Q: Outside of committed lifestyle changes, can metformin also be a key to slow aging, mitigate age-related diseases, extend lifespan and increase healthspan?
Scott Stoll, MD Response:
Thank you for your question on the hot topic for the potential benefit of metformin to improve healthspan and lifespan.
For more than 60 years metformin has been used to effectively treat type 2 diabetes with the observed secondary benefit of reducing the risk of cardiovascular disease and cancer. These observations led researchers to study the possible impact of metformin as an anti-aging intervention. Early research using flies, worms, mice, and rats, appears to show slowed aging, improved healthspan and extended lifespan. Larger human trials are now underway to test the benefits in healthy individuals. (MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin).
Metformin’s exact mechanism of action is still not fully understood but is believed to be through the activation of AMPK and inhibition of mTOR resulting in improved insulin sensitivity, reduced inflammation, and positive changes to the microbiome.
New research insights reveal that metformin appears to act via small physiologic concentrations of ROS (reactive oxygen species) that mildly inhibit the respiratory chain or electron transport chain in mitochondria. In a process called hormesis, small amounts of ROS may have a beneficial effect through a compensatory response to a mild stressor, whereas larger exposure to ROS would activate the inflammatory cascade. The small amount of ROS induces an anti-oxidative stress response via NrF2 (nuclear factor erythroid 2-related factor) and glutathione peroxidase resulting in the activation of positive cellular responses including resistance to apoptosis and cell proliferation, inhibition of mTOR, enhanced endothelial function, improved mitochondrial metabolism and cell senescence.
Preliminary results from MILES indicate that metformin may induce anti-aging transcriptional changes; however, it is still unknown as to whether metformin is protective in people free of disease and any risk or benefit in healthy individuals using a whole food plant-based lifestyle.
Stepping back from the reductionist research, it’s also important to evaluate metformin through a wholistic lens with any proposed anti-aging benefits viewed cautiously and critically until it’s proven to be advantageous and relevant to those free of disease and/or living a whole food plant-based lifestyle. Additionally, an inherent risk of “anti-aging” therapies like metformin is the magical thinking of the power of a pill over plants/lifestyle that can result in reduced dietary and lifestyle rigor and an overestimation of the long term protective and preventative benefits.
References
Udono, Heiichiro, and Mikako Nishida. “Metformin-ROS-Nrf2 connection in the host defense mechanism against oxidative stress, apoptosis, cancers, and ageing.” Biochimica et Biophysica Acta (BBA)-General Subjects 1866.8 (2022): 130171.
Bharath, Leena P., et al. “Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation.” Cell metabolism 32.1 (2020): 44-55.
Calabrese, Edward J., et al. “Metformin-enhances resilience via hormesis.” Ageing research reviews 71 (2021): 101418.
Bubak, Matthew, et al. “The acute removal of metformin induces mitochondrial remodeling and increases mitochondrial respiration.” Physiology 38.S1 (2023): 5732402.
