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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 literature review at the time of the blog and may change as new evidence evolves.

Writer's pictureCoach Chuck

Glycine: Great Things Come in Small Packages, A Remarkable Health Opportunity Hiding in Plain Sight.

Within the 20 amino acids required for protein synthesis, glycine is the smallest and simplest in terms of structure. Its name comes from the Greek word for “sweet,” due to its taste. The data on glycine supplementation for general health and life extension has been building over the years, and in the aggregate, it makes a very compelling case for many reasons that we will explore in this blog.


Glycine Supplement - Coach It Forward Chuck

Supplementation with single amino acids at supra-physiological doses is fascinating, and the targeted health effects may be under appreciated. For example, supplementation with the amino acid glutamine is a proven way to rebuild the gut, prevent neuropathy, and support the immune system during radiation treatment and chemotherapy. Another remarkable study found that taking 10–20 grams of taurine (a non-protein amino acid) daily reduced premature atrial contractions by half and prevented premature ventricular contractions in people with frequent arrhythmias. Adding 4–6 grams of the amino acid l-arginine stopped most remaining premature atrial contractions and pauses, and continued treatment maintained a normal cardiac rhythm1. Taurine supplementation has also promoted longevity and slowed the aging process in worms, mice, and monkeys. A recent study demonstrated that taurine supplementation can extend the healthy lifespans of middle-aged mice by up to 12% (2).


Back to glycine. First, a little history for context. In 1935, Clive McCay, a nutritionist and gerontologist at Cornell University, discovered that rats on a calorically restricted diet lived up to 33% longer than rats that ate normally. McCay’s discovery sparked a curiosity in gerontology: Was it simply the reduction in calories that extended the rat's lives, or could the lifespan increase be isolated to the restriction in specific diet components? Over 50 years later, researchers discovered that the limitation of a single amino acid, methionine, had almost the same effect as overall caloric restriction. The researchers performed an experiment where they restricted methionine from 0.86 to 0.17% in the diet of mice, which resulted in a 30% longer life span, nearly that seen by caloric restriction (3).

Methionine Chemical Structure - Coach It Forward Chuck

Researchers were not entirely sure why methionine reduced life span. But they knew that another amino acid, glycine, was intimately connected to methionine because glycine was part of a biochemical pathway that disposed of excess methionine.


This raised an immediate question: Could glycine alone extend the life span of animals fed a normal, unrestricted diet by reducing the amount of methionine lingering within the cells? 


Soon after, small studies suggested that glycine supplementation could increase worms and rats' life span. These compelling studies led to testing glycine supplementation at the National Institute of Aging's Interventional Testing Program (IPT), the absolute gold standard in life span testing. The study fed the mice an 8% glycine diet (a very high amount!), leading to a small (4%-6%) but statistically significant lifespan increase and an increase in maximum lifespan in both males and females (4). When evaluating any compound for health, lifespan data in mice is critically important, and if there is data from the ITP, it is even better. Why? It's an excellent filter to uncloak any unintended deleterios effects from long-term use, and it addresses a refreshingly simple question that short-term studies fail to address: Does the use of the compound result in a longer life or not?


The ability of glycine to help the recycling of methionine is not the only salubrious role it plays in the body. Glycine is one of three amino acids that are necessary to manufacture the critically crucial intracellular antioxidant glutathione. Levels of glutathione decline with age. A group at Baylor School of Medicine showed that they could replenish glutathione in aged mice by giving them the two rate-limiting amino acids in glutathione production: glycine and cysteine. The group found that the amino acid combination improved impaired mitochondrial fatty acid oxidation and decreased insulin resistance, body fat, and liver fat content.


Additionally, they ran an experiment to see how the combination affected life span, which showed a 24% increase in the treatment group compared to the control group (5). It was a tiny study, with only 32 mice in the treatment groups and 16 in the control group, far less compelling than the massively powered and replicated trials at different sites that the IPT does. Nevertheless, the result was tantalizing.


Even better, the group tested the combination in older adults. They randomized 24 older adults into two groups: 12 received cysteine in the form of n-acetylcysteine (NAC) and glycine, and the other group of 12 received a placebo for 16 weeks. At the end of the study period, the group taking NAC + glycine showed increased glutathione and a plethora of biochemical improvements, including decreased oxidative stress and multiple aging hallmarks affecting mitochondrial dysfunction, mitophagy, insulin resistance, endothelial dysfunction, genomic damage, stem cell fatigue, and cellular senescence. What caught my eye was the striking improvement in inflammatory markers. Systemic inflammation is known to be predictive of chronic disease. The treatment group demonstrated dramatically reduced inflammatory cytokines:  IL-6 was decreased by 78%, TNFα reduced by 54%, hs-CRP was reduced by 41%; and the anti-inflammatory cytokine IL-10 increased after 2 weeks by 50%, and at 16 weeks by 94% (6).


As compelling as the results were, we must consider that it is only a 16-week trial. What about the real world, where people may have a glycine deficiency that lingers for years? Lower circulating levels of glycine are associated with various cardiometabolic diseases, including: obesity, type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, acute myocardial infarction, and coronary heart disease. Yet, researchers were never sure if the lower levels of glycine were causative or correlative to these disease states. In 2022, a group set out to illuminate this critical question. First, they did a very well-conceived study to establish that glycine was lower in coronary artery disease patients. The analysis was blinded, included an exhaustive list of exclusion criteria, and controlled for potential confounding factors with applied case-control matching and randomization. The result confirmed that adults with proven coronary disease had significantly lower circulating glycine. Next, they turned to mice prone to atherosclerosis. The mice fed glycine had significantly less plaque formation than a control group. Biochemical analysis attributed this to the cholesterol-lower effects of glycine and a significant decrease in oxidation due to enhanced glutathione production (7). 


Now, as interesting as all of these studies are, there is another fascinating potential for glycine supplementation that is even more interesting because it centers on what I believe are the actual cellular changes that cause aging. To make the final connection to the potential health benefits of glycine supplementation, we now have to travel across the Pacific to the University of Tsukuba in Japan.


Petri Dish - Coach It Forward Chuck

The experiments led by Professor Jun-Ichi Hayashi did not set out to examine the effects of glycine on aged cells; instead, the group was led to glycine by a series of surprising results. The group was curious as to why mitochondrial energy generation diminishes with age. First, the group took skin cells from older people and reprogrammed them in a petri dish. Cellular reprogramming, first discovered in 2012 by Francis Yamamanka, induces cells to become stem cells, and then the cells can be allowed to dedifferentiate back to their original cellular type. When this cellular round trip is done in the lab, the old cells reset to biological age zero. This finding reveals a powerful clue into the true nature of aging. Because aging can be "reset" in cells by reprogramming the epigenome, it suggests that aging is a software problem, not a hardware problem. In other words, our cells slowly change the genes they are expressing over time. Liver cells start expressing skin cell genes; tumor suppressor genes slowly dial down, oncogenes up – the finely tuned software in each cell slowly loses its fidelity over time.


When the researchers explored which genes were affecting the diminished capacity of old mitochondria to generate energy, they zeroed in on two nuclear genes involved in glycine production within the mitochondria, CGAT and SHMT2. These two genes were "turned down" in the aged cells, thus starving the mitochondria of the glycine necessary to build the electron transport proteins required to generate ATP efficiently. And sure enough, when the aged cells were de-aged by cellular reprogramming, the two genes were turned back on, allowing the mitochondria to produce glycine able to be incorporated into the proteins needed for building the electron transport chain – presto, the old mitochondria now showed youthful energy generation! To test their results further, the group added glycine to the culture medium of fibroblast cell lines taken from 97-year-olds for ten days. They found that supplementation alone restored the old cell’s respiratory function (8). Interesting! Mitochondrial dysfunction as we age is one of the most salient hallmark features of aging.


The data makes a compelling case that glycine is essential for long-term health and disease prevention. Glycine is a non-essential amino acid because the body manufactures it endogenously. OK, great -- so, If someone eats a good diet, they shouldn’t worry about supplementing with glycine because their body will manufacture all the glycine it needs, right? Not necessarily. It is easy to make the case that glycine, like some other amino acids, should be considered "conditional," meaning that your body will manufacture enough to get by, but not enough for optimal health. Here's the rub:  our bodies evolved with insufficient glycine production because, for most of our evolution, we consumed much more glycine, and our metabolism simply didn't have to develop the ability to manufacture more. Glycine is present in cartilage, tendons, and bones, the parts of the animal that mostly get discarded in favor of the select, "prime" cuts of muscle that stock our grocery stores (see chart below). It’s safe to assume that for most of our evolutionary history, our ancestors ate the whole animal out of necessity and thus ingested much more glycine than we do today. As such, the pathologies that result from a glycine deficiency did not emerge as a "selection pressure" that would preferentially select for the genetic subtypes able to manufacture enough glycine for optimal long-term health endogenously. And so here we are, a species starved of the optimal amounts of glycine. 


Food that contain Glycine - Coach It Forward Chuck

Some other notable glycine-rich foods include:

  • Bone broth

  • Chicken skin (3.3 g per 100g)

  • Fish (especially carp, catfish, mollusks, clams, sturgeon, and wild salmon)

  • Lean beef and lamb (approximately 2 g per 100g)

  • Legumes (soybeans, peanuts, lentils, kidney beans)

  • Dairy products

  • Spinach

  • Dried seaweed

  • Watercress

  • Asparagus

  • Cabbage


It's worth noting that animal proteins, particularly from connective tissues, tendons, ligaments, skin, cartilage, and bones, are generally richer sources of glycine compared to plant-based foods[a]b][c].

  

The data on glycine are compelling overall. It is safe and exhibits a surprising array of health benefits. The adage may be true: good things come in small packages.  

  • Glycine increases the lifespan of worms, rats, and mice

  • Glycine, when studied by a group at Baylor School of Medicine, was found to improve markers of health, especially systemic inflammation, dramatically 

  • Low levels of circulating glycine may be causative to a spectrum of disease states, including cardiovascular disease.

  • Glycine reverses the age-related decline in mitochondrial function.


Glycine and NAC supplementation customized to a master plan for longevity and supportive cancer management are just a few tools in the arsenal at MeakinMetabolicCare.com.


We look forward to a conversation about your health goals.


Travis Christofferson MS

Chuck Meakin MD




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.


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References

  1. Diao Y, Nie J, Tan P, Zhao Y, Zhao T, Tu J, Ji H, Cao Y, Wu Z, Liang H, Huang H, Li Y, Gao X, Zhou L. Long-term low-dose ethanol intake improves healthspan and resists high-fat diet-induced obesity in mice. Aging (Albany NY). 2020 Jul 8;12(13):13128-13146. doi: 10.18632/aging.103401. Epub 2020 Jul 8. PMID: 32639947; PMCID: PMC7377878.

  2. Kimoto A, Izu H, Fu C, Suidasari S, Kato N. Effects of low dose of ethanol on the senescence score, brain function and gene expression in senescence-accelerated mice 8 (SAMP8). Exp Ther Med. 2017 Aug;14(2):1433-1440. doi: 10.3892/etm.2017.4633. Epub 2017 Jun 20. PMID: 28810607; PMCID: PMC5525595.

  3. Castro PV, Khare S, Young BD, Clarke SG. Caenorhabditis elegans battling starvation stress: low levels of ethanol prolong lifespan in L1 larvae. PLoS One. 2012;7(1):e29984. doi: 10.1371/journal.pone.0029984. Epub 2012 Jan 18. PMID: 22279556; PMCID: PMC3261173.

  4. https://www.news24.com/life/archive/tiny-amounts-of-alcohol-extend-a-worms-life-20120721

  5. Kankaanpää A, Tolvanen A, Joensuu L, Waller K, Heikkinen A, Kaprio J, Ollikainen M, Sillanpää E. The associations of long-term physical activity in adulthood with later biological ageing and all-cause mortality - a prospective twin study. medRxiv [Preprint]. 2023 Jun 5:2023.06.02.23290916. doi: 10.1101/2023.06.02.23290916. PMID: 37333101; PMCID: PMC10274991.

  6. McMahan RH, Najarro KM, Mullen JE, Paul MT, Orlicky DJ, Hulsebus HJ, Kovacs EJ. A novel murine model of multi-day moderate ethanol exposure reveals increased intestinal dysfunction and liver inflammation with age. Immun Ageing. 2021 Sep 23;18(1):37. doi: 10.1186/s12979-021-00247-8. Erratum in: Immun Ageing. 2021 Oct 21;18(1):39. PMID: 34556145; PMCID: PMC8459518.

  7. Rom O, Liu Y, Finney AC, Ghrayeb A, Zhao Y, Shukha Y, Wang L, Rajanayake KK, Das S, Rashdan NA, Weissman N, Delgadillo L, Wen B, Garcia-Barrio MT, Aviram M, Kevil CG, Yurdagul A Jr, Pattillo CB, Zhang J, Sun D, Hayek T, Gottlieb E, Mor I, Chen YE. Induction of glutathione biosynthesis by glycine-based treatment mitigates atherosclerosis. Redox Biol. 2022 Jun;52:102313. doi: 10.1016/j.redox.2022.102313. Epub 2022 Apr 13. PMID: 35447412; PMCID: PMC9044008.

  8. Hashizume, O., Ohnishi, S., Mito, T. et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep 5, 10434 (2015). https://doi.org/10.1038/srep10434


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