Newsletter #281

This week, I’d like to talk about glutathione. Glutathione is a key antioxidant compound which can directly inactivate free radicals. Cellular levels of glutathione are linked to health and longevity, and abundance of glutathione tends to deteriorate with age.

So, why don’t people just supplement glutathione? Well…it doesn’t seem to work. Directly administering glutathione through oral supplementation does not consistently translate to increased blood levels of the compound.

Fortunately, providing two key precursors does seem to be effective. The human body requires cysteine and glycine in order to synthesize glutathione, and providing relatively large amounts of those two amino acids reliably boosts levels of glutathione in most people.

The antioxidant effect of glutathione may be especially important in the brain because of its high metabolic activity, which naturally results in the production of lots of reactive oxygen species. Furthermore, depletion of glutathione has been implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease.

Two recent studies suggest that boosting glutathione in the brain could improve aspects of cognitive function, with both short- and long-term benefits. Let’s take a look.

Motivation propels individuals to engage in goal-directed behavior. Because motivation is essential for progress and achievement, it is often viewed through a moral lens: we laud highly motivated people, and tend to assign negative value to those who are slow to exert effort and pursue goals. But what if variation in motivation was driven by biological differences? After all, we know that motivational deficits (apathy, anhedonia) are a hallmark of common psychological and neurological disorders. Even better, what if this were modifiable? You can imagine the benefits this might have not just for individual success, but for the advancement of entire societies.

To better understand neurobiological mechanisms that might affect motivation, researchers at the École Polytechnique Fédérale de Lausanne in Switzerland used a technique called proton magnetic resonance spectroscopy to measure levels of glutathione in rat and human brains. They zeroed in on a region of the brain called the nucleus accumbens, which plays a key role in circuits of the brain involved with effort and reward. Then, after quantifying levels of glutathione in the nucleus accumbens, they had participants (both human and rodent) go through effort-based motivation tasks. Sure enough, higher levels of glutathione in that part of the brain were associated with better and most consistent performance in these tasks.

Then, the researchers performed a series of experiments manipulating brain levels of glutathione in rodent models, in order to establish whether these variations were indeed responsible for the differences in performance.

First, they injected a compound that interferes with glutathione synthesis directly into the nucleus accumbens of the rodents, and tested the rats' motivation through a task that forces them to exert effort in order to obtain a reward (sugar pellet). And indeed, blocking glutathione in the brain reduced their willingness to work to acquire sugar pellets.

Then, they took two groups of rats and supplemented one group with NAC through their drinking water. Rats treated with NAC exerted more effort and obtained more rewards in the task than rats treated with placebo. Analysis of the brains of supplemented animals also confirmed that NAC supplementation led to increased levels of glutathione in the nucleus accumbens.

In a previous study, researchers affiliated with the Baylor College of Medicine in Houston had discovered that older adults are frequently deficient in glutathione, due to decreased availability of the precursor amino acids. In other words, they can't make enough glutathione because they lack sufficient amounts of the two key building blocks. In a short trial with older adults, supplementing glycine and N-acetylcysteine (GlyNAC) for two weeks effectively increased glutathione concentrations and lowered levels of reactive oxygen species to what is typically seen in young adults.

To see what would happen with a longer duration of supplementation, the same research team recruited eight older adults (71-80 years old) and eight young adults (21-30 years old). The younger adults were enrolled only to serve as a comparator to the older adults, and were not a part of the supplementation trial.

All participants underwent a battery of testing, including blood work, measures of physical function, and cognitive assessment. Once this testing was completed, the younger adults were released from the study, and the older adults were supplemented with GlyNAC in doses that were prepared based on the body mass of each subject. Measurements were taken again after the participants had used the supplement daily for 24 weeks, and then once more after they had ceased to use GlyNAC for 12 weeks.

So what happened?

Well, the GlyNAC led to an array of benefits in these older adults, including improvements in inflammation, glycemic control, and body composition. If you want to know all the details, I would encourage you to check out this extraordinary paper (free access!). However I am going to focus mainly on the cognitive effects here.

At baseline, much as you would expect, the older adults had significantly lower scores on all of the cognitive measures. Notably, they also had lower levels of brain-derived neurotrophic factor (BDNF), which we've discussed in previous newsletters. After GlyNAC supplementation, they observed significant improvements in all measured cognitive functional assessments. For instance, their performance on the verbal fluency test started out lagging behind that of the younger subjects (mean of 42.5 vs mean of 53.5), but after taking Gly NAC for 24 weeks their scores rivaled their younger counterparts (mean of 51.5).

This was accompanied by an increase in plasma BDNF. At the onset of the study, the young adults had mean plasma BDNF concentrations of 33.6 ng/mL, versus a mean of 21.4 ng/mL for the older adults. Supplementing GlyNAC caused the older adults' BDNF levels to rise up to 33.0 ng/mL.

So why did GlyNAC have this remarkable effect on their cognition?

The antioxidant power of glutathione probably plays a key role here. At the start of the study, red blood cell levels of glutathione in the older adults were 76% lower than young controls. Meanwhile, two biomarkers of oxidative stress, plasma thiobarbituric acid reducing substances (TBARS) and F2‐isoprostane, were 845% and 318% higher respectively in the older adults. After the older adults took GlyNAC, concentrations of glutathione increased by 200%, and the markers of lipid peroxidation fell by 74-75%.

So, we see that providing glutathione precursor amino acids leads to a major boost in the body's ability to fight oxidative stress.

This, in turn, improved mitochondrial function in the older adults, who entered the study with impaired whole-body mitochondrial fatty acid oxidation. This means that most of the tissues in their body had become metabolically inflexible, and were relying upon glucose for energy instead of fatty acids. This is a problem from a cognitive standpoint because the brain depends upon glucose, and if the pool of available glucose is being directed to other tissues, the brain is going to be short-changed. After taking GlyNAC, these tissues were able to switch to fatty acids, leaving more glucose for the sugar-hungry brain.

Finally, most of the effects associated with GlyNAC were attenuated or reversed after ceasing supplementation, suggesting that the supplement was indeed responsible for these benefits.

🍻 Beer has been shown to increase levels of glutathione.

I was digging around for nutrition-based methods of enhancing glutathione, and happened to stumble upon this study.

A group of 29 nuns, all living in a convent and adhering to a homogeneous diet and lifestyle, were asked to drink 500 mL of non-alcoholic beer for 45 days. At the end of the trial, blood levels of glutathione had risen by 29%. Decent for a basic diet intervention, although nowhere close to what was seen with GlyNAC.

You might wonder if this also applies to normal alcoholic beer (i.e. what most people actually drink)? In theory, it should, since the source of the glutathione seems to be polyphenols that are pretty universal to beer. One problem is that glutathione is involved with the detoxification of ethanol, meaning that chronic alcohol consumption could deplete glutathione. So alas, drinking beer might not be the most productive path to boosting glutathione.

Dan Pardi: Understanding GHB, the Four-Part Model of Behavior Change + How to Define and Measure Health. Via Smarter Not Harder.

This week, Dan had the opportunity to join Scott Sher on the Smarter Not Harder podcast to discuss his past research and his current work. On the show, he tackled the following questions:

Glutathione synthesis depends on two steps. First, cysteine needs to be added to glutamic acid to form glutamylcysteine. Then, glycine is added to glutamylcysteine to form γ-l-glutamyl-l-cysteinyl-glycine (also known as glutathione).

As previously noted, the most efficient way for most people to enhance glutathione levels is by supplementing the precursor cysteine, in the form N-acetyl-cysteine (NAC).

And don’t forget to take glycine too! The cheapest trustworthy option, as far as I know, is the Bulk Supplements powder. Three grams should be plenty.

https://mailchi.mp/humanos.me/newsletter-281