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N-Acetyl Cysteine: A Warning Shot

I’ve highlighted several articles here over the years that cast doubt (to say the least) on the popular belief that Antioxidants Are Always Good For You. These other views do not seem to have penetrated the public consciousness yet, though, to judge by the way that foods and supplements are advertised. Today brings another example, and it vividly illustrates how the simple story gets things very wrong.

You would imagine that if any tissue is going to be susceptible to oxidative damage, it would be the lungs (where all that oxygen is absorbed in the first place). And indeed, such damage is seen as a component of many lung diseases, from COPD to various cancers. The antioxidant N-acetylcysteine has been widely used as a supplement in general (here in the US, you can find piles of it in the appropriate aisles of drug stores and vitamin/supplement stores), and it’s been particularly recommended for lung disease, both for its antioxidant effects and its ability to thin out mucus production.

Now, there are already data to suggest that that’s a problem. In mice with activating mutations in K-Ras or B-Raf, which are commonly seen in human lung cancers, antioxidants (NAC and vitamin E) actually seem to accelerate the growth of the tumors. That was reported in 2014, and you won’t hear much about it down at the drug store. Now there’s a study looking at not just growth of existing tumors, but tumor initiation itself, and the news is disturbingly similar. But it’s even more important to realize that (up to a point) NAC supplementation looks like it’s doing a lot of good.

This paper, from a multicenter French team, looked at three populations of aging mice: normal controls (+/+ for JunD), others that had had the JunD gene knocked out (-/-), and heterozygotes (+/-) who had reduced expression of the protein. JunD is recognized to regulate a whole suite of antioxidant responses in cells – Nrf2 is another example of this, and both of those have been found to be deficient (at both the mRNA and protein level) in the lung tissue of human patients with COPD.

Both the normal mice and the JunD-deficient ones got either NAC-laced water along with their mouse chow, or just water+vehicle as a control: a perfectly reasonable experimental design to assess the effects of aging, JunD levels, and NAC supplementation across each combination of these. And as each cohort aged, there were several interesting changes (which have been noted in some other studies as well). For example, JunD was upregulated with age in the mice who still had the gene, and its down stream oxidative-stress proteins (such as superoxide dismutase, Hmox, and others) increased as well (although not in the -/- animals, as you might have figured). Consistent with an earlier study from this same group, loss of JunD exacerbated oxidative stress in the lungs as the animals aged, as well.

Here’s the good part: the animals who got NAC supplementation really did show significantly fewer of those signs of oxidative damage in their lung tissue. It also reduced signs of cell senescence and overt histological damage of aging as well, such as emphysema lesions (all of these were markedly worse in the JunD knockouts, but NAC improved them as well). So far, so good, and this is exactly the case you’d make if you were pitching NAC as something people should take for healthy lungs as they age. But hold on.

None of the aged normal mice showed signs of adenocarcinoma developing in their lung tissue. But 10% of the aged normals getting NAC supplementation showed it. None of the aged JudD knockouts showed any, either, but 50% of the aged JunD knockouts getting the NAC supplementation had it. The best guess is that cell senescence pathway that seemed to be inhibited with the NAC: some of these are in fact cells that should have died and didn’t, and went on to become cancerous:

Our results therefore support a direct role for NAC in tumor initiation. This role seems independent from antioxidant gene expression, since opposite variations in antioxidant enzyme expression were seen in healthy mice and JunD–/– mice during aging. The protective effect of NAC against lung emphysema is an expected consequence of the decrease in lung senescent-cell accumulation. Altering the cell senescence process, however, may produce undesirable consequences, since senes- cent cells are well known to constitute a barrier to cell transformation and tumorigenesis.

Now that’s something to think about, isn’t it? It comes with the usual caveats about mouse models, but it ties in with the other reports that cancer is a complex enough situation that trying to prevent it (or treat it) with antioxidants is ill-advised at the very least. All of our cellular processes involve tradeoffs, and we’ve had a billion years or two for them to come into balance. Now, we may not agree with some of the equilibria we’ve reached, but we need to have a better understanding of all these checks and balances before we go in messing around with them. For example, I find longevity research very interesting indeed, and many of us would prefer to live longer than evolution cares about us living, but lifespan is a tradeoff between several other factors, too (one of which is the eventual development of cancer).

As for antioxidants, well. . .I’d say that taken together the idea that we can generally improve ourselves by taking them appears far too simplistic (to put things in their mildest form). It’s not that life has spent a billion years bumbling around not realizing that all that was needed was some extra vitamin E and N-acetylcysteine. Things are more complicated. They generally are.

36 comments on “N-Acetyl Cysteine: A Warning Shot”

  1. luysii says:

    The use of antioxidants in medicine has a checkered history. 25 years ago a trial of antioxidants (alpha-tocopherol and beta-carotene) in 29,000 people to reduce the incidence of lung cancer had exactly the opposite effect (an increase in the antioxidant group of 18%). The following subsequently appeared [ Science vol. 264 pp. 501 – 502 ’94 ] “In our heart of hearts, we don’t believe [ beta carotene is ] toxic” says one researcher. This is not science.

    This year another study (in an animal model) described a mechanism by which antioxidants ‘can also promote tumor formation’ — [ Cell vol. 178 pp. 265 – 267, 316 – 329, 330 – 345 ’19 ].

    For the gory details please see — https://luysii.wordpress.com/2019/07/21/antioxidants-the-dark-side/

  2. Polynices says:

    “All of our cellular processes involve tradeoffs, and we’ve had a billion years or two for them to come into balance.”

    Very much this. I’ve often thought it’s sort of remarkable that ANY small molecule drugs (that aren’t antimicrobials or otherwise not directed at our own mechanisms) work at all. That antioxidants might not help isn’t too shocking from this way of thinking.

    Am I crazy to think this?

    1. Ian Malone says:

      Although you do have to remember that that evolutionary optimisation has gone towards reproductive success, not the longevity of individuals.

      1. Derek Freyberg says:

        True, but you have to live long enough to (a) have offspring, and then (b) raise them to the point that they are capable of looking after themselves.

        1. X says:

          I suppose a parent in a relatively primitive society could do that by age 40.

          So, evolutionarily speaking, we can all safely die at 40. Certainly by 60.

          Elders probably add some survival capability to groups (as well as potentially being a drag on their survivability in hard times), but…

    2. Dylan Richards says:

      Yes, “All of our cellular processes involve tradeoffs, and we’ve had a billion years or two for them to come into balance.”

      BUT

      What were we eating when our bodies “came into balance”???? Our lifestyle and diet has changed SOOOO fast in the past hundred years, that maybe we need to rediscover what’s best for our bodies (e.g., pesticides, PFOS levels in water, BPA, processed food, non-seasonal diets, city vs rural microbiome, exercise levels…)

  3. bhip says:

    Whether or not antioxidants could help prevent a disease i.e. cancer, I suspect (naively perhaps) that what a really aggressive, metabolically active tumor really needs to be happy is a good antioxidant….

  4. Chairman Mao says:

    Its well established that decreasing ROS in immune cells causes decreased oxidative burst in them and their ability to phagocytose tumor cells and pathogens alike.

    A dirty little secret the supplement industry ignores while they have their heads up their asses.

  5. SA23 says:

    I am a biochemist working on aging and longevity research at a major university.

    There are some examples of ‘pure upside’ interventions that extend healthy lifespan with no tradeoff. These include: caloric restriction, autophagy enhancement, senescent cell ablation, and AAV-mediated telomerase expression. Lifespan has not been perfectly optimized. Indeed, there is little selective pressure to maximize healthy lifespan, because the power natural selection is strongest prior to reproductive age.

    Two evolutionary theories of aging cover this question: the Disposable Soma theory and the theory of Antagonistic Pleiotropy.

    This is the key review article in the aging field, ‘The Hallmarks of Aging’: https://www.cell.com/abstract/S0092-8674(13)00645-4

    1. ScientistSailor says:

      Caloric Restriction comes with the side effect of severe grumpiness.
      As for your other mechanisms, how do you accomplish them without side effects?

      1. Hap says:

        Caloric restriction means that the calorically restricted can’t do as much – everything (thinking, walking, etc.) requires energy, and if you don’t have the energy to spend, you can’t spend it. So caloric restriction isn’t exactly a free ride, either.

        1. Angi says:

          Ich meine, man bekommt eher mehr Energie durch Kalorienreduktion.
          Ich kenne viele Sportler die das durchziehen und die sind nicht im Slow Modus!

  6. loupgarous says:

    “The protective effect of NAC against lung emphysema is an expected consequence of the decrease in lung senescent-cell accumulation. Altering the cell senescence process, however, may produce undesirable consequences, since senes- cent cells are well known to constitute a barrier to cell transformation and tumorigenesis.”

    This is something to think about for those of us who are impressed by the idea that cellular senescence is the bad guy and we ought to be winding our telomeres back to let us live longer. Maybe not.

  7. Red Agent says:

    Flipping channels, I just saw an ad for bottled water supplemented with antioxidants and another ad for bottled water with added oxygen, during the same commercial break. You have got to love the charlatans who come up with this stuff, and the suckers who buy it. I wonder if you wired these two concoctions together, maybe put out enough juice to charge an iPhone.

  8. Anonymous says:

    Previously posted In The Pipeline:

    Oxygen Radical Absorbance Capacity (ORAC). The US Dept of Agriculture used to maintain an ORAC table of various foods that would then be used by companies to hype their offerings to the hoi polloi. However, from the USDA … “In 2012 USDA’s Nutrient Data Laboratory (NDL) removed the USDA ORAC Database for Selected Foods from the NDL website due to mounting evidence that the values indicating antioxidant capacity have no relevance to the effects of specific bioactive compounds, including polyphenols on human health. … There is no evidence that the beneficial effects of polyphenol-rich foods can be attributed to the antioxidant properties of these foods. The data for antioxidant capacity of foods generated by in vitro (test-tube) methods cannot be extrapolated to in vivo (human) effects and the clinical trials to test benefits of dietary antioxidants have produced mixed results. We know now that antioxidant molecules in food have a wide range of functions, many of which are unrelated to the ability to absorb free radicals.”

    The USDA full announcement link no longer works: “page not found.” See wikipedia and elsewhere:
    https://en.wikipedia.org/wiki/Oxygen_radical_absorbance_capacity
    https://jandonline.org/article/S2212-2672(13)00242-6/fulltext
    “What Has Happened to the ORAC Database?”

  9. You better work !!!!!!! says:

    Idiots….,,I cannot wait until postdocs learn their lesson and just completely think it through that PIs are dumb.

  10. New student says:

    I need to be a prof now!!!!!!!!! I need respect !!!!!!!!! I need my own blog!!!!!! You better kiss my a)& as)(!!!!!!!!!!. I’m smart and I went to Avad

  11. Lane Simonian says:

    This might be one of those cases where you don’t want to throw the baby out with the bathwater. Certain antioxidants may help kill cancer cells because they become pro-oxidants. Other antioxidants may allow the immune system to detect and kill cancer cells.

    It is not a case of all antioxidants being a problem; it is a case of choosing your antioxidants wisely.

  12. gippgig says:

    One general principle of cell defensive mechanisms seems to be that turning them up a little is good but turn them up too far and you fall off a cliff. (Remember the p53 story? Overexpress it some and it reduces cancer. Overexpress it strongly & you get premature aging.) Try lower dosages of NAC. I’d be very interested in the dose-response relation.

  13. On the other hand, there are lots of other studies showing conflicting results. For example, one random study with human data shows that NAC might decrease markers of aggressive tumor behavior. https://www.sciencedaily.com/releases/2017/11/171120141534.htm

    It’s unfortunate that there are not more systematic reviews for basic/translational research such as this. This is a widely studied topic and reading too much into one individual study is not wise.

  14. drsnowboard says:

    I do have a problem with ageing being seen as a disease state and something to be cured. Who wants to live 50 years longer in the body of decrepit 80 year old? Are we really going to ‘treat’ healthy 25 year olds with supplements/ small molecules in the hope of preserving their youth into their 80/ 100s? That’s going to have to have a big old control group in the trial….

    1. kismet says:

      Of course you do, if you assume the conclusion. That treating, slowing or curing aging will increase the time spent suffering. What it will do in reality, is increase the time people spend being young and decrease frailty and suffering of the elderly. Will it also give you more years at the tail end? Sure, however, by that logic you could argue against any life extending treatment, like statins, etc.

      1. drsnowboard says:

        Yup, and people are already questioning the risk benefit ratio of statins for the ‘healthy’ patient population , those not carrying the risk factors of familial disease or previous MI etc.
        Ageing as a chronic disease to be treated is , in my opinion, too vague a syndrome.

  15. Cb says:

    Anti-oxidants with free thiol groups such as NAc-Cysteine, Glutathione and DTT (as present in your buffers!) are not always ‘save’ anti-oxidants because the molecular oxygen that is present (unfortunately needed for many living organisms) can be reduced to the more unfriendly hydrogen peroxide (what a paradox!) causing e.g. much damage to unsaturated fatty acids and biomacro-molecules. The formation of hydrogen peroxide can be catalyzed by numerous compounds catalyzing the redox reactions. As a medicinal chemist I deselected many of such false positive redox cyclers in screening campaigns on targets with sensitive thiols and when DTT is in the buffer. Oxidation sensitive targets (e.g. cysteine proteases) were not oxidized if instead of the anti-oxidant DTT a different anti-oxidant is used: TCEP, which cannot donate the hydrogen to molecular oxygen. So indeed it is tricky to generalize the benefits of anti-oxidants and perhaps too much thiols can lead to too much hydrogen peroxide in those organisms who use oxygen and in particular if they also biosynthesize/consume redox cyclers…………

    1. HTSguy says:

      Are you sure about TCEP not driving redox cycling? The experimental evidence says otherwise:
      doi:10.1089/adt.2008.151

      1. Cb says:

        sure, but certainly examples where TCEP was better than DTT (and also Cysteine could be better than DTT)

  16. Barry says:

    Weiss wrote (“Tissue Destruction by Neutrophils”) thirty years ago that much of what killer T-cells do is mediated by super oxide, peroxide, and hypochlorite. Sopping these up leaves one (partially) immuno suppressed. And among the things we rely on killer T-cells to kill are cancers and cancer precursors

  17. Paul Brookes says:

    Tell you what though – NAC is a great hangover preventer/cure. If you’re headed out “on the pop” as they say, some NAC beforehand to elevate liver GSH levels is likely a good thing (N=1, YMMV).

    1. passionlessDrone says:

      This is the real reason NAC is the MVP! Well over a hundred discrete trials with a N=2 performed.

  18. AIC says:

    I thought antioxidants were good not just for cancer but because they make your body “alkaline” and help “flush out” your toxins and lose weight.

  19. Otto says:

    High dosages of thiols (such as NAC) chelate necessary minerals from the body, such as zinc/copper/manganese. Low levels of such minerals may contribute to cancer. So it’s not the high dosages of NAC which are the problem, but the secondary mineral deficiency.

  20. Dylan Richards says:

    Wait a minute…so are there benefits to things we’re told are bad for us? (e.g. benefits of BPA, benefits of consuming pesticides, benefits of process food/nitrates in food?)

    1. Vader says:

      This idea was explored long ago by the literary intellectual side of C.P. Snow’s Two Cultures.

      https://youtu.be/Vrb9A4t39ko

    2. loupgarous says:

      “Radiation hormesis” has long been presented as a viable alternative to the “no threshhold for radiotoxicity” hypothesis. The caveat, of course, usually being that it’s an external dosage of radiation, like the residents of that apartment in Taiwan where some of the steel reinforcement elements had been contaminated by enough Co60 to register on radiation meters.

      I’m unaware of any population studies showing lowered or extended life span for residents of the Colorado high plains, who get higher doses of external radiation from cosmic rays (having one mile less of protective atmosphere above their heads) as well as actinides in their soil (uranium is more abundant in the soil statewide, and much more abundant in seams of the relevant ores in the Rockies foothills).

  21. JIA says:

    NAC has been studied seriously in idiopathic pulmonary fibrosis (IPF) for many years. A randomized controlled trial suggested a detriment: link in my handle.

  22. Nile says:

    Interesting: you’ve raised the point that some cells actually need to senesce and die – something we al knew, but rarely get to see laid out so clearly in a review of the relevant research.

    So this is a very useful illustration for teaching the challenges facing the search for effective life-prolonging therapies; and these limitations, of antioxidants, will probably apply to other approaches too.

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