Eat Glutathione

Every supplement has its downside.  Metformin and rapamycin are the best candidates among fully-developed products, and metformin can dissipate the benefits of exercise, while rapamycin can suppress immune response and raise insulin resistance.  NAD enhancers can affect epigenetic methylation and damage the liver.  I’ve written about the adverse effects of anti-oxidants, which are the most highly publicized treatments for aging.  But glutathione (GSH) is one anti-oxidant for which I’ve read multiple benefits, and I’ve never seen a negative word. As far as I know, the more glutathione you have, the healthier you can expect to be.  


Gutathione is akin to a miniature protein with just 3 amino acids (glutamate, cysteine, and glycine).  Our bodies manufacture glutathione regularly from the three constituent amino acids, but we make less of it when we are older, and need it more.  (In my book, this is an example of programmed aging, the body deliberately turning to self-destruction, but you don’t have to believe in programmed aging.

Glutathione

It was originally discovered as a recyclable anti-oxidant.  The most active and toxic ROS are reduced to the less toxic form, hydrogen peroxide, H2O2, and it is the job of glutathione to take care of the H2O2. The active (reduced) form is abbreviated GSH, and the ‘second-hand’ form, ready to be recharged, is GSSG.  Glutothione reductase is the enzyme that does the honors of restoring GSSG to GSH. Glutathione antioxidant activity depends on an enzyme containing the trace element selenium, which is available in a quirky variety of foods (brazil nuts, mushrooms) and in trace mineral supplements.

As the number of supplements I take has multiplied over the years, I have begun to randomize my intake, selecting from a shelf full of pills each morning based on whim as much as anything.  Through this transition, N-Acetyl Cysteine (NAC) is the one supplement that I keep handy and continue to take several times each day. NAC is a precursor and recharger of glutathione. After researching the present article, I’ve added raw glutathione to my pill shelf, for reasons you’ll read below.

Image result for n-acetyl cysteine

N-Acetyl Cysteine

Cancer is a counter-indication (?)

H2O2 is not just a toxic byproduct; it is also a signaling molecule with multiple functions, including self-destruction of the cell.  GSH can lessen the propensity for apoptosis (cell suicide). This is generally a good thing in anyone over 50, but you might think twice about it if you’re actively battling cancer.

 

Not just an ordinary anti-oxidant

In addition to anti-oxidant activity, GSH is now known to have many other roles, including DNA repair, protein synthesis, and chemical signaling.  It is not obvious that the health benefits of GSH come from its role as anti-oxidant.

In the liver and kidneys, GSH binds to a broad variety of toxins and carcinogens, helping to neutralize them while they are being eliminated.  There are several common genetic variants that affect the hormones that assist in this process, glutathione S-transferases, or GSTs. People with GSTM-1 variants are more susceptible to most cancers, asbestos, lead and mercury poisoning, etc. The herb silymarin (milk thistle) increases the presence of glutathione selectively boosts glutathioneIn the liver. Hospital ERs use NAC for emergency detox, and in my personal experience a relative’s life was recently saved and liver damage avoided with intravenous NAC.

 

Animal evidence

Supplementation with NAC has been found to increase lifespan in several animal models, most important in male mice

(Female mice in this study with or without NAC live as long as male mice with supplementation.)

 

Human evidence

To my knowledge, there is no direct evidence in humans regarding lifespan or mortality benefits of NAC or glutathione.

Glutathione is produced within each cell, and cells produce less of it in older humans.   This is the reason glutathione levels decline as we age, about 40% between ages 30 and 70.  Not only do older people have less glutathione, but levels tend to be lowest in people with chronic disease of any sort [ref].

NAC can extend the capacity of muscles to resist fatigue, both in rodents and in humans [ref].  This is probably related to recharging glutathione in and around mitochondria as they expend energy.  Glutathione is especially useful in the energy metabolism, and there is evidence it is continually pumped into mitochondria.

 

Eating glutathione?

I have believed for a long while that GSH doesn’t survive stomach acid, and it’s worthless to take it orally.  This was based on the idea that GSH is a miniature protein, and the peptide bonds that hold proteins together are efficiently broken in the stomach.  Hence the time-honored way to get more GSH is to take NAC, which is a precursor which the body uses to make GSH.

I’ve learned there are several things wrong with this story.

  • Oral GSH is more bioavailable than I had thought.
  • NAC only can lead to more glutathione if the body is flush with the other two amino acids, glutamate and glycine.  For people who take NAC, glycine commonly becomes the bottleneck, so it helps to supplement with glycine as well.
  • NAC often doesn’t increase total glutathione, but “recharges” the GSSG form back to GSH.  So NAC can increase available glutathione up to a limit, but may not be sufficient to restore youthful levels in those of us who are past our youth.  Alpha lipoic acid also helps to regenerate GSH, and so supplementing with ALA also tends to increase GSH levels.
  • Liposomal and sub-lingual versions of glutathione are supposed to be more bio-available, but there’s not much data to support this, and the data seems to show only marginal improvement in bioavailability–not enough to justify the big difference in price.

 

Raw and Liposomal

Oral glutathione (raw) 250mg/day increased levels in red blood cells by about 30% over 6 months.   Increasing to 1000mg/day didn’t do significantly better [ref].  

Liposomal delivery is the encapsulation of the payload (glutathione) in microscopic droplets of vegetable oil, which protects the glutathione through digestion, and helps it pass through cell membranes.

I could only find a shorter-term study of liposomal glutathione [ref], and results were only marginally better than with raw glutathione.

In this study, a genetic defect that impairs glutathione efficiency is associated with low HDL and high trigycerides in the blood, which are two of the most telling indicators of cardiovascular disease.  In this study, people who come into the ER with heart attacks tend to have much lower glutathione than a control population that doesn’t have heart attacks.

 

The Bottom Line

Glutathione serves multiple protective functions.  The body manufactures less of it as we age.  There is good indirect evidence from several angles that glutathione is an anti-aging supplement.  In recent years, it has become clear that it can be taken orally with good effect.

Glutathione GSH is constantly being used as an antioxidant, after which it becomes GSSG, which needs to be recycled to GSH.  NAC helps in the recycling, so more glutathione is available in its active form. The action is short-term and doesn’t increase the total amount of glutathione.  Taking glutathione orally has a long-term benefit, increasing the total amount of glutathione in blood and in cells. Liposomal glutathione may be more readily absorbed than the simple glutathione pills, but it is so much more expensive that it’s hard to justify.  There is independent evidence for NAC as an anti-aging supplement in rodents. 

Chris Masterjohn has posted a review which seems to ask all the right questions, and I have taken much of my analysis from him.   

37 thoughts on “Eat Glutathione

        • Yes, I’ve seen articles that some anti-oxidants attenuate the benefit of exercise, and this article includes vitamin C. But the effect for vitamin C is small compared to other anti-oxidants. I don’t worry about vitamin C. It has, of course, a central role to play in energy metabolism.

          It’s also true that you can increase glutathione w/o vitamin C.

    • Glutathione is produced naturally in every cell. Oral ingestion of Glutathione is difficult as the fragile Glutathione molecule is destroyed in the digestive tract.

      Riboceine, invented by Dr Herbert Nagasawa is a peer reviewed, clinically proven supplement that substantially boosts Glutathione levels much more reliably than N-Acetyl Cysteine.

  1. I was wondering if anyone could help with the understanding of this paragraph “H2O2 is not just a toxic byproduct; it is also a signaling molecule with mutiple functions, including self-destruction of the cell. GSH can lessen the propensity for apoptosis (cell suicide). This is generally a good thing in anyone over 50, but you might think twice about it if you’re actively battling cancer.” I think the idea is that GSH reduces H2O2 and therefore can lessen apotosis, correct? I would label that a potentially significant downside, which is at odds of the premise that GSH doesn’t have a significant downside. Hence a little confusion if I have the correct understanding. Thanks – Dave

    • Theoretically, messing with apoptosis could be a significant downside, but this is based on biochemistry not actual observation, and I don’t know of any evidence that the problem is realized in vivo

      • But also cancer cells tend to increase H2O2 levels as a way of boosting their growth. So more glutathione should make this more difficult for potential cancer, and in fact the oxidised products made by reducing H2O2 can then used by the cell for useful processes.

        My guess is that cancer is more likely to arise from too little Glutathione than too much.

  2. Josh’s blog is always interesting, but it also reminds me of just how little we know, and can do to address the whole process of aging. The best option as far as I can tell is to take a reasonable mix of supplements together with metformin and rapamycin. Then track the effectiveness of one’s efforts via frequent blood tests to confirm that inflammation markers that lead to heart disease and cancer are being kept to a minimum. However, none of the above will stop aging, or (miracle of miracles) reverse it! In a sense, we are just fiddling while Rome burns, but hopefully we will get to play the fiddle for as long as possible…

  3. First of all glutathione doesn’t enter cells, so that why it’s lipid encapsulated. I tried it for a while, felt an effect at first, slept deeper than usual (and I’m having sleep problems now, so I wish I had some – but in India? ) but that effect was gone by the second day – maybe met some need, and that was it. I’ve also tried NAC combined with glycine (which I take 2 gms every day – seems to give me more energy even without NAC and/or glut).[By the way in the ‘literature’ reduced glutathione is designated as GSH (emphasizing the sulfhydral group) and oxidized is GSSG (where a disulfide bond joins two monomers). Also it is not a straight tripeptide, the glutamic acid moiety is attached by a gamma glutamyl bond. The body decides how much glutathione it needs (programmed aging) and trying to force-fed GSH to cells just doesn’t work. Our elixir raised GSH to near youthful levels a month after the first treatment (3 weeks actually) and it contains no hydrogen donors or amino acids. (to our knowledge). It just directs cells to raise GSH to youthful levels – the cell can if it ‘wants’ to. Glutathione is pretty unpleasant tasting, but somehow tastes familiar. Bottom line: it can’t hurt, is cheap and might help, but it’s not the answer.

    • If the rate of GSH synthesis is largely controlled by the activity of γ-glutamyl cysteine ligase, Nrf2 activation compounds like sulphorophane could be one simple strategy to raise GSH levels. Although glycine and cysteine are non-essential amino acids, endogenous levels drop significantly as part of programmed aging. Supplementing with whey and gelatine/glycine will make sure we have the building blocks needed.

    • You might have read this already Harold, but it turns out you can reverse age related blood rises in IL-1β, IL6 and TNFα in humans by applying a skin cream!

      https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.15540

      I found it interesting that aging of one organ, i.e. the skin, presumably in part due to UV exposure, could then ‘enforce’ an age related decline in other organs via inflammatory signalling.

      • That seems almost too good to be true. As best I can figure this doesn’t require some sort of exotic hard-to-obtain skin lotion but that most of the ordinary over-the-counter stuff will work.

        • Yes you can buy it on Amazon.

          Don’t think I’ll do it just yet. But I do consider skin state to be a good indication of aging.

  4. I found interesting NAC also emerged by AI/ML algorithms in the process which brought LEF and Insilico Medicine to define a specific formulation (called Ageless Cell, check LEF site). “The Ageless Cell™ formula was created through a unique partnership with Insilico Medicine, Inc., a medical technology company who created a database of 200+ geroprotectors shown to extend life span, then used a proprietary algorithm based on 21st century artificial intelligence computing techniques to score these compounds’ impact on pathways associated with normal aging. Without Insilico’s A.I., this process could have taken decades.” The formula highest ingredient is NAC (450mg) followed by vitamin E, green tea extract and Myricetin (which is similar to quercetin IIRC).

  5. Are there any known markers of glutathione deficiency? There are some mitochondria-health-protecting substances (resveratrol, PQQ, etc). As glutathione’s action is about mitochondrias one wonders how such mitochondria-health-protecting substances influnce glutathione metabolism. Is there anything known about that?

  6. NAC seems to be a good supplement but maybe should be used intermittently since studies have shown it interfering with post weight-training muscle inflammation phase and also the final ‘clean up’ (autophagy).

    Using hydrolyzed whey protein has been shown to increase plasma glutathione. A study in HIV patients showed 44% increase vs. none for group using regular whey. Other benefits are shown in this article:

    https://www.ironmanmagazine.com/5-reasons-why-hydrolyzed-whey-is-worth-the-expense/

  7. Josh,
    I would love to see another article with your thoughts on the Thioredoxin pathway. I think you may have posted this already, but it deserves way more attention than it generally gets. Thioredoxin is something that has caused one of the greatest mouse lifespan increases. It is the only thing known to have effectively cured hypertension long-term in mice. It occupies a unique and indispensable biological role. There was also the recent study last year with the claim that TXNIP increase is one of the major causative factors of aging. TXNIP having the opposite effect of Thioredoxin. Finally, TRX is directly regulated by the Klotho pathway, which already known to be a superstar of anti-aging, and TRX may play an outsized role in the Klotho pathway.

    As you can see I’m convinced already. But the major problem for both TRX1 and Klotho is delivery. There could be three strategies. First, raising Klotho, in any form (even soluble). Second, raising TRX1. Third, lowering TXNIP. All three of these are very difficult and expensive to do. And I’m sure the cancer objection will be raised like it is with any powerful regenerative pathway. Would love to see your thoughts on this.

  8. I seem to recall reading that taking NAC nullifies some of the anti-aging benefits of taking glycine. I cannot find the reference anymore. Is this true?

    If true, would it be better to take these separately? If so, how long in between staggered doses? I.e. NAC in the morning, glycine at night? Or each a different day?

    Also, are these more bio-available when taken on an empty stomach?

  9. I take NAC and sublingual Glutathione occasionally but worry about it since I have seen evidence (see below), that like all anti-oxidants, it interferes with what I believe to be the most proven anti-aging strategy to date, specifically increasing Ampk and reducing mTor. Hopefully more studies will be done on glutathione to show that it works either with the strategy of activating Ampk or despite it’s repression of Ampk. In the mean time, continuous use of anti-oxidants could negate the benefits of most of the supplements we all take, which for the most part, work by increasing Ampk and reducing mTor. I hope someone responds to this comment with studies showing my concerns are misplaced!

    Cell Rep. 2017 Oct 3;21(1):1-9. doi: 10.1016/j.celrep.2017.09.026.
    AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species.
    Jones.
    “We next transfected cells with a construct expressing Sod2 and mitochondrion-targeted Catalase (Sod2-mCat) to reduce mitochondrial ROS in cells (Xiong et al., 2015; Figure 1G). Phosphorylation of AMPKα and ULK1 following glucose withdrawal (Figure 1H) or AA treatment (Figure 1I) was reduced in cells expressing Sod2-mCat compared with control cells. Collectively, these data indicate that mitochondrial ROS is a physiological activator of AMPK that affects distinct effectors downstream of AMPK signaling.”

    also this:
    J Immunol. 2018 Jan 15;200(2):623-631. doi: 10.4049/jimmunol.1700474. Epub 2017 Dec 15.
    Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species.
    Tateda
    ” … glutathione treatment abolished metformin effects on lung bacterial clearance. “

  10. Josh don’t certain enzymes need to be activated through something like cold stress in order to even start making glutathione useful? You can take it but unless the enzymes are activated it’s useless. Rhonda Patrick was talking about this in a video with Joe Rogan once, the one on cryotherapy.

  11. What product of Glutathione should one buy? Looking at amazon.co.uk, there’s an overwhelming amount of different products in various price ranges.

  12. SAM-e is another of GSH’s precursors, and oral supplementation of SAM-e has also been shown to significantly increase hepatic GSH levels. (Vendemiale, et al)

  13. I’ve read (Dr Bredesen in Alzheimer’s I think it was) that taking glutathione exogenously signals the body to produce less of it, and the rationale was to go between taking NAC and taking GSH, to get around this.

    But from my understanding, what the nrf2 inducing polyphenols do is to signal the body that it needs to make more GSH. So I wonder where they come in?

    Maybe the ideal situation is rotating between some exogenous GSH / building blocks like NAC, glycine, sulfur rich foods / NRF2 inducers like sulforaphane ashwagandha curcumin etc.

  14. Aren’t you concerned about NAC eroding the blood brain barrier and increasing Amyloid Beta plaque load in the cortex of hypersensitive stroke prone rats at doses equivalent to human supplemental ones?

    “SHRSP treated with NAC had an age-dependent increase of BBB breakdown (assessed by the presence of IgG positive small vessels) and small perivascular bleeds, mainly in the cortex. NAC significantly increased the Aβ plaque load in the cortex ”
    https://www.ncbi.nlm.nih.gov/pubmed/24898644

    • I can’t imagine this is practical for most of us. It would have to be done on a daily basis, and is bound to be much more expensive than simply eating enough GSH to overcome the bioavailability factor.

  15. That is a bit off topic, but I hope someone could shed some light on it:

    As a layman, active gym goer and outdoor man, I struggle to understand the mTOR pathway in the context of exercise and aging. On one hand exercise, especially resistance exercise is said to activate the mTOR signaling pathway to enhance protein synthesis to build more muscles. On the other hand, inhibiting the mTOR pathway is mentioned, besides other importing effects, to slow down aging.

    Does that mean that I, a very active person in his 60ties, might stay healthy for longer but age faster and will die prematurely?

Leave a Reply

Your email address will not be published. Required fields are marked *