We could say that something has an anti-aging effect if it positively affects the duration of health, the period of life spent in good health and free of crippling diseases.
Following a comprehensive review, Campbell et al. concluded that, regardless of its therapeutic efficacy as an antidiabetic drug, the use of metformin results in a reduction in all-cause mortality, including cancer and cardiovascular disease.
Dr. Alfonso Galán González – Neolife Medical Team
Metformin and Microbiota
Metformin also alters our microbiota – the bacteria that live with us in symbiosis in our gut – and this action is a determining factor in both its positive hypoglycemic and “anti-aging” effects.
The numerous health benefits associated with the use of metformin in treating patients with type 2 diabetes (DM2), together with data from preclinical animal studies, such as in the worm (nematode) C. Elegans and in mice, have prompted research into whether metformin also has effects as an anti-aging drug capable of increasing our longevity. In fact, several clinical trials such as MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin) have been designed to evaluate these potential benefits of metformin as an anti-aging drug and to overcome the doubts that the current evidence raises.
In this blog post, we would like to explain in a simple way what we know today about its influence on the state of health and longevity in humans and other species and the mechanisms proposed for these actions.
Metformin is an antidiabetic drug, specifically a synthetic biguanide, which is used orally and improves insulin sensitivity. It is a first-line hypoglycemic drug for the treatment of type 2 diabetes mellitus (DM2). Metformin was first synthesized in 1922 when the purported medicinal properties of a plant, the French lilac () were investigated. Metformin was introduced to treat DM2 in France in 1958, and today, more than 60 years later, it is still used daily by some 150 million people worldwide.
It is an inexpensive, safe drug (the main adverse effect, which occurs in 20-30% of patients, is intestinal discomfort)… and it is effective.
The use of metformin leads to weight loss in many patients and lowers HbA1c (glycated hemoglobin or glycosylated hemoglobin, a fundamental marker for monitoring DM2, and which indicates the evolution of our blood sugar levels in the last 2-3 months).
Its use was strongly supported by the publication in 1998 of the UKPDS study, a 20-year prospective, randomized, multicenter study of patients with DM2 on metformin, which reported cardiovascular benefits of its use.
Because metformin is so widely used, there is an opportunity to determine whether metformin has anti-aging properties.
And what do we call anti-aging? We could say, and we hope you agree with us on this definition, that something has an anti-aging effect if it positively affects the duration of health, the period of life spent in good health and free of crippling diseases.
In this blog post, we are going to summarize what is typically very complex information, which might help us answer, …or not, the question of whether metformin has other positive effects on the aging process, in addition to its effects as a hypoglycemic agent.
The presumed relationship between metformin and aging
Based on a systematic review of 53 studies, with a total population of more than 400,000 people, Campbell et al. concluded that, regardless of its therapeutic efficacy as an antidiabetic drug, the use of metformin results in a reduction in all-cause mortality, including cancer and cardiovascular disease2. This seems like a very interesting starting point in the investigation of the properties of a drug, doesn’t it?
AMPK and mTOR
Metformin appears to act on the AMPK and mTOR metabolic pathways (which we have described extensively here). Specifically, it activates the AMPK pathway and inhibits signaling through the mTOR pathway. This mTOR pathway has important functions in the regulation of cellular metabolism, including nutrient signaling and IGF-1 (Insulin-like growth factor 1) mediated growth. Signaling through mTOR is associated with accelerated aging, and dysregulation of mTOR signaling is also associated with cancer progression, inflammatory and neurological diseases, as well as DM2.
AMPK functions as an energy sensor that coordinates multiple signals related to energy production and the control of glucose and lipid metabolism.
It is worth noting that AMPK sensitivity decreases with age, which furthers the argument that AMPK activators, such as metformin, may delay aging.
Studies conducted on worms (C. Elegans) and mice, indicate that adding metformin to the diet may delay aging and increase the life expectancy of these beings.
However, we also know that in these studies with C. Elegans, very high concentrations of metformin were used, which would be equivalent to about 5 kg of metformin daily for a human being. For an idea of magnitude here, the usual doses for treating type 2 diabetes (DM2) are between 850 mg and 2 g/day.
Such doses in humans would be fatal, and the same would be expected for the C. Elegans, but in them, it appears that the toxicity is offset by the effects of metformin on the microbiota and inhibition of bacterial folate metabolism.
These same effects have, of course, been investigated in humans. And indeed, metformin also alters our microbiota – the bacteria that live with us in symbiosis in our gut – and this action is a determining factor in both its positive hypoglycemic and “anti-aging” effects, as well as in its negative gastrointestinal adverse effects. In fact, metformin is only absorbed, it has a bioavailability of 50%, with half of what we ingest being eliminated with our bowel movements.
Metformin, in another action that occurs in the intestine, elevates the release of GLP-1 or incretins. Incretins are part of an endogenous system involved in the physiological regulation of blood sugar. They increase insulin release in the presence of glucose, decrease glucagon release (a hyperglycemic hormone), and regulate appetite.
This effect of metformin on the intestine is likely to be significant, so much so that metformin does not work by any route apart from orally.
We also now know that metformin raises levels of something called GDF15 (Growth/differentiation factor-15) involved in weight loss and positive cardiovascular effects. In fact, in a study based on a proteomic analysis of plasma from 240 healthy, disease-free humans in the age range of 22 to 93, GDF15 was identified as the protein that correlates most positively with chronological age and is also known to reduce appetite.
Metformin seems to play an important role in the regulation of mitochondrial function and to exert a kind of quality control. It helps to eliminate damaged mitochondria and enhance mitophagy, a special form of autophagy that recycles poorly functioning mitochondria. The mitochondrion, as we may recall, is at the very core of aging, as we reported here.
The endothelium (the innermost layer of our arteries) plays a fundamental role in the regulation of vascular function and is a source of a molecule like nitric oxide (NO), a vasodilator and signaling agent. Endothelial dysfunction is an early marker of cardiovascular disease.
If we ask ourselves whether metformin can have a direct anti-aging effect on the endothelium, the answer based on clinical and preclinical data should be a clear YES, although it is true that the clinical data on this effect are difficult to separate from its effect on lowering blood sugar and improving insulin sensitivity.
Metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence.
Therefore, if it protects us from the progression of vascular diseases, we can safely say that it increases our disease-free life expectancy.
Inflammation is related to all diseases associated with aging, and the aging process itself involves an inflammatory state that has come to be called Inflammaging. Several elemental studies using different cell types have reported that metformin inhibits the activation of the NF-kß inflammatory signaling pathway and downregulates the production of proinflammatory cytokines and genes that encode for the inflammatory response.
Autophagy is a necessary process for getting rid of damaged proteins and organelles at the cellular level and plays an important role in the regulation of cellular aging. We know that calorie restriction, which is quite popular right now, is a powerful inducer of autophagy.
There appears to be a relationship between autophagy and metformin, but it is not clear that it can occur at the doses we would use in humans.
Diabetes has been associated with a higher risk of developing several types of cancer, and a retrospective study published in 2005 reported that type 2 diabetic patients treated with metformin had a lower risk of developing cancer and pointed to a possible link between metformin and the tumor suppressor LKB13. Its effect on the AMPK pathway has also been linked to its antiproliferative effects.
The truth is that there is quite a bit of literature supporting these effects…but not all of them.
And so, further studies, which are ongoing, are needed to prove this important link and whether it is due to metformin or simply secondary to its effects as a hypoglycemic, insulin sensitizer, or its inhibition of the mTOR pathway.
Diabetes causes hyperglycemia and hyperinsulinemia, and increases oxidative stress, vascular disease, and inflammation…and yes, all of these things are linked to cognitive impairment.
There is pretty solid evidence that links the use of metformin in type 2 diabetics with cognitive improvements. The search for the precise molecular mechanism that mediates it is underway.
This is where we wish to place the focus of this article.
Exercise activates AMPK, which in turn increases glucose uptake in muscles and improves insulin sensitivity, helping to offset the negative effects of obesity, diabetes, and cardiovascular disease, thereby reducing morbidity and improving health. And metformin, as we have mentioned above, has incredible effects on our health.
Therefore, given that both exercise and metformin can improve glycemic control and that both mediate their effects through the activation of AMPK, if we combine the two, we should have an additive effect, right?
Unfortunately, that does not appear to be the case.
A prospective, double-blind, randomized, and controlled study in which men and women with prediabetes were put on an exercise regime for 12 weeks with placebo and metformin, or placebo only, or metformin only, reported the following results:
Both metformin and exercise improved skeletal muscle insulin sensitivity by 55% and 90%, respectively, but the combination resulted in only a 30% improvement.
The results were similar for the effects on systolic blood pressure and C-reactive protein (CRP) -a marker of inflammation- which were reduced by 7 to 8% with metformin and exercise versus 20 and 25%, respectively, which were lowered separately. Additionally, metformin attenuated the exercise-induced increase in VO2max4.
Additional questions about the benefits of combining metformin and exercise come from two studies with older adults. Konopka et al. reported that metformin (2000 or 1500 mg/day for those who experienced gastrointestinal discomfort) attenuated exercise-induced increases in insulin sensitivity and also reduced exercise-induced increases in mitochondrial respiration5.
In the MASTERS (Metformin to Augment Strength Training Effective Response in Seniors) study, metformin, despite an increase in AMPK signaling, slowed the strength exercise-induced muscle hypertrophy response in healthy men and women over 65 years of age who participated in a supervised progressive resistance exercise training program for 14 weeks after a 2-week metformin treatment (1700 mg/day or placebo)6.
And so, in view of these results, all the positive effects of metformin that we are enumerating could be overshadowed by apparently minimizing the positive adaptations that the anti-aging and pro-health measure par excellence, exercise, has on our bodies.
There are mainly two ongoing studies that will give us that answer as to whether we may consider metformin an anti-aging drug.
The Metformin in Longevity Study (MILES) is a double-blind study in which subjects act as their own placebo control group. It began in October 2014 and was conducted in 14 elderly participants with glucose intolerance to determine whether metformin (1700 mg/day) can cause physiological and transcriptomic changes in muscle and adipose tissue after 6 weeks of treatment. It also determined which pathways are affected by metformin and outlined possible molecular intermediates involved in metformin’s action mechanism.
We already have data on the results of this study, although the conclusions have not been published. Preliminary analysis of the MILES results indicates that metformin can indeed induce anti-aging transcriptional changes in the tissues studied.
The Targeting Aging with Metformin (TAME) study is a multicenter, double-blind, placebo-controlled trial that is planned to involve 14 research centers in the US and will enroll 3000 non-diabetic individuals aged 65 to 80 who will receive 1700 mg of metformin daily for 6 years. Follow-up will be at 3.5 years.
Its objectives are:
- Clinical outcomes, measured as the occurrence of new age-related chronic diseases
- Functional outcomes, such as changes in mobility
- Biomarkers of the aging process such as inflammation and senescence
After all this being said, as you can see, the jury is still out on whether we may consider metformin an anti-aging drug. The final results of these studies may give us the definitive verdict. We also need to know if the above mentioned study regarding exercise + metformin is really so, as it would be an almost insurmountable obstacle for its consideration as an anti-aging therapy.
(1) 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.
(2) Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-Analysis. Ageing Res Rev (2017) 40:31–44. doi: 10.1016/j.arr.2017.08.003
(3) Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and Reduced Risk of Cancer in Diabetic Patients. BMJ (2005) 330:1304–5. doi: 10.1136/bmj.38415.708634.F7
(4) Malin SK, Braun B. Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. Exercise Sport Sci Rev (2016) 44:4–11. doi: 10.1249/JES.0000000000000070
(5) Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, et al. Metformin Inhibits Mitochondrial Adaptations to Aerobic Exercise Training in Older Adults. Aging Cell (2019) 18:e12880. doi: 10.1111/ acel.12880
(6) Walton RG, Dungan CM, Long DE, Tuggle SC, Kosmac K, Peck BD, et al. Metformin Blunts Muscle Hypertrophy in Response to Progressive Resistance Exercise Training in Older Adults: A Randomized, Double- Blind, Placebo-Controlled, Multicenter Trial: The MASTERS Trial. Aging Cell (2019) 18:e13039. doi: 10.1111/acel.13039