The unknown benefits of one of the world’s most popular supplements.
If you’re interested in preventive health and aging science, you've probably heard of the diabetes drug metformin. Over decades, as evidence piled up that this cheap and safe drug may delay the aging process, it quickly became the darling of the anti-aging community – especially in Silicon Valley, where there is a high concentration of biotechnology companies. "Metformin is undergoing a renaissance in Silicon Valley tech circles -- among people who do not have diabetes,” wrote health reporter Christina Farr.
The excitement surrounding metformin soon extended beyond the techy set and into the popular media.
The most well-known champion of metformin is Nir Barzilia, the director of the Institute for Aging Research at the Albert Einstein College of Medicine. Barzilia is one of the principal architects of the TAME trial (Targeting Aging with Metformin). The ambitious goal of TAME is to conduct a massive clinical trial that follows healthy people on metformin and see if they age healthier, have less chronic disease, and live longer.
For Barzilia, the epiphany moment of metformin's potential to impact aging came from a wildly publicized U.K. study. "I want to tell you the moment I knew we must do this study," said Barzilia. In the study, researchers looked at the prescription records at U.K. pharmacies to identify people on metformin. They then tracked 78,000 types two diabetes on metformin and compared their mortality to 90,000 healthy matched controls. The results were shocking. Compared to the disease-free control group, the metformin group had 15% less mortality at the end of the study. "That shows metformin has a significant effect on aging,” said Barzilia (1).
However, another pill demonstrates anti-aging effects similar to metformin, yet, strangely, seems to be hidden in plain sight, garnishing a fraction of the press and excitement surrounding metformin.
For decades glucosamine has been one of the most popular supplements globally. Approximately 7.4% of older Americans take glucosamine for osteoarthritis and joint pain. In fact, if you were to open the door of older Americans' medicine cabinets, you be just as likely to find glucosamine as you would acetaminophen (2).
Glucosamine quickly gained popularity when it was discovered that it might be a safe and effective treatment for osteoarthritis, one of the older population's most common complaints. Researchers found a broad and potent anti-inflammatory effect that pointed to glucosamine effectiveness. This finding sparked curiosity. Indeed, if glucosamine could safely reduce systemic inflammation, it could help prevent the sweeping array of common inflammatory diseases afflicting the older population, like cardiovascular disease, cancer, and chronic obstructive pulmonary disease.
Epidemiologists quickly seized the opportunity to study glucosamine. The fact that it is a commonly used supplement made the studies much more accessible. The first of a series of studies came from the University of Washington. The study tracked 77,510 participants aged 50-70 starting in 2000. The study followed the participants for eight years. What they found was surprising: compared to the participants that did not take glucosamine, the users of glucosamine demonstrated an 18% reduction in mortality from all causes (3).
Two additional studies quickly followed. The largest, published in the prestigious British Medical Journal, tracked 466,039 individuals for an average of 7 years. After adjustment for age, sex, body mass index, race, lifestyle factors, dietary intakes, drug use, and other supplement use, they found that glucosamine use reduced by 15% the risk of total cardiovascular disease (CVD) events, a 22% lower risk of CVD death, an 18% lower is of coronary heart disease and a 9% lower risk of stroke (4).
Indeed, these studies suggested that the millions of people taking glucosamine for joint pain were reaping a full benefit to their overall health that extended far beyond the relief of joint pain.
The surprising results of these studies sparked the curiosity of the gerontology community. Specifically, they wondered if glucosamine, like metformin, slowed the aging process.
To address this question, gerontologists started with mice. The simple experiment went directly to the heart of the aging question: feed the mice glucosamine and see if they live longer than a control group not given it.
The results were as expected: glucosamine slowed the aging process. The mice fed glucosamine (red) had a significantly longer median and maximal lifespan than those not fed glucosamine (black) (5).
Glucosamine vs Metformin
One of the most glaring criticisms of metformin is that most of the data suggesting that it slows aging is in the diabetic population, leaving it open to whether metformin would have the same effect in the healthy, non-diabetic population. Even so, most researchers are willing to assume that it does. Indeed, this is the aim of the TAME trial – to determine if metformin slows aging and prevents disease in ordinary, healthy people.
This variance is precisely where the data sets between metformin and glucosamine diverge – the data on glucosamine is from a broad swath of the general population.
“The evidence for glucosamine in the worm C. elegans and mice is about the same as for metformin. In humans, there is evidence that type 2 diabetics live longer if they take metformin than if they don't, but this doesn't apply to the public. Whereas the evidence for glucosamine is in normal, healthy people, which is a different target group,” said Dr. Michael Ristow, a professor of energy metabolism at ETH Zurich and a proponent of glucosamine. “I can easily anticipate that metformin will also extend lifespan in healthy people, but that still needs to be proven because that data isn't out there yet like it is for glucosamine.”
Ristow explains the purported mechanism of action behind glucosamine's anti-aging effect. Glucosamine “looks” like glucose, so it mildly inhibits the use of glucose by the cell, forcing it to rely more on mitochondria for energy. “It’s like the cell being on a diet,” says Ristow. “Glucosamine interferes with one of the enzymes used in glycolysis or the breakdown of glucose into lactate or pyruvate. So now the mitochondria must try to burn other sources of energy instead, including fat and some amino acids. What glucosamine essentially mimics a low carb diet, because the cell is forced to activate the mitochondria to survive.”
The evidence on glucosamine's anti-aging effects begs the question: Does it deserve a trial like the TAME trial for metformin? Ristow certainly thinks so. "There should be. I think it's long overdue. It's an ideal supplement because it's cheap, has no I.P. attached to it, and could improve healthspan significantly at almost no cost. A yearly dose is about $15. And the return on investment for insurers and individuals would be significant.”
Please put out the spark before there is a fire!
Sadly, our healthcare system overwhelmingly focuses its vast resources on interventions that treat disease after it presents itself, even though preventing those diseases from occurring in the first place stands to benefit society enormously. Interventions that slow aging, in effect, target every age-related chronic disease and offer the best potential return on investment in healthcare. In 1736 Benjamin Franklin advised Philadelphians of the increasing risk of fires in the city: "An ounce of prevention is worth a pound of cure," he famously said. This approach is precisely our mission at Meakin Metabolic Care, and glucosamine is one of our five carefully chosen supplements in Core 5 of the Metabolic Optimization Protocol (MOP - Metabolic Optimization Protocol - Meakin Metabolic Care). Metformin is also carefully considered as one of the off label pharmaceutical choices on the protocol as indicated by the extensive onboarding survey and laboratory inquiry (HOMA-IR, HemA1c, Pheno Age, and more) that is part of the program.
Stay Curious and be your own Best Doctor,
Charles Meakin MD, MS, MHA
Travis Christofferson MS
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Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
1 Bannister CA, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched non-diabetic controls. Diabetes Obes Metab. 2014 Nov;16(11):1165-73.
2 Qato DM, Alexander GC, Conti RM, et al.. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 2008;300:2867–2878
3 Bell GA, Kantor ED, Lampe JW, Shen DD, White E. Use of glucosamine and chondroitin in relation to mortality. Eur J Epidemiol. 2012 Aug;27(8):593-603.
4 Ma H, Li X, Sun D, Zhou T, Ley SH, Gustat J, Heianza Y, Qi L. Association of habitual glucosamine use with risk of cardiovascular disease: a prospective study in U.K. Biobank. BMJ. 2019 May 14;365:l1628.
5 Weimer S, Priebs J, Kuhlow D, Groth M, Priebe S, Mansfeld J, Merry TL, Dubuis S, Laube B, Pfeiffer AF, Schulz TJ, Guthke R, Platzer M, Zamboni N, Zarse K, Ristow M. D-Glucosamine supplementation extends the life span of nematodes and of aging mice. Nat Commun. 2014 Apr 8;5:3563.