Sulfur is the
third most abundant mineral in your body. Sulfur-containing amino acids
increase your levels of glutathione and N-acetylcysteine (NAC), which
play important roles in health and fitness
Glutathione
metabolism influences the control of epigenetic mechanisms at several
levels, including substrate availability, enzymatic activity for DNA
methylation and the expression of microRNAs
NAC
supplementation may be useful for the prevention of cardiovascular
problems in older people by lowering oxidative stress and improving
mitochondrial function
Glutathione
deficiency can induce epigenetic changes in genes that regulate vitamin D
metabolism in the liver, and research suggests glutathione
supplementation could help reduce the risk of vitamin D deficiency in
obese individuals
Glutathione and
NAC also ameliorate exercise-induced stress and reduce muscle fatigue.
Glutathione may also play a central role in chronic fatigue syndrome
As explained in "The Health Benefits of MSM,"
sulfur is the third most abundant mineral in your body and plays
important roles in a variety of bodily processes, including metabolism
and detoxification, and for maintaining the proper shape and structure
of proteins and enzymes.
Sulfur-containing amino acids increase your levels of glutathione and
N-acetylcysteine (NAC), and these two play important roles in health
and fitness.
Glutathione Basics
Glutathione
comprises three amino acids: cysteine, glutamate and glycine. It's
commonly referred to as "the master antioxidant," as it is your body's
most powerful antioxidant, and is found inside every cell in your body.
Antioxidants combat free radicals — highly reactive particles that
bounce around the cell, damaging everything they touch. Most originate
during the process of metabolism but they can also arise during
exercise, and from exposure to toxins, irradiation and toxic metals.
Because free radicals are so destructive, cells have a network of
defenses designed to neutralize them. This antioxidant network is
composed of numerous components that include vitamins, minerals and
special chemicals called thiols (glutathione and alpha-lipoic acid).
Glutathione differs from other antioxidants in that it is
intracellular, and has the unique ability of maximizing the activity of
all the other antioxidants, including (but not limited to) vitamins C
and E, CoQ10
and alpha lipoic acid. It also removes toxins from your cells and
protects you from the damaging effects of radiation, chemicals and
environmental pollutants.
NAC Basics
NAC is a precursor to and rate-limiting nutrient for the formation of glutathione.1 Glutathione is poorly absorbed so, in many cases, it's easier to raise your glutathione by taking NAC instead.
In emergency medicine, NAC is used as an antidote for acetaminophen toxicity resulting from an overdose.2 Mortality due to acetaminophen toxicity has been shown to be virtually eliminated when NAC is promptly administered.
It is believed the liver damage acetaminophen causes is largely due
to the fact that it can deplete glutathione, which is secreted by your
liver in response to toxic exposure.
On a side note, NAC supplementation can also help "pre-tox" your body
when taken before alcohol, thereby minimizing the damage associated
with alcohol consumption — a tidbit that may be useful to know in light
of approaching New Year's celebrations.
Taking NAC (at least 200 milligrams) 30 minutes before you drink can
help lessen the alcohol's toxic effects. Vitamin B6 may also help to
lessen hangover symptoms.
While the most common use of NAC is for liver support, it's also showing promise as a neuroprotectant.3 Scientists are currently investigating it as a treatment for Parkinson's disease, which has been linked to glutathione deficiency in the substantia nigra, a region that houses dopamine neurons.4
Research looking at autopsied brains suggests Parkinson's patients
have barely detectable levels of glutathione in this brain region.
Subsequent studies have found glutathione deficiency in the substantia
nigra is common in a number of other neurodegenerative conditions as
well, including Alzheimer's disease.5
Another area where NAC shows particular promise is in the treatment
of mental health disorders, including post-traumatic stress disorder,6depression7 and substance use disorders.8 Dozens of additional health benefits are also reviewed in a November 29, 2019, SelfHacked article.9
One factor that can help explain the wide-ranging benefits of NAC and
glutathione is glutathione's role in the regulation of epigenetic
disease mechanisms.10 As noted in a November 2017 paper in Free Radical Biology and Medicine:11
"Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence.
Histone H3, one of the basic proteins in the nucleosomes that
make up chromatin, is S-glutathionylated in mammalian cells and tissues,
making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a
physiological antioxidant and second messenger in cells, a new
post-translational modifier of the histone code that alters the
structure of the nucleosome.
However, the role of GSH in the epigenetic mechanisms likely goes
beyond a mere structural function. Evidence supports the hypothesis
that there is a link between GSH metabolism and the control of
epigenetic mechanisms at different levels (i.e., substrate availability,
enzymatic activity for DNA methylation, changes in the expression of
microRNAs, and participation in the histone code)."
The following graphic12 illustrates how glutathione influences pathological changes in gene expression.
NAC Improves Cardiovascular and Mitochondrial Function
According to a 2018 study,13
NAC supplementation may be useful for the prevention of cardiovascular
problems in older people. As you might expect, oxidative stress can over
time induce metabolic and functional changes that speed cardiovascular
aging and dysfunction, and your glutathione levels declines with age,
putting you at greater risk.
In this study, aging mice received either NAC or a combination of NAC
and glycine. After seven weeks, their cardiac function was assessed,
showing those receiving NAC plus glycine had improved several parameters
of their cardiovascular function, including:
Improved diastolic function
Increased peak early filling velocity
Reduced relaxation time
Reduced left atrial volume
Reduced left ventricle end diastolic pressure
NAC alone did not impart these cardiovascular benefits, although both
groups had decreased levels of inflammatory mediators. The NAC and
glycine combination also improved mitochondrial function and upregulated
mitochondrial genes in the heart that are normally downregulated with
age.
According to the authors, "Our data indicate that NAC+Gly
supplementation can improve diastolic function in the old mouse and may
have potential to prevent important morbidities for older people."
Glutathione Deficiency Lowers Vitamin D Levels in the Obese
Other recent research14
published in Scientific Reports shows that glutathione deficiency can
induce epigenetic changes in genes that regulate vitamin D metabolism in
the liver. Emerging evidence also suggests glutathione metabolism plays
a role in the epigenetic regulation of oxidation-reduction (redox)
reactions, the authors note.
According to this paper,15
obesity has been correlated with low levels of glutathione and
25-hydroxyvitamin D3 — especially in Type 2 diabetics and the obese16
— and when obese mice were fed a glutathione-deficient diet, it
downregulated vitamin D metabolism genes and vitamin D receptors in the
liver. As a result, oxidative stress increased.
According to the authors, their findings suggest glutathione supplementation could help reduce the risk of vitamin D deficiency
in obese individuals. Supplementation with L-cysteine, a rate-limiting
precursor to glutathione, has also been shown to increase vitamin D
levels and reduce oxidative stress, the paper notes, which supports the
link between glutathione and vitamin D.
Glutathione and NAC Ameliorate Exercise-Induced Stress
As mentioned earlier, exercise is one of the ways through which free
radical production increases and, with it, oxidative stress. Provided
you get enough rest between bouts, this oxidative stress is actually
part of what makes exercise so beneficial.
That said, as noted in a 2005 paper,17
"Effective regulation of the cellular balance between oxidation and
antioxidation is important when considering cellular function and DNA
integrity as well as the signal transduction of gene expression." In
other words, excessive exercise can cause more harm than good. As
explained by the authors:18
"Exercise enthusiasts and researchers have become interested in
recent years to identify any means to help minimize the detrimental
effects of oxidative stress that are commonly associated with intense
and unaccustomed exercise. It is possible that a decrease in the amount
of oxidative stress a cell is exposed to could increase health and
performance …
To protect against the deleterious effects of ROS [reactive
oxygen species], our bodies have a complex system of endogenous
antioxidant protection in the form of enzymes such as superoxide
dismutase, catalase, and glutathione peroxidase. Under normal, resting
conditions reactive oxygen species are removed from the cell preventing
any subsequent damage.
However, under more extreme conditions such as: 1) inadequate
intake of foodstuffs containing the antioxidants, 2) excessive intake of
pro-oxidants, 3) exposure to noxious chemicals or ultraviolet light, 4)
injury/wounds, and/or 5) intense exercise, especially eccentric
exercise, the body's endogenous antioxidant system is not able to
effectively remove excessive ROS production.
In situations such as the ones listed above in which the
production of pro-oxidant molecules increase to a point where the
antioxidant system cannot effectively remove them is when oxidative
stress is known to occur.
Oxidative stress has been implicated in a number of diseases
which include atherosclerosis, pulmonary fibrosis, cancer, Parkinson's
disease, multiple sclerosis, and aging. Research on oxidative stress
during exercise has begun to indicate that regular training enhances the
ability of these mechanisms to effective respond to the increase of
oxidative product."
Exercise Boosts Your Glutathione Level
The 2005 paper above goes on to explain how exercise affects your
glutathione level, and thus your health, fitness and risk of disease. In
short, when you engage in intense exercise, your blood level of
glutathione significantly decreases while circulating levels of oxidized
glutathione increases, indicating that it's been used inside the muscle
to quench free radicals produced during the exertion.19
Considering the importance of glutathione to counteract free
radicals, effective regulation of glutathione levels when exercising is a
significant concern. The good news is that the more you exercise, the
higher your base levels of glutathione get.
This adaptation allows your body to effectively deal with the
increase in free radicals that the exercise brings about. While exercise
itself will boost your glutathione level over time, raising glutathione
through supplementation is an oft-used strategy among athletes.
As mentioned, glutathione supplementation is ineffective due to its
poor absorption, so NAC is generally considered a much better choice.
According to the authors of the 2005 paper cited above:20
"In addition to the role glutathione and other thiols have on
maintaining the cellular redox state, many studies have begun to explore
if NAC supplementation can actually improve performance due to its
ability to promote a more favorable cellular environment to achieve
higher levels of performance …
One of the first studies to utilize NAC to determine its role in
improving muscle performance was conducted by Reid and colleagues. They
pretreated subjects with n-acetyl-cysteine infusion (150 mg/kg) or a 5%
dextrose placebo while undergoing an extended fatiguing bout of
electrical stimulation of the ankle dorsiflexors.
N-acetyl-cysteine was found to have no impact over the
nonfatigued muscle, but a significantly increased force output of
approximately 15% was found after 3 minutes of repetitive contractions
which persisted throughout the 30-minute protocol. The authors concluded
that NAC resulted in improved performance suggestive of oxidative
stress having a causal role in the fatigue process."
Other studies have also confirmed that NAC supplementation helps
delay muscle fatigue during exercise, thereby improving endurance. In
one study,21 NAC infusion increased the time to exhaustion by 26.3%.
NAC's ability to reduce fatigue and improve cellular redox (oxidation
reduction) also hints at its potential benefit for those struggling
with chronic fatigue syndrome (CFS).
The Glutathione Depletion Theory of CFS
As explained by the U.S. Centers for Disease Control and Prevention,
CFS, also known as myalgic encephalomyelitis or ME, is characterized by
"overwhelming fatigue that is not improved by rest."22
The fatigue is frequently such that it challenges your ability to
perform even the most common of daily life tasks, such as showering or
preparing a meal.
The role of glutathione in this condition is addressed in "A Simple
Explanation of the Glutathione/Methylation Depletion Theory of ME/CFS"23 by the late Rich Van Konynenburg, Ph.D., developer of the methylation protocol used by many in the CFS community.24,25
According to Van Konynenburg, oxidative stress "is probably the
best-proven biochemical aspect of chronic fatigue syndrome," and in
order for your oxidative stress to overwhelm your system, something must
be placing excessive demands on your glutathione supply.
Several examples were already listed above, such as inadequate
antioxidant and/or excessive pro-oxidant intake, toxic exposures and
physical injuries. Long-term emotional stress can also be a factor. As
noted in Van Konynenburg's article:
"All people experience a variety of stressors all the time, and a
healthy person's body is able to keep up with the demands for
glutathione by recycling used glutathione molecules and by making new
ones as needed.
However, if a person's body cannot keep up, either because of
extra-high demands or inherited genetic polymorphisms that interfere
with recycling or making glutathione, or both, the levels of glutathione
in the cells can go too low …
One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins …When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins.
Also, the levels of toxins rise in the body when there isn't
enough glutathione to take them out, so there are two unfortunate things
that work together to sabotage your B12 when glutathione goes too low."
The B12-Glutathione Connection
Vitamin B12 helps your body convert food into glucose for energy, and fatigue is one of the symptoms of low B12 levels.26
Interestingly, many with CFS have elevated B12 levels. Their bodies
simply cannot use it properly, and one potential culprit is low
glutathione.
"The best test to reveal this is a urine organic acids test that
includes methylmalonic acid. It will be high if the B12 is being
sidetracked, and this is commonly seen in people with CFS," Van
Konynenburg states, adding:27
"The most important job that B12 has in the body is to form
methylcobalamin, which is one of the two active forms of B12. This form
is needed by the enzyme methionine synthase, to do its job. An enzyme is
a substance that catalyzes, or encourages, a certain biochemical
reaction.
When there isn't enough methylcobalamin, methionine synthase has
to slow down its reaction. Its reaction lies at the junction of the
methylation cycle and the folate cycle, so when this reaction slows
down, it affects both these cycles …
The methylation cycle has some important jobs to do. First, it
acts as a little factory to supply methyl (CH3) groups to a large number
of reactions in the body. Some of these reactions make things like
creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and
lots of other important substances for the body.
It is not a coincidence that these substances are found to be low
in CFS … Not enough of them is being made because of the partial block
in the methylation cycle.
The methylation cycle also supplies methyl groups to be attached
to DNA molecules, and this helps to determine whether the blueprints in
the DNA will be used to make certain proteins according to their
patterns.
The 'reading' of DNA is referred to as 'gene expression.' Methyl
groups prevent or 'silence' gene expression. Overexpression of genes has
been observed in CFS patients, and I suspect this is at least partly
due to lack of sufficient methylation to silence gene expression."
The Basic Biochemical Mechanism of CFS
The methylation cycle also regulates your body's use of sulfur, and
the production of sulfur-containing substances, including glutathione.
CFS patients often have abnormal levels of sulfur metabolites. Once you
understand the interconnectedness of glutathione, B12 and the
methylation cycle, it becomes easier to see how chronic CFS arises. As
explained by Van Konynenburg:28
"When glutathione goes too low, the effect on vitamin B12 slows
down the methylation cycle too much. The sulfur metabolites are then
dumped into the transsulfuration pathway (which is connected to the
methylation cycle) too much, are oxidized to form cystine, pass through
hydrogen sulfide, and are eventually converted to thiosulfate and
sulfate and are excreted in the urine.
This lowers the production of glutathione, which requires
cysteine rather than cystine, and now there is a vicious circle
mechanism that preserves this malfunction and keeps you sick … That's
the basic biochemical mechanism of CFS … everything else flows from this
…
Here's how I believe the fatigue occurs: The cells have little
powerplants in them, called mitochondria. Their job is to use food as
fuel to produce ATP (adenosine triphosphate). ATP acts as a source of
energy to drive a very large number of reactions in the cells.
For examples, it drives the contraction of the muscle fibers, and
it provides the energy to send nerve impulses. It also supplies the
energy to make stomach acid and digestive enzymes to digest our food,
and many, many other things.
When glutathione goes too low in the muscle cells, the levels of
oxidizing free radicals rise, and these react with parts of the
'machinery' in the little powerplants, lowering their output of ATP.
So the muscle cells then experience an energy crisis, and that's
what causes the fatigue. Over time, because of the lack of enough
glutathione, more problems accumulate in the mitochondria, including
toxins, viral DNA, and mineral imbalances."
All of these factors will ultimately decimate your immune function as
well, allowing pathogenic bacteria, viruses and fungi to take over. CFS
patients will frequently have several infections ongoing at the same
time. Low glutathione also impedes your body's natural detoxification
pathways, allowing toxicity to build over time, thereby causing
ever-increasing dysfunction.
The Answer for CFS
So, how do you turn this chain of events around? As noted in Van Konynenburg's article:29
"The main key to turning this process around is to help the
methionine synthase enzyme to operate more normally, so that the partial
block in the methylation cycle and the folate cycle are lifted, and
glutathione is brought back up to normal. That is what the simplified
treatment approach is designed to do, and so far, the evidence is that
it does do these things in most people who have CFS.
I recommend that people with CFS have the Vitamin Diagnostics
methylation pathways panel run to find out if they do in fact have a
partial methylation cycle block and glutathione depletion before
deciding, with their doctors, whether to try this treatment.
This also provides a baseline so that progress can be judged
later on by repeating it every few months during the treatment. Symptoms
may not be a good guide to judge progress during treatment, because
detoxing and die-off can make the symptoms worse, while in fact they are
exactly what is needed to move the person toward recovery."
An outline of Van Konynenburg's simplified methylation treatment plan for CFS can be found in HealthRising.org.30
At the core of this treatment is the use of specific supplements,
including folate, B12, a multivitamin, SAMe and phosphatidyl serine.
In his protocol, he explains the theory behind the use of each of
these supplements, how they impact the methylation cycle, and their
interactions with other supplements.
My take-home message here is that glutathione and NAC supplementation
may not always be the ideal way to go. People with CFS may be better
supported by a customized assessment by an experienced clinician that
may also include methyl folate and methyl vitamin B12.
General Dosing and Safety Guidelines for NAC
For many others, however, NAC can be safely used to boost glutathione
levels. For more information about how NAC can benefit your health, see
"The Many Benefits of NAC."
It's widely available as an oral dietary supplement and is relatively
inexpensive. Unfortunately, like glutathione, NAC is poorly absorbed
when taken orally, although it's better than glutathione.
According to some studies,31,32
NAC's oral bioavailability may range between 4% and 10%, which is why
the recommended dosage can go as high as 1,800 milligrams (mg) per day.
Its half-life is also in the neighborhood of two hours, which is why
most study subjects take it two or three times a day.
No maximum safe dose has yet been determined, but as a general rule,
it's well-tolerated, although some do experience gastrointestinal side
effects such as nausea, diarrhea or constipation. Should this occur,
reduce your dosage. It's also best taken in combination with food, to
reduce the likelihood of gastrointestinal effects.
Also keep in mind that since NAC boosts glutathione, which is a
powerful detox agent, you may experience debilitating detox symptoms if
you start with too high a dose. To avoid this, start low, with say 400
to 600 mg once a day, and work your way up.
Also, if you are currently taking an antidepressant or undergoing
cancer treatment, be sure to discuss the use of NAC with your physician,
as it may interact with some antidepressants and chemotherapy.
No comments:
Post a Comment