If You're Missing This Nutrient, You're Aging Way Faster
This universal and all-important molecule is the mother of all antioxidants: glutathione. It is a ubiquitous molecule that is present in all human tissues, designed to defend against damage caused by free radicals, harmful chemicals, and inflammation. It does all of this (and more) in an effort to protect us against a myriad of insults from environmental toxins, allergens, and infections in our modern world. Indeed, glutathione plays one of the most critical roles in the body—and its deficiency plays a role in many causes of disease. In fact, deficiency of glutathione is recognized as contributing to many conditions, including aging, autoimmune disease, cancer, chronic fatigue syndrome, diabetes, heart disease, liver disease, Parkinson’s disease, and pulmonary fibrosis, to name a few. Increasing glutathione production can help us to detoxify, age more gracefully, perform better, lose weight, and prevent disease.
The Basics of Glutathione Production
Glutathione is made by the body from three key amino acids: cysteine, glutamine, and glycine. Cysteine is the most crucial of these three building blocks, and it is usually the rate-limiting step in the production of glutathione. It is a sulfur-containing amino acid that contributes the important “sulfhydryl group” to glutathione. This sulfur component is what scavenges destructive molecules and helps convert them to harmless compounds.
Methylation is important to production and recycling of glutathione. Methylation refers to an important biochemical process that adds a methyl group (a single carbon and three hydrogens) to other molecules. This occurs all over the body and is in involved in many critical functions. One of those critical functions is production of glutathione. Methylation pathways depend on a lot of things, but adequate levels of vitamins B6, B12, and folate are particularly important.
Our body’s ability to create and recycle glutathione also depends on the function of glutathione S‐transferase (GST) genes. This family of genes encodes critical processes for detoxification of pharmaceuticals, environmental pollutants, heavy metals, and many other toxins via glutathione. During times of oxidative stress and high toxic load, these genes are upregulated. However, we did not evolve to handle such stressors, and these genes don’t always work that well. Common genetic variations, called single nucleotide polymorphisms (SNPs), affect function for many people. SNPs of the glutathione S-transferase genes (like GSTT1, GSTM1, GSTP1) have been linked to increased risks for a multitude of environmental-related diseases—everything from asthma to cancer.
Here’s the problem: the demand for glutathione in our modern world often exceeds our ability to make it, and we end up depleted. Without enough glutathione, our body builds up too many reactive oxygen species and environmental toxins—the end result of which is DNA damage, oxidative stress, and chronic disease.
The Role of Glutathione in Oxidative Stress
Simply put, oxidative stress is like rust in our body formed by oxidation, and it accelerates aging and disease. While oxygen free radicals are normal components of cell metabolism, they can become a problem if they are produced in an uncontrolled fashion. Similarly, antioxidants can become a problem if there are not enough of them to quench free radicals. Too many reactive oxygen species or too few antioxidants create an imbalance that causes damage to DNA, proteins, and membrane lipids—called oxidative stress.
Glutathione helps to prevent oxidative stress by acting as a reducing agent, antioxidant, and free-radical scavenger. It is a cofactor for the enzyme glutathione peroxidase, which neutralizes reactive hydrogen peroxide species and turns them into water. The process by which glutathione neutralizes damage from oxidation is called reduction. It does this by donating an electron to a reactive oxygen species, thereby neutralizing a free radical (this is what defines an antioxidant). Glutathione is then recycled and restored, assuming it is not depleted. However, severe oxidative stress can deplete cellular glutathione.
Other antioxidants depend on glutathione for their proper function. This is what gave glutathione its well earned title as the master antioxidant. Importantly, it maintains antioxidants like alpha lipoic acid, vitamin C, and vitamin E in their active forms, and recycles them so they can be reused by the body. For example, vitamin C gives up an electron to neutralize a free radical. Glutathione then gives its electron to Vitamin C, returning it to work as an antioxidant. Thus glutathione lowers the required intake for vitamin C and helps our body to be more efficient. These other antioxidants work synergistically with glutathione, helping to prevent depletion of either.
The Role of Glutathione in Detoxification
Glutathione also plays a critical role in detoxification of toxic chemicals in the liver. Metabolic detoxification refers to the body's ability to get rid of waste. It works through a series of enzymes and pathways in the liver that transform chemicals, hormones, and toxins into water-soluble metabolites. These metabolites can then be excreted by the intestines, kidneys, and skin.
The first pathway, called Phase I, primarily uses cytochrome P450 enzymes to help transform fat-soluble toxins into less harmful chemicals. This process produces free radicals, which are quenched by antioxidants (as we’ve learned, glutathione does a good job of neutralizing reactive oxygen species).
Phase II detoxification makes these reactive intermediate metabolites water-soluble via a process called conjugation. This process involves specific pathways that attach (conjugate) molecules to toxins so they can be excreted by the body. Glutathione is one of the primary molecules responsible for this process. Glutathione conjugation makes toxic chemicals more water-soluble so we can excrete them through the urine or bile. Under times of high toxic load, Phase II liver detoxification enzymes attempt to upregulate production of glutathione in an effort to keep up with demands.
Glutathione and Chronic Disease
Glutathione proves to be particularly important across a spectrum of illnesses. Mitochondrial health, autoimmunity, and cancer provide helpful models to show how it works to prevent a multitude of chronic diseases.
Glutathione is particularly important in defending against oxidative stress in the mitochondria. These are the energy powerhouses of our cells where we make ATP. Poor mitochondrial health is implicated in most age-related diseases, and it has a lot to do with energy and metabolism. Think: brain fog, fatigue, slow metabolism and poor muscle recovery. Glutathione can help the mitochondria to resist oxidative damage and perform better.
Glutathione also plays an important role in modulating the immune system in order to control the inflammatory and autoimmune response. Studies show that glutathione deficiency is associated with many autoimmune conditions, from Hashimoto’s Thyroiditis to Multiple Sclerosis. This is mediated by oxidative stress and healthy T regulatory cell function. There are many diseases with an immunological component, so glutathione proves once again to be extremely important.
The role of glutathione in cancer is an important area of research. As we’ve learned, glutathione plays a vital role as an antioxidant. The chain reaction of oxidative stress, if left uncontrolled,can cause DNA damage, cell death, and cell mutation. Glutathione helps mitigate the damage and repair DNA. It’s also critical in the detoxification of carcinogenic compounds. It’s important to note, however, that glutathione may confer resistance to a number of chemotherapeutic drugs.
What Depletes Glutathione?
Depleting glutathione levels may lead to cell damage, oxidative stress, and chronic disease… But improving and maintaining levels can help us to optimize health and prevent disease. In fact, increasing and maintaining glutathione production is a target in the treatment of many chronic diseases. For these reasons, keeping up with the supply and demand of glutathione becomes an important concept when it comes to health.
Decreasing demand for glutathione by mitigating sources of oxidative stress and environmental toxins is the first step. This is easier said than done, but clean air, food, and water is the goal. The most important place to focus on this is in your own home, and especially your bedroom, where you spend the most time. In my home, I do this by following these principles:
- Use a high-quality water filter for drinking (ideally for bathing as well)
- Use high-quality HEPA air filters, especially in the bedrooms
- Open windows regularly to purge stale air
- Invest in a non-toxic organic mattress and bedding
- Use a HEPA vacuum and keep dust to a minimum
- Avoid toxic cleaning products
- Avoid spraying with weed or pest killers
- Test for and address issues with environmental molds and mycotoxins
- Swap out plastic for glass
- Avoid nonstick pots and pans
- Buy organic non-GMO foods, free of things like pesticides, hormones and mercury
- Avoid sugar, excessive alcohol, and refined or processed carbohydrates
- Reduce EMF exposure and turn off wifi at night
- Maintain good sleep hygiene
- Manage stress
Optimizing glutathione production is the second step. For many, this can be achieved through healthy lifestyle practices. Principles that apply here are:
- Get moderate exercise and make movement a part of your daily routine.
- Avoid medications that deplete glutathione, like acetaminophen (Tylenol).
- Eat garlic, onions, and other alliums daily. The allium family provides organosulfur compounds and allicin, which possess antioxidant properties and increase glutathione.
- Eat broccoli, cabbage, cauliflower, kale, and other cruciferous vegetables daily. Crucifers are rich in glucosinolate-derived isothiocyanates (like sulforaphane) which increase glutathione and induce the glutathione S-transferase (GST) enzymes.
- Eat antioxidant rich plant foods, which work synergistically with glutathione.
- Eat glycine rich foods, like gelatin, collagen and bone broth.
- Liberalize healthy fats, like avocados, extra virgin olive oil, nuts and sardines. This can help improve mitochondrial function.
- Don’t forget about high-quality protein which provides the amino acid building blocks that are critical for other detoxification pathways in the liver.
Supplementing with Glutathione
Glutathione is one of my favorite supplements. I use it personally and recommend it regularly in my functional medicine practice, but with caveats. Not all supplements (especially glutathione) are created equally. As always, I recommend only pharmaceutical-grade supplements from reputable companies that test raw materials and utilize third-party verification.
Here’s the catch with glutathione: most oral preparations are poorly absorbed because the three amino acid building blocks are degraded in the stomach before it can reach the cells. For this reason, effective supplements have a special delivery system - typically this is liposomal glutathione - which protects it from breakdown in the digestive system and improves bioavailability and intracellular delivery. Glutathione can also be delivered effectively as an intravenous (IV) nutrient.
There are a handful of other supplements that support glutathione production and recycling, like glutathione precursors and other antioxidants. These include:
- N-acetylcysteine (NAC): Remember that for most people, cysteine is the rate limiting amino acid for production of glutathione. Interestingly, NAC has been used in conventional medicine for years. In the emergency room, it is used to treat Tylenol overdose. It is also used to prevent kidney damage from contrast dye used in some imaging studies.
- Glycine: For some people, the rate limiting amino acid in glutathione production may be glycine vs cysteine. Supplementing with glycine has been shown to increase glutathione biosynthesis and protect against oxidative stress. It can also be helpful for its calming effects.
- Alpha Lipoic Acid (ALA): ALA is an important antioxidant that helps to regenerate glutathione. It is also a big player in mitochondrial health and blood sugar control.
- B Vitamins: If methylation is a problem, glutathione production will be an issue. Using active, or methylated, nutrients helps to bypass issues with methylation genes. Look for active B6 (P5P), B12 (methylcobalamin), and folate (methylfolate, 5 methyltetrahydrofolate, or 5-MTHF).
- Selenium: Adequate selenium is important for glutathione peroxidase enzyme activity.
- Curcumin: Turmeric contains a naturally occurring flavonoid called curcumin that works as both an antioxidant and antiinflammatory, and has been shown to increase glutathione levels.
- Milk Thistle: Milk thistle (aka silymarin) is known to support liver detoxification, and this herb has been shown to increase cellular glutathione levels.
- Vitamin D: Optimal stores of the fat soluble vitamin D are positively associated with plasma glutathione levels.
- Whey Protein: While I’m not a fan of dairy and don’t use whey protein myself, there's good evidence that high-quality whey protein is one of the best food sources of glutathione. However, this comes with a lot of caveats, and the large majority of whey protein you’ll find in stores is not what you’re looking for. Whey protein should be biologically active, non-denatured, cold processed and derived from organic, grass-fed and hormone-free raw milk (and only used by people who tolerate dairy well).
Side effects of Glutathione
As always, discuss dietary supplements with your doctor. In general, If you start glutathione and feel side effects, then back down to a lower dose. Sometimes it’s necessary to address other issues first, such as methylation.
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