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The nitric oxide (NO) theory of aging

Discussion in 'Scientific Studies' started by haidut, Nov 27, 2013.

  1. haidut

    haidut Member

    I recently found this study and decide to make a post about it. Ray has written a lot about NO, but in the allopathic medicine NO has pretty good reputation due to drugs like Viagra and drugs for pectoral angina (chest pain). So, I did not expect to run into that study on PubMed and thought that the study deserves a discussion.


    The study makes some pretty sweeping conclusions, mainly along the lines that NO is one of the main causes of aging. In addition, the study talks about two major themes of Peat's - i.e. endotoxin generating NO in the body and brain, and tetracycline antibiotics directly helping reduce NO production.
    Finally, this study overlaps a bit with my most recent post on tryptophan depletion (ATD). ATD causes daramatic drop in levels of both NO and its precursors arginine and citrulline, which probably explains many of the life-extending effects of tryptophan-restricted diets.

    Here are some quotes from study, with some of the salient points underlined.:

    "...At the Third International Symposium on the Neurobiology and Neuroendocrinology of Aging, I (McCann, 1997) presented evidence to suggest that excessive production of the free radical, nitric oxide (NO), in the central nervous system (CNS) and its related glands, such as the pineal and anterior pituitary, may be the most important factor in aging of these structures. Evidence for this hypothesis has been accruing rapidly. Because of the fact that the synthesis of inducible NO synthase (iNOS) following injection of bacterial lipopolysaccharide (LPS) in the rat was much greater outside the blood– brain barrier (Wong et al., 1996), for example, in the anterior pituitary and pineal gland, than inside this barrier, it occurred to us that NO might play a role in aging of every organ system of the body. The evidence for this concept is particularly well developed to explain the pathogenesis of coronary arteriosclerosis."

    "...NO blocks cellular enzymes required in metabolism and also activates soluble guanylate cyclase (sGC), a soluble enzyme present in the cytoplasm of cells. The activation occurs via interaction of NO with the Fe21 in the heme portion of the molecule, thereby altering its conformation and activating it."

    "...Furthermore, NO also inhibits the release of both norepinephrine and dopamine from the medial basal hypothalamus, constituting another negative feedback of pulsatile LHRH release by feeding back on the terminals of the noreadrenergic and dopamineric neurons to inhibit the release of both of these transmitters, one of which, and probably both of which, stimulate the release of NO that drives LHRH release (Seilicovich et al., 1995b)."

    "...We hypothesize that the pulsatile release of GH that occurs under normal conditions is brought about principally by NO stimulation of GH-releasing hormone (GHRH) release."

    "...The IL-induced prolactin release is also mediated by NO (Rettori et al., 1994b) probably by NO stimulation of prolactin releasing peptides, such as oxytocin (Rettori et al., 1997) and by inhibition of the release of dopamine, a potent prolactin release inhibiting hormone, into the hypophyseal portal vessels (Duvilanski et al., 1995)."

    "...Adenosine is secreted by the FS cells, and is the most powerful stimulant of prolactin secretion from anterior pituitaries in vitro yet identified, increasing release at concentrations of 10e10–10e5 M with maximal release of three times basal at 10e28 M."

    "...These results raise the possibility that even moderate infection, without direct CNS involvement, can increase iNOS levels and lead to production of toxic levels of NO. Therefore, it is possible that repeated infections over the life span could lead to brain damage in areas where there is large induction of iNOS in neurons, such as the PVN—the site of the cell bodies of most of the releasing and inhibiting hormone neurons—and the AN-median eminence region, which is also the site of production of GHRH, many neurotransmitters, and the site of passage of axons of many of the releasing hormone neurons, such as LHRH neurons, which project to the median eminence. There may also be damage to glial elements, meninges, and to the choroid plexus over the lifespan. The induction of IL-1a neurons in the temperature-regulating regions of the preoptic area should also be followed by induction of iNOS. Exposure to high levels of NO in this region may kill thermosensitive neurons and thus be responsible for the decreased febrile response to infection in the elderly. Measurement of iNOS activity in aged male rats (greater than two years of age) revealed a significant increase in NOS activity in comparison with that in young adults, which provides the first experimental support for this concept (Rettori,
    unpublished data)."

    "...These findings provide an explanation for the high incidence of early onset Parkinsonism in many people who served in World War I and developed influenza. There was a major epidemic of influenza with encephalitis, which presumably led to generation of large amounts of NO in the region of the substantia nigra that then caused loss of dopaminergic neurons and eventual development of Parkinsonism many years before it would have appeared as a result of normal aging. The appearance of Parkinsonism with age is probably related to the quite rapid decline, beginning at age 45, in dopaminergic neurons in this region even in normal individuals (Knoll, 1997), which may also be caused by enhanced NO generation during infections."

    "...A great deal of evidence has accrued, suggesting the possibility that chronic infections may have a relationship with coronary heart disease (CHD) (Danesh et al., 1997). In the 1970s, experimental infection of germ-free chickens with avian herpes virus induced pathologic changes resembling those in human CHD (Fabricant, 1978). There have been many studies showing the presence of high titers of antibodies against various organisms in patients with CHD. Although there is always some question about such studies, the incidence is such as to make it appear very likely that antibodies against Helicobacter pylori, Chlamydia pneumonia, Cytomegalovirus, or other herpes viruses are very common in these patients. There is even an association with severe dental carries (Danesh et al., 1997). Stimulated by these reports, there have now been two reports of treatment of patients with CHD with tetracycline derivatives (Gurfinkel et al., 1997; Gupta, et al., 1997). In both studies further complications of CHD were significantly reduced in the treated groups. In one study,
    treatment reduced the complications 10-fold (Garfinkel, 1997)

    "...Tetracyclines have now been studied in chondral cell cultures from patients with osteoarthritis and in cell cultures from animals with experimentally produced arthritis. They have been shown to have chondro-protective effects (Amin et al., 1996). NO is spontaneously released from human cartilage affected by osteo- or rheumatoid arthritis in quantities sufficient to cause cartilage damage. In a recent report, tetracyclines have been shown to reduce the expression and function of human osteoarthritis-effected NOS (iNOS) (Amin et al., 1996). It appears that in addition to the antibacterial action of these drugs, tetracyclines inhibit the expression of NOS, leading to reduction in the toxic consequences of production of NO. It is likely that these compounds will be beneficial in the treatment of osteoarthritis, as well as CHD. They will also probably be of therapeutic value in rheumatoid arthritis and cardiomyopathy, both thought to be autoimmune diseases caused largely by excess NO."

    "...The current theory of CHD is that it is induced by an elevation of plasma cholesterol above the normal limit of 200 mg%. However, if one looks at the incidence of CHD vs. the concentration of plasma cholesterol, one finds that as cholesterol passes the 200 mg% concentration, there is only a very slight increase in the incidence of the disease as one reaches 250mg% and the slope of the incidence begins to rise between 250 and 300 and rises quite rapidly as one approaches 400 mg%. There are many cases of CHD in patients with perfectly normal cholesterol. Indeed, increased LDL cholesterol has been considered particularly ominous, whereas HDL cholesterol has been thought to be protective. However, in many cases, CHD develops and has its downward progression in the presence of normal cholesterol and other

    "...The fact that injection of moderate amounts of LPS to mimic the effect of bacterial infection induces increased numbers of IL-1a immunoreactive neurons in the region of the thermosensitive neurons in the preoptic hypothalamic region, plus increased IL-b mRNA and iNOS mRNA in the PVN, AN, median eminence, choroid plexus, meninges, and in massive amounts in the anterior pituitary and pineal with consequent release of NO, suggests that toxic amounts of NO could exist in these regions during moderate infections, even though there is no direct involvement of the brain"

    "...Indeed, CNS AIDS has led to Alzheimer-like changes in the brain (Griffin, 1988). Therefore, NO may cause much of the
    neuropathologic changes in CNS AIDS."

    "...In conclusion, although much work needs to be done, it is already known that treatment of patients with antioxidants, vitamin C and E, which would reduce the toxic effects of NO, is of value in patients with CHD. This is probably the mechanism of their protective effects against CHD. Finally, compounds that inhibit the production of NO directly, such as inhibitors of NOS or agents that inhibit the production of NOS, such as corticoids, the tetracyclines, and a-MSH may prove useful in slowing the aging process. Aspirin blocks cyclooxygenase I, thereby reducing production and toxicity of prostanoids produced by NO, accounting for its protective effect in CHD."

    One last point - one of the quotes above talks about how adenosine is one of the most potent stimulators of prolactin. This would suggest that adenosine antagonists like caffeine would be really good for lowering prolactin. I posted some studies several days ago that suggest just that - i.e. caffeine acts as functional dopamine agonist and inhibits prolactin release.


    Attached Files:

  2. Blossom

    Blossom Moderator

    I am very thankful for your post!
  3. Lisbon boy

    Lisbon boy Member

    Also here niacinamide has a beneficial action:

    “Niacinamide, like progesterone, inhibits the production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et al., 2008).” RP

    “The inflammatory factors that can promote cell growth can, with just slight variation, deplete cellular energy to the extent that the cells die from the energetic cost of the repair process, or mutate from defective repairs. Niacinamide can have an “antiinflammatory” function, preventing death from multiple organ failure, by interupting the reactions to nitric oxide and peroxynitrile (Cuzzocrea, et al., 1999). The cells’ type, environment, and history determine the different outcomes.” RP
  4. Valtsu

    Valtsu Member

    Nitric oxide can bind to cytochrome c oxidase (Cox) in the mitochondria. Red and near-infrared light improves tissue metabolism by photodissociating nitric oxide from Cox.

    That could be one mechanism.
  5. dukez07

    dukez07 Member

    Minocycline has benefit for excessive NO.

    I guess that eating a whole watermelon per day, or even eating an array of foods that increase NO (such as beets/pomegranate) might be a bad idea, then? I've never heard Ray talk about foods that are super high in L-citruline/arginine such as watermelon. I eat one 2kg watermelon, each day. It's effects on blood flow are definitely not placebo!
  6. BingDing

    BingDing Member

    According to Nutrition Data gelatin is the 8th best source of arginine, per 100g serving.
  7. Kasper

    Kasper Member

    Some things that make me doubt this theory:

    http://www.normalbreathing.com/CO2-natu ... lators.php
    Excess NO may be a bad thing, but I guess too little NO may be bad as well. NO has be shown to imrove blood circulation, and I guess that having too little NO, may cause blood circulation problems. If NO was really primarily bad, it may be a good idea if we all start mouthbreating.
  8. haidut

    haidut Member

    Just like estrogen, NO has physiological role but it is limited and reserved for times of stress. With the exception of Viagra pretty much all other drugs on the market that deal with NO actually try to lower it, not raise it. And in the case of Viagra, look at its side effects and the studies on PubMed for its long term use - short term it can cause heart attacks and/or strokes, while chronically elevated NO causes CVD, MS, AD, PD, and other degenerative conditions. So, NO has its use but is not a marker of health and just like the study you posted said, if you want broncho/vasodilation you can get it from CO2. If NO was that good for bronchodilation, why would doctors try to lower it in patients with asthma? See this:

    http://www.atsjournals.org/doi/full/10. ... 310-1473OC

    Caffeine opposes the effects of NO and its release pretty much anywhere in the body, so if caffeine is in general beneficial and it acts in a manner opposite to NO then I don't see how chronically elevated NO can be good. Similar to aspirin and estrogen. Estrogen is needed for cell division, growth, healing, but unopposed becomes carcinogenic and that's why we need aspirin to restrain it.
  9. The reason that mouth-breathing is bad is that it reduces the amount of CO2 that you breathe. There is more anatomical "dead space" in the nasal passages to trap the air you just breathed out, which in turn has a much higher concentration of CO2 than the outside air. Nearly all animal anatomies are elegantly designed to create this "dead space" for trapping as much CO2 as the animal's metabolism needs.

    Here Peat explains the "upside down paradigm" that nitric oxide is regarded by the drug industry as a "vaso-dilator" (bold in the original):
  10. dd99

    dd99 Member

    I just stumbled across this comment on Scott's red light website:

    I just bought myself a 650nm led grow board. Should I be worried?
  11. Scott seems to be relying on what Peat calls "intracellular" understandings, such as the assumption that the release of NO is good, which are upside down, if Peat is right. In other words, Scott is searching for explanations of the benefits of redlight, and assumes that the release of NO would be such a benefit.

    I think if he assumed NO was harmful, his theory about the supposed release of NO may change?

    [Edit: IMHO, I agree with what milklove said, below... Scott's view may be that NO is a beneficial "vasodilator" through other pathways, see where his page says, eg. "Almost certainly, other mechanisms through which LLLT produces its effects are at play in addition to the one just described. For example, NO is a potent vasodilator via its effect on cyclic guanine monophosphate production."]

    Peat has so far not said anything I've seen about LED boards for red light, and is said himself to use 250 watt white light incandescent (four of them for a total of 1,000 watts). But milklove asked him a question about the safety of LEDs for redlight in Charlie's 20 question thread, so that may illuminate the topic for us? :)
  12. dd99

    dd99 Member

    Thanks, VoS. With the ban on incandescents in the EU and the - to my mind - lack of consensus as to what kind of setup could work in the UK/EU, I took the easy solution and got the LED board!

    I am very much looking forward to reading RP's replies to the 20 questions.
  13. Milklove

    Milklove Member

    Actually we want the NO to be released from the mitochondria, since NO inhibits cytocrome oxidase. Red light "kicks" the NO out of the cytochrome oxidase by photodissociation. This is the very effect by which red lights increases the metabolism.


    The presence of NO synthetase in mitochondria suggests that physiological small amounts of NO could be involved in cellular respiration regulation by inhibition of cytochrome oxidase. Long exposure of cells to NO results in an irreversible inhibition of cellular respiration not dependent on a generalized superoxide or peroxynitrite formation.


    It has been proposed that LLLT might work by photodissociating NO from Cox, thereby reversing the mitochondrial inhibition of respiration due to excessive NO binding.

    So don't worry dd99, you got the "right" wavelenght. I am quite curious what Ray is going to say about the LEDs.
  14. dd99

    dd99 Member

    I just stumbled across this comment by Mittir in the Red light, infrared, DPL thread:
  15. Yes, the potential caution here is when is redlight too much? If redlight "activates" cells, then, for Peat, cells should be activated only under certain conditions, but ideally be at rest.

    For example, cells can typically achieve a balance with CO2, since they are equipped to dispose of excess CO2 (either in the kidneys or the lungs). But they can't dispose of excess redlight (can they?), so what to do? In nature, there would almost never be a condition of too much, too intense and on/off redlight, so cells would seem poorly adapted for it?
  16. redlight or CO2 for alopecia?

    dd, I am guessing that redlight might be a treatment for alopecia? But CO2 may be an equally effective treatment, without the risk of overdosing that we can't say for sure redlight may have.

    The trick is to get the CO2 through the outer layer of skin and into the fully active cells where it is needed. Some patents say you can do this by applying a carrier to the skin (where the alopecia is) and then apply CO2 to the area, for example, by using a shower cap to trap the CO2. The patents explain that CO2 needs water or oil to diffuse deeper into the skin.

    Not Peat approved: emu oil is known to be a good lipid based carrier through the skin, so it may work well for diffusing the CO2. DMSO is also known to be a good carrier through the skin, so it may also work, if you dilute it at least 50% (typically, with glycerin, but maybe emu oil?).

    For a manufacturer, jacoblabs.com is the only source of DMSO (and MSM) that I use.
  17. dd99

    dd99 Member

    Re: redlight or CO2 for alopecia?

    Haha, good memory VoS! Yes, I'm doing most of your Ripped protocol but would like to introduce red light and CO2 (hence my question about the altitude training mask in your CO2 thread).

    This sounds very interesting, but I'm such a neophyte in these things. How would I do it? Apply the carrier, put on the cap, then spray in some CO2 from a cannister? If it's not too much trouble, could you post a link to the patent?
  18. Remember that eNOS can do much worse than simple nitric oxide [http://www.ncbi.nlm.nih.gov/pubmed/17327434] [http://www.ncbi.nlm.nih.gov/pubmed/12697739]
    Theoretically (but potentially NO-active plasma concentrations (above the EC50 of 50 nm for NO stimulation) are maintained for about 3 h after a single oral dose of 80 mg aspirin) aspirin can "release" nitric oxide probably by acetylation of eNOS [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575268/#!po=64.2857]

    SIRT1 DEACETYLATES eNOS [http://www.ncbi.nlm.nih.gov/pubmed/17785417]
    Cigarette smoke ACETYLATES eNOS [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830376/]
    Resveratrol ATTENUATES the acetylation by cigarette smoke as well as the reduction in SIRT1

    Inhibition of SIRT1 deacetylase SUPPRESSES ESTROGEN RECEPTOR signaling (they used "sirtinol" to inhibit SIRT1 activity)

    Sirtinol kills breast cancer cells [http://www.ncbi.nlm.nih.gov/pubmed/22751989]

    What's in cigarette smoke? Carbon monoxide (can do something akin to uncoupling respiration) <<CO treatment also inhibited LPS-induced [endotoxin] NO production and iNOS expression via its inactivation of NF-κB.>>

    <<We have found that ASA [aspirin] inhibits neuronal damage at concentrations lower than those previously reported (0.1-0.5 mM), and that these effects correlate with the inhibition of excitatory amino acid release, of NF-kappaB translocation to the nucleus and iNOS expression caused by ASA.>> [http://www.ncbi.nlm.nih.gov/pubmed/10760373] <- Ray Peat quoted this one

    See my other thread for more reasoning about these gases: Hydrogen sulfide uncouples respiration, saves mitochondria


    Finally here is a Ray Peat quote to wake you back up:

    A localized stress or irritation at first produces vasodilation that increases the delivery of blood to the tissues, allowing them to compensate for the stress by producing more energy. Some of the agents that produce vasodilation also reduce oxygen consumption (nitric oxide, for example), helping to restore a normal oxygen tension to the tissue.
  19. Milklove

    Milklove Member

    I don't think of the effect of red light as "activating" the cells. It restores healthy functioning of the mitochondria and can put the cell in a relaxed state. It also has anti-excitatory and anti-imflammatory actions.

    Then there is this very interesting quote by Ray Peat:
    The older the person is, the more emphasis should be put on protective inhibition, rather than immediately increasing energy production. Magnesium, carbon dioxide, sleep, red light, and naloxone might be appropriate at the beginning of therapy."

    Furthermore, we should be aware that red light has effects that reaches far beyond COX. For example, red light can break the free radical chain reactions and limit the procuction of toxic substances.
    I also believe that red light has important signaling fuctions.

    And another Peat quote:
    Penetrating red light is possibly the fundamental anti-stress factor for all organisms. The chronic deficiency of such light is, I think, the best explanation for the deterioration which occurs with aging. Enzyme changes, free radical changes, structural and respiratory changes are all involved as consequences of darkness stress.
  20. Re: redlight or CO2 for alopecia?

    Yes, that's pretty much it. The good thing is, there is no wrong or risky way to do it. Just try things and see how they work. Basically, you're an inventor, paving the way for future inventors.

    Glad to do it. Here are a few results I looked at briefly from a search for transcutaneous infusion of carbon dioxide on google patents:
  21. Yes, completely agree. The interesting question (if only for me) is whether Peat will feel dosing is needed, as the paper you cited above, for example, seems to conclude, proposing a "biphasic" dose response that limits the irradiance and the time, and concluding that the controversy over redlight therapy is a misapprehension of "biphasic" dose response.
    [Idealized biphasic dose response curve (often termed Arndt-Schulz curve) typically reported in LLLT studies.]

    In contrast, it would seem Peat feels that the first three therapies are evidently self-limiting, magnesium from coffee, carbon dioxide and sleep.

    Very glad you asked Peat the question!
  22. Mittir

    Mittir Member


    RP has talked about a study that showed bright light suppressing cortisol after
    sunset. RP always insist on using at least several hundred watts of incandescent
    to get benefit of light Therapy. You will definitely get benefit of red light from
    using red LED. It is not clear to me if those LED board has enough bright light
    to suppress cortisol after dark. I remember reading a study that sounded similar
    to the one RP talked about. IIRC they used 10,000 lux. You can use LED for
    red light therapy and bright incandescent for regular lighting.
  23. I think the various parts of the respiratory chain have different bands of resonance. Just buying "any red LED" will not cut it. An incandescent or halogen will always cover more less all of them however.
  24. dd99

    dd99 Member

    Thank you all for your comments. I use the LED board during the day whenever I'm sitting at my desk. I have halogens everywhere else in the house. There's a big campaign here in the UK to get people to switch from halogen to LEDs for energy efficiency. If I were to get warm white LEDS (with colour temperature of 3000 Kelvin, similar to a 200-watt incandescent, apparently), would that be good for regular lighting?
  25. Mittir

    Mittir Member

    I was considering regular LED lighting. I think there are regular LED bulb with
    much less Kelvin, 2400-2600 kelvin seems more preferable to me.
    You want yellowish light like incandescent. My understanding is that
    cortisol suppression required higher luminosity, studies usually use 10,000 lux
    for depression treatment. Day light ( not direct sun light) has between
    10,000 to 25,000 lux. I think Idea is to mimic luminosity of day light.
    LED bulbs have much higher lumen per watt than incandescent.
    You can experiment with different watts of LED to figure out the
    similar effect you are getting from halogen.

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