Aging is a natural biological process, in which cells slowly degenerate and break down over time, leading to various illnesses including diabetes mellitus, cardiovascular disease, neurodegenerative disorders and cancer 1.
Researchers have recently revealed that metformin can reverse aging by improving dysregulated nutrient sensing pathways and modulating several proteins related to aging and apoptosis 4. In other words, metformin modulates several proteins linked with aging and apoptosis 4, thus slowing its progression and thus reverse aging processes.
1. Metformin Activates Autophagy
Autophagy plays an essential role in maintaining cell homeostasis and protection against stress, clearing misfolded proteins that could be toxic to cells as well as protecting mitochondria from oxidative stress by improving mitochondrial function. Unfortunately, insufficient or abnormal autophagy has been linked with numerous pathological processes and diseases including diabetes, atherosclerosis, inflammation, neurodegeneration cardiovascular disease and cancer – though Metformin may promote autophagy through various studies; its exact mechanism remains unknown at this time.
Metformin is an extremely potent activator of AMPK, the protein responsible for controlling various cellular processes including autophagy. Studies have shown that metformin can bidirectionally regulate autophagy under different circumstances – for instance it inhibited elevated autophagy levels in leukocytes while simultaneously increasing decreased levels of autophagy among blood mononuclear cells of type 2 diabetic patients and increasing anti-tuberculosis effects through inducing autophagy in their cells.
Metformin can also stimulate autophagy in various animal models by activating the AMPK/SIRT1/FOXO1 pathway. One study in rats that received 24 hour treatments of metformin showed higher LC3-II immunoreactivity compared with controls, while transmission electron microscopic examination revealed increased autophagosomes with double membrane structures.
Additional studies showed that metformin could induce autophagy in hepatitis B virus-infected mice by activating SIRT1 and FOXO1. Furthermore, it enhanced muscle function through increasing autophagy among normal mice as well as reduce oxidative stress by up-regulating LC3-II expression and decreasing AMPK/mTOR/GSK3b signaling in models for atherosclerosis, fibrosis, hepatic steatosis, Parkinson’s disease, among others.
Metformin has also been shown to promote autophagy in naturally aged mice and d-galactose-induced senescence rats by down-regulating SIRT2 gene expressions, leading to improved brain health in both cases. Furthermore, metformin may prevent the development of hepatocellular carcinoma and xenogeneic tumorigenesis by targeting Beclin1 as a key autophagy activating protein while simultaneously decreasing expression levels of its inhibitor p62/SQSIP; this mechanism corresponds to the AMPK/SIRT1/mTOR-p53/ULK1 pathway.
2. It Lowers Oxidative Stress
Oxidative stress is a key contributor to many age-related conditions, including heart disease, COPD, neurodegenerative disorders, cancer, sarcopenia (muscle loss) and frailty. Telomere shortening and DNA damage may also result from too much oxidative stress; metformin as an established AMPK activator has been shown to significantly reduce this stressor. Furthermore, animal models have demonstrated it can prevent or reverse some hallmarks of aging such as fatty liver, protein glycation mitochondrial dysfunction cell senescence and decreased autophagy – hallmarks often associated with ageing such as fatty liver, protein glycation mitochondrial dysfunction cell senescence and decreased autophagy.
Metformin’s most significant effects include increasing cellular energy production through increasing complex 1 activity in the mitochondrial electron transport chain and decreasing oxidative stress and DNA damage, possibly through its ability to inhibit the mTORC1 and sirtuin pathways that directly control nutrient sensing signals within cells.
Researchers recently conducted an experiment to test metformin’s anti-oxidant properties against human umbilical vein endothelial cells that had been exposed to high glucose levels or H4II rat hepatocellular carcinoma, and discovered it reduced oxidative stress by decreasing ROS production, inducing MnSOD expression, and stimulating mitochondrial biogenesis through activating AMPK – findings consistent with other research showing that metformin can protect both diabetic mice as well as non-diabetic mice against oxidative stress protection against oxidative stress.
Metformin also showed similar effects when administered to mice exposed to high glucose, significantly decreasing oxidative stress levels in their pancreas and liver by inhibiting hepatic gluconeogenesis and improving glucose tolerance, while decreasing hepatic steatosis and hepatocellular carcinogenesis. These findings indicate that metformin can effectively prevent or reverse several major conditions associated with metabolic syndrome including obesity, hepatic fibrosis, fatty liver, impaired glycolysis, protein glycation cellular senescence apoptosis cellular senescence apoptosis, diminished autophagy.
While current studies on metformin’s longevity-increasing effects are promising, more studies need to be conducted in order to verify its anti-aging benefits and see if these extend beyond people living with diabetes or prediabetes. Furthermore, it would be useful to understand how metformin influences individual markers of aging so as to develop more targeted therapies that mimic its effects.
3. It Reverses Insulin Resistance
Metformin acts as an insulin sensitizer, helping the body more efficiently utilize its own insulin production and use. This improves blood sugar levels while decreasing risk for prediabetes and type 2 diabetes as well as complications such as neuropathy, retinopathy, cardiovascular disease and kidney damage associated with these conditions.
Metformin has also been shown to reduce aging in mice and humans alike, with its effects similar to caloric restriction (CR), an intervention proven to extend health span and lifespan across many species. Studies have also demonstrated that metformin’s therapeutic benefits can be seen through many of the same biological pathways associated with CR such as gene expression changes and metabolism regulation.
Metformin may help increase protein synthesis and decrease inflammation through activating AMPK and inhibiting mTOR, among other mechanisms. Furthermore, other cellular signaling pathways related to aging may also be affected such as ribosomal S6 protein kinase activity, glycolysis metabolism, mitochondrial biogenesis processes, protein phosphatase 3 activity and DNA mismatch repair genes MSH2 and MSH3.
Metformin may also reduce insulin resistance at the level of skeletal muscles, given research showing that its in vivo correlates with decreased complex 1 respiration in these muscles. Unfortunately, several clinical trials that compared metformin’s effects with those of exercise on insulin sensitivity and metabolic syndrome components did not detect an additive or null impact on glycemic control.
Metformin may have beneficial effects on adipose tissue, glucose and insulin metabolism, oxidative stress and protein glycation independent from its effects on glycemic control, possibly explaining why this drug has shown to improve cardiovascular disease risk factors and even increase life span in obese individuals. More research needs to be conducted in order to ascertain why this occurs and to establish whether metformin should be used preventively as a drug to promote healthy aging; considering its long history of use as an anti-diabetic medication and its relatively low cost it seems reasonable that further exploration of this potential effect could take place.
4. It Reverses Age-Related Memory Loss
As our global population ages, it becomes ever more essential to find ways to slow or reverse age-related diseases. Metformin, already prescribed to treat type 2 diabetes patients, has become widely acknowledged for its anti-ageing benefits – thanks to its ability to inhibit cellular senescence and promote autophagy; furthermore it appears to reduce buildups of amyloid plaques in the brain while protecting cells against oxidation, all without altering insulin levels.
Research has also demonstrated that metformin extends animal longevity. It improves health span and lifespan by directly targeting key cellular processes related to age-related conditions like inflammation, fatty liver, oxidative stress, protein glycation, impaired autophagy, senescence and cancer (Table 1).
Metformin’s anti-aging effects are enhanced through both its AMPK-dependent and independent mechanisms, with direct inhibition of mTORC1 and sirtuins contributing to its action against aging. Studies have identified this mechanism as attenuating age-associated imbalances in protein abundance and trafficking that wreak havoc with proteins from degradation or destabilization – also helping mitochondrial function improve and lower oxidative stress.
Metformin may help slow cellular senescence through increasing expressions of BDNF in both astrocytes and neurons. BDNF is a neurotrophic factor which supports growth of new neurons and synapses while inhibiting senescence-related apoptosis. Furthermore, research suggests it attenuates microglial activation as well as astrocyte hypertrophy to delay neurodegeneration in aged mice.
Recent studies examining Alzheimer’s disease have demonstrated that metformin can significantly reduce memory loss in a mouse model. The research shows that metformin significantly increased BDNF levels in the hippocampus and thus improved cognitive functions of old animals. Furthermore, its memory-enhancing effects were determined to be due to Adenosine monophosphate-activated protein kinase activation and reduced proinflammatory cytokines. Furthermore, no neurogenesis or neosynaptogenesis was necessary.
Though some drugs have been shown to slow aging in animals, few have been tested on humans. Metformin has an outstanding safety profile and thus researchers are eager to see its efficacy tested against human participants. One such trial is the TAME Trial by American Federation for Aging Research that will test whether metformin can delay development and/or accelerate progression of age-related chronic diseases by targeting biological aging rather than specific conditions. Enrolling participants for this six-year clinical trial is expected to begin in 2020.
