Dan’s Plan Better Aging Part 5

Should We Take This Diabetes Drug to Age More Slowly? (Better Aging Part 5)

Dan's Plan Better Aging Part 5

Much of the research on aging is directed towards identifying substances to slow biological deterioration and extend lifespan. By studying how animals and humans respond to dietary restrictions as discussed in previous articles, researchers have identified several physiological pathways that influence how rapidly age-related damage accumulates. Generally, these age-modifying substances  work in two ways: by stimulating pathways that slow down aging, and/or by inhibiting pathways that accelerate it. In this article, we will look at an how the diabetes drug metformin appears to slow the aging process by triggering cells to switch to an energy conservation state.

The AMPK Pathway

Adenosine monophosphate kinase, or AMPK, is an enzyme found in organisms (like humans) made up of cells that have mitochondria (eukaryotes). This enzyme senses energy levels in the cell, and it arose early in the evolution of eukaryotes as an adaptation to allow them to survive periods of starvation. When stimulated, AMPK switches the cell to an energy-conserving state. Let me pause and comment that starvation is an evocative term. It readily conjures images of people so emaciated that they are near death, and it is usually not associated with a healthful state. Certainly, we do not want to spend too long a period in a state of starvation. It is also likely that periods longer than 12 hours of absence from food were normal during the course of our evolution, and therefore, we have evolved mechanisms that help us deal with food absence. It also appears likely that triggering these conservation mechanisms in the right way may be a goldmine for our health. Indeed, stimulating the AMPK pathway appears to be one of the ways by which dietary restrictions exert their lifespan-extending effects. For example, caloric restriction does not make worms live longer when this enzyme is absent.

How AMPK Works

The mechanisms by which AMPK fulfills its role have acquired secondary effects over the course of evolution that may explain how it might help slow down aging. One effect is the inhibition of energy-intensive processes, like the cell division that happens during ordinary tissue growth (a process called mitosis). Another effect is the stimulation of autophagy, which is the process by which cells recycle their damaged or dysfunctional components, including mitochondria. These effects, and their impact on the health of humans and laboratory animals, have been demonstrated in studies on substances that activate the AMPK pathway. One especially important substance that does this is metformin.

MetforminMetformin

Metformin is a drug that has a well-established role in the treatment of type 2 diabetes mellitus (shortened to “diabetes” in the remainder of this article). It has been used to treat this condition since the 1950s and is currently the drug of choice recommended by the American Diabetes Association and the European Association for the Study of Diabetes. New evidence suggests that metformin may slow down aging independently of its effects on diabetes, and the idea that such a familiar and well-researched substance, with a excellent safety profile, might help us achieve our goal of prolonging lifespan is particularly exciting news.

Diabetes

In diabetes, persistently elevated blood sugar leads to negative effects on vessels and nerves. Thus, most drug treatments have been designed to lower blood glucose. Several newer classes of such drugs, many of which are much more potent at decreasing blood glucose, have been introduced over the decades. However, many major studies suggest that metformin provides health benefits that are not mediated via blood glucose control. These findings, along with studies showing that metformin increases longevity in rats, mice, and worms, stimulated research on the potential of metformin as an anti-aging drug in humans. This new research has significantly advanced our understanding of the benefits of this drug beyond treating diabetes.

Heart Benefits

Cardiovascular benefits are seen with metformin administration and these benefits are mediated via the activation of AMPK and not by its ability to lower blood glucose. For instance, in mice and rats, metformin protects cultured heart muscle exposed to low-oxygen conditions enabling heart tissue to survive episodes of energy deprivation. In rats, metformin limits abnormal and unhealthy heart muscle growth in response to stresses like hypertension. In humans with impaired ability to tolerate glucose, one year of treatment with metformin 850 mg twice daily led to heart-healthy improvements in lipoprotein subfractions: it significantly reduced small and dense LDL, and raised small and large HDL (effects that were independent of glucose-regulating hormone adiponectin, as well as the BMI, and insulin resistance status of the subject). In a quote from study author Ronald Goldberg, MD in Medpage Daily, “Our findings demonstrate that the same therapies used to slow the onset of diabetes also may help allay the risk of heart disease.” Please note that some of these benefits may be from AMPK stimulation, while some may also be attributable to improved blood glucose control.

Cancer Suppressor

Because metformin has been so widely used, it eventually became apparent that diabetic patients treated with this drug had a substantially lower risk of developing cancer compared to those treated with other agents. But all the studies that showed these effects were retrospective reviews of medical records and so were vulnerable to a variety of potential biases. Nevertheless, this is sufficient reason to investigate further. Indeed, there are more than 200 ongoing clinical trials studying the effect of metformin in preventing and even treating cancers. An important issue to resolve is whether the antitumor effect of metformin extends to non-diabetics. It is reasonable to suppose that it would, because there are plausible mechanisms by which metformin could exert these effects. High levels of circulating insulin are known to favor the growth of some common cancers. Metformin reduces hyperinsulinemia and may thus suppress insulin-mediated tumor growth. Its glucose-lowering effect may also cause a relative deprivation of energy sources to cancer cells, which are particularly sensitive to energy starvation. However, treatment of a non-diabetic, tumor-prone mouse model with AMPK activators, including metformin and another biguanide called phenformin, significantly delayed tumor development, suggesting that AMPK activation is at least part of the cancer-suppressing benefits of metformin.

From Andel, 2013 (Hat tip to Suppversity)

At this point, hundreds of study on isolated cells, experimental animal models and retrospective studies in patients have shown preventive effect of metformin therapy on manifestation tumors of pancreas, breast, colorectum, liver, endometrium and ovary. More over, the prognosis of diabetic cancer patients on metformin therapy seems be better, than in diabetics without metformin treatment.

 

Metformin on the Microbiota

MicrobiotaMetformin also appears to exert beneficial effects by mechanisms other than AMPK activation, improving metabolic markers even in obese mice that lack AMPK. In 2014, Lee et al., showed that in mice, as expected, metformin improved serum glucose levels, body weight, and total cholesterol levels, and it also significantly increased the composition of certain microbiota, Akkermansia muciniphila and Clostridium cocleatum. The microbial landscape of the gut significantly influences energy balance and metabolism. For example, the composition of our microbiota can influence: insulin sensitivity, energy extraction from eaten foods, peptide hormone production that influence appetite, fat deposition direction, and metabolic pathway activity. In the Lee study, a total of 18 metabolic pathways, including fatty acid metabolism, were significantly up-regulated in the gut microbiota during metformin treatment. Interestingly, an unhealthy colony of microbiota can decrease AMPK activity which can impair the breakdown of lipids and increase fat deposition.

Conclusion

Metformin clearly has strong potential for use as an anti-aging drug. The question that researchers are now attempting to answer is whether significant protective effects will be seen in healthy, non-diabetic humans given clinically practicable doses. If so, metformin could become an important agent for slowing down aging in a large segment of the world’s population.

  

References

  1. Foretz M, et al., (2014) Metformin: From Mechanisms of Action to Therapies. Cell Metabolism.
  2. Hardie, DG (2011) AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function. Genes & Development.
  3. Hur KY, Lee MS (2015) New mechanisms of metformin action: Focusing on mitochondria and the gut. J Diabetes Investig.
  4. Longo VD et al., (2015) Review: Interventions to Slow Aging in Humans: Are We Ready? Aging Cell.

 

 

 



  • Very nice summary of some fascinating properties of metformin use. I’m curious if these therapeutic effects of metformin can be induced via life-style factors, such as low-carb or even cyclical ketogenic diets, HIT (high intensity training, e.g., sprinting), and/or intermittent fasting?

    • danpardi

      Thanks, @aaronblaisdell:disqus. CC’ing @jeffrothschild:disqus here. Yes! Lifestyle factors, like muscular contractions via strength training / sprinting, can activate AMPK. Additionally, metformin is considered a calorie-restriction mimetic in that this drug activates some pathways that energy restriction activates, including autophagy and AMPK activation. There are also other substances that will activate AMPK, including: Alpha lipoid acid, berberine (which also has similar effects another anti-aging compound, resveratrol, to promote brown fat production), green tea, and more. I think metformin may be a great choice to mimic SOME of the health promoting effects of lifestyle in those who are unable or unwilling to maintain those lifestyle factors with regularity.

      • Sveta

        Dan, do you take metformin or berberine … in small doses perhaps?

        • danpardi

          Hi @disqus_cyYYsUmEL4:disqus, are you saying I look good for my age? Just kidding. Yes, I do. I take 1g of berberine a day, 300 mg of alpha lipoid acid, and I drink green tea. I also fast and exercise. I have not taken metformin.

          • Sveta

            Haha! Whatever you do, keep on doing it. Looking great there! Re Berberine dose, would you recommend 1g as maintenance for most people with normal blood sugar?

          • danpardi

            Ha! Well, thanks Sveta. There isn’t good data available on berberine and aging outcomes. I just take one serving a day according to the recommended serving size on the product label. Here is the product description from Thorne:

            Product Description

            Berberine is an alkaloid that is present in a number of plants, including Berberis vulgaris (barberry), Berberis aristata (tree turmeric), Berberis aquifolium (Oregon grape),Hydrastis canadensis (goldenseal), and Coptis chinensis (goldthread). This important plant extract demonstrates important benefits for glucose metabolism, maintenance of healthy lipid levels, insulin sensitivity, cardiac support, weight management, gastrointestinal health, immune modulation, and cognitive support.*

            https://www.thorne.com/products/immune-support/dp/berberine-500

          • Sveta

            Thank you, this is interesting. I’ll experiment with the herb. The manufacturer doesn’t say this but some recommend cycling berberine. I came across the advice on Gottfried’s blog post: “It’s recommended that you take berberine for only 8 weeks at a time and then take a holiday owing to the effect of the herb on cytochromes P450 (CYPs) in the liver.” She cites the study in the footnotes.

            http://www.saragottfriedmd.com/for-the-love-of-berberine-what-it-is-and-why-i-take-it-to-lower-blood-sugar-bad-cholesterol-and-weight-plus-5-faqs/

          • danpardi

            Hi @disqus_cyYYsUmEL4:disqus, thank you for forwarding this. The problem with many-to-most supplements is that we don’t have the type of long term safety and efficacy data that we do with drugs. So, many recommendations are based on limited information, and so it’s wise to be conservative. I cycle all the supplements I take for this and other reasons. I usually take a bottle and then switch to something else and then circle back eventually.

          • Sveta

            Smart. I should be doing the same.

  • Good stuff! I haven’t read much about it, but I believe berberine works in part by increasing AMPK? Would that then have similar effects?

  • Frederik Ackermann

    You write: “…an unhealthy colony of microbiota can decrease AMPK activity which can impair the breakdown of lipids and increase fat deposition.”

    Should this be understood as:
    A. A microbially derived decrease in AMPK impairs breakdown of lipids in the intestines, minimising absorption, and thus providing potentially more fuel for microbes?

    or

    B. A microbially derived decrease in AMPK impairs lipolysis in adipose tissue?

    Also can you provide the source for this, I havn’t heard of it before, and find it quite interesting.

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