N-Acetyl-L-Cysteine as a Dietary Supplement

I was planning to write about N-acetyl-L-cysteine (NAC) much earlier, but then NAC-containing products that are labeled as dietary supplements came under investigation by the Food and Drug Administration (FDA) in the US. In a nutshell, the FDA has determined that NAC is excluded from the dietary supplement definition under the FD&C Act because NAC was approved as a prescription drug before it was marketed as a dietary supplement or as a food. As a result, all major retailers in the US have started to phase out related products from their catalogues. This does not affect me personally, because I live in Canada and NAC is still freely available as a supplement here. For anybody in the US this means that NAC as a supplement is now in the gray-zone of enforcement discretion by the FDA. ^[1]

Why has NAC been getting so popular in recent years?

When taken as a supplement, NAC increases the concentration of L-cysteine, an important and essential amino acid, in the body. Cysteine promotes the production of natural antioxidants such as glutathione (GSH), also called the "master detoxifier", which effectively helps the body deal with oxidative stress and other toxins. GSH not only relieves oxidative stress but also supports the functions of vital organs and helps eliminate heavy metals from the body. ^[2]

Naturally, NAC can be found in different fruits, herbs, and vegetables that, along with a healthy diet, are usually sufficient to fulfill the body's needs. However, as we are getting older it becomes increasingly more difficult for our cellular machinery to extract, generate, and supply an optimal amount of NAC. Other factors, such as poor nutrition, an unhealthy lifestyle, and environmental stress, also contribute to inadequate levels of NAC or cysteine in the body. Supplementation can help counteract these shortcomings. ^[3]

In clinical practice, NAC is approved and being used for the neutralization and treatment of paracetamol toxicity. Medical research studies have mostly attributed the health benefits of NAC to its antioxidant activity both via GSH and itself. It scavenges free radicals such as hydrogen peroxide and reactive oxygen species to prevent organ damage, especially to the liver. NAC is one of the most potent liver protectants known, which is why it gained popularity as a hangover cure and preventative. In any case, NAC helps maintain optimal cellular integrity and supports important cleansing functions of the body, which is what makes it interesting as a supplement for the purpose of delayed aging and prolonged longevity. ^[2][3]

It is important to note that aging does not necessarily mean getting older by numbers or appearance. Aging or pre-mature aging is the weakening and fading of our vital physiological functions. Thus, keeping all organs healthy and functioning optimally is directly related to enhanced longevity and a better quality of life. Among other threatening factors to organs, oxidative stress is one of the most common factors generated by the presence of free radicals and toxins. Oxidative stress can damage cells, tissues, and nerves, especially those that are prone to pre-mature aging, and increase the risk of chronic medical conditions, including neurodegenerative diseases. ^[5]

Health Benefits of NAC

To summarize, NAC is typically considered as an anti-aging and lifespan extending supplement for its strong antioxidant activity. Following are details on medical research studies related to the health benefits as well as physiological functions of NAC and how those can contribute to longevity and an overall better quality of life.

Delayed Aging

NAC helps keep the integrity of organs which creates an anti-aging effect. Medical research studies reported that it increases the resistance of the body against free radicals, environmental stress, and ultraviolet radiation. These functions of NAC specifically protect cells against unwanted cell death (apoptosis), reduce the risk of cancer, and promote other cellular functions that all eventually have a positive effect on lifespan. ^[2][4][6][7]

Medical studies have shown that NAC elevates the production of GSH which effectively relieves oxidative stress in different body parts. Furthermore, NAC modulates different signaling pathways that positively impact cell growth and arrest, slow down apoptosis, and relieve inflammation. NAC also helps the body against the causative actions of heavy metals, including lead, arsenic, and mercury via cellular detoxification. ^[2][3][5]

Moreover, studies reported that NAC provides neuroprotection and prevents mitochondrial decay which is highly associated with aging and age-related neurodegenerative diseases such as Alzheimer’s disease, Parkinsonism, and Huntington’s disease. The possible mechanisms include; an increase in the glutathione level in the brain, reduction of oxidative damage, increased mitochondrial protection, improve brain synaptic and non-synaptic activities, and a reduced risk of dopamine-induced cell death. ^[2][3][5]

Studies also suggested that NAC improves mental health and wellness via regulating neurotransmitters in the brain. It helps normalize glutamate and dopamine levels which boost overall activity of the brain and can improve the symptoms of psychiatric conditions, including schizophrenia, memory ailments, and bipolar disorders. An optimal level of glutamate supports memory, improves cognition and enhances learning capabilities. ^[6][8]

Another possible anti-aging effect includes the stimulation of hydrogen sulfide (H2S) biosynthesis that plays an important role in longevity and stress resistance. An optimal amount of H2S in the body influences aging-related pathways and improves certain biological activities. These activities are bioenergetics, cellular metabolism, stem cell proliferation and differentiation, autophagy, stress resistance, apoptosis, and inflammation. ^[7]

Quality of Life

NAC acts as a precursor for cysteine which replenishes the “master detoxifier” GSH in the body and helps prevent various medical conditions. It supports the physiological functions of the heart, lungs, and other vital organs via its antioxidant activity. Medical research studies demonstrated that NAC boosts the immune system, reducing the risk of developing chronic medical conditions. It does so by restoring the concentration of natural killer cells and supporting the functions of lymphocytes and phagocytes, increasing resilience to pathological agents. ^{[2][9][10][14]}

Adding more, NAC helps physical performance and may ease muscle fatigue. It enhances force output and improves muscle activity to support a healthy lifespan. Furthermore, NAC supports optimal reproductive and gastrointestinal health. It improves the symptoms of ulcerative colitis via softening the colonic tissue, relieving oxidative stress, decreasing the risk of cell apoptosis, enhancing injured colon recovery, and supporting tightening of junctions. ^[3][11]

Studies also confirmed that NAC improves the symptoms of various respiratory disorders. It helps chronic bronchitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, nasal congestion, and airway hyper-responsiveness (AHR). NAC decreases the frequency of symptom aggravation and relieves inflammation in the airways, including bronchial tubes and lung tissues. Moreover, it acts as an expectorant and softens the mucus for easier expulsion. In the case of chronic obstructive pulmonary disease (COPD), NAC improves lung function, reducing exacerbation. All these health benefits may help reduce the risk of respiratory disorders when using NAC as a preventative supplement. ^{[2][3][15][16][17]}

Furthermore, NAC supports optimal functioning of the kidneys and liver via detoxifying harmful agents such as drugs and environmental toxins. It may also help various hepatic disorders, including liver cancer via its antioxidant and anti-inflammatory activities. In the case of sexual health, NAC showed a positive impact on fertility, semen quality and also improved symptoms of polycystic ovary syndrome (PCOS) in women. ^{[2][3][12][13]}

Medical research studies also reported that NAC prevents the risk of diabetes by regulating blood sugar levels and relieving inflammation in fat cells. It reduces insulin resistance, improves glucose tolerance, and increases insulin sensitivity. Adding more, it not only reduces diabetic complications but also decreases the risk of heart diseases and supports optimal cardiovascular functions. All these health benefits may not only improve the overall quality of life, but also help delay aging, prevent pre-mature aging, and increase longevity through their positive action on organs. ^[18][19]

Precautions

More likely than not, the use of NAC as a supplement is safe for adults. However, it can cause gastrointestinal symptoms such as nausea, vomiting, diarrhea, and constipation at high doses. Also, other adverse effects include drowsiness, runny nose, chest tightness, and mouth swelling. Its relative safety is also evident in the guidance of the FDA, which states: "Unless we identify safety-related concerns during our ongoing review, [the] FDA intends to exercise enforcement discretion until either of the following occurs: we complete notice-and-comment rulemaking to allow the use of NAC in or as a dietary supplement (should we move forward with such proceedings) or we deny the NPA citizen petition’s request for rulemaking." - meaning, most importantly, that the FDA does not currently have any safety-related concerns about NAC. ^[1]

Lastly, please note that I am only talking about my personal experience and opinion. This is not medical advice and what works for me might not work for you. Please make sure to always consult your primary care physician about any information obtained from or through my site.

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Take a look at this page for a full overview of all the supplements that I am currently taking on a regular basis: Fundamental Longevity Supplements. You will find links to other detailed articles, such as this one, about other supplements significant to longevity. There are also product endorsements and recommendations from me, based on the supplements that I am personally taking after spending years experimenting with different products.

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References:

1. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-policy-regarding-n-acetyl-l-cysteine
2. Vida Mokhtari et al. "A Review on Various Uses of N-Acetyl Cysteine." Cell Journal, vol. 19(1), 2017: 11–17. https://doi.org/10.22074/cellj.2016.4872
3. Špela Šalamon et al. "Medical and Dietary Uses of N-Acetylcysteine." Antioxidants, vol. 8(5), 2019: 111. https://doi.org/10.3390/antiox8050111
4. Seung-Il Oh, Jin-Kook Park & Sang-Kyu Park. "Lifespan extension and increased resistance to environmental stressors by N-Acetyl-L-Cysteine in Caenorhabditis elegans." Clinics, vol. 70(5), 2015: 380–386. https://doi.org/10.6061/clinics/2015(05)13
5. Sonja K. Soo et al. "Compounds that extend longevity are protective in neurodegenerative diseases and provide a novel treatment strategy for these devastating disorders." Mechanisms of Ageing and Development, vol. 190, 2020: 111297. https://doi.org/10.1016/j.mad.2020.111297
6. Deepmala et al. "Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review." Neuroscience & Biobehavioral Reviews, vol. 55, 2015: 294–321. https://doi.org/10.1016/j.neubiorev.2015.04.015
7. Mikhail V. Shaposhnikov et al. "Effects of N-acetyl-L-cysteine on lifespan, locomotor activity and stress-resistance of 3 Drosophila species with different lifespans." Aging, vol. 10(9), 2018: 2428–2458. https://doi.org/10.18632/aging.101561
8. Lianne Schmaal et al. "N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study." Neuropsychopharmacology, vol. 37, 2012: 2143–2152. https://doi.org/10.1038/npp.2012.66
9. Lorena Arranz et al. "The glutathione precursor N-acetylcysteine improves immune function in postmenopausal women." Free Radical Biology and Medicine, vol. 45(9), 2008: 1252–1262. https://doi.org/10.1016/j.freeradbiomed.2008.07.014
10. B. de Quay, R. Malinverni, B. H. Lauterburg. "Glutathione depletion in HIV-infected patients: role of cysteine deficiency and effect of oral N-acetylcysteine." AIDS, vol. 6(8), 1992: 815-819. PMID: 1418777.
11. Qingjing Wang et al. "Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model." BMC Gastroenterology, vol. 13, 2013: 133. https://doi.org/10.1186/1471-230X-13-133
12. Kívia Queiroz De Andrade et al. "Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine." International Journal of Molecular Sciences, vol. 16(12), 2015: 30269–30308. https://doi.org/10.3390/ijms161226225
13. D. Quig. "Cysteine metabolism and metal toxicity." Alternative Medicine Review, vol. 3(4), 1998: 262–270. PMID: 9727078.
14. Wulf Dröge & Raoul Breitkreutz. "Glutathione and immune function." Proceedings of the Nutrition Society, vol. 59(4), 2000: 595–600. https://doi.org/10.1017/s0029665100000847
15. Claudio M. Sanguinetti. "N-acetylcysteine in COPD: why, how, and when?" Multidisciplinary Respiratory Medicine, vol. 11, 2015: 8. https://doi.org/10.1186/s40248-016-0039-2
16. C. Stey, J. Steurer, S. Bachmann, T. C. Medici, M. R. Tramèr. "The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review." European Respiratory Journal, vol.16 (2), 2000: 253-262. https://doi.org/10.1034/j.1399-3003.2000.16b12.x
17. Elham Pirabbasi et al. "Efficacy of Ascorbic Acid (Vitamin C) and/N-Acetylcysteine (NAC) Supplementation on Nutritional and Antioxidant Status of Male Chronic Obstructive Pulmonary Disease (COPD) Patients." Journal of Nutritional Science and Vitaminology, vol. 62(1), 2016: 54–61. https://doi.org/10.3177/jnsv.62.54
18. Phiwayinkosi V. Dludla et al. "A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications." American Journal of Cardiovascular Drugs, vol. 18, 2018: 283–298. https://doi.org/10.1007/s40256-018-0275-2
19. Alona Falach-Malik et al. "N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice." American Journal of Translational Research, vol. 8(9), 2016: 3744–3756. PMID: 27725855.

A Critical View on Proof-of-Stake; Why Bitcoin is Here to Stay

There are fundamental differences between ETH and BTC when it comes to their capabilities, intended use cases, and their respective ecosystems overall. I won't be discussing those in this post. I am merely using them as representatives for two radically different philosophies in the blockchain space, that of proof-of-stake and that of proof-of-work.

When we read about these things in mainstream news, on social media or any other space where these topics are being discussed, the primary consideration for one over the other is often cited as the environmental impact that they have - especially when it comes to power consumption.

There is no denying that a proof-of-stake blockchain has radically lower power requirements compared to a proof-of-work blockchain. Since the vast majority of power generated all over the world is currently not considered clean, sustainable energy, there is also no denying that at present a proof-of-stake blockchain will have a radically smaller energy footprint, and therefore much less of a negative environmental impact, than a proof-of-work blockchain.

However, in my opinion, while the above seems like a perfect argument to pivot towards proof-of-stake, it is also an extremely dangerous view that is both short-sighted and diverts attention away from a severe underlying issue with any proof-of-stake blockchain.

Mining ETH versus BTC

To understand the issue, first, let's take a small step back and look at why, especially recently, mining ETH has been more profitable than mining BTC.

The short answer is gas fees; they make up a significant amount of revenue for ETH miners but are largely insignificant for BTC miners. Ever since the NFT craze in late 2021 gas fees on ETH have skyrocketed and are often cited as one of the main issues of Ethereum when it comes to its viability in terms of mass adoption; you can read more about those scaling issues directly on the Ethereum website.

This video is a perfect landmark for when that NFT craze peaked in the mainstream.

This is what mining revenues recently looked like when comparing ETH and BTC. Mining ETH is still more profitable than mining BTC, despite the initial NFT craze having largely subsided.

The gas fees on Ethereum are still out of control and often make trading small amounts of ETH or low-value NFTs that live directly on the Ethereum blockchain prohibitively expensive, which in turn limits the overall potential and specific use cases of Ethereum. This is not a new or recent realization. In fact, to name two examples, it's the primary reason why Dapper Labs decided to build their own L1 blockchain Flow after their experience with Crypto Kitties on Ethereum - and the primary reason why L2 solutions and ZK-rollups like Immutable X exist.

Now add the negative environmental impacts, due to the escalating power demands of proof-of-work blockchains, on top of all of that and we have the perfect narrative for why proof-of-stake is supposedly the future of blockchain.

The Problem With Proof-of-Stake

In order to understand the issue, we first need to look at value creation, the foundation of every business and our capitalist society. The foundation of every business is to create and deliver value in an efficient enough manner so that it will generate a profit after cost. In the broadest terms possible, value is created through work. In scientific terms, entropy is reduced by investing energy, turning something that's chaotic and useless into something that is more useful to humans. In simple terms, you have to spend time and/or money in order to make money.

This is essentially the concept behind every proof-of-work blockchain, such as Bitcoin.

Institutional investing works very differently. Institutional investors are usually large market actors such as banks, mutual funds, pensions, and insurance companies that pool together funds on behalf of others and invest those funds in a variety of different financial instruments and asset classes. Those businesses do create value like any other - however, their investors don't, they just give them money to turn it into more money. The more money an investor will give to these institutions to invest into ETFs, mutual funds, crypto tokens, or similar assets, the more they will get in return. In other terms, the richer those investors already are, the richer they will get, without doing any work or spending any money.

This is essentially the concept behind every proof-of-stake blockchain, such as Ethereum will be.

One could say that there is nothing wrong with this, that's just how our society works, deal with it. I think that's a valid position to take, if being honest about it. However, the entire crypto scene has become a huge echo chamber about how blockchain, DAOs, decentralization, a free metaverse, and other buzzwords are going to be our salvation and the future of humankind; finally a way out of end-stage capitalism! The reality is that everything that is currently happening in the blockchain space is leading us into the exact opposite direction, the tokenization of everything, everything having some kind of precisely measurable monetary value associated with it, essentially capitalism on steroids. In the world of NFTs and blockchain, at least as it is being steered right now, you will be even less relevant than you already are if you're not already rich. If this future happens as it is being envisioned, it'll be the most extreme divide between the wealthy and the poor that has ever existed in the history of humankind. If put into the terms of a free-to-play video game, in the long run, all that's going to be left are the whales and the gold farmers.

Proof-of-Work is Not a Long-Term Issue

The current impact of the energy needs of proof-of-work blockchains is undeniable, even more so in these most recent times of international turmoil and war. However, I believe the right approach is not to get rid of proof-of-work as a concept, but to see this as an opportunity and argument to radically increase investments into clean and renewable energy sources.

Significant advances have already been made in the field of fusion energy. In a recent milestone at the LLNL, published this summer, researchers recorded a net-positive energy yield of more than 1.3 megajoules during only a few nanoseconds. For reference, that's enough clean energy to power a few thousand homes for a year. This is what we need to double down on.

Bitcoin and the proof-of-work concept were conceived with the Kardashev scale of civilization in mind, originally proposed by Soviet astronomer Nikolai Kardashev in 1964. Kardashev wondered about civilization, which he defines by its capacity to access energy, to maintain itself and to integrate information from its environment. I encourage you to read more about his ideas and how contemporary physicists expanded on it.

In this context, and by looking at those premises, it becomes clear how those ideas relate to a proof-of-work blockchain and Bitcoin specifically:

• Access to energy; an ever increasing amount is required based on how proof-of-work creates an ever increasing complexity to solve. Over a period of time, this automatically accounts for radical breakthroughs in our ability to access energy.
• Maintaining itself; the concept of decentralization, there is no single controlling entity or group of entities.
• Integrating information from the environment; the concept of immutable information being publicly accumulated and stored on the blockchain.

All of the above is also one of the main reasons why Bitcoin has now become lot more like a naturally occurring commodity rather than something that's human-made and maintained, even though it factually is.

These are the same reasons why I believe that it's a huge mistake to switch Ethereum to a proof-of-stake blockchain. It's the antithesis to those concepts - access to energy becomes access to capital, maintaining itself becomes maintained through the people with the most money, because all crypto tokens have monetary value. Besides, there are already solutions that fix all the everyday issues this change is supposedly solving, namely L2 networks and ZK-rollups. It's basically an unnecessary band-aid for Ethereum to work around the energy issue, with potentially devastating results.

I do believe there is a perfectly valid and important place for more commercially oriented blockchain projects like BNB, FLOW, SOL, IMX, and way too many others to create an exhaustive list, especially when it comes to addressing the everyday practical needs of projects building on top of them, but nothing like those should be the foundation on which we build our digital future.

The right solution would be to fix the underlying issue, specifically the current energy scarcity, reliance on fossil fuels and other non-renewable energy sources that pollute our environment. That's a solution that would benefit all of humankind, all of us that are currently around as well as all future generations - not just the richest 1%.

I realize these are lofty, maybe even idealist thoughts. Then again, people should at least be honest about what their end-game is with proof-of-stake; it's about maintaining control and keeping our current societal order intact in the upcoming digital age, and a +1 at that.