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Berberine & Metformin. Role Behind Longevity and Healthy Living.

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One-quarter of the world’s population is expected to be over 60 by 2050. As age-related disorders can cause a substantial burden on healthcare systems. However, what if we could “cure” aging itself to prevent these diseases from ever occurring? It has been debated for years that a balanced diet and active lifestyle may help you live a longer, healthier life. Over-the-counter supplements are also gaining popularity these days, each promising to improve one’s health. Can metformin and berberine be along them too? Let’s deep dive into these supplements’ health benefits and dosage.

Metformin.

Metformin (known by its brand name, Glucophage), is a well-established medication typically used as the first-line treatment for Type 2 diabetes, a prevalent age-related condition. Metformin has a long and illustrious history. In Europe, Galega officinalis was commonly used for digestive health and to cure urinary issues. In 1918, a scientist discovered that guanidine in the Galega officinalis (French lilac) reduces blood sugar. Metformin and phenformin are guanidine-containing diabetic drugs used today. It has been used by patients since 1958 in England and 1995 in the United States. It does its job by reducing gluconeogenesis- the de novo synthesis of glucose in the liver.

One of the most remarkable effects of Metformin is its capacity to activate a route called AMPK, short for the AMP-Protein Kinase pathway, which is responsible for both the hypoglycemic and non-hypoglycemic actions of Metformin. By blocking mitochondrial respiratory chain complex 1, metformin blocks mitochondrial ATP generation, triggering AMPK activation. Activated AMPK is a metabolic regulator that promotes the body’s fat and sugar metabolism. It plays a role in regulating the metabolism of glucose and ATP too. mTOR pathway, which regulates organism growth and most anabolic and catabolic activities in response to nutrient-induced signals like insulin, is inhibited by metformin.

Those with diabetes who cannot regulate their blood sugar levels through diet and exercise have turned to this medicine as the most common treatment option.

Benefits of metformin. 

We do not yet know enough to prescribe this medicine for anti-aging purposes alone. If you’re taking it for other reasons, there’s a considerable possibility you’ll experience additional benefits. And subsequent research might provide us with more knowledge regarding metformin’s anti-aging advantages.

In animal experimentation, metformin extended the lives of mice, rats, worms, and fleas. Although not the same as a human study, the excellent results of these animal trials may eventually lead to human testing of metformin’s anti-aging capabilities.  Despite the need for additional research on the anti-aging effects of metformin, there is solid evidence of its other benefits, some of which could lead to a longer life span.

  • Lowers All-Cause Mortality. Patients with type diabetes who used metformin were found to have decreased all-cause mortality due to major review of research. Older diabetics treated with metformin were shown to have a lower incidence of other age-related disorders and a longer life expectancy.
  • Enhances Insulin Sensitivity. Metformin has been studied to increase the body’s sensitivity to insulin, which assists the body in better regulating insulin levels. Insulin resistance is directly related to inflammation, another condition that naturally occurs with aging. That indicates that there is a possibility that metformin, by managing insulin levels, could combat the inflammatory effects of aging.
  • Reduces Oxidative Stress. Oxidative stress occurs when the cells are damaged by free radicals, which are unstable molecules. It is a factor in aging-related disease and death, as it causes inflammation. Metformin may be able to counteract some of the aging-related consequences of oxidative stress and inflammation. By activating the enzyme AMPK, metformin reduces oxidative damage and inflammation (adenosine monophosphate-activated protein kinase or AMP-activated protein kinase).
  • Cardiovascular Health. A longer life expectancy is possible if we safeguard our hearts, which has been one of the leading causes of death since 1975. A meta-analysis of 40 trials suggests that metformin may strengthen the heart. It has been proven in 2019 research that fewer cardiac events (such as heart attacks) and cardiovascular disease fatalities occurred among people with type 2 diabetes who used metformin compared to patients who did not. In one trial, metformin reduced heart attack patients’ risk of dying by 75% after 30 days and 68% after 12 months.
  • Reduces Frailty. The deterioration of physical strength and frailty is a common consequence of aging. Researchers are now investigating the potential impact of metformin on elderly frailty. Metformin use may protect against frailty by reducing inflammation and insulin resistance.
  • Reduces Body Weight and Fat. To treat obesity, metformin’s ability to activate AMPK is particularly useful. AMPK increases youthful cellular responses such as burning fat (instead of storing it), removing sugar from the blood and recycling cellular contents to eliminate harmful proteins. In a 6-month experiment, women with PCOS were given metformin or a placebo. Weight and blood sugar increased in the placebo group. In contrast, metformin-treated women dropped 9.24 pounds and had decreased glucose.
  • Prevent Certain Cancers. According to research, metformin may protect against specific types of cancer and boost cancer survival rates. This presumably produces an anticancer impact by inhibiting mTOR (mammalian target of rapamycin) activation. In a study of head and neck malignancies, diabetes patients had a 46% lower risk than non-diabetic patients. Similar results have been observed for the risk of gastric (stomach) malignancies, with metformin users seeing a 55% reduction in stomach cancer risk compared to non-users. Even in already diagnosed, early-stage colon and rectum cancer patients, metformin enhanced recurrence-free survival by 37%, overall survival by 31%, and cancer-specific survival by 42%.
  • Targets Neurodegeneration. Studies indicate that diabetic patients taking metformin have a decreased incidence of Alzheimer’s disease compared to those taking a placebo. As of 2016, human research found that taking 1,000 mg of metformin twice a day for a year helped older persons with amnestic moderate cognitive impairment recall their memories better than they had previously.
  • Calorie Restrictor Mimic. Metformin induces the same nutrition sensing pathways as calorie restriction, acting as a calorie restriction mimic.

The American Federation for Aging Research (AFAR) has launched a series of clinical trials named TAME (Targeting Aging with Metformin) to investigate the effects of metformin on human aging. Over the course of six years, 3,000 patients will be studied to see if metformin can slow the onset of age-related disorders. The FDA has approved this first-ever anti-aging trial. The study aims to show that you can target aging with a drug and slow it down.

Dosage. It is derived from a French Lilac compound and is safe and effective at dosages as high as 2,000 mg daily for diabetics. Anti-aging benefits can be achieved by taking 250 to 850 mg twice a day with meals. Dr. Sinclair himself takes 800mg metformin in the evening. Its long-term effects on healthy patients are still unknown. Remember that the FDA hasn’t approved Metformin as anti-aging medicine.

Metformin For Non-Diabetics. Metformin is sometimes used off-label. PCOS and prediabetes are two conditions where doctors may prescribe metformin to prevent type 2 diabetes. A study was done in 2017 and proposed metformin to minimize or prevent weight gain from psychiatric medicines. Another suggested that it may help in conditions with chronic inflammation such as arthritis. Metformin’s unapproved uses are being researched. We don’t know how well metformin works or the correct dose.

Side Effects: Metformin has few adverse effects, but gastrointestinal (GI) disorders, including diarrhea, nausea, metallic taste in the mouth, vomiting, and lack of hunger, are typical.

  • Metformin may cause GI side effects in up to 30% of people.
  • Other than that, long-term metformin use causes vitamin B12 insufficiency.
  • Metformin can cause lactic acidosis in rare circumstances. This can cause renal damage and other issues and can be fatal.

Metformin Effectiveness Timeline & Dosage.

Metformin has been shown in numerous research to extend life expectancy.

1 week: After a week of metformin usage of 750mg/day, there were reports of increased AMPK phosphorylation.

3 weeks: The intake of 1500-2500mg/day for 3 weeks has proven effective in reducing the growth of malignant cells. Another research in 2014 also points out the exact dosage (1500-2250 mg daily for four to six weeks) for 4-5 weeks of Vivo growth of inhibited uterine cancer cells.

6 weeks: The intake of 1-2 capsules (500-850mg/per capsule) has been studied to affect metabolic, collagen, mitochondrial, and DNA repair genes and pathways.

8 weeks: Improvements in executive functioning of the brain were seen with the dosage of 2000mg/day for 8 weeks.

4 months: The usage of 500mg/twice a day for 4 months has been proven effective for reducing cardiovascular risk sufficiently.

6 months: Metformin 850 mg twice daily for six months was given to women between 18 and 45 with polycystic ovary syndrome (PCOS). It reduced HDL levels, reduced insulin sensitivity and resistance at the same time.

1 year:

3 years or above: Another research has been done, with the dosage of 850mg/twice daily for 4 months to reduce coronary artery disease.

Berberine.

It is a bioactive chemical derived from numerous plants, including the Berberis shrub family.

Berberine behaves similarly to conventional pharmacological medications in that it is carried from the bloodstream to the targeted cells, binds with the cells, and modifies their functions. Berberine’s primary role is activating an enzyme called AMPK, which is critical for cellular health. This enzyme is critical to human metabolism. When ATP (the cell’s energy source) levels are low, berberine activates AMPK, which regulates the signaling pathways to replenish ATP supplies and increase fatty acid oxidation in cells.

Berberine is commonly found in various plants, including barberry, Oregan grape, tree turmeric, Philodendron, and Goldenseal. It is a bright yellow hue that is frequently used as a dye. Traditional Chinese medicine and the Indian Traditional Ayurvedic System of Medicine have utilized it to treat oriental sores, digestive disorders, and microbial infections.

Benefits of Berberine.

Numerous studies have documented the positive benefits of berberine on several systems, and some possibilities on how it exerts its anti-aging properties are included below.

  • Regulates Blood Sugars. A study of 14 research found that berberine is just as good in controlling blood sugar as common diabetes treatments like rosiglitazone, glipizide, or metformin. It has also been proven that berberine is a safe and effective type 2 diabetes medication. 116 participants with type 2 diabetes and dyslipidemia were 1 gram of berberine per day. This reduced fasting blood sugar levels from diabetic to normal (7.0 to 5.6 mm/L). Several parallel mechanisms are involved in berberine’s ability to reduce blood sugar in the body. A study published in the International Journal of Endocrinology explains how these mechanisms work.
  •  -Boosting stomach probiotics.
    -Slowing carb breakdown.
    -Glycolysis increases cell sugar breakdown.
    -Lowering insulin resistance boosts hormonal insulin’s effectiveness
  • Effect on Blood Cholesterol Levels.  Berberine can protect against a wide range of heart conditions. An evaluation of the scientific literature and meta-analysis of 11 researches determined that berberine can:

-Raise the HDL cholesterol level by 2 mg/dL (0.05mmol/L).
-Reduce triglycerides in the blood by 44 mg/dL (0.5 mmol/L).
-Reduce cholesterol levels by 24 mg/L (0.61 mmol/L).
-Reduce the LDL cholesterol level by 25 mg/dL (0.65 mmol/L).

  • Fat loss. There are numerous studies to support this claim. In the study, it was found that berberine can help people lose weight. In one study, Obese participants received 500 mg/three times daily for three months as part of the investigation. The subjects dropped 3.6% of their body fat and 5 pounds during the experiment.  Another study examining the weight loss advantages of berberine included 37 patients with metabolic syndrome. Participants received 300 mg of berberine three times per day for three months. The results showed potential for berberine’s weight loss benefits. The participants’ average BMI dropped from 31.5 to 27.4.  Its weight loss effects may be due to improved hormones (leptin, adiponectin, and insulin) that regulate fat production and intake.
  • Supports Longevity. Berberine may enhance the function of the SIRT1 sirtuin protein, which promotes longevity and the health of multiple organs, including the heart and brain. This antioxidant-rich molecule may also promote healthy aging by protecting DNA and minimizing cellular senescence. In a recent study, in mice, it was observed that berberine extended the lives of both yeast colonies and old mice by 28% and 16%, respectively. Although it is uncertain whether berberine supplements will similarly prolong the human lifespan, these first findings are encouraging and demand further investigation.
  • Prevent recurring UTIs and cystitis. Cystitis and recurrent urinary tract infections (UTIs) can both be prevented with the use of berberine. In a 2018 randomized experiment published in the Journal of Chemotherapy, plant extracts (containing berberine) were used to reduce UTI recurrence and bacterial load.
  • Antibacterial effect. Studies have revealed that berberine has antimicrobial properties and may protect against heart failure. Bacteria, viruses, fungi, and parasites are a few of the hazardous microbes it has been found to combat.
  • Works well in Conjunction. It works very effectively in conjunction with lifestyle modification, and it also enhances the benefits of other blood sugar-lowering medications.
  • Anti-inflammatory. In several research projects (1)(2), it was demonstrated to possess potent anti-inflammatory and antioxidant properties. Berberine’s anti-inflammatory and antibacterial properties may support the gut microbiome of individuals with gastrointestinal disorders, diarrhea, and bacterial overgrowth resulting from irritable bowel syndrome, ulcerative colitis, and other inflammatory bowel diseases. In research, patients with diarrhea-predominant irritable bowel syndrome were administered 400 mg of berberine daily for eight weeks, reducing diarrhea frequency, urgency, and abdominal pain.
  • Protective against fatty Liver. It can reduce the accumulation of fat in the liver, which, in turn, should help protect against non-alcoholic fatty liver disease (NAFLD). A research study showed that those who took 1500 mg of berberine per day for 16 weeks had considerable reductions in liver fat content, particularly with healthy lifestyle adjustments. The berberine group reduced liver fat by 53%.
  • Fights Against Cancer. https://pubmed.ncbi.nlm.nih.gov/19704371/ Recent research has demonstrated that berberine exhibits anticancer effects in vitro and in vivo via distinct mechanisms. According to the researchers, berberine may be a low-cost and risk-free option for colorectal cancer prevention. In addition, no severe adverse effects were reported. Other cancer research is listed here.

Dosage. In many of the researches listed in the article, doses of 900 to 1500 mg per day were employed. 500 mg 3 times daily before meals are typical (a total of 1500 mg per day). 500 mg to 1 gram of berberine per day is safe and beneficial for diabetes 2 individuals. 300 mg daily helps with weight loss. So, your dosage depends on why you’re taking berberine.

Always consult your doctor before having any medications, as it may also interfere with blood sugar lowering drugs.

Side Effects. It is safe to say that berberine has an excellent reputation. There have been some reports of cramps, diarrhea, gas, constipation, and stomach pain due to using this medication.

Berberine Effectiveness Timeline & Dosage.

8 weeks: The use of berberine 400 mg of berberine daily for eight weeks, reducing diarrhea frequency, urgency, and abdominal pain in people with irritable bowel syndrome (IBS).

3 months:

4 months: The intake of 1500mg/daily of berberine daily was associated to reduce liver fat by up to 53% in patients with NAFLD.

6 months: In persons with high blood pressure, taking 900mg of berberine orally daily with the blood pressure-lowering medication amlodipine reduces blood pressure more effectively than taking amlodipine alone.

Cautions.

Berberine  Metformin
  • As a precaution, using berberine may further drop your already low blood pressure; therefore, if you already have low blood pressure, you should use it with caution and only under the guidance of your doctor.
  • If diabetics are on insulin or medicine to manage their blood sugar, berberine may cause their blood sugar to drop too low.
  • Berberine has a lengthy half-life; therefore, you must take it numerous times a day to maintain steady blood levels.
  • Breastfeeding mothers shouldn’t consume berberine. Berberine can enter breast milk and harm a baby.
  • It has been advised that patients with advanced kidney disease shouldn’t use metformin.
  • Patients taking antimicrobials (cephalexin & rifampin), anti-cancer drugs (Vandetanib and tyrosine kinase inhibitors), iodine contrast for imaging, and excessive alcohol drinkers must avoid using this drug.
  • When taking metformin, it is recommended to take vitamin B12 (and ideally a B vitamin complex comprising all B vitamins) as it reduces the absorption of Vit B12.

Berberine Vs Metformin.

The blood sugar-regulating properties of berberine and the weight-loss and cholesterol-lowering properties of metformin complement each other quite well. But there are certain things in which both differ,

Berberine  Metformin
  • Berberine is a supplement, not a medication, available without a prescription.
  • It is poorly bioavailable and poorly absorbed. About 80% of what’s ingested is processed in the liver, where it’s useless.
  • We lack sufficient knowledge regarding berberine as an anti-aging molecule.
  • Less known side effects as yet.
  • Metformin requires a prescription to be taken.
  • It is well-absorbed and bioavailable.
  • Extensively researched and holds many upcoming types of research as an anti-aging molecule.
  • More side effects as compared to berberine.

Can we Take Berberine with Metformin? Berberine has been shown to work similarly if taken in a dosage of 1g to metformin in reducing blood sugar for diabetes and also preventing diabetes.  But it has not yet been proven to work for longevity purposes. Dr. Sinclair himself mentions that he used to take berberine before metformin. He also said that taking both supplements under the doctor’s supervision is beneficial in case metformin isn’t sufficient to bring the sugar levels down, and the same goes for berberine. However, if a person’s physician has prescribed metformin, they should not consider berberine as a substitute without consulting their physician.

While metformin and berberine receive a great deal of attention, we should explore beyond it to affect all pathways of aging synergistically. By doing so, we will have the most significant impact on health spans and longevity.

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