Breathwork enhances endogenous antioxidant enzyme activity to counter oxidative stress. www.frontiersin.org

Vitamin C Mortality Sulforaphane Glutathione Nitric Oxide Antioxidant Oxidative Stress Breathing Technique

Breathwork has shown promise in ameliorating oxidative stress – a driver of many chronic diseases – in healthy people and those with chronic conditions. However, scientists don’t fully understand the underlying mechanisms that drive these effects. A recent review found that breathwork promotes the activity of endogenous antioxidant enzymes.

Researchers analyzed the findings of 10 randomized controlled trials (519 participants) investigating the effects of breathwork. The studies encompassed a range of breathwork styles and measured various biomarkers, including malondialdehyde, superoxide dismutase, glutathione, nitric oxide, vitamin C, and total antioxidant capacity levels.

They found that participants who engaged in breathwork exhibited greater changes in the biomarkers than those who did not. In particular, breathwork increased the activity of the endogenous antioxidant enzymes superoxide dismutase and glutathione activities and decreased levels of malondialdehyde, a marker of oxidative stress.

Breathwork is an umbrella term that refers to various breathing exercises and techniques. Evidence suggests that breathwork improves heart rate variability and promotes resilience to stress. People often engage in breathwork as part of general relaxation practices, yoga, or meditation.

These findings suggest that breathwork reduces oxidative stress by promoting the activity of endogenous antioxidant enzymes. Only 10 studies were included in the analysis, however, so more research is needed to support the findings. Sulforaphane, a bioactive compound derived from broccoli, reduces oxidative stress, too. Learn more in this clip featuring sulforaphane expert Dr. Jed Fahey.

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Glutathione depletion as a mechanism of Parkinson's disease: midlife depletion in animals induces symptoms and disability www.sciencedaily.com

Parkinson's Glutathione
Depleting glutathione may cause Parkinson’s:

Mice induced to have glutathione depletion as young adults did not develop Parkinsonian-like nerve damage and symptoms, while those who suffered from the depletion in late middle age did develop a loss of dopaminergic neurons specifically related to PD.

Tthe study suggests that loss of glutathione in the affected neurons may impact on energy production in the mitochondria, the “power plant” of the cells. This appears to involve a particular enzyme complex called mitochondrial complex I. Enzymatic activity of this complex has been found to be compromised in PD patients, but to date it has not been clear how this inhibition occurs.

Ameliorating with intravenous glutathione:

A pilot study in 1996 in which a small group of untreated PD patients were given daily intravenous infusions of glutathione over the period of a month reportedly resulted in a significant improvement in disability.“

Note: Studies have shown sulforaphane may be able to increase glutathione in the brain by an average of 25%.
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Sulforaphane from broccoli sprouts increase glutathione in the brain by an average of 30% with a 100 micromole per day dose www.sciencedaily.com

Brain Alzheimer's Parkinson's Schizophrenia Glutathione Antioxidant Neurodegeneration
Increases of glutathione reverse pattern of brain cell activity associated with schizophrenia:

They used the chemical sulforaphane found in broccoli sprouts, which is known to turn on a gene that makes more of the enzyme that sticks glutamate with another molecule to make glutathione. When they treated rat brain cells with glutathione, it slowed the speed at which the nerve cells fired, meaning they were sending fewer messages. The researchers say this pushed the brain cells to behave less like the pattern found in brains with schizophrenia.

However, the impact of sulforaphane may be broader due to the broader effect of increasing glutathione, including in the hippocampus (region impacted by Alzheimer’s disease):

For their study, published in April 2018 in Molecular Neuropsychiatry, the researchers recruited nine healthy volunteers (four women, five men) to take two capsules with 100 micromoles [17.729mg] daily of sulforaphane in the form of broccoli sprout extract for seven days.

[…]

The researchers used MRS again to monitor three brain regions for glutathione levels in the healthy volunteers before and after taking sulforaphane. They found that after seven days, there was about a 30% increase in average glutathione levels in the subjects' brains. For example, in the hippocampus, glutathione levels rose an average of 0.27 millimolar from a baseline of 1.1 millimolar after seven days of taking sulforaphane.
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Altered central and blood glutathione in Alzheimer’s disease and mild cognitive impairment. alzres.biomedcentral.com

Alzheimer's Glutathione
People with Alzheimer’s disease or mild cognitive impairment have low glutathione levels. Oxidative stress is a biological phenomenon that manifests when highly reactive molecules produced during metabolism accumulate in the body, damaging DNA and cells and driving a wide of range of chronic diseases, including Alzheimer’s disease and mild cognitive impairment. The body produces antioxidant molecules to counter the effects of oxidative stress, but its capacity to produce the molecules varies based on a person’s lifestyle and overall health. A recent meta-analysis reveals that people with Alzheimer’s disease and mild cognitive impairment have low brain and blood levels of the antioxidant molecule glutathione.

Glutathione is a potent antioxidant compound produced in the body’s tissues, particularly those that experience high levels of oxidative stress, such as the eyes, liver, and brain. Glutathione scavenges harmful reactive molecules, thereby preventing damage from oxidative stress, but evidence suggests glutathione levels decrease with aging, contributing to many aging-related diseases.

The authors analyzed data from studies in which researchers measured glutathione levels in the brains (eight studies) or blood (33 studies) of people with Alzheimer’s disease or mild cognitive impairment and compared those levels to healthy people. They conducted a sub-analysis of the data collected in the brain studies that used an advanced measurement technique called MEGA-PRESS, which may be more accurate than traditional techniques.

They found that when using traditional measurement techniques, researchers did not observe differences in brain glutathione levels among people with Alzheimer’s disease or mild cognitive impairment versus healthy people. However, when researchers used the MEGA-PRESS technique, brain glutathione levels were indeed lower in people with Alzheimer’s disease or mild cognitive impairment. The data also revealed lower blood glutathione levels in both Alzheimer’s disease and mild cognitive impairment, compared to healthy people.

These findings suggest that people with Alzheimer’s disease or mild cognitive impairment have lower levels of glutathione in their brains and blood. Interestingly, some dietary compounds or lifestyle behaviors may increase endogenous glutathione production. For example, evidence suggests that sulforaphane, a bioactive compound derived from broccoli and broccoli sprouts, increases glutathione in the brain. In addition, sauna use, which induces mild hyperthermia, increases the production of heat shock proteins, which are involved in glutathione maintenance and activity.
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A pilot trial finds sulforaphane treatment increases glutathione levels in the brain. www.karger.com

Brain Sulforaphane Glutathione NRF2 Moringa
Cellular damage incurred by oxidative stress underlies the pathophysiology of many chronic health disorders, including neuropsychiatric conditions such as schizophrenia. Glutathione, an antioxidant compound produced by the body’s cells, helps prevent damage from oxidative stress. Evidence from a 2018 study suggests that sulforaphane increases glutathione in the brain.

Scientists typically rely on magnetic resonance spectrometry (MRS) for measuring glutathione levels in brain tissue. Evidence suggests MRS is inadequate, however, and often yields inconsistent results across studies. These inconsistencies have prompted some investigators to explore the reliability of glutathione level measurements in blood as an indicator of oxidative stress-associated brain changes.

The pilot clinical study involved nine healthy adults. Eight of the participants were between the ages of 21 and 26 years; one was 56 years old. Each of the participants took 100 micromoles of sulforaphane (from a standardized broccoli sprout extract) by mouth every morning for one week. The authors of the study collected urine and blood specimens from the participants and performed MRS scans on their brains prior to the first dose of sulforaphane and within four hours of the final dose.

At the end of the week-long study, the participants' blood cell glutathione levels increased 32 percent. The MRS scans revealed similar increases in the thalamus, a region of the brain involved in information processing and a key player in schizophrenia. These observations were consistent regardless of age, sex, or race of the participants.

These findings suggest that sulforaphane shows promise as a therapeutic strategy for modulating oxidative stress in the brain, an underlying feature of schizophrenia. Some evidence that moringin, an isothiocyanate compound derived from moringa, may be useful in treating some of the symptoms of schizophrenia. Watch this clip in which Dr. Jed Fahey describes the health benefits associated with moringin and discusses the chemical structure differences between it and sulforaphane.
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Nrf2 pathway is a major target for sulforaphane. www.sciencedirect.com

Nutrition Sulforaphane Glutathione NRF2
Nrf2 (nuclear factor erythroid 2-related factor 2) is a cellular protein that regulates the expression of antioxidant and stress response proteins. It participates in the Keap1/Nrf2/ARE biological pathway – the primary mechanism by which sulforaphane exerts its beneficial effects. A 2017 review describes the role of sulforaphane in the Keap1/Nrf2/ARE pathway and summarizes the beneficial health effects associated with the compound.

The Keap1/Nrf2/ARE pathway is a key mediator of cytoprotective responses to oxidative and electrophilic stressors. Under normal cellular conditions, Keap1 tethers Nrf2 in the cytoplasm (the region of the cell outside the nucleus), where it can be tagged and delivered for degradation. However, following exposure to stressors, Keap1 undergoes modifications that impair its ability to bind to and target Nrf2 for degradation. As a result, Nrf2 is free to travel to the nucleus, where it binds to antioxidant response elements (AREs) of DNA. AREs are sequences in the regulatory regions of genes that activate transcription of a diverse group of cytoprotective enzymes.

Isothiocyanates react with certain regions on Keap1, eliminating Keap1’s ability to target Nrf2 for degradation – effectively serving the role of stressor. Sulforaphane, an isothiocyanate derived from broccoli and broccoli sprouts, is the most potent naturally occurring inducer of Nrf2.

The authors of the review presented evidence that sulforaphane protects against carcinogenesis in models of skin, oral, stomach, colon, lung, prostate, and bladder cancer. They also reported that feeding studies involving humans and consumption of isothiocyanate-rich cruciferous vegetables have demonstrated measurable Nrf2 activity, reflected in increased levels antioxidant proteins and enzymes, including glutathione S-transferase and NQO1. Future research will inform optimal dosages and formulations for clinical trials.

Watch this clip in which Dr. Jed Fahey describes the early co-discoveries of sulforaphane and Nrf2 and describes the importance of the Nrf2 pathway.
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Fish oil supplementation provides protection against fine particulate air pollution www.onlinejacc.org

Omega-3 Glutathione Protein Dairy
An estimated 4.2 million deaths each year, many of which are cardiovascular disease-related, are associated with exposure to air pollution. The mechanisms that drive this association include systemic inflammation, endothelial dysfunction, oxidative stress, hypertension, and metabolic dysfunction. Findings from a recent study suggest that supplemental omega-3 fatty acids may reduce the risk of cardiovascular disease-related death associated with exposure to particulate air pollutants.

Particulate matter in air pollution is a mixture of solid particles and liquid droplets. It is present in fine inhalable particles, with diameters that are generally 2.5 micrograms (PM2.5) or less. The daily standard for PM2.5 in the United States is 35 micrograms per cubic millimeter per day, as long as the average annual exposure is less than 12 micrograms per cubic millimeter daily.

Omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are derived from marine sources, elicit a wide array of health benefits. The American Heart Association recommends that people who have coronary heart disease consume approximately 1 gram of DHA and EPA daily in foods or supplemental form.

The randomized, double-blind study involved 65 healthy students attending Fudan University in Shanghai, China. Participants received either a 2.5-gram EPA- and DHA-rich fish oil supplement or a placebo daily for a period of four months. The authors of the study measured PM2.5 levels throughout the study. They also collected blood samples from the participants to assess levels of 18 cardiovascular disease-related biomarkers.

The average PM2.5 level during the study period was 38 micrograms per cubic millimeter. Whereas the participants who took the fish oil supplement had biomarker profiles that were cardioprotective, the participants who took the placebo had biomarker profiles associated with inflammation and cardiovascular disease. In particular, taking the fish oil supplement was associated with having higher levels of glutathione peroxidase (an enzyme that protects against oxidative stress) but the supplement was associated with having higher levels of C-reactive protein (a driver of inflammation).

These findings suggest that the intake of fish oil supplements rich in EPA and DHA may provide cardiovascular protection to people living in areas of high air pollution.
- Link to study abstract.
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Cognitive-behavioral therapy reduces symptoms of social anxiety disorder and improves biomarkers of aging. www.nature.com

Aging Anxiety Glutathione
Telomeres are distinctive structures comprised of short, repetitive sequences of DNA located on the ends of chromosomes that prevent chromosomes from losing genes or sticking to other chromosomes during cell division. Telomere attrition, a biomarker of aging, is commonly associated with mental health conditions such as social anxiety disorder. Protection against telomere shortening is provided by activation of the enzymes telomerase and glutathione peroxidase. Findings from a new study suggest that cognitive behavior therapy reduces telomere attrition by activating these protective mechanisms.

Social anxiety disorder, also known as social phobia, is a mental health condition characterized by an intense, persistent fear of being judged, negatively evaluated, or rejected by others. Approximately 15 million people living in the United States have been diagnosed with social anxiety.

The study involved 46 people with social anxiety disorder. The participants' plasma levels of telomerase and glutathione peroxidase were measured before and nine weeks after receiving cognitive behavior therapy. The participants' anxiety was assessed via self-report.

Following cognitive behavioral therapy, the participants' social anxiety symptoms decreased significantly. Increases in telomerase and glutathione peroxidase activity were associated with reduced social anxiety, suggesting that cellular protective mechanisms may be involved in mediating anxiety symptoms and adding to a growing body of evidence that stress and anxiety accelerate biological aging.

Lifestyle factors such as exercise and meditation have also been shown to improve symptoms of anxiety and biomarkers of aging. Meditation, in particular, slows biological aging by slowing the shortening of telomeres. Studies by telomere experts Elizabeth Blackburn at UCSF and Elisa Epel show that meditation buffers the stress that shortens telomeres and activates the gene that encodes for telomerase.
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Another pilot clinical study finds sulforaphane increased blood glutathione levels and increased levels in brain. www.ncbi.nlm.nih.gov

Sulforaphane Glutathione NRF2

Another pilot clinical study finds sulforaphane (abundant in broccoli sprouts and other cruciferous vegetables) increased blood glutathione levels and this correlated with increased glutathione in certain brain regions in healthy people.

Sulforaphane is one of the strongest inducers of the Nrf2 genetic pathway which activates genes involved in glutathione production. Other studies have found that sulforaphane increased blood glutathione levels in people but this study is the first to show that glutathione was also increased in certain brain regions and this correlated with increased plasma glutathione.

The increased glutathione in the brain may be one mechanism by which sulforaphane helps improves symptoms of autism which it has been shown to do in multiple clinical studies. Schizophrenia is also linked to increased oxidative stress in the brain and sulforaphane has been shown to improve symptoms of schizophrenia in a small open-label study. A larger randomized placebo-controlled study investigating the effects of sulforaphane on schizophrenia is ongoing and is expected to end in July of 2019.

The dose of sulforaphane used in this study was approximately 17.7 mg for 7 days.

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Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1 papers.ssrn.com

Brain Aging Circadian Rhythm Neuron Glutathione Neurons Protein

Abstract

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism, and via a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a novel mechanism by which the circadian clock could influence many aspects of brain function and neurologic disease.

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