Metformin Reduces Incidence of Deadly Diseases – Does it Also Slow Ageing?
Metformin was prescribed 92 million times in the US and 22 million in the UK (based on 2020 figures).
It is prescribed to people with type 2 diabetes. It works on multiple pathways – effectively lowering blood sugar levels, reducing atherosclerosis, and protecting against certain cancers. First prescribed in 1958, Metformin is safe. There are few side effects outside of people with existing kidney issues.
The reason for writing about a diabetes drug here at the Age Well Times is that Metformin is protective against many of the diseases associated with ageing.
Two clinical trials aim to test the hypothesis that Metformin extends healthy lifespan. They are the TAME study and the MILES study.
This page introduces Metformin for people interested in longevity and healthy ageing.
Here is what you’ll find below:
- Metformin and Disease: Overview of the therapeutic effects and pathways activated.
- Negatives of Taking Metformin: Muscle development, upset stomach and more.
- Longevity Effects: Does Metformin have healthy ageing effects?
- Clinical Trial Controversy: Would scarce funding be better spent on Rapamycin?
- Wrap Up: Will I be taking Metformin?
Overview: What Metformin Treats
Nobody is sure exactly how Metformin works.
Metformin works using different pathways in different places. AMPK in the liver, mTOR in cells around the body, antioxidant effects, anti-inflammatory effects, second order effects microphages, and apoptosis.
There are 1000’s of papers showing successful uses in chronic diseases – the key successes are listed below:
Type 2 Diabetes:
This is the primary clinical use case. Metformin lowers glucose production in the liver, via the AMPK pathway. It also decreases insulin resistance in muscle and peripheral tissues – and reduces glucose uptake in from the gut. It is prescribed to people with Type 2 diabetes worldwide, and effective in preventing it for pre-diabetic individuals.
Polycystic Ovary Syndrome:
This condition affects the function of ovaries, leading to irregular periods, hormone imbalance and enlarged ovaries. It is related to high levels of insulin, which Metformin can be prescribed to treat this aspect.
Coronary Heart Disease:
Placebo controlled clinical trials found Metformin significantly reduced mortality from heart disease compared to a placebo. Weight loss and lower blood pressure contribute, along with a reduction in inflammation and insulin resistance.
Risk of Certain Cancers:
Following observations that people taking Metformin developed cancer at lower rates than the general population, clinical trials are investigating the pathways involved. In vitro and animal models have shown promise, though the mechanisms are still being uncovered.
Dementia and Alzheimer’s Disease:
Another area where Metformin is showing promise involves dementia and mild Alzheimer’s. Improvements in cognitive function were demonstrated among a sample of people with diabetes – though no improvement in biomarkers used to assess these conditions were observed. Note than papers have associated cognitive impairment in long term users.
An observational study found that Metformin has a protective role in stroke. Those most at risk of stroke showed the biggest benefits. Improved outcomes from strokes were observed for patients taking Metformin.
Weight Gain via Antipsychotic Medicines:
Weight gain is a common side effect of antipsychotic medicines. Metformin helps mediate this weight gain, which can help with non-adherence to taking the antipsychotic drugs.
The Big Longevity Science Question: Does Metformin Slow Ageing?
Metformin boosts the healthy lifespan of millions of people by reducing the incidence and severity of major age-related diseases.
It also reduces excess weight – which is a major contributor to ageing processes.
The fact that diabetics who take Metformin live longer than age-matched people that do not is shocking when you consider the chronic conditions linked to Type 2 diabetes and the excess weight associated with it.
There are two questions I’d like to see answered before I personally take Metformin:
- Does it show ageing independently of the benefits against specific conditions listed above?
- What are the mechanisms by which ageing is slowed, and does another drug (or lifestyle change) do an even better job?
A large-scale trial is working on funding. TAME (see below) will test the first question. Pathways by which Metformin will aid longevity are being actively studied. They include:
- Antioxidant Properties: A reduction the damage from Reactive Oxygen Species (ROS)
- AMPK activation: Which leads to mTOR inhibition (a scarcity mimetic which upregulates autophagy).
- Anti-Atherosclerosis: Promise has been demonstrated in heart disease outcomes among non-diabetics over and above weight loss / insulin resistance.
Downsides of Taking Metformin?
Before getting to the longevity trials, a word on side-effects.
Anyone with kidney disease should not take Metformin, as the knock-on effects include the medical emergency of lactic acidosis.
There are also effects on vitamin B12 metabolism. Fortunately, those are easily solved with supplements.
Other potential side effects are nausea, stomach upsets or diarrhoea. Loss of appetite and a metallic taste in the mouth are also possible.
Note that taking Metformin along with other diabetes medicines can cause more serious issues including hypoglycaemia (chronically low blood sugar). This is a prescription drug and you should always let your doctor know about other drugs you are taking, including supplements.
Clinical Trials on Longevity with Metformin: MILES, TRIMM, and TAME
While evidence of benefits in diabetes, cardiovascular health and polycystic ovary syndrome is strong – the evidence that Metformin boosts lifespan is weaker.
Clinical trials have been set up to test the hypothesis that it extends life in the general population. The key point is to show an effect over and above that expected by reducing the incidence of heart attacks, strokes and other effects of diabetes and the associated extra weight.
Here are the current trials:
- Metformin in Longevity Study (MILES): This ongoing small-scale study has found evidence that transcription factors associated with longevity are improved. It is too early to draw strong conclusions.
- Thymus Regeneration, Immune Restoration, and Insulin Mitigation Extension Trial (TRIMM-X): This trial combined Metformin, HGH and DHEA. It found an effect on the Thymus, which shrinks with age, showing promise of healthy ageing via boosted immune function.
- Targeting Ageing with Metformin (TAME): This proposed trial generated significant excitement as the first FDA approved clinical trial to specifically target ageing. It is still in the fundraising process at the time of writing.
Find out more about the TAME trial at afar.org
Controversy: Why Not Everyone is Happy with Metformin and Longevity Trials
The TAME trial’s choice of Metformin is controversial.
There are two major strands of argument:
- That Metformin is a bad choice of drug to test with, as the effects on longevity are tiny (if any can be demonstrated at a statistically significant level). Better choices are already available if the FDA were to authorise it, most importantly Rapamycin. Opponents believe that this trial is wasting money that could be better used elsewhere.
- Counter to this, the argument goes that the fact the FDA allowed a trial to specifically measure ageing is more important than the drug used. This sets a precedent that will allow for future trials. Metformin is a safe drug, which has positive effects on many of the diseases associated with ageing. Even if it shows no improvement over and above years added by fewer strokes or better heart-attack recovery, the groundwork for future trials is there.
Personally, I want to see both sides.
Nir Barzilai is a respected veteran and the perfect figurehead for the first approved trial directly targeting ageing. If TAME runs, then I’d hope to see significant funding targeting ageing from the big pharma funds and elsewhere.
Rapamycin is showing significant promise already. I’m looking forward to seeing the results of clinical trials on that.
There appears to be an implicit assumption that the money is fungible. That any cash saved on the TAME trial would immediately jump to testing rapamycin. I’m not convinced this would be a one-to-one shift… at least not yet!
Wrapping Up: Will I Be Taking Metformin?
The short answer is no.
I’m in the target age group, though my low sugar diet combined with low BMI mean that insulin resistance and the associated conditions are thankfully not a problem for me. If I was on the path to type 2 diabetes, or had significant excess fat, then I’d certainly discuss it with my doctor.
The effects on the conditions associated with type 2 diabetes and insulin resistance are significant. When you add heart disease, stroke and dementia to this list, the positives are obvious.
Berberine supplements are an alternative to Metformin. I’ll do a deep-dive on that in the coming weeks.
Let’s hope that Metformin lives up to its promise for other conditions and longevity pathways.
I’ll report here at the Age Well Times as soon as those results are available.
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