A new study has appeared to support an old idea: Aging is inevitable and immutable, so anti-aging research is doomed in advance to failure.

In 1957, George Williams wrote

This conclusion banishes the “fountain of youth” to the limbo of scientific impossibilities where other human aspirations, like the perpetual motion machine and Laplace’s “superman” have already been placed by other theoretical considerations. Such conclusions are always disappointing, but they have the desirable consequence of channeling research in directions that are likely to be fruitful.

In 2002, three prominent aging scientists wrote (in Scientific American):

No Truth to the Fountain of Youth:
…no purported anti-aging intervention has been proved to modify aging…We find it ironic that a phony anti-aging industry is proliferating today…Some [researchers] Some assert that aging’s complexity will forever militate against the development of anti-aging therapies.

One of the three was Len Hayflick, who is most famous for having discovered and documented one of the clearest and most preventable mechanisms of programmed aging.

In 2017, Joanna Masel wrote

“Aging is mathematically inevitable. Like, seriously inevitable. There’s logically, theoretically, mathematically no way out.”

This new study is based on statistical analysis of human and primate populations. Among the 42 authors (!) who signed it, I am chagrined to find the name of J. W. Vaupel. Et tu, James? Over several decades, Vaupel has been the optimist of demography, telling us that somewhere in the world, human lifespan is always continuing to increase, as it has done since 1840, at the rate of about 1 year of new lifespan for every 4 years that passes. For the first 130 years of this advance, the improvement in lifespan was predominantly about preventing infant mortality and combatting infectious disease. But since about 1970, lifespan improvements have continued to benefit the elderly. My informal index is the number of 80-year-olds I see on the tennis courts. Vaupel and his former student, Annette Baudisch, also were prime movers in a comprehensive 2013 study of Aging Across the Tree of Life, which catalogued species that don’t age at all for decades at a time, and others that become demographically younger.

This new computer model—like all computer models—is a translation into mathematical language of a set of assumptions about a natural phenomenon. The crank turns, and out pops a prediction. The sleight-of-hand, the conjuror’s trick, is that we are tempted to look at the mathematical machinery to see where these predictions come from. But equally important is to look at the assumptions on which the mathematics is built.

Specifically, what does the new study find? Looking at populations of humans and other primates, they find that longer average lifespans are associated with less variability in lifespan. In other words, the short-lived primates have deaths that are spread out, with some living much longer lives; but in the longer-lived primates, age-at-death is clustered up near the high end. This gives the appearance of some kind of wall at the high end of lifespan.

A crucial caveat

Long before NAC saved the life of someone dear to me, it was a staple of my supplement stack. I notice that now N-Acetyl Cysteine has become my favorite supplement, the one I reach for 3 or 4 times a day when I pass the kitchen cabinet. It’s been such a gradual process, that I don’t remember the reasons that installed NAC in my subconscious as a reliable life extension aid. I’m taking this opportunity to review the literature.

In the 1980s and 1990s, the oxidative theory of aging reached its pinnacle, and anti-oxidant supplements were all the rage. Trials of anti-aging supplements failed time and again, and often they led to shorter lifespans of test animals. Aging of animals turns out to be more complicated than rusting of iron, and part of the complication is hormesis, and ROS (Reactive Oxygen Species), particularly H₂O₂, are part of the signaling cascade that turns on hormetic protections.

One anti-oxidant that survived the massacre was glutathione. I continue to believe that glutathione promotes health, despite its close association with H₂O₂. Supplementing with N-Acetyl Cysteine (NAC) is the commonly-recommended strategy for raising glutathione levels, and it seems to work. The best promise of NAC (through glutathione) is in preserving our mitochondria, which weaken and reduce in number as we age.

Chemistry

Glutathione is a tripeptide, a mini-protein consisting of the 3 amino acids glutamate, cysteine, and glycine.

Our metabolisms (like all eukaryotes) use REDOX reactions to store and deploy energy, because they are far more energy-dense than the covalent chemistry of organic molecules. The energy metabolism has waste products which must be neutralized so they don’t latch on to delicate organic molecules and damage them. There are various toxic waste products (ROS), and various pathways for reducing them. The last stage is always H₂O₂, which must be neutralized to water. This is the primary job of glutathione. (Also catalase.) Unlike catalase, glutathione can perform diverse other detoxifying roles as well.

Glutathione acts like a rechargeable battery. Its reduced form (GSH) is available to detoxify H₂O₂, after which it exists as an oxidized form (GSSG), which must be “recharged”. GSSG is just two molecules of glutathione that are linked together by a disulfide bond, and a more complex protein called glutathione reductase comes along to separate the two molecules, recharging the battery. Another supplement, Alpha Lipoic Acid (ALA) is also helpful in recycling GSSG back to its useful form, GSH. Cells sense the ratio of GSH to GSSG to determine if they are in trouble. If the ratio becomes too low, the cell turns on NFkB [ref], which, in turn, initiates an inflammation cascade. A healthy cell has GSH:GSSG in the ratio 100 to 1, but a severely stressed sell can have more GSSG than GSH. Low ratios GSH:GSSG ratios can send a cell down a senescence pathway, terminating in apoptosis.

Glutathione’s importance is underscored by its large concentrations in every cell in the body. Your average human cell is using glucose for fuel, but the cell has as much glutathione as glucose in the cytoplasm.

Glutathione levels normally decline with age. 

In addition to anti-oxidant activity, glutathione is now known to have many other roles, including DNA repair, protein synthesis, and chemical signaling. These functions may be even more important than detoxifying H₂O₂. Most important for slowing age-related degeneration, glutathione has anti-inflammatory effects [ref], especially in the lungs [ref], which may be why NAC has been helpful in protecting against COVID [ref] It is well-established that severe COVID depletes glutathione, especially in late stages involving a cytokine storm [ref].

Table from J Pizzorno [2014]

Dietary Glutathione

Fruits and vegetables are a substantial source of dietary glutathione [ref], but bioavailability is low, so most of the body’s glutathione is home-made.

Can you just take glutathione pills? Yes, but they are expensive and poorly absorbed. Does supplementation with NAC really increase availability of glutathione where it is useful? Evidence is good [ref, ref, ref]. Just two years ago, I advised readers of this blog to eat glutathione, but I’m backing off from that suggestion now, because I think NAC supplementation is not just cheaper but more effective.

“The rate-limiting step of glutathione synthesis does not appear to be the activity of either enzyme under normal conditions, but rather the provision of one of the amino acids (L-cysteine) making up the tripeptide.” [ref]

Agricultural and industrial chemicals, ubiquitous in our environment, are not the primary cause of aging, but they cause severe symptoms for some, and may be degrading the metabolisms for all of us in subtle ways. Glyphosate has become impossible to avoid. Glyphosate, mercury, and other chemicals increase the body’s need for glutathione, as glutathione is essential to the body’s detox machinery. IBS, Crohn’s disease, and other inflammation syndromes increase the need for glutathione, and can potentially benefit from NAC supplementation.

What benefits of NAC have been documented in humans?

Best evidence is for preservation of the eyes with age. This is from an article on eye health and aging by BIll Sardi:

Numerous studies link glutathione with the prevention of cataracts, glaucoma, retinal disease and diabetic blindness. Here is a sampling of the evidence concerning glutathione and eye health.

Glutathione has been shown to detoxify the aqueous fluid of the inner eye [ref] and may help maintain adequate fluid outflow among glaucoma patients. [ref, ref]

Glutathione exists in unusually high concentrations in the lens and is essential to maintain its transparency. [ref] However, glutathione levels decline in the lens with advancing age; the decline is especially rapid prior to cataract formation. [ref]

NAC has been observed to have neuroprotective properties, but whether it lowers risk of dementia or PD is still not established [ref]. Emerging evidence suggests that NAC supplementation protects the brain in the event of ischemic stroke [ref]. Intravenous glutathione has been tried as a therapy for Parkinson’s disease with unimpressive results. Psychiatric applications are still under development. NAC has shown promise for treating addiction, AD, PD, autism, OCD, schizophrenia, depression, and bipolar disorder [ref].

Infusion of NAC increased endurance in trained cyclists [ref].

Intravenous NAC is used in ERs for detoxification of acetaminophen. It is also used for heavy metals [ref, ref], chloroform, monoxide and other poisons. [ref]

Table from J Pizzorno [2014]

Old mice have half as much glutathione in their muscles, compared to young mice [ref]

Life extension in lab animals, including rodents

There are many studies in worms and flies demonstrating life extension via NAC. There is just one study in mice [ref], but it was so successful that I don’t know why it hasn’t been replicated. 24% increase in mean lifespan and 45% increase in maximal lifespan in the only arm of this Jackson Lab broad screening study that showed promise.

FDA regulation

Glutathione and NAC have both been readily available supplements, available without prescription for many years. NAC is preferred as a less expensive pathway to augmenting GSH levels within cells. Recently, NAC was reclassified as a prescription drug by FDA. There is no concern with safety, and the only reason offered by FDA is that NAC has been promoted as a hangover remedy after excess alcohol consumption. Since glutathione can detoxify alcohol breakdown products in the liver, NAC probably has some usefulness in this role. I believe the real motivation for making NAC harder to get is that it is useful in treating COVID, and there appears to be an agenda for suppressing inexpensive and effective treatments (chloroquine, ivermectin, vitamin D, zinc, quercetin) in favor of vaccination.

(Off-topic: If you’re interested in a comprehensive guide to the general principles and the subtleties treating COVID, I highly recommend this interview by Dr Darrell Demeo of Mumbai.)

The Bottom Line

The evidence for NAC as a life extension supplement is mostly indirect, but there are many good reasons to boost our glutathione levels, especially as we age, and especially in an age of ubiquitous chemical toxins.