All about Metformin
To continue with our focus on health span and anti-aging, Dr. Dominique Fradin-Read will address a very interesting topic: What do we know about metformin and its protective effects for anti-aging? Should everyone take the medicine for this purpose?
Metformin was discovered by the French physician Jean Sterne in 1957 and was introduced as a medication for hyperglycemia in the early 60s in Europe. It has since then been used as the most prescribed agent for Type 2 diabetes.
In a retrospective study published in 2014 by Bannister et al., the results suggested that metformin monotherapy could increase survival in the general population. These findings raised considerable interest in the use of metformin as a preventative agent against age-related conditions and prolongation of lifespan.
A recent retrospective Danish study by Keys et al., published in the International Journal of Epidemiology in September 2022, brought some shadow to the existing data as the conclusion was that: “Treatment initiation by metformin monotherapy in Type 2 diabetes was not associated with survival equal or superior to that of the general population without diabetes.”
So, what are the questions to ask, and should we still recommend metformin as a potential preventative /anti-aging agent?
A first argument to consider is that both studies are retrospective cohort studies which present a high risk for many research biases. These studies have limitations in determining the difference between association of effects and direct causation. Which one was more accurate in its methodology and results? Hard to tell!
A second argument is that the endpoints of both studies were “mortality and survival.” This is limited data to evaluate the benefit of a molecule for disease prevention. What about quality of life and morbidity during the survival in both populations? The true question still remains: How will my years of survival be with metformin on board? Will I have less age-related conditions, less cardiovascular disease, less cancer, less diabetes risk, less Alzheimer? As Dr. Fradin-Read often states in her articles, more than lifespan we need to look at “health span” as the real goal of well aging.
The large clinical trial TAME (Targeting Aging by MEtformin) is on its way and should help bring definitive answers. However, the results will take years to be published.
Disturbed by the recent study as a physician responsible for providing current evidence before recommending a treatment, Dr. Fradin-Read decided to review the recent literature on publications about metformin. A summary of her research is presented below as well as her experience with the molecule as a prescriber since the early 80s first in France and later in the United States . The goal is to give the best information available so that patients can decide if they believe it useful to start taking the medication.
Let’s start by reviewing the various mechanisms of action of metformin that can potentially attenuate the hallmarks of aging.
Metformin activates AMPK and SIRT1 pathways. These pathways are important clues for optimal metabolism and energy production at the cellular level. The activation of the AMPK suppresses the negative effect of the AGEs (Advanced Glycation End products) that are responsible for the expression of inflammatory cytokines. AMPK and SIRT1 are also involved in nutrients-signaling cascades that regulate aging and determine longevity.
Metformin directly inhibits the mTORC1 pathway mimicking the benefits of dietary caloric restriction and autophagy on the body. It protects against the abnormal buildup of proteins (protein misfolding) or neurotoxins in animal models of Alzheimer and Parkinson. At the same time Metformin can activate p53 gene by activating AMPK and thereby ultimately stopping the cell cycle reducing cancer risk.
Without going into all the details of other beneficial effects of metformin the following targets of action for the molecular have been identified:
It suppresses pro-inflammatory cytokines and appears as a potent systemic anti-inflammatory drug.
It improves insulin sensitivity and metabolism and supports both body weight loss and weight maintenance over time.
It improves the gut microbiome and reduces age-associated intestinal dysbiosis, consequently helping strengthen the immune system.
It presents with a protective effect on DNA damage and telomeres shortening that occur with age.
It has substantial benefits on mitochondrial dysfunction secondary linked to oxidative stress.
It seems to induce stem cell rejuvenation and delays stem cell decline due to age thereby promoting tissue repair.
Just by looking at these numerous modes of action, mostly seen in animal models so far, we can understand why metformin appears as an attractive anti-aging drug.
Let’s look at several publications that corroborate these results in human research:
Metformin and weight
Large cohort studies have shown weight loss benefits associated with metformin therapy in insulin resistant and pre-diabetic patients as well as Type 2 diabetic patients. The total weight loss depended on adherence to the treatment and in average patients on metformin experienced a 2.1 kg weight loss. Due to the modest and inconsistent effects of weight loss the FDA has not approved metformin as a weight loss agent. The current use of metformin as an agent exclusively for weight loss remains off-label but is frequently utilized in patients at high risk for metabolic or cardiovascular complications.
Metformin has been examined in multiple disease processes as a weight gain prevention tool. It has shown great benefit in preventing weight gain in patients started on antipsychotic medications for mood disorders. It helped prevent insulin-induced weight gain in diabetic patient on insulin. Dr. Fradin-Read has found it helpful for long-term weight maintenance among her patients finishing a weight loss program.
Metformin and cancer:
There are numbers of published studies and observations that indicate a reduction in the risk of cancer and its mortality among diabetic patients that use metformin in doses of 1,500–2,250 mg per day. A comprehensive review of recent advances was just presented in Cancer Management and Research in April 2023 by Saraei and al. CMAR_A_200059 3295..3313 (dovepress.com)
A few trials have clearly identified the benefits of metformin in cancer therapy as a potential anticancer agent on its own or as an adjuvant with other immunotherapeutic agents. A publication from 2020 by Ruixia Ma et al. offers a good overview of the current knowledge: https://www.nature.com/articles/s41401-020-00508-0
The American Diabetes Association and The American Cancer Society have reported that metformin may be associated with a decreased risk of certain cancers such as breast cancer, bladder cancer, prostate cancer, and colorectal cancer.
Metformin and cardiovascular disease
There is clear evidence of the benefit of metformin as a protective agent in various cardiovascular diseases. A mini review of the literature published in fall 2022 in the Journal of Cell Molecular Biology by BU et al., summarizes the clinical evidence of metformin benefits in several widely studied cardiovascular diseases, such as atherosclerosis, ischemia post myocardial infarction, and even arrhythmia, both in patients with and without diabetes. https://onlinelibrary.wiley.com/doi/10.1111/jcmm.17519
Metformin and Alzheimer
The Sydney Memory and Aging Study, a prospective study published in 2020, confirmed previous data that older people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. https://pubmed.ncbi.nlm.nih.gov/32967921/
The topic is still controversial: if numerous observational studies have found metformin use to be associated with a reduced risk of dementia among individuals with diabetes a few others have found an increased risk. We need to keep in mind that observational studies are at a high risk of biases and may result in spurious associations. It is therefore hard to draw final conclusions. No direct effect has been demonstrated for non-diabetic individuals.
Metformin and Exercise
When reviewing fully what was published about metformin and exercise, it is important to mention a very recent study confirming the idea that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Good evidence existed through previous clinical trials and observational studies.
A temporary doubt was created when, in 2019, articles were published stating that the drug blunted the benefits of metformin on healthy older adults by impacting the ability to build muscle with PRT. The new study conducted by the Institute for Aging Research in New York demonstrated that, although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have other beneficial effects on aging-associated pathways in muscle from older adults, in particular as it promotes youthful gene expression.
So before jumping in and asking for a prescription, what should patients know about the risks and potential side effects of metformin?
As mentioned earlier, Dr. Dominique Fradin-Read has been prescribing the medication since the early 80s and none of her patients developed serious side effects.
Interestingly, after moving to the United States she realized that even if this was related to a small number of patients, there were a few more complaints of digestive issues such as nausea, diarrhea, stomach aches, and impression of a metallic taste with the molecule offered in the US, which is a generic of the original French Glucophage. She herself noticed experimenting with mild stomach aches when taking her medication purchased in the US. She decided to go back using Glucophage. For the anecdote she had to bring back a 6- month treatment in her suitcase after a trip to France as the brand name is unfortunately not available in the US. There was definitely a difference in the tolerability of the products. She has now been able to get Glucophage with a special prescription for patients who cannot tolerate the “American” generic metformin, either in France if patients travel there or through a pharmacy located in the UK. She can also prescribe it safely through compounding pharmacies in Los Angeles with better tolerability as a whole.
Although we still do not have the results from a good placebo-controlled randomized trial to confirm the benefits of Metformin as an anti-aging drug, Dr. Fradin-Read shares the same confidence as her friend David Sinclair, PhD and researcher at Harvard University, in the role of the molecule for disease prevention and health span support. She will continue taking this medication daily. Dr Dominique Fradin-Read recommends taking the medicine at bedtime if tolerated without food and at reasonable dosage to avoid interference with exercise.
Patients are welcome to ask more questions!