Metformin in Aging & Longevity: A Layman’s Guide
Metformin is a well-known drug used globally to manage type 2 diabetes, but recent research shows it has broader health benefits beyond diabetes. Derived from a plant commonly called French Lilac, metformin regulates blood sugars by reducing liver glucose production and improving muscle uptake of glucose without causing low blood sugar.
What's exciting is its potential role in promoting longevity and preventing age-related diseases. Studies suggest metformin may reduce the risk of heart disease by improving cholesterol levels and lowering inflammation. It also shows potential in preventing cancer by affecting cancer cell metabolism and in protecting against cognitive decline, like dementia and Alzheimer's. Additionally, there's growing evidence that metformin could slow down the aging process, and a major study called the TAME trial is investigating this in well designed clinical trial. While promising, metformin isn't free of side effects and is not yet approved for anti-aging use. However, it remains a powerful tool in diabetes management and possibly beyond, contributing to healthier aging
Clinical Highlights: Metformin & Longevity (Dr. Kastoori Iyengar, MD MBA)
Since 2015, the World Health Organization has officially recognized aging as a disease, which greatly stimulates the research on aging and aging-related diseases as well as the development of relevant therapeutic strategies.
Several epidemiological studies demonstrated that metformin reduced the incidence of multiple age-related diseases as well as all-cause mortality. Importantly, this phenomenon was observed not only in diabetic patients but also in non-diabetic patients.
Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence.
Clinical applications:
Diabetes:
Changes the redox state of liver cells and reduce hepatic gluconeogenesis
Reduces blood glucose in mice
Improves blood glucose control and lipid concentration in patients with non-insulin-dependent diabetes mellitus (NIDDM)
Musculoskeletal diseases:
Osteoporosis:
Enhances the differentiation and mineralization of osteoblast and inhibits osteoclast differentiation, prevent bone loss in ovariectomized rats
Metformin is associated with a lower risk of fracture
Osteoarthritis:
Inhibits the expression of inflammatory factors, matrix metalloproteinases and hypertrophy markers in chondrocytes through bone marrow stromal stem cells in co-culture model
Delays the progression of osteoarthritis and reduce pain in primate and mice with osteoarthritis
Protects joint by anti-inflammatory, regulating skeleton and reducing weight
Intervertebral disc degeneration:
Protects nucleus pulposus cells against apoptosis and senescence or exert an anti-inflammatory effect; Reduce local mechanical hyperalgesia in the nucleus pulposus and annulus fibrosus
Other bone disorders:
Increases glycolytic activity and decrease the expression of inflammatory factors primary synovial fibroblast
Decreases the inflammatory response, oxidative stress and bone loss in ligature-induced periodontitis in rats
Prevents against oxidative stress-induced senescence in human periodontal ligament cells
Inhibits the ossification and inflammation of ankylosing spondylitis fibroblasts
Inhibits the proliferation and metastasis of osteosarcoma cells
Cardiovascular disease:
CAD (Coronary Artery Disease): Protect hyperglycemia-induced endothelial impairment
Reduce coronary endothelial dysfunction and early progression of coronary plaque
CHF (Congestive Heart Failure): Reduce myocardial oxygen consumption and left ventricular mass index, left ventricular mass, office systolic blood pressure and oxidative stress in patients
CAD with pulmonary hypertension (HTN): Benefit rats in a rodent model of metabolic syndrome and pulmonary hypertension associated with heart failure with preserved ejection fraction
Obesity and other metabolic diseases:
Obesity:
Inhibits adipogenesis in adipocytes
Prevents obesity in mice and rats
Promotes weight loss in patients who gain weight as a result of antipsychotic treatment
Fatty liver disease:
Improves fatty liver disease, reversing steatosis and aminotransferase abnormalities
Neurodegenerative diseases:
Decreased the risk of Alzheimer’s and parkinson’s disease
Cancers:
Bladder cancer:
Blocks bladder cancer growth and survival through SREBP-1c/FASN axis by targeting the expression of clusterin
Lung cancer:
Associated with low risk of lung cancer; Co-treatment with EGFR-TKIs therapy could improve progression-free survival in patients with advanced lung adenocarcinoma
Colorectal cancer:
Reduces the risk of colorectal cancer and improve the survival rate of colorectal cancer patients
Multiple myeloma:
Co-treatment with bortezomib could enhance the anti-myeloma effect of it leading to delaying the growth of myeloma xenotransplants
Melanoma:
Inhibits melanoma cancer cell motility and growth through inducing cell cycle arrest and promoting cell apoptosis
Thyroid cancer:
Inhibits growth of thyroid cancer cells by downregulating the expression of mGPDH and inhibiting OXPHOS in vitro and in vivo.
Osteosarcoma:
Suppress the self-renew of osteosarcoma stem cells through ROS-mediated apoptosis and autophagy
Hepatocellular carcinoma:
Suppress the self-renew of osteosarcoma stem cells through ROS-mediated apoptosis and autophagy
Side effects of metformin:
The most common side effect of metformin is its gastrointestinal irritation, which causes flatulence, diarrhea, nausea, vomiting, and cramps. These symptoms are most common when metformin is used for the first time or when the dose is high. This discomfort can be usually avoided by starting with a low dose and gradually increasing the dose or using sustained-release formulations.
The most serious adverse effect of metformin is lactic acidosis. This complication is rare and the vast majority of cases seem to be related to liver and kidney damage, rather than metformin itself .
In addition, it has been reported that high-dose and prolonged use of metformin increases the incidence of vitamin B12 deficiency.Therefore, it is helpful to screen patients taking metformin for vitamin B12 deficiency.
Although high-dose administration of metformin can cause a series of side effects, results from studies in cultured cells treated with high concentration of metformin are interesting. For example, Virtanen et al showed that 600 μg/mL metformin significantly inhibited angiogenesis, while 5 or 50 μg/mL metformin had no effect. In line with it, Dallaglio et al revealed that 10 mM (about 1290 μg/mL) metformin, which greatly exceeds the concentration in vivo, had an antiangiogenic effect in endothelial and tumor cells. These results suggest that high-dose administration of metformin may be beneficial for antiangiogenic therapy for diseases, such as cancer.
Scientific Highlights: Metformin & Aging (Rangaprasad Sarangarajan, PhD)
Scientific studies have demonstrated several key benefits of metformin beyond its well-established role in diabetes management.
One of the most significant is its cardiovascular benefits, with research showing that metformin can reduce the risk of heart disease by improving lipid profiles and lowering inflammation, even in non-diabetic individuals.
It also decreases the formation of harmful molecules known as advanced glycation end products (AGEs; molecules formed when sugars sticks to proteins, fats and DNA/RNA) and reactive oxygen species (ROS), both of which are linked to aging and heart disease.
Metformin's ability to activate important metabolic pathways, such as AMPK (adenosine monophosphate-activated protein kinase), has been shown to influence energy metabolism in cells, which may protect against a range of diseases.
Its anti-cancer effects have also been widely studied, with evidence showing that metformin can inhibit cancer cell growth and improve the effectiveness of traditional cancer therapies by disrupting cancer cell metabolism.
Metformin's impact on the gut microbiome, which plays a role in overall health, has been identified as another area where it can contribute to improved metabolic health.
A major scientific reason to explore the use of metformin for aging is its potential to slow down age-related cellular processes and reduce the risk of chronic diseases associated with aging. Scientific research has shown that metformin influences key biological pathways that affect metabolism, inflammation, and oxidative stress, all of which are closely linked to aging. By activating the AMPK pathway, metformin helps regulate energy production and reduces damage caused by harmful molecules like reactive oxygen species (ROS). These effects can improve cellular health, protect organs, and may delay the onset of age-related conditions such as heart disease, cancer, and cognitive decline. Additionally, studies have indicated that metformin users may experience lower all-cause mortality rates, suggesting that it could enhance both healthspan (the healthy, disease-free period of life) and lifespan. With ongoing trials like the TAME study exploring its anti-aging benefits, metformin shows promise as a scientifically supported tool for promoting healthier aging.
Should everyone take Metformin? For now, metformin is a drug with promising influences on the biological processes that influence aging but is not a substitute for a healthy lifestyle. As research continues to confirm its role in influencing longevity will enable its broader acceptance and availability in the near future.
While research is promising, it's essential to approach any supplementation thoughtfully:
Individual Variation: Multiple factors including genetics, environment, food, lifestyles and overall health can impact supplement requirements.
Always consult with a healthcare professional before starting any new supplementation regimen, as individual needs can vary significantly.