Aging is an unfortunate and presumably, inescapable aspect of living; the termination of which is the only certainty we can accurately predict: death. Science is, however, on the perimeters of understanding these complex processes, and metformin is one emerging agent that may blunt the impact of aging. There have been numerous studies in animals including the worm, C. elegans, and rodents, showing efficacy in many indices of aging and overall longevity. There are also ongoing randomized controlled clinical trials in humans assessing indices of aging and aging-related diseases and the impact metformin has on them.
What is metformin?
Metformin is a biguanide derivative that was first discovered in the early 1920s and has been used as a therapeutic drug to combat type 2 diabetes since 1957. It is, in fact, the first line in treatment for type 2 diabetics. Metformin, through complex cellular biochemical pathways, impedes energy production in the mitochondrial powerhouses in cells, resulting in a reduction of circulating blood glucose or sugar. This anti-diabetic action is driven by a reduction of liver gluconeogenesis (production of de novo glucose from the non-carbohydrate substrate), increasing insulin sensitivity by increasing cellular uptake of glucose, and decreasing glucose uptake in the gut. However, in recent years, the utility has expanded to the far and unintended reaches of science from endocrinology and diabetes, and into the realm of gerontology and anti-aging science.
Mechanisms of action
ROS
Reactive oxygen species or ROS are byproducts of normal energy production in cellular mitochondria and also in cellular vacuoles that house digestive, oxidative chemicals to degrade pathogens and old cell parts. However, an accumulation of these chemicals and an inability to properly neutralize them through cellular antioxidative mechanisms may cause damage to DNA, protein, carbohydrate, lipids, and lipids that comprise cells. This oxidation of cells and tissues cause age-related destruction and inflammation of the skin and organs and precipitate diseases including cancer, Alzheimer’s disease, diabetes, and cardiovascular disease.
Metformin has direct inhibiting and modulating effects on the energy-producing electron transport chain, which regulates ROS production in cellular mitochondria. It also helps to inhibit cell senescence, which is non-dividing, yet metabolically active cells that accumulate, produce inflammatory chemicals and contribute to aging. In short, it is a senolytic that rejuvenates cells. It also has effects on upregulating the transcription of genes and the expression of their products that contribute to this overall antioxidative benefit.
Protein Homeostasis
Metformin helps to maintain protein homeostasis and attenuates the production and accumulation of cell-damaging proteins such as the inhibition of the expression and translation of the progerin protein which induces premature cell senescence. It also hastens the clearance of progerin in fibroblast cells, responsible for the formation of connective tissues in the body. Metformin is also responsible for the production of proteins that imbue some anti-aging properties. It upregulates an endogenous enzyme that helps combat oxidative hydrogen peroxide made in cells, called glutathione peroxidase. Additionally, metformin has been shown to promote and induce a process called autophagy, which results in the self-destruction and digestion of worn-out and dysfunctional cell parts; it recycles and upgrades cells.
Effects on telomeres
Telomeres are stretches of specific and redundant nucleotide sequences located at the ends of DNA strands which protect the coding sequences from being damaged and degraded. However, with each replication cycle of cells, telomeres tend to shorten and are associated with aging and reduced longevity. Telomere attrition is prevented by the administration of metformin in human participants, and telomeres were ultimately re-established and maintained through various mechanisms known and hypothesized.
Epigenetics
Metformin has numerous direct and indirect impacts on modulating gene expression by controlling a process called epigenetics which uses proteins called histones and DNA methylation to express or silence certain genes. In short, metformin promotes genomic stability and integrity by promoting DNA repair, controlling gene expression, and preventing oxidative damage to the genetic material.
Microbiome
In human and animal studies, the administration of metformin has been demonstrated to improve gut mucosal integrity, reduce inflammation, prevent dysbiosis and promote the growth and proliferation of beneficial commensal bacteria. The underlying mechanisms of this are yet to be elucidated by further study.
Clinical significance
Current evidence and ongoing TAME trials in humans illustrate the benefits metformin has on cancer and neurodegenerative diseases, in addition to promoting longevity. These benefits are evident from metformin’s ability to promote ROS scavenging in cell structures such as the mitochondria, regulating protein homeostasis and enzyme activity, and the epigenetic stabilizing effects it has on DNA and modulation over gene transcription.
Metformin can also:
- Suppress appetite
- Improve blood lipid levels and lower blood cholesterol
- Increase insulin sensitivity,
- Lower blood glucose
- Rejuvenate cells
- Lower proinflammatory chemicals
- Improve vascular endothelial function.
As evidenced by the aforementioned impacts on metabolism, metformin may prevent or help treat and attenuate metabolic disorders such as:
- Obesity
- Cardiovascular disease
- PCOS
- Diabetes
When in combination with healthy lifestyle practices such as attaining adequate sleep, easing stress, exercise, modest caloric restriction, and following a balanced diet, theorized metformin anti-aging benefits may be activating certain helpful longevity pathways.
References
Hu, D., Xie, F., Xiao, Y., Lu, C., Zhong, J., Huang, D., Chen, J., Wei, J., Jiang, Y., & Zhong, T. (2021, April 1). Metformin: A potential candidate for targeting aging mechanisms. Aging and disease. Retrieved October 10, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990352/.
Kulkarni, A. S., Gubbi, S., & Barzilai, N. (2020, July 7). Benefits of metformin in attenuating the hallmarks of aging. Cell metabolism. Retrieved October 10, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/.
Soukas, A. A., Hao, H., & Wu, L. (2019, October). Metformin as anti-aging therapy: Is it for everyone? Trends in endocrinology and metabolism: TEM. Retrieved October 10, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779524/.
Wang, C., Chen, B., Feng, Q., Nie, C., & Li, T. (2020, December 1). Clinical perspectives and concerns of metformin as an anti‐aging drug. Wiley Online Library. Retrieved October 10, 2021, from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12135.
