{"id":1071,"date":"2021-06-07T13:04:23","date_gmt":"2021-06-07T13:04:23","guid":{"rendered":"https:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=1071"},"modified":"2021-06-07T13:04:23","modified_gmt":"2021-06-07T13:04:23","slug":"paean-to-nac","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2021\/06\/07\/paean-to-nac\/","title":{"rendered":"Paean to NAC"},"content":{"rendered":"

Long before NAC saved the life of someone dear to me, it was a staple of my supplement stack. I notice that now N-Acetyl Cysteine has become my favorite supplement, the one I reach for 3 or 4 times a day when I pass the kitchen cabinet. It\u2019s been such a gradual process, that I don\u2019t remember the reasons that installed NAC in my subconscious as a reliable life extension aid. I\u2019m taking this opportunity to review the literature.<\/i><\/p>\n

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In the 1980s and 1990s, the oxidative theory of aging reached its pinnacle, and anti-oxidant supplements were all the rage. Trials of anti-aging supplements failed<\/a> time and again, and often they led to shorter lifespans of test animals. Aging of animals turns out to be more complicated than rusting of iron, and part of the complication is hormesis, and ROS (Reactive Oxygen Species), particularly H2<\/sub>O2<\/sub>, are part of the signaling cascade that turns on hormetic protections.<\/p>\n

One anti-oxidant that survived the massacre was glutathione. I continue to believe that glutathione promotes health, despite its close association with H2<\/sub>O2<\/sub>. Supplementing with N-Acetyl Cysteine (NAC) is the commonly-recommended strategy for raising glutathione levels, and it seems to work. The best promise of NAC (through glutathione) is in preserving our mitochondria<\/a>, which weaken and reduce in number as we age.<\/p>\n

Chemistry<\/b><\/p>\n

Glutathione is a tripeptide, a mini-protein consisting of the 3 amino acids glutamate, cysteine, and glycine.<\/p>\n

Our metabolisms (like all eukaryotes) use REDOX reactions to store and deploy energy, because they are far more energy-dense than the covalent chemistry of organic molecules. The energy metabolism has waste products which must be neutralized so they don\u2019t latch on to delicate organic molecules and damage them. There are various toxic waste products (ROS), and various pathways for reducing them. The last stage is always H2<\/sub>O2<\/sub>, which must be neutralized to water. This is the primary job of glutathione. (Also catalase<\/a>.) Unlike catalase, glutathione can perform diverse other detoxifying roles<\/a> as well.<\/p>\n

Glutathione acts like a rechargeable battery. Its reduced form (GSH) is available to detoxify H2<\/sub>O2<\/sub>, after which it exists as an oxidized form (GSSG), which must be \u201crecharged\u201d. GSSG is just two molecules of glutathione that are linked together by a disulfide bond, and a more complex protein called glutathione reductase<\/i> comes along to separate the two molecules, recharging the battery. Another supplement, Alpha Lipoic Acid (ALA) is also helpful<\/a> in recycling GSSG back to its useful form, GSH. Cells sense the ratio of GSH to GSSG to determine if they are in trouble. If the ratio becomes too low, the cell turns on NFkB<\/a> [ref<\/a>], which, in turn, initiates an inflammation cascade. A healthy cell has GSH:GSSG in the ratio 100 to 1, but a severely stressed sell can have more GSSG than GSH. Low ratios GSH:GSSG ratios can send a cell down a senescence pathway, terminating in apoptosis<\/a>.<\/p>\n

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Glutathione\u2019s importance is underscored by its large concentrations in every cell in the body. Your average human cell is using glucose for fuel, but the cell has as much glutathione as glucose<\/a> in the cytoplasm.<\/p>\n

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Glutathione levels normally decline with age.\u00a0<\/b><\/p>\n

In addition to anti-oxidant activity, glutathione is now known to have many other roles, including DNA repair, protein synthesis, and chemical signaling. These functions may be even more important than detoxifying H2<\/sub>O2<\/sub>. Most important for slowing age-related degeneration, glutathione has anti-inflammatory effects [ref<\/a>], especially in the lungs [ref<\/a>], which may be why NAC has been helpful in protecting against COVID [ref<\/a>] It is well-established that severe COVID depletes glutathione, especially in late stages involving a cytokine storm [ref<\/a>].<\/p>\n\n\n\n
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Table 1 Functions of Glutathione<\/b><\/h3>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
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  1. Direct chemical neutralization of singlet oxygen, hydroxyl radicals, and superoxide radicals<\/li>\n
  2. Cofactor for several antioxidant enzymes<\/li>\n
  3. Regeneration of vitamins C and E<\/li>\n
  4. Neutralization of free radicals produced by Phase I liver metabolism of chemical toxins<\/li>\n
  5. One of approximately 7 liver Phase II reactions, which conjugate the activated intermediates produced by Phase I to make them water soluble for excretion by the kidneys<\/li>\n
  6. Transportation of mercury out of cells and the brain<\/li>\n
  7. Regulation of cellular proliferation and apoptosis<\/li>\n
  8. Vital to mitochondrial function and maintenance of mitochondrial DNA (mtDNA)<\/li>\n<\/ol>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

    Table from J Pizzorno [2014<\/a>]<\/small><\/p>\n

    Dietary Glutathione<\/b><\/p>\n

    Fruits and vegetables are a substantial source of dietary glutathione [ref<\/a>], but bioavailability is low, so most of the body\u2019s glutathione is home-made.<\/p>\n

    Can you just take glutathione pills? Yes<\/a>, but they are expensive and poorly absorbed. Does supplementation with NAC really increase availability of glutathione where it is useful? Evidence is good [ref<\/a>, ref<\/a>, ref<\/a>]. Just two years ago, I advised readers of this blog to eat glutathione<\/a>, but I\u2019m backing off from that suggestion now, because I think NAC supplementation is not just cheaper but more effective.<\/p>\n

    \u201cThe rate-limiting step of glutathione synthesis does not appear to be the activity of either enzyme under normal conditions, but rather the provision of one of the amino acids (L-cysteine) making up the tripeptide.<\/i>\u201d [ref<\/a>]<\/em><\/p><\/blockquote>\n

    Agricultural and industrial chemicals, ubiquitous in our environment, are not the primary cause of aging, but they cause severe symptoms for some, and may be degrading the metabolisms for all of us in subtle ways. Glyphosate has become impossible to avoid. Glyphosate, mercury<\/a>, and other chemicals increase the body\u2019s need for glutathione<\/a>, as glutathione is essential to the body\u2019s detox machinery. IBS, Crohn\u2019s disease, and other inflammation syndromes increase the need for glutathione<\/a>, and can potentially benefit from NAC supplementation.<\/p>\n

    What benefits of NAC have been documented in humans?<\/b><\/p>\n

    Best evidence is for preservation of the eyes with age. This is from an article on eye health and aging by BIll Sardi<\/a>:<\/p>\n

    Numerous studies link glutathione with the prevention of cataracts, glaucoma, retinal disease and diabetic blindness. Here is a sampling of the evidence concerning glutathione and eye health.<\/p>\n

    Glutathione has been shown to detoxify the aqueous fluid of the inner eye [ref<\/a>]<\/em> and may help maintain adequate fluid outflow among glaucoma patients. [ref<\/a>, ref<\/a>]<\/em><\/p>\n

    Glutathione exists in unusually high concentrations in the lens and is essential to maintain its transparency. [ref<\/a>]<\/em> However, glutathione levels decline in the lens with advancing age; the decline is especially rapid prior to cataract formation. [ref<\/a>]<\/em><\/p><\/blockquote>\n

    NAC has been observed to have neuroprotective properties, but whether it lowers risk of dementia or PD is still not established [ref<\/a>]. Emerging evidence suggests that NAC supplementation protects the brain in the event of ischemic stroke [ref<\/a>]. Intravenous glutathione has been tried as a therapy for Parkinson\u2019s disease with unimpressive results<\/a>. Psychiatric applications are still under development. NAC has shown promise for treating addiction, AD, PD, autism, OCD, schizophrenia, depression, and bipolar disorder [ref<\/a>].<\/p>\n

    Infusion of NAC increased endurance in trained cyclists [ref<\/a>].<\/p>\n

    Intravenous NAC is used in ERs for detoxification of acetaminophen. It is also used for heavy metals [ref<\/a>, ref<\/a>], chloroform, monoxide and other poisons. [ref<\/a>]<\/p>\n\n\n\n
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    Table 2\u00a0<\/b>Diseases Associated with GSH Depletion<\/h3>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
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