Antioxidants proved a bust for life extension almost 25 years ago, but glutathione stands out as an exception. We lose glutathione as we age, and supplementing to increase glutathione levels has multiple benefits, possibly on lifespan.
Glutathione is manufactured in the body via an ancient mechanism taking as input cysteine, glutamic acid, and glycine. Supplementing N-Acetyl Cysteine (NAC) and glycine are independently associated with health benefits, and possibly increased lifespan. Glutamine seems to be in adequate supply for most of us.
Each cell manufactures its own glutathione. (GSH is an abbreviation for the reduced form of glutathione.) Concentrations of GSH within a cell a typically 1,000-fold higher than in blood plasma. When we look for glutathione deficiency, we measure the blood level, because that is convenient. It is much harder to measure intracellular levels of GSH. These two studies [2011, 2013] demonstrated that intracellular levels decline with age more consistently and more severely than blood levels. People in their 70s have less than ¼ the glutathione (in red blood cells) that they had when they were in their 20s. The same study also found that intracellular levels of cysteine and glycine but not glutamate decline with age.
Supplementing with NAC is already known to boost glutathione levels. But here is a motivation to try a combination of glycine and NAC, dubbed “GlyNAC” to see if we can do even better. This work has been spearheaded by Rajagopal Sekhar.
In humans, “Supplementing GlyNAC for a short duration of 2 wk corrected the intracellular deficiency of glycine and cysteine, restored intracellular GSH synthesis, corrected intracellular GSH deficiency, lowered OxS, improved MFO, and lowered insulin resistance.” [Sekhar] Most of these benefits are theoretical. Lowering oxidation levels is a double-edged sword. MFO=mitochondrial fatty acid oxidation, and this benefit is on firmer footing. Membranes are made of fatty acids, and mitochondrial efficiency, like most everything in the body, depends on highly selective membranes. The crowning benefit is improved insulin sensitivity, and we can be fairly confident this leads to longer healthspan.
The two recent studies, in humans and mice, are indeed impressive.
The small human study found that “GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference.” Though they didn’t measure methylation age, this constellation of improvements gives us confidence that people were looking and acting younger.
In older (71-80 yo) subjects 24 weeks of GlyNAC supplementation raised intracellular GSH levels from 0.4 mmol to 1.2, compared to 1.8 in young adults. (Levels were measured in red blood cells.)
Two central players in aging are inflammation and insulin resistance; both showed excellent response.
Inflammation decreased markedly: Average C-reactive protein (CRP) dropped from 4.9 to 3.2 (compared to 2.4 for young people). IL-6 dropped from 4.8 to 1.1 (ref 0.5 for young). TNFα dropped from 98 to 59 (ref 45).
Insulin resistance fell just as dramatically, along with fasting glucose and plasma insulin.
Cognitive performance improved markedly! as did grip strength, endurance, and gait speed.
GlyNAC subjects lost a lot of weight — 9% of body weight in 24 weeks. This is both very good news and a hint that some of the benefits of GlyNAC may be caloric restriction mimetic effects, indirectly due to suppression of appetite or of food absorption.
Is all this evidence of a decrease in biological age?
But the effects faded weeks after the treatment stopped. This, I believe, is different from resetting methylation age. There is not a lot of data yet to test this, but I believe that methylation is close to the source of aging; in other words, the body senses its age by its epigenetic state, and adjusts repair and protection levels accordingly. Thus changing epigenetics to a younger state, IMO, effectively induces an age change in the body.
If this is correct, then my guess is that GlyNAC does not set back methylation age, based on the fact that the effects must be continually renewed by daily doses of glycine and NAC. On the other hand, mitochondria are such a central player in expressing multiple symptoms of aging that it may well be that continuous treatment with GlyNAC leads to longer lifespan.
…and indeed that is what was just reported in a mouse study. 16 mice lived 24% longer with GlyNAC supplementation, compared to 16 controls. 24% is impressive (see table below). For example, rapamycin made headlines a decade ago with an average lifespan increase of 14%. (In other studies, rapamycin was associated with even greater life extension.) The winner in this table is a Russian pineal peptide, which claims 31% increase in lifespan. I have previously bemoaned the fact that this eye-popping work from the St Petersburg laboratories of Anisimov and Khavinson has not been replicated in the West (though Russian peptides are now commercialized in he West).
Table source: https://genomics.senescence.info/drugs/browse.php#details-549
(This is a sample — not a complete list.)
| Treatment | Lifespan increase |
| Epithalamin | 31% |
| Thymus Peptide | 28% |
| Rapamycin | 26% |
| N-Acetylcysteine | 24% |
| GlyNAC 2022 | 24% |
| Spermidine | 24% |
| Acarbose | 22% |
| Phenformin | 21% |
| Ethoxyquin | 20% |
| Vanadyl sulfate | 12% |
| Aspirin | 8% |
An asterisk must be placed next to the new 24% life extension from GlyNAC. Eleven years ago, Flurkey, found the same 24% life extension with NAC alone. NAC supplementation without glycine is known to increase glutathione production. Do we need glycine in addition, or is cysteine the bottleneck? Levels of both free glycine and cysteine decline with age. This would suggest that supplementation of both should be more effective than supplementing NAC alone. But I was unable to find any study that asked whether GSH levels are raised to a greater extent by GlyNAC than by NAC alone.
Glycine supplementation in large amounts mimics methionine restriction, which is a known but impractical life extension strategy.
If you decide to take glycine, it should be at bedtime, and in large amounts, a teaspoon or two. (I did this for awhile using glycine as a sweetener in hot chocolate soymilk, until I decided it ruined the taste of the chocolate drink. Whether this is a sound reason for tailoring an anti-aging agenda I’ll leave you to decide.)
All this work comes out of the laboratory of Rajagopal V. Sekhar at Baylor College of Medicine in Texas. It’s time that a broader life extension community joined in the action. I’m grateful to Dr Sekhar for commenting on earlier drafts of this article.
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Just curious your thoughts on using s-acetlyl l-glutathione (SALG). Given that liposomal glutathione can cause dangerously high levels of glutathione, is SALG of any benefit? I have experimented with GDF-11 & BPC-157. Couldn’t tell any benefit from GDF-11, but BPC-157 is quite the miracle worker for injuries. I use SALG for inflammation aches & pains…seems to work, could be placebo.
why glycine at night? Thanks.
Because other studies have shown that it improves sleep, I believe. I don’t have any links at present, but you can do some research in that direction if interested.
Can you suggest an appropriate amount (in mg or g) of either NAC or glycine for those who want to try it? Thanks
The study used 100mg/kg/d each of cysteine and NAC which is a very high dose. For typical 70kg body weight, that would be 7000mg/day of cysteine + 7000mg/day of NAC!
I’ve been using glycine for some time now because it helps with sleep but NAC gives me heart palpitations at doses greater than 1 gram. The studies are certainly impressive, especially the human study which showed remarkable improvements in performance.
This recent study suggests that GlyNac doesn’t improve glutathione levels except in those with marked oxidative stress:
https://www.frontiersin.org/articles/10.3389/fragi.2022.852569/full
Mice are characterized as being under very high oxidative stress.
I’m somewhat concerned about very high dosing over long periods of time. Would these doses suppress your natural glutathione production via a negative feedback loop? Do you need to wean off of it after prolonged use?
The body does not produce NAC, but it does produce glutathione.
Is there a feedback loop? That might suppress natural production
For the last several months, I’ve been taking three grams each of NAC and glycine every other night (as opposed to nightly, in the perhaps vain hope of diminishing any potential homeostatic response). I’ve benefited from the somnorific effect of glycine (at least partly a placebo effect?) and have noticed no negative side effects.
Speaking of mitochondria, I wonder why the old Ames study dating 20 years back never gained traction. Ames showed that alpha lipoic acid in combination with ALCAR made old mitochondria act young again. I’m off glycine, as it made my BHP worse, unfortunately.
Do you mean BPH? Not BHP (Brake Horse Power)
Please reply soon, I need to go to the bathroom.
Still don’t get why no one here seems to look at taking glutathione directly, either IV or in a LF (liposomal formulation). Been going LF for months and very happy with the results.
The issue with direct supplementation is that the glutathione is distributed to cells in a random fashion, as opposed to taking the precursor and having the natural mechanisms for regulating/distribution send the glutathione where it is needed, ie cells with greater oxidative stress that need the glutathione. Glutathione in cells that don’t need it may have a negative effect on the cell.
With direct glutathione supplementation another problem arises: your body will detect its levels going up and will reduce its own production. And that’s no good news. Providing your body instead with two of three building blocks of glutathione, glycine and NAC, now in low levels due to the aging process, you give your organism the chance, by consuming them, to put itself into naturally rise its production back to more youthful levels.
BHT fed to rats increased glutathione.
https://www.sciencedirect.com/science/article/abs/pii/000629528390271X
Perhaps that is why lifespan was increased 45% in a forgotten study done 50 years ago.
Interesting.
In high amounts, like many other substances, BHT may increase cancer risk. Here is a recent publication on BHT risk assessment.
https://ec.europa.eu/health/system/files/2021-12/sccs_o_257.pdf
I haven’t forgotten it but perhaps the internet did. Does anyone remember the experiments where dogs were made to sleep 23 hrs a day and it doubled their lifespan or even more (as they were torn apart by baboons)? There may be many paths to life extension, but I’ll still go with rejuvenation.
I have taken 1 gram BHT for 46 years. I’m 83 now in perfect health and look much younger. The FDA says 3 gm per day is safe for humans. The rodents that developed lung tumors received a human equivalent dose of 80 gm per day.
I have wondered why promising life extension results of BHT in rodents were never replicated.
Excellent review by Josh. Agreed with everything Josh wrote including using glycine as a sweetener. It ruins the taste.
First of all, it was a ‘pre-clinical’ study and the statistics were not impressive but hey, every little bit counts (especially as you want to really cure aging), The very fact that the effects ended with ending treatment showed it was a downstream process (but that’s not a bad thing as both NAC and glycine are cheap and readily available (or could be made so). The effects I saw were modest, but better than nothing. The sample size was small so that the probabilities given were rough, but glycine (the simplest of amino acids) and cysteine (NAC n-acetyl-cysteine is a form of cysteine that will easily enter the cell), so those are two of the three amino acids that make up glutathione. (the other is glutamic acid – attached by an unusual g-carboxyl group to the cysteine). Anyway, I’ve always believed on first principles that the amount of glutathione in a cell was a measure of its “life-energy” – so I was please that our treatment brought about increased to almost youthful levels in old animals. Reduced glutathione stores “reducing potential” – electrons that are unstabally associated with it an would gladly jump downwards towards the most stable relation (with oxygen to make water) losing their chemical potential energy which the cell uses in the cytoplasm and nucleus (at least ) for synthesis and repair,
“Glycine supplementation in large amounts mimics methionine restriction, which is a known but impractical life extension strategy.”
Why is glycine in large amounts impractical? The last time I tried NAC I had really bad stomach ache. So I guess NAC was impractical for me personally.
I think he’s saying methionine restriction is impractical
I think this is methionine restriction which is impractical
I meant to say that methionine restriction is impractical. Nothing impractical about glycine. Sorry for the confusion.
I take glycine every night for years, i do not know if it helps. i would though never put this fine amino into soymilk!!, this would be counteractive as soy is not good at all for the human body!
You mention that Glycine should be taken at night, but what about NAC? At the same time? I’ve been taking NAC on an empty stomach upon waking. Why is Glycine taken at bedtime?
I’ve been using 3g of glycine an hour before bed, and I’ve been sleeping like a rock for the last 4-6 weeks. Is there a specific reason/mechanism that you recommend using “a lot” more? Also, what’s the recommended dosage and timing for the NAC?
Did you know about the probiotic Lactobacillus fermentum ME-3 (often referred to as ME-3)? It is a strain of probiotic bacteria that has been found to produce glutathione. When taken orally, glutathione is only minimally effective due to degradation during the processes. ME3 is revolutionizing glutathione therapy as results from human clinical trials reveal that daily supplementation with ME-3 substantially increases plasma glutathione levels.
After its discovery, testing revealed that the probiotic strain Lactobacillus fermentum ME-3 actually synthesizes glutathione. In subsequent human clinical trials, it was reported that individuals taking ME-3 gained a remarkable 49% increase in the ratio of reduced to oxidized glutathione https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670518/
Glutathione at 1 gram/day shown to replace 30% lost by age 60, per Penn State study and others. https://www.psu.edu/news/research/story/research-shows-oral-supplement-increases-bodys-storage-antioxidant/ So more than minimally effective.
Genuine question – thoughts on below study which found it conversely ‘induces’ cancer? (I haven’t looked in depth but I think it is a common theme with antioxidant supplements perhaps interferes with cell clearance/apoptis pathways)
The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice – https://pubmed.ncbi.nlm.nih.gov/31578304/
Apparently all antioxidants cause cancer when taken in very large amounts: SOD, BHT, NAC, etc.
The study states quantities given were in mmol/kg – not mg. Does anyone know approximately how much glycine and NAC the subjects were given in mg?
Thanks
what drives the drop in glutathione levels? Epigenetic change, blood factors, something else? How to force the body to remember longer what to do to produce GSH? As it did when it was younger.
“Glutamine seems to be in adequate supply for most of us.” How many of us do not fall into this “most of us” category? Am I the only one? Supplementing glutamine (as GAKG) with NAC and glycine makes THE difference between no noticeable effect (of GlyNAC) at all and a noticeable effect.
Hi Josh.
I just can’t believe the peptide studies out of Russia. I’d love to believe they were true – especially epitalon activating telomerase – but why not a single replicating study? I know scientists don’t like to replicate because it brings no kudos, but…
Natural selection is an unbridled force of innovation, in the sense it can assemble any combination of genes to build a species, which will dominate other species and the ecosystem given enough time. This unconstrained nature of the force of natural selection will eventually destroy itself, unless there is a force to counter it. The force of Aging/limited reproductive span is precisely this force. Without aging/limited reproductive span, the force of natural selection would not flourish and there would be no sustainable ecosystem.
But for the force of the aging program to succeed, it is critical that it is stable, because on its stability lies the stability of the ecosystem.
The selection of cell types which control this aging program by nature is critical, because these cell types have to be shielded from external threats such as infections, injuries, toxins etc., which in the natural course of survival the various tissues and organs of the species have to bear the brunt of.
It is important for the species to recover its reproductive capability once it overcomes these threats and the average reproductive span of the species remains stable.
What follows is the possibility that any gene which is not part of the birth/conception process is likely not part of the aging program. Even here we see that diseases like dystrophies/progeria in existence where genes(mutated) critical to birth being involved, where the reproductive span of those individuals being severely curtailed. The stability of the reproductive span/aging span requires that all genes critical for birth are part of the aging program.
Reproductive span curtailment seems to be a recent experiment of evolution
Not really Tom, the nematode, C. elegans spends its later life in a non-reproductive state – like menopause.
According to the evolutionary view of aging this shouldn’t happen, as these ‘senescent’ worms would be taking resources away from their productive offspring.
My own view of evolution is that it is much more haphazard than is commonly supposed, and gets fine tuned to the environment only very belatedly and imperfectly.
It seems that evolution has optimized the llifespan of each species for its environment.
Clearly not; if they were optimised the old worms should die without a ‘menopause’.
According to what Harold is saying, it would be better if such worms lived shorter lives, at least in the environment that we are examining them in.
Individuals near menopause/post menopause are as good as dead in the wild. These individuals cannot compete for survival.
From the standpoint of the ecosystem, pre pubertal individuals and post menopausal individuals are equivalent as both consume resources which may be used by individuals with active reproductive spans, and both types cannot compete effectively in the wild.
Humans can choose to limit reproduction.
Also, people will still die in catastrophes.
We do not need additional space for evolution to produce a new species. That can happen now.
The world will be a better place if people remain strong and youthful. They will be able to work and maybe change careers at some points.
To add:
Humans do not live in the wild. Our environment is structured.
Orcas experience menopause well before women, at 40. They lcan live till 90- Despite not being reporductive, old females are key to their pods, as wisdom owners and devoted educators. When a matriarch dies, often the pod divides, daughters and sisters moving to found new pods.. And the matriarchs’s sons survive her a median of 3 years, despite being much younger that his deceased mother. So nature has many exceptions. Other whales also experience menopause to live a long period after that.
New species arise out of mutation in the origin species, which can result in a superior species compared to the origin species competing in the same ecosystem, in which case the origin species needs to find itself a new space in the ecosystem to survive, this results in both the species surviving. It can also result in an inferior species compared to the origin species in the same ecosystem, but which maybe adapted to different food sources/locomotion etc. In this case too it requires space in the overall ecosystem to thrive. Limited reproductive span/aging gives that space in the ecosystem for diversity due to natural selection to thrive.
Correct. In Hinduism, the god Shiva is the Destroyer but is worshipped, for, as all know, in order that the new to replace the old, the old must first be destroyed. This presumes a zero-sum world, but in truth, once we conquer aging and death, the entire cosmos is open to us and nothing needs to be destroyed to create the new. There will be “world enough and time”.
If the ecosystem has space for near menopause/post menopause individuals, then it can be assumed that the ecosystem has space for a new species. Then it can also be hypothesized that the ecosystem is not optimized for individual species, but it is optimized for diversity due to natural selection to thrive.
What is “Thymus Peptide”?
Hi Nathan:
You can read a good compilation of peptide information here:
https://www.age-regression.com/peptides
Michael
One more study showing Josh post goes in the correct direction: https://medicalxpress.com/news/2022-08-glynac-supplementation-reverses-aging-hallmarks.html
The source from Journals of Gerontology here (precise abstract): https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/glac135/6668639