin has been investigated for its potential in influencing the aging process, more specifically its role as an anti-cancer agent (Romero et al., 2017).

It’s capabilities were first observed in a population-based study of type 2 diabetics, which saw a significant reduction in cancer formation frequency (after values were adjusted for lifestyle habits including smoking and BMI) when metformin was administrated. In another study based on data published by the UK Clinical Practice Research Datalink those that had received the drug had survival rates similar or better than a matched non-diabetic control group (Bannister et al., 2014). This is despite the experimental diabetic group suffering from previous conditions including obesity. Furthermore, numerous epidemiologic studies have suggested reduced cancer incidence and mortality, as well as attenuation of tumorigenesis, following metformin administration (Landman et al., 2009). In fact, following a meta-analysis of patients receiving metformin, 1/3 of the patients saw a reduction of cancer incidence, whereas 34% saw a decrease in cancer mortality (Romero et al., 2017). However, the severity and scale of tumorigenesis have not been indicated in the study, thus impeding any analysis into the effectiveness of metformin.

The molecular mechanism of the drug was elucidated in detail, yet the mechanism by which it promotes longevity remains uncertain. Previously, it has been proposed metformin suppresses cancer stem cells (via inhibition of the epithelial-to-mesenchymal transition), reduces insulin levels while improving insulin action, decreases IGF-1 signalling, and activates AMPK (Romero et al., 2017). Other studies suggest it may have a role in inhibiting the mitochondrial complex 1 in the electron transport chain and reducing the production of reactive oxygen species, overall contributing to a reduction in DNA damage (Batandier et al., 2006). Within Caenorhabditis elegans, cellular aging and growth have been reduced via the inhibition of the mitochondrial electron transport chain. This, in return, limits the passage of the RagC protein through the nuclear pore complex decreasing the activity of mTORC1, its target. Both Skn-1 and Nrf-2 antioxidant transcription factors are upregulated as a result. This leads to an influx of the ACAD10 gene, which promotes beta-oxidation and is believed to induce autophagy and inhibit cell growth (Romero et al., 2017). Similarly, the intracellular activation of AMPK leads to increased inhibition of mTOR, a regulator of the aging process. Downstream processes are believed to mediate the effects of oxidative stress, reducing mutation rates although this process remains convoluted. This promotes autophagy as well as stress defence, reducing the effects of aging (Barzilai et al., 2012). Therefore, metformin has a potential beneficial influence on cellular processes associated with the development of age-dependent illnesses, including inflammation and cellular senescence (Saisho, 2015).

However, it remains unclear whether metformin affects multiple molecular pathways or influences one key mechanism which results in enhancement further downstream. One explanation suggests metformin initially inhibits mitochondrial complex 1, which leads to a change in the AMP/ATP ratio along with other downstream changes. The prior activates AMPK, suppressing lipid synthesis, and stabilizing plasma insulin levels, thus decreasing mTOR, a positive proliferation regulator, as mentioned prior (Foretz et al., 2014). Despite this, it may be possible metformin’s true singular target has not been identified and thus its mechanisms need further investigation. Additionally, not all studies have shown similar effects of metformin on life or health span. In Drosophila, metformin has increased AMPK activation but failed to increase longevity (Slack, Foley and Patridge., 2012). The same effect has also been observed in mice. Similarly, a 10-fold dosage increase that showed some benefit to mice in another study increased mortality rates in rats (Martin-Montalvo et al., 2013). Therefore, the scientific community must work on fine-tuning the administration of metformin to successfully promote longevity. 

On a molecular basis, metformin may be promising, yet it certainly has an extensive path ahead of itself to be proven to be an effective anti-aging agent. Large placebo-controlled trials are in the planning to determine metformin suitability to combat an aging population crisis in numerous countries. There are currently 100 trials investigating the role of metformin in cancer prevention, including on indented to analyse the drug’s effects on cancer and cardiovascular health in three-thousand 65-79-year-olds (Romero et al., 2017). Metformin is already widely accessible in developed nations and may therefore not be something solely available to the affluent. Therefore it is certainly a promising solution to mankind’s most pressing age-related diseases.  

References:

Bannister, C.A., Holden, S.E., Jenkins-Jones, S., Morgan, C.Ll., Halcox, J.P., Schernthaner, G., Mukherjee, J. and 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), pp.1165–1173.

Barzilai, N., Huffman, D.M., Muzumdar, R.H. and Bartke, A. (2012). The critical role of metabolic pathways in aging. Diabetes, [online] 61(6), pp.1315–22. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22618766 [Accessed 29 Mar. 2019].

Batandier, C., Guigas, B., Detaille, D., El-Mir, M., Fontaine, E., Rigoulet, M. and Leverve, X.M. (2006). The ROS Production Induced by a Reverse-Electron Flux at Respiratory-Chain Complex 1 is Hampered by Metformin. Journal of Bioenergetics and Biomembranes, 38(1), pp.33–42.

Foretz, M., Guigas, B., Bertrand, L., Pollak, M. and Viollet, B. (2014). Metformin: From Mechanisms of Action to Therapies. Cell Metabolism, 20(6), pp.953–966.

Landman, G.W.D., Kleefstra, N., van Hateren, K.J.J., Groenier, K.H., Gans, R.O.B. and Bilo, H.J.G. (2009). Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes: ZODIAC-16. Diabetes Care, 33(2), pp.322–326.

Martin-Montalvo, A., Mercken, E.M., Mitchell, S.J., Palacios, H.H., Mote, P.L., Scheibye-Knudsen, M., Gomes, A.P., Ward, T.M., Minor, R.K., Blouin, M.-J., Schwab, M., Pollak, M., Zhang, Y., Yu, Y., Becker, K.G., Bohr, V.A., Ingram, D.K., Sinclair, D.A., Wolf, N.S., Spindler, S.R., Bernier, M. and de Cabo, R. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, [online] 4(1). Available at: https://www.nature.com/articles/ncomms3192 [Accessed 21 Oct. 2019].

Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B.H. and Grossman, L.I. (2017). Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. American Journal of Obstetrics and Gynecology, [online] 217(3), pp.282–302. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0002937817307391 [Accessed 21 Oct. 2019].

Saisho, Y. (2015). Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. Endocrine, Metabolic & Immune Disorders-Drug Targets, 15(3), pp.196–205.

Slack, C., Foley, A. and Partridge, L. (2012). Activation of AMPK by the Putative Dietary Restriction Mimetic Metformin Is Insufficient to Extend Lifespan in Drosophila. PLoS ONE, 7(10), p.e47699.