This Supplement Is Older Than Life - And May Help You Live Longer | Lifespan - S2, Ep. 10
In a Nutshell
Glycine extends lifespan in multiple animal models by mimicking methionine restriction: at 3-5g daily it activates glycine N-methyltransferase, depleting methionine stores and triggering AMPK activation, mTOR inhibition, and sirtuin upregulation. Human trials show 100 mg/kg/day (≈7g for a 70kg adult) of glycine plus NAC improves glutathione levels, reduces oxidative stress and inflammation, increases muscle strength, and lowers insulin resistance within 16 weeks. The molecule is extremely safe and inexpensive, with benefits tied to collagen synthesis, glutathione production, and methionine restriction rather than direct sirtuin or AMPK effects.
These notes were generated by AI and may contain inaccuracies.
Glycine is a molecule that has been around since the dawn of time, even before life existed. This amino acid was discovered by Henri Braconnot in 1820 when he boiled gelatin with acid while attempting to create different types of sugar. Originally named "sugar of gelatin," it was later renamed glycine from the Greek word "glicus" meaning sweet.
Glycine is the simplest amino acid, consisting of just two carbons, one nitrogen, and two oxygen atoms. It has been found in meteorites and comets, confirming its presence throughout the universe.
David Sinclair spent years studying glycine during his PhD approximately 30 years ago, working on the catabolism and processing of glycine in yeast cells. This research was conducted in Ian Daw's lab at the University of New South Wales. His first paper on glycine was published in 1995 and still receives citations today. Sinclair now consumes glycine daily, adding it to his morning drinks as a sweetener and reports improved sleep quality.
Glycine is classified as a conditional amino acid, meaning it is not strictly essential since the body can generate it from serine. However, it is required for numerous biological processes including collagen synthesis, glutathione production, and methylation reactions.
Three key longevity pathways form the survival circuit: sirtuin activation, mTOR inhibition, and AMPK activation. These pathways evolved to help organisms survive periods of adversity and are found across plants, bacteria, and humans. In modern life with abundant food and minimal stress, these survival genes are not activated as frequently, leading to accelerated aging.
Sirtuins stabilize cellular information including DNA and the epigenome. mTOR senses amino acid abundance, particularly branched-chain amino acids like leucine, isoleucine, and valine. AMPK activates when cellular energy (ATP) is low.
Caloric restriction activates AMPK, inhibits mTOR, and increases NAD+ levels to activate sirtuins. Exercise similarly affects all three pathways. Metformin inhibits cellular respiration, lowering ATP levels and thereby activating AMPK while also inhibiting mTOR and activating sirtuins.
Glycine does not fit neatly into the three longevity pathways. It does not affect sirtuins, downregulates AMPK (opposite of expected for longevity), and boosts mTOR when applied to cells. Despite these counterintuitive effects, research suggests glycine extends lifespan through alternative mechanisms.
The molecule's structure is remarkably simple, which explains why it can form in space environments. The discovery process involved using sulfuric acid on various organic materials, with glycine being one of several sugars created from different starting materials.
During his PhD work, Sinclair identified three genes necessary for glycine utilization as a carbon source in yeast cells. Gene sequencing in the 1990s required toxic chemicals and thin glass plates with high voltage, taking three months to sequence 150 letters. Modern sequencing can read a million letters in an afternoon using devices the size of a Twinkie.
Glutathione Production
Glutathione is a tripeptide antioxidant composed of glutamate, cysteine, and glycine. The liver produces significant amounts of glutathione for tissue protection. Supplementing with glycine, sometimes combined with N-acetylcysteine, may increase glutathione levels and enhance cellular protection.
Collagen Synthesis
Collagen, derived from gelatin, is glycine's primary natural source. The body experiences a collagen deficit with aging. Supplementing with glycine may improve collagen synthesis, benefiting skin and other tissues. Degradation products of collagen, including hydroxylated glycine, may act as signaling molecules.
Methionine Restriction Mimicry
Glycine may act through methionine restriction, a well-established longevity intervention. When glycine intake reaches 3-5 grams, the enzyme glycine N-methyltransferase adds a methyl group to glycine, forming sarcosine for excretion. This reaction consumes S-adenosyl methionine, effectively reducing methionine levels and triggering the body's perception of methionine restriction.
Methionine is found in red meat, fish, dairy, and legumes. While essential, excessive methionine intake is associated with heart disease, oxidative stress to endothelial cells, stroke, cancer, and dementia. The glycine supplementation approach allows maintenance of healthy methionine levels while creating the beneficial perception of restriction.
The body requires some methionine, so supplementation should not create chronic deficiency. Proper dosing and monitoring through blood tests for sarcosine levels are recommended when implementing this approach.
Glycine is one of the safest molecules known and has been taken for decades even in high quantities. It extends the lifespan of many animals. However, always be careful because nothing is perfectly safe. Even drinking too much water can kill you. When taking glycine, stick to what's currently known as apparently safe and don't take ten times the dose shown in clinical trials. Monitor with doctor's supervision.
Dudley Lamming, who completed his PhD in the host's lab, now runs his own laboratory studying how amino acids affect lifespan and healthspan. His research shows that restricting methionine produces big effects on metabolism and health similar to exercise, even in mice that weren't exercising. These "couch potato mice" had their methionine restricted from normal dose to minimal survival levels while eating as much as they wanted. They experienced 70% fat reduction without exercise.
Human studies have shown that restricting methionine in obese adults increases fat oxidation and stimulates autophagy, the recycling of old proteins that occurs during fasting.
Methionine restriction, which glycine is believed to cause by taking large amounts, has been shown to downregulate protein synthesis, activate AMPK, reduce mTOR signaling, and upregulate sirtuins. These are the effects expected from longevity interventions.
The theory is that short-term experiments showing glycine had no effects missed the chronic methionine depletion, which takes time and doesn't happen within hours. Large amounts of glycine should mimic methionine restriction effects, which is being shown in animals and now in people.
The human body makes about 3 grams of glycine per day and can take in another 2.5 to 3 grams from food. To make all the collagen needed, especially for older people, supplementation up to about 10 grams is needed. Some people take more than the 1-gram dose commonly used.
The Withings Body Scan scale measures body fat, muscle mass, visceral fat, and includes an FDA-cleared ECG. The host has used Withings products for over 10 years and recommends their watches that track heart rate, sleep, activity, temperature trends, and blood oxygen. The Wing silver scan watch Nova resembles an expensive diving watch. Withings also makes blood pressure monitors, sleep analyzers, and smart thermometers.
Glycine is cheap at about 25 dollars per kilo, seemingly very safe, and sweet. It can be sprinkled on food as a sweetener or dissolved in tea or water. It tastes like weak sugar.
Many studies examine glycine NAC combinations because glutathione synthesis requires both glycine and cysteine. NAC provides cysteine. Glycine benefits in animals and people appear enhanced when NAC is added.
A study gave 100 mg per kilogram of body weight per day (7 grams daily for a 70 kg person) to young adults and older people. Results showed improved glutathione deficiency, reduced oxidative stress, reduced mitochondrial impairment, reduced inflammation, reduced insulin resistance, increased physical function and strength, reduced waist circumference, and improved blood pressure. All occurred within 16 weeks.
While individual studies may be small and short-term, the evidence includes scores of animal studies, human trials, and cross-sectional studies showing consistent associations. In animals: lifespan extension and improvements in body weight. In humans: type 2 diabetics taking 5 grams daily had less inflammation and better blood sugar levels within weeks.
- 1999 UK: glycine improves memory in middle-aged adults
- 2000 Russia: glycine improves stroke recovery
- 2012 Germany: higher serum glycine concentrations associated with reduced risk of impaired glucose tolerance
- 2015 Norway: 4,100 people over 7.5 years showed plasma glycine associated with 11% reduced risk of heart attack
- 2017 Canada: type 2 diabetics have lower serum glycine levels
- 2017 Australia: glycine protects muscles during wasting conditions
The GNMT gene methylates glycine to deplete methionine. Upregulating this gene extends lifespan in flies and lowers methionine levels, consistent with the methionine restriction theory.
Worms: glycine feeding extends lifespan 10-20%
Flies: overexpressing GNMT gene (converting glycine to sarcosine to deplete methionine) extends lifespan 10% in both males and females
Mice (ITP study, 2019): reproducible lifespan extension across three universities in outbred mice. 4% extension in females, 6% in males with glycine alone
Mice (Baylor, 2022): GLYNAC supplementation increased lifespan 23% in females, 24% in males. Reduced oxidative stress, improved SIRT3 levels, increased genomic stability and DNA repair
Rats (2011): glycine supplementation mimicking methionine restriction showed up to 28% increase in mean lifespan and 31% in maximum lifespan
Whoop continuously tracks sleep, resting heart rate, heart rate variability, respiratory rate, daily strain and recovery. A 2022 study in Sensors journal found Whoop among the most accurate for measuring overnight heart rate and HRV compared to six leading wearable devices against clinical grade measurements.
Trimethylglycine, also called betaine (named after beets), protects cells from oxidative stress and is required to make methionine. It became popular because it was thought to prevent methyl group depletion from NAD boosters like NMN or NR, though this remains controversial.
Betaine decreases homocysteine levels (cardiovascular disease risk marker) and increases power in upper body exercises (2010 study). It also improved VO2 max and sprint ability in 29 professional soccer players.
Betaine works differently than glycine - it helps make more methionine rather than depleting it, so they shouldn't be taken together as they could counteract each other.
Dosing above 4 grams daily increases risk of higher LDL cholesterol, though some clinical studies used up to 9 grams. For weight of evidence, betaine shows stronger results for strength performance while glycine appears better for longevity, weight loss, and metabolism.
Betaine has long been known to be good for skin. Former lab member Dr. Kyle Landry developed a skincare line using bacterial extracts from NASA research. Bacillus pumilus provides UV protection and activates sirtuins, with betaine protecting skin cells. The product is called Aonia from Delavie Sciences.
The host takes about 2 grams of glycine daily, starting low and working up while monitoring with doctor and blood work, particularly liver function. Blood work has never looked better.
Glycine helps make collagen for skin and glutathione for antioxidant activity. It may mimic methionine restriction benefits, shifting the body toward maintenance and repair. GLYNAC combines glycine with N-acetylcysteine but has a sulfur smell. Always consult a doctor before taking glycine or GLYNAC, especially at high doses. More isn't necessarily better.
Only and is not medical advice. Please consult a qualified healthcare provider as individual results may vary. Views expressed are my own and not those of Harvard University or Harvard Medical School. Full disclaimer is in the show notes.
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