Aging - stages in human development

Health

Is metformin the new anti-aging drug?

By Juman Hijab

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Original date: October 27, 2023  

Updated: March 31, 2024

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Anti-aging: image of an elderly couple

DALL·E-2023. Is anti-aging possible? Photo-of an elderly man and woman both in their nineties, 10/21/2023

Is Anti-aging possible?

Who doesn't want to live a long and healthy life?


Unfortunately, ill-health is not uncommon for those of us in our senior years. The data supports this: In the United States, according to the Centers for Disease Control, 1 in 5 adults older than 65 rated their health as "fair" or "poor". 


Is ill-health inevitable? In this article, I would like to review one drug - Metformin - that may have the potential to decrease disability from diseases such as dementia and cancer. After all, many of us take vitamins in the hopes that we can maintain our health. Is Metformin our newest anti-aging "vitamin"?

What is Metformin?

Metformin is a drug from the biguanide family. Interestingly, its development is linked to the use of a herb in medieval Europe. French Lilac (also known as goat's rue) was used to treat multiple conditions, but over time, it garnered attention for its glucose lowering effects. Extracts from the plant were found to be rich in guanidine. Fast forward, and safer, semi-synthetic formulations led to the use of metformin by a French Physician, Jean Sterne, in 1957 in diabetics. He called this biguanide Glucophage or "glucose eater) (1).  

Currently, metformin has been in use for more than 60 years and over 150 million people have used the drug on a daily basis (2).

The positive effects of metformin: Is anti-aging possible?

It took some time for metformin to become a first line medication. What propelled it to the forefront was that metformin produced glucose lowering without weight gain as well as avoiding hypoglycemia. Further studies showed that metformin (2): 

  • decreased one's risk of dying from cardiovascular disease if one were an overweight type 2 diabetic patient.
  • was effective in preventing the development of diabetes in those of us with pre-diabetes 
  • seemed to lower the atherosclerotic (microvascular disease) burden in those of us at risk for becoming diabetic
  • decreased glucose uptake in the intestine as well as blocked the liver from producing glucose (lowering glucose levels).
  • also made muscle and fat cell's more responsive to insulin (lowering blood levels of insulin)

Reducing cardiovascular risk in of itself is a huge benefit, but can metformin do more to prevent other diseases associated with an aging body (like dementia, macular degeneration, and cancer)?

Can Metformin be an anti-aging drug?

Metformin and cancer

In cell systems and animal models, metformin creates a healthier microvascular environment improving the sensitivity of a tumor to chemotherapy. Furthermore, in cell cultures, metformin seems to target genes that are important for tumor proliferation and invasion. Does this experimental data show promise in humans?

Yes! Case-control studies reviewing a prescription data base in Scotland involving more than 300,000 patient records showed that over an 8 year period there was evidence of a reduced risk of cancer in patients taking metformin compared to other glucose-lowering medications (2). Furthermore, a review article on metformin's anti-cancer benefit highlights the following (3): 

  • Metformin targets the insulin resistance that exists in both obese and diabetic persons. Insulin resistance is a condition where insulin is less able to attach to its receptor to facilitate glucose entry into the cell. Metformin acts directly on the insulin receptor making it more adept at attaching to insulin. 
  • Metformin decreases circulating levels of insulin by 25-33% in both diabetic and nondiabetic patients. 
  • Patients with many types cancer (lung, breast, colorectal, hepatic, prostate) who were taking metformin for their diabetes showed improvement in survival compared to patients who are on alternate anti-diabetic regimens.

Mechanism of metformin's anti-tumor actions

Metformin seems to have multiple actions for its anti-tumor activity. First, as mentioned, it decreases circulating insulin values. High insulin levels are linked to some cancers. Second, metformin seems to promote catabolism in cells, such that cancer cells are deprived of new building blocks (like fatty acids). Third, metformin seems to increase the effectiveness of chemotherapeutic drugs against tumor cells. In particular, metformin  seems to inhibit the proliferation of poorly differentiated cells. Those tend to produce the most aggressive tumors.

The latter effect is particularly important as metformin enables drug-resistant cancer cells to once more become sensitive to chemotherapy. All in all, in combination with other drugs, or as a sole agent, metformin seems to create a series of road blocks that stalls cancer cell growth. 

Metformin and dementia

Two of the most feared diseases of aging are cancer and dementia. Both cause significant morbidity, are associated with high caregiver burden, as well as a potentially catastrophic financial cost. 

I discussed cancer above. What about cognitive dysfunction? Does metformin help reduce its incidence and severity? Studies that demonstrate the benefit of metformin on delaying cognitive would be exceptionally welcome.

What evidence is there that metformin helps our brain stay younger? Here are several pieces of evidence (2):  

  • Studies on mice brains suggest that metformin helps protect young neuronal cells, supporting the growth and development of nervous tissue in animal brains. 
  •  Metformin prevented a decline in memory and learning in mice in whom obesity was induced.
  • Metformin seemed to decrease the presence of inflammatory cells in the brain (always a plus).
  • A longitudinal study followed  365 diabetic subjects for 4 years: Patients that had used metformin for more than 6 years had a decreased risk of cognitive impairment.

These studies are reflective of many more studies that also support the finding that metformin has a protective effect against cognitive impairment and dementia in diabetics (4, 5). In particular, any therapy (including calorie deprivation) that reduces insulin resistance and higher than normal glucose levels shows benefit at decreasing abnormal protein accumulation in neuronal cells. 

Consequently, such therapies can be neuro-protective in various neurodegenerative conditions. This includes Parkinson's, Huntington's, multiple sclerosis, and stroke, in addition to dementia (4).

Metformin and macular degeneration

I have to say, when I am researching studies on metformin, any information of metformin in relationship to macular degeneration peaks my interest. I have a strong predisposition to developing this disease, thus, I would seriously consider measures to preserve  my eyesight.

There is some evidence that metformin is associated with a decreased risk of macular degeneration in retrospective studies. Macular degeneration is related to oxidative stress and chronic inflammation in the retina and metformin has a beneficial role in decreasing both pathologies. In addition, metformin seems to regulate the levels of adenosine triphosphate (ATP, the energy molecule in cells) in the retina in mouse models. This is important, given the high energy needs of the retinal pigment epithelium (5). More studies are needed, but the data is promising thus far.

Should one take Metformin as an anti-aging drug?

Is metformin a good idea to take for someone who is older to prevent the dreaded diseases of aging? I have to confess that I started taking metformin at 500mg/day a few months ago, as I had left-over pills from another family member and the data seemed to support an "anti-aging" effect for this drug.

However, as I was closer to running out of the medication, I knew that I could not get a prescription from my regular doctor's office:  metformin is not standard of care for older, overweight individuals without diabetes. The effort/cost of getting a reliable prescription from a concierge physician was looming on the horizon, so I buckled down to look into this issue. 


Pros and cons for taking metformin

The thing is, one needs to probably take 1000mg/day (possibly 2000mg/day) to get an effect, and many of us may have diarrhea and bloating at such doses. It is also important to supplement vitamin b12, as metformin messes with this vitamin's absorption from the gut (6, 7).

Here are the pros to taking metformin (6, 7, 8, 9): 

  • Metformin has a very strong safety profile, as long as one does not have major liver or kidney disease
  • Many of us fall short on achieving healthy weights and moderate intake of calories, even though we have the best of intentions (and, thus, many of us are pre-diabetics)
  • There is clear evidence for metformin helping move plasma molecules in the right direction (less insulin, less pro-inflammatory molecules; healthier processing of glucose and fatty acids; increased levels of anti-inflammatory molecules - 69)
  • Metformin has clear benefit on the arterial circulation cells (endothelial cells) even in non-diabetics
  • There are convincing benefits for diabetics (less Cardiovascular disease, less mortality) from using metformin 
  • Metformin seems to reduce the incidence of cancer

However, it behooves us to be prudent. Not all the research gives a hands-down support to metformin's effect on anti-aging. Here the cons to taking metformin (6, 7, 8, 9):

  • lifestyle modifications are more effective at reducing the incidence of diabetes in pre-diabetics
  • treatment with metformin seems to negate the positive effects of exercise on muscle
  • the same positive effects of less cancer/cardiovascular disease seen in diabetics is not clearly seen in non-diabetics. Furthermore, some studies dispute metformin's ability to reduce cancer risk.
  • some studies suggest there is an increased incidence of Alzheimer's disease on metformin. 
  •  Another wrinkle that metformin only helps decrease incidence of cognitive dysfunction in people who were normal to start with: In other words, metformin will not help once the horse is out of the barn (6)
  • Similarly, supplementing metformin at an older age does not seem to have a positive effect in non-diabetics. 
  • Metformin use has been linked to a slight increase in the incidence of genital defects in male offspring of fathers taking the drug in the 3 months prior to conception (10)

In addition to the "cons" listed above, we don't actually know which is the most beneficial dose to take to get the most benefit from metformin's "pros". In diabetics, a dose of at least 850mg BID seems best, but there are suggestions that lower doses may be better (9). 

Will I continue to take metformin knowing what I now know?

Hands down for diabetics.....

Metformin clearly helps people with diabetes (decreasing CV, dementia, cancer, and mortality). Its effect is from the positive role on decreasing insulin and glucose levels as well as decreasing insulin resistance. In contrast, there is no proof or even a strong suggestion that metformin does similar things in older people without diabetes (possibly only for pre-diabetics). Indeed, there may be evidence for harm (less effective changes in muscle, more dementia, more b12 deficiency). 


It seems that metformin does a great job when a person has diabetes as it normalizes processes within the cells to make them less dysfunctional (less oxidative stress, less inflammation, less fatty acids, better utilization of glucose).


...not so much for non-diabetics

On the other hand, if one does not have a diabetic cellular makeup and/or there is already significant damage to the organ (cognitive dysfunction has already started, for example), metformin does not seem to add much value. I want to believe it can help because metformin has so many positive effects on cellular/hormonal systems. However, the data is mixed and confusing. 
A major reason for the murky landscape is that much of the positive effects of metformin has to do with patients with a background of diabetes. Clearly, normalizing glucose levels and insulin resistance will help the body cut down its pro-inflammatory and oxidative stress profile. 


A final cautionary tale

Metformin is not broken down into a simpler molecule. When I am taking it, the molecule is excreted in the urine unchanged. Thus, given that there are millions of people taking metformin, waste water is showing evidence of noticeable levels of metformin. Unfortunately, when this drug ends up in fresh water, it can affect the development of animals in the aquatic environment negatively. There is data suggesting the metformin disrupts the endocrine systems in fish at the levels that is found in wastewater systems. 


In conclusion, metformin does not seem to possess any magic powers beyond its effect on helping dysfunctional diabetic systems get back on track. I'm somewhat disappointed as metformin seemed to have added anti-inflammatory actions, positive mitochondrial and nuclear effects, and vascular endothelial cell protection  over and above its insulin-sensitizing effects. However, it seems that metformin as an anti-aging must wait for another chapter to open before it can be formerly introduced to the general non-diabetic population. 


In the meantime, a renewed focus on a healthier diet and more rigorous exercise is in order. 

References

  1. Bailey C, Day C. Metformin: Its Botanical Background. Pract Diabetes Int (2004) 21:115–7.   10.1002/pdi.606
  2. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front Endocrinol (Lausanne). 2021 Aug 5;12:718942. doi: 10.3389/fendo.2021.718942. PMID: 34421827; PMCID: PMC8374068.
  3. Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA. Metformin: multi-faceted protection against cancer. Oncotarget. 2011 Dec;2(12):896-917. doi: 10.18632/oncotarget.387. PMID: 22203527; PMCID: PMC3282095.
  4. Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther. 2023 Jun 26;17:1907-1932. doi: 10.2147/DDDT.S409373. PMID: 37397787; PMCID: PMC10312383.
  5. Romdhoniyyah DF, Harding SP, Cheyne CP, Beare NAV. Metformin, A Potential Role in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis. Ophthalmol Ther. 2021 Jun;10(2):245-260. doi: 10.1007/s40123-021-00344-3. Epub 2021 Apr 12. PMID: 33846958; PMCID: PMC8079568.
  6. Bai B, Chen H. Metformin: A Novel Weapon Against Inflammation. Front Pharmacol. 2021 Jan 29;12:622262. doi: 10.3389/fphar.2021.622262. PMID: 33584319; PMCID: PMC7880161.
  7. Rae M. A TAME Attempt to Slow Aging Part 5: Winning the Game with a Weak Hand. Sens Research Foundation, February 8, 2023. 
  8. Soukas AA, Hao H, Wu L. Metformin as anti-aging therapy: is it for everyone? Trends Endocrinol Metab. 2019;30(10):745–755. doi: 10.1016/j.tem.2019.07.015 
  9. Triggle CR, Mohammed I, Bshesh K, Marei I, Ye K, Ding H, MacDonald R, Hollenberg MD, Hill MA. Metformin: Is it a drug for all reasons and diseases? Metabolism. 2022 Aug;133:155223. doi: 10.1016/j.metabol.2022.155223. Epub 2022 May 29. PMID: 35640743.
  10. Wensink MJ, Lu Y, Tian L, Shaw GM, Rizzi S, Jensen TK, Mathiesen ER, Skakkebæk NE, Lindahl-Jacobsen R, Eisenberg ML. Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring : A Nationwide Cohort Study. Ann Intern Med. 2022 May;175(5):665-673. doi: 10.7326/M21-4389. Epub 2022 Mar 29. PMID: 35344380; PMCID: PMC9844982.


Tags

aging, chronic disease, diabetes, inflammation


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