Every supplement has its downside. Metformin and rapamycin are the best candidates among fully-developed products, and metformin can dissipate the benefits of exercise, while rapamycin can suppress immune response and raise insulin resistance. NAD enhancers can affect epigenetic methylation and damage the liver. I’ve written about the adverse effects of anti-oxidants, which are the most highly publicized treatments for aging. But glutathione (GSH) is one anti-oxidant for which I’ve read multiple benefits, and I’ve never seen a negative word. As far as I know, the more glutathione you have, the healthier you can expect to be.
Glutathione is akin to a miniature protein with just 3 amino acids (glutamate, cysteine, and glycine). Our bodies manufacture glutathione regularly from the three constituent amino acids, but we make less of it when we are older, and need it more. (In my book, this is an example of programmed aging, the body deliberately turning to self-destruction, but you don’t have to believe in programmed aging.
It was originally discovered as a recyclable anti-oxidant. The most active and toxic ROS are reduced to the less toxic form, hydrogen peroxide, H2O2, and it is the job of glutathione to take care of the H2O2. The active (reduced) form is abbreviated GSH, and the ‘second-hand’ form, ready to be recharged, is GSSG. Glutothione reductase is the enzyme that does the honors of restoring GSSG to GSH. Glutathione antioxidant activity depends on an enzyme containing the trace element selenium, which is available in a quirky variety of foods (brazil nuts, mushrooms) and in trace mineral supplements.
As the number of supplements I take has multiplied over the years, I have begun to randomize my intake, selecting from a shelf full of pills each morning based on whim as much as anything. Through this transition, N-Acetyl Cysteine (NAC) is the one supplement that I keep handy and continue to take several times each day. NAC is a precursor and recharger of glutathione. After researching the present article, I’ve added raw glutathione to my pill shelf, for reasons you’ll read below.
Cancer is a counter-indication (?)
H2O2 is not just a toxic byproduct; it is also a signaling molecule with multiple functions, including self-destruction of the cell. GSH can lessen the propensity for apoptosis (cell suicide). This is generally a good thing in anyone over 50, but you might think twice about it if you’re actively battling cancer.
Not just an ordinary anti-oxidant
In addition to anti-oxidant activity, GSH is now known to have many other roles, including DNA repair, protein synthesis, and chemical signaling. It is not obvious that the health benefits of GSH come from its role as anti-oxidant.
In the liver and kidneys, GSH binds to a broad variety of toxins and carcinogens, helping to neutralize them while they are being eliminated. There are several common genetic variants that affect the hormones that assist in this process, glutathione S-transferases, or GSTs. People with GSTM-1 variants are more susceptible to most cancers, asbestos, lead and mercury poisoning, etc. The herb silymarin (milk thistle) increases the presence of glutathione selectively boosts glutathioneIn the liver. Hospital ERs use NAC for emergency detox, and in my personal experience a relative’s life was recently saved and liver damage avoided with intravenous NAC.
Supplementation with NAC has been found to increase lifespan in several animal models, most important in male mice
(Female mice in this study with or without NAC live as long as male mice with supplementation.)
To my knowledge, there is no direct evidence in humans regarding lifespan or mortality benefits of NAC or glutathione.
Glutathione is produced within each cell, and cells produce less of it in older humans. This is the reason glutathione levels decline as we age, about 40% between ages 30 and 70. Not only do older people have less glutathione, but levels tend to be lowest in people with chronic disease of any sort [ref].
NAC can extend the capacity of muscles to resist fatigue, both in rodents and in humans [ref]. This is probably related to recharging glutathione in and around mitochondria as they expend energy. Glutathione is especially useful in the energy metabolism, and there is evidence it is continually pumped into mitochondria.
I have believed for a long while that GSH doesn’t survive stomach acid, and it’s worthless to take it orally. This was based on the idea that GSH is a miniature protein, and the peptide bonds that hold proteins together are efficiently broken in the stomach. Hence the time-honored way to get more GSH is to take NAC, which is a precursor which the body uses to make GSH.
I’ve learned there are several things wrong with this story.
- Oral GSH is more bioavailable than I had thought.
- NAC only can lead to more glutathione if the body is flush with the other two amino acids, glutamate and glycine. For people who take NAC, glycine commonly becomes the bottleneck, so it helps to supplement with glycine as well.
- NAC often doesn’t increase total glutathione, but “recharges” the GSSG form back to GSH. So NAC can increase available glutathione up to a limit, but may not be sufficient to restore youthful levels in those of us who are past our youth. Alpha lipoic acid also helps to regenerate GSH, and so supplementing with ALA also tends to increase GSH levels.
- Liposomal and sub-lingual versions of glutathione are supposed to be more bio-available, but there’s not much data to support this, and the data seems to show only marginal improvement in bioavailability–not enough to justify the big difference in price.
Raw and Liposomal
Oral glutathione (raw) 250mg/day increased levels in red blood cells by about 30% over 6 months. Increasing to 1000mg/day didn’t do significantly better [ref].
Liposomal delivery is the encapsulation of the payload (glutathione) in microscopic droplets of vegetable oil, which protects the glutathione through digestion, and helps it pass through cell membranes.
I could only find a shorter-term study of liposomal glutathione [ref], and results were only marginally better than with raw glutathione.
In this study, a genetic defect that impairs glutathione efficiency is associated with low HDL and high trigycerides in the blood, which are two of the most telling indicators of cardiovascular disease. In this study, people who come into the ER with heart attacks tend to have much lower glutathione than a control population that doesn’t have heart attacks.
The Bottom Line
Glutathione serves multiple protective functions. The body manufactures less of it as we age. There is good indirect evidence from several angles that glutathione is an anti-aging supplement. In recent years, it has become clear that it can be taken orally with good effect.
Glutathione GSH is constantly being used as an antioxidant, after which it becomes GSSG, which needs to be recycled to GSH. NAC helps in the recycling, so more glutathione is available in its active form. The action is short-term and doesn’t increase the total amount of glutathione. Taking glutathione orally has a long-term benefit, increasing the total amount of glutathione in blood and in cells. Liposomal glutathione may be more readily absorbed than the simple glutathione pills, but it is so much more expensive that it’s hard to justify. There is independent evidence for NAC as an anti-aging supplement in rodents.
Chris Masterjohn has posted a review which seems to ask all the right questions, and I have taken much of my analysis from him.