GLYNAC Stimulates Mitochondrial Biogenesis

#1

In 70+ year-olds, mitochondrial biogenesis returns to levels comparable to those of young adults in their 20s. Simply amazing.

I. Executive Summary

GlyNAC (Glycine combined with N-Acetylcysteine) directly modulates the cellular hallmarks of human aging by correcting systemic, age-associated intracellular glutathione (GSH) deficiencies. Chronic intracellular GSH deficits underwrite elevated oxidative stress (OxS) and secondary mitochondrial decay, which ultimately compromise skeletal muscle strength, systemic metabolic kinetics, and vascular endothelial function in older populations. This double-blind randomized clinical trial (RCT) provides clear structural proof-of-concept for targeted precursor nutraceutical intervention. It validates that 16 weeks of GlyNAC supplementation robustly upregulates peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1Ī±)ā€”the master molecular orchestrator of mitochondrial biogenesis. This targeted up-regulation restores cellular transcription markers in septuagenarians to levels indistinguishable from healthy cohorts in their twenties.

The underlying trial randomized 24 older adults into parallel 16-week arms receiving either GlyNAC or an isonitrogenous alanine placebo, while utilizing 12 young adults as a baseline comparator. The specific dosage of 100 mg/kg/day for both glycine and N-acetylcysteine highlights a high-dose metabolic priming strategy rather than standard over-the-counter micro-dosing. Crucially, the study establishes that direct administration of pre-formed glutathione is biologically flawed due to the tight intracellular regulation needed to prevent systemic reductive stress. Instead, GlyNAC operates via a precursor loading mechanism, serving as a flexible substrate repository that empowers tissues to synthesize GSH on-demand according to precise localized metabolic requirements.

The clinical outcomes cross multiple translational domains: treated older adults experienced complete or near-complete reversals of cellular senescence markers, mitophagy blocks, genomic instability, and stem cell exhaustion. These structural improvements directly manifested as objective phenotypic upgrades, including enhanced muscle force generation, improved gait velocity, corrected systolic blood pressure, and decreased visceral adiposity. However, critical gaps remain; while PGC-1Ī± upregulation provides an excellent biomarker of active mitochondrial transcription, the immediate study lacks direct physiological measures of net ATP synthesis and functional electron transport chain capacity. Furthermore, long-term safety outside the 16-week window and exact pharmacodynamic optimization across heterogenous patient cohorts with varying baseline levels of oxidative damage remain undefined. Despite these gaps, GlyNAC moves anti-aging nutrition out of speculative, single-target pathways into a broad, multi-hallmark regulatory framework supported by human data receipts.

II. Insight Bullets

  1. Intracellular Glutathione Depletion: Biological aging induces a severe systemic deficit in intracellular glutathione (GSH) concentrations, primarily driven by a cellular synthesis bottleneck of precursor amino acids.
  2. Precursor Deficiencies as a Primary Driver: The down-regulation of endogenous GSH synthesis in older adults is directly tied to the inadequate availability of its raw materialsā€”glycine and cysteineā€”rather than a structural loss of synthesizing enzymes.
  3. Flaws of Direct Glutathione Delivery: Exogenous oral supplementation of pre-formed glutathione fails to safely optimize tissue redox balance because it bypasses the cellā€™s autonomous synthesis control mechanisms.
  4. The Hazard of Reductive Stress: Forcing high amounts of pre-formed glutathione into the body can disrupt the delicate intracellular redox equilibrium, shifting cells from oxidative stress into destructive reductive stress.
  5. The Precursor Substrate Repository: GlyNAC provides a balanced, on-demand substrate pool of glycine and cysteine, allowing individual organs to synthesize glutathione autonomously based on localized homeostatic needs.
  6. Master Regulation of Mitochondrial Biogenesis: 16 weeks of continuous GlyNAC supplementation upregulates PGC-1Ī±, the key transcriptional coactivator responsible for generating new mitochondria.
  7. Reversal of Transcriptional Senescence: Septuagenarians treated with GlyNAC achieved muscle PGC-1Ī± expression levels that were statistically indistinguishable from healthy control subjects in their early twenties.
  8. Placebo Ineffectiveness (Alanine Arm): Older adults randomized to the isonitrogenous alanine placebo exhibited no improvement in PGC-1Ī± or mitochondrial markers, confirming the effect is specific to the glycine-cysteine combination.
  9. Mitochondrial Fatty-Acid Oxidation (MFO) Recovery: Correcting intracellular glutathione concentrations directly restores impaired mitochondrial fuel-oxidation capacity, enabling efficient metabolic clearance of lipids.
  10. Suppression of Systemic Oxidative Stress: GlyNAC supplementation systematically drives down elevated circulating lipid peroxides and reactive oxygen species (ROS) back to youthful baselines.
  11. Ablation of Genotoxic and Genomic Damage: High redox control via GlyNAC limits the accumulation of double-strand DNA breaks and secondary chromosomal abnormalities common in senescent cells.
  12. Mitigation of Sarcopenic Decline: Restoring mitochondrial energy mechanics translates directly into improved skeletal muscle contractility and significant increases in absolute physical force generation.
  13. Phenotypic Speed Restoration: The clinical trial captured statistically significant increases in objective functional measures like gait speed and total distance covered in a 6-minute walk test.
  14. Correction of Visceral Adiposity: Enhanced mitochondrial fatty-acid oxidation induced by GlyNAC correlates with reductions in abdominal waist circumference, signifying an optimization of lipid distribution.
  15. Vascular Endothelial Rehabilitation: GlyNAC-mediated oxidative stress reductions directly enhance nitric oxide bioavailability, reversing age-associated endothelial stiffening.
  16. Systolic Blood Pressure Normalization: The structural restoration of endothelial compliance led to objective drops in resting systolic blood pressure among the aged treatment group.
  17. Amelioration of Insulin Resistance: Enhancing mitochondrial efficiency and reducing intracellular lipid stress directly normalized fasting insulin metrics and tissue insulin sensitivity.
  18. Resolution of Stem Cell and Senescence Hallmarks: The underlying randomized trial verified that GlyNAC repairs multiple abstract hallmarks of aging simultaneously, including cellular senescence, stem cell fatigue, and mitophagy defects.
  19. The High-Dose Prime Strategy: The human trial utilized an aggressive weight-dependent dosing protocol of 100 mg/kg/day for both individual amino acids, indicating that low-dose over-the-counter multi-vitamins are sub-therapeutic.
  20. Lack of Functional Kinetic Metrics: A critical baseline limitation noted by the video narrator is the reliance on proxy protein expression (PGC-1Ī±) rather than active, real-time measurements of dynamic mitochondrial oxygen consumption or net ATP production.
  21. The Post-Withdrawal Clearance Cascade: Prior open-label exploratory data reveals that stopping GlyNAC leads to a rapid decay of its health benefits, proving that continuous substrate availability is required to maintain youthful cellular mechanics.

IV. Actionable Protocol (Prioritized)

High Confidence Tier

Protocols backed by Level B evidence.

  1. GlyNAC Protocol for Reversing Age-Related Mitochondrial Decay:
  • Protocol: Supplement with a 1:1 ratio of pure Glycine and N-Acetylcysteine (NAC) at an aggressive, weight-dependent target dosage of 100 mg/kg/day for each compound (e.g., for a 70 kg individual, this equals 7.0 grams of Glycine and 7.0 grams of NAC daily). Divide into two daily doses to maximize plasma substrate availability and maintain continuous intracellular glutathione synthesis.
  • Evidence: Level B evidence from a 16-week placebo-controlled randomized clinical trial confirms that this specific high-dose regimen safely corrects intracellular glutathione deficiencies, upregulates muscle PGC-1Ī± expression to youthful standards, lowers systemic oxidative stress, improves endothelial compliance, reduces systolic blood pressure, and boosts objective physical markers such as gait speed and grip strength [Kumar et al., 2023].

Experimental Tier

Protocols backed by Level C/D evidence with high safety margins.

  1. Continuous Maintenance Scheduling:
  • Protocol: Maintain continuous daily supplementation of the GlyNAC stack rather than cyclical or pulsed scheduling, ensuring a steady state of precursor availability to sustain systemic cellular improvements.
  • Evidence: Level C/D evidence from open-label withdrawal phases establishes that the functional reversals of cellular aging hallmarks, metabolic optimization, and redox balancing rapidly decay upon stopping supplementation, returning cellular markers to their baseline damaged states within 12 weeks of cessation [Sekhar et al., 2021].

Red Flag Zone

Claims debunked or lacking adequate safety data.

  1. High-Dose Oral Pre-Formed Glutathione Supplementation:
  • Claim: Supplementing with massive over-the-counter doses of pre-formed or liposomal glutathione capsules to resolve age-associated oxidative damage and mitochondrial decline.
  • Verdict: Debunked / High Homeostatic Risk. Direct oral ingestion of pre-formed glutathione disrupts the bodyā€™s autonomous organ-specific feedback loops. Bypassing cellular regulation can over-correct oxidative stress and plunge the intracellular space into ā€œreductive stress,ā€ causing secondary protein misfolding and cell damage [Kumar et al., 2023]. Endogenous generation via precursor loading (GlyNAC) is the mandatory physiological standard.
  1. Sub-Therapeutic Micro-Dosing (Standard Over-the-Counter Multi-Vitamins):
  • Claim: Relying on common commercial longevity supplements or multivitamin blends containing tiny micro-gram or low milli-gram quantities of glycine and NAC to achieve anti-aging advantages.
  • Verdict: Ineffective. Human clinical efficacy requires high-gram metabolic saturation (100 mg/kg/day). Low-dose formulas provide insufficient substrate to overcome age-associated synthesis bottlenecks and do not alter PGC-1Ī± expression or mitochondrial biogenesis markers.
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Anyone takes NAC? Plus maybe Glycine? Extends mouse lifespan by 24%. Glycine extends mouse lifespan by 5% in ITP study
#2

I. Executive Summary

The core thesis focuses on the critical, underappreciated role of glycine as a rate-limiting metabolic substrate in the human aging process. While traditionally classified as a non-essential amino acid due to endogenous synthesis pathways, clinical and tracer data reveal a progressive, age-associated depletion in tissue and circulating glycine concentrations. This decline creates a severe metabolic bottleneck that impairs cellular maintenance, genomic integrity, and somatic longevity. The video filters out speculative noise to clarify that glycine is an indispensable building block for de novo purine nucleotide synthesis. Specifically, the entire glycine molecule is directly incorporated into the purine ring, providing critical carbon-4, carbon-5, and nitrogen-7 atoms. Furthermore, mitochondrial breakdown via the glycine cleavage system serves as a dominant secondary source for one-carbon units (5,10-methylenetetrahydrofolate and mitochondrially derived formate), which are absolutely required for cytosolic nucleotide synthesis and methyl group biogenesis.

Metabolically, an age-induced shortage of cellular glycine directly chokes de novo purine synthesis, causing downstream failures in efficient DNA replication, cellular division kinetics, and nuclear DNA double-strand repair pathways. This structural deficit accelerates genomic instability, triggers cellular senescence, and undermines tissue regeneration. Beyond nucleotide synthesis, glycine status dictates the rate of endogenous glutathione synthesis; when glycine levels fall, cells lose their primary line of antioxidant defense, leaving mitochondria highly vulnerable to unchecked reactive oxygen species (ROS) and secondary macromolecular damage. Pre-clinical evidence from the National Institute on Aging Interventions Testing Program (ITP) confirms that resolving this amino acid bottleneck via dietary glycine supplementation safely and significantly extends median and maximal lifespans in both male and female mammalian models. Translating this signal into a clinical framework demonstrates that targeted glycine restoration acts as a multi-hallmark geroprotective strategy. It relieves the internal metabolic constraints that accelerate cellular senescence, drives DNA repair efficiency, and restores systemic tissue homeostasis in the aging organism.

II. Insight Bullets

  1. The Glycine Depletion Paradigm: Mammalian aging is strongly characterized by a systemic, progressive down-regulation of tissue and circulating glycine concentrations.
  2. Associative to Causal Vector: The decline of systemic glycine isnā€™t merely a passive marker of advanced chronological age, but a metabolic bottleneck that impairs cellular repair.
  3. Primary Purine Backbone Substrate: Glycine serves as a mandatory precursor for de novo purine nucleotide synthesis, dictating the structural assembly of the purine ring.
  4. Direct Atomic Incorporation: A single intact glycine molecule is directly absorbed into the purine ring structure, contributing carbon-4, carbon-5, and nitrogen-7 atoms.
  5. Mitochondrial One-Carbon Provision: The mitochondrial glycine cleavage system processes the amino acid to yield 5,10-methylenetetrahydrofolate, a key source of cellular one-carbon units.
  6. Formate Flux to Cytosol: Mitochondrially derived formate from the breakdown of glycine enters the cytosol to act as a core building block for nucleotide and methionine biosynthesis.
  7. The DNA Replication Bottleneck: Deficient cellular glycine directly limits purine ring availability, slowing down DNA replication kinetics and cellular division.
  8. Impairment of Nuclear DNA Repair: Inadequate purine synthesis due to low glycine undermines the cellā€™s capacity to execute efficient double-strand DNA repair pathways.
  9. Upregulation of Genomic Instability: Unmitigated glycine shortfalls leave the genome vulnerable to accumulated mutations, accelerating the onset of cellular senescence.
  10. Pre-clinical Lifespan Validation: Rigorous, multi-site mammalian testing confirms that dietary glycine supplementation increases median and maximal lifespans in both sexes.
  11. The Metformin and Glycine Connection: Metforminā€™s clinical utility overlaps with one-carbon pathways, highlighting nucleotide synthesis as a shared target for life extension.
  12. Glutathione Rate-Limiting Barrier: Glycine is one of three structural amino acids required for glutathione (GSH) synthesis, and its loss leaves cells exposed to oxidative stress.
  13. Mitigation of Sarcopenic Muscle Decay: High-dose glycine availability protects aging muscle tissue by fueling protein synthesis and restoring functional mitochondrial biogenesis.
  14. One-Carbon Metabolism Remodeling: Glycine supplementation upregulates mitochondrial one-carbon metabolism enzymes, restoring youthful methylation markers.
  15. Endothelial Compliance Preservation: Reversing chronic glycine deficits increases local nitric oxide bioavailability, protecting aging blood vessels from stiffening.
  16. Methionine Cycle Counter-Balancing: Exogenous glycine acts as a metabolic sink that clears toxic excesses of methionine, effectively mimicking the longevity benefits of methionine restriction.
  17. NF-Kappa B Anti-Inflammatory Signal: Glycine suppresses hyperactive nuclear factor-kappa B signaling, down-regulating the production of chronic pro-inflammatory cytokines.
  18. Sleep Quality Optimization: Supplementing glycine enhances deep sleep architecture by acting as an inhibitory neurotransmitter and facilitating core temperature cooling.
  19. Flaws of Collagen-Only Sourcing: Relying purely on intact collagen molecules fails to optimally resolve deep cellular glycine bottlenecks due to complex digestive and metabolic limits.
  20. Rejection of Multi-Target Shotgunning: Therapeutic anti-aging strategies must use high-dose, single-variable precursor loads rather than speculative micro-dosed supplement blends.
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#3

GlyNAC, a combination of glycine and N-Acetylcysteine (NAC), has shown promising effects in improving various age-associated defects in older adults. Letā€™s explore how GlyNAC impacts kidney health and compare it to rapamycin:

  1. GlyNAC and Kidney Health:

    • Mitochondrial Function: GlyNAC optimizes mitochondrial function, which is essential for overall health. Healthy mitochondria play a crucial role in maintaining kidney function.
    • Reducing Oxidative Stress: GlyNAC increases intracellular levels of the antioxidant glutathione, which helps reduce oxidative stress. Lower oxidative stress can benefit kidney healthĀ¹Ā².
    • Metabolic Health: GlyNAC may improve metabolic health in conditions characterized by high oxidative stress, such as type 2 diabetes (T2D) and agingĀ¹.

  2. Rapamycin and Kidney Health:

    • Renal Protective Effects: Rapamycin (sirolimus) appears to be renal protective and can ameliorate renal interstitial inflammation and fibrosisāµ.
    • Mechanism: Rapamycin inhibits the mTOR pathway, which affects cell growth and immune response.
    • Nephrotoxicity: While rapamycin is generally safe for healthy kidneys, evidence suggests that it can be nephrotoxic in certain disease statesā“ā¶.

  3. Comparison:

    • GlyNAC vs. Rapamycin:
      • GlyNAC: Supports overall health, including kidney function, by reducing oxidative stress and improving metabolic parameters.
      • Rapamycin: Renal protective but can be nephrotoxic in specific contexts. It has immunosuppressive properties and affects the mTOR pathway.

  4. Conclusion:

    • Both GlyNAC and rapamycin have potential benefits, but their effects on kidney health differ. GlyNAC seems to enhance overall well-being, while rapamycinā€™s impact depends on the contextĀ¹ā“āµ.

Remember that individual responses to supplements and medications can vary, and consulting a healthcare provider is crucial for personalized advice.

Source: Conversation with Bing, 3/14/2024
(1) GlyNAC benefits, dosage, and side effects - Examine. GlyNAC benefits, dosage, and side effects.
(2) Guide To GlyNAC: Benefits, Dosage & Risks | Vitality Pro. https://vitality-pro.com/glynac/benefits-dosage-side-effects-gly/.
(3) Rapamycin and chronic kidney disease: beyond the inhibition of inflammation. https://www.kidney-international.org/article/S0085-2538(15)51426-9/pdf.
(4) Nephrotoxicity of rapamycin: an emerging problem in clinical medicine. Nephrotoxicity of rapamycin: an emerging problem in clinical medicine | Nephrology Dialysis Transplantation | Oxford Academic.
(5) Rapamycin Ameliorates Kidney Fibrosis by Inhibiting the ā€¦ - PLOS. Rapamycin Ameliorates Kidney Fibrosis by Inhibiting the Activation of mTOR Signaling in Interstitial Macrophages and Myofibroblasts.
(6) GlyNAC and Aging: Whatā€™s the Science Behind | HealthNews. https://healthnews.com/longevity/longevity-supplements/glynac-increase-longevity-science-behind/.
(7) The potential benefits of rapamycin on renal function, tolerance ā€¦ https://www.kidney-international.org/article/S0085-2538(15)54443-8/pdf.

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#4

Thanks for sharing, great comparison of NAC and Rapamycin. Consider the detox affect of NAC, if you take both of them, will you stop NAC the day when you take rapamycin?

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#5

Nac doesnā€™t detox, ir is necessary for the production of glutathione which protects the cell against free radicals when breaking down toxins. The breaking down of toxins will happen regardless of glutathione status

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#6

I read more about NAC and decided to take it only once per week, when not taking Rapamycin. A possibility of developing a lung cancer scared me. I take Glycine separately and more often with my collagen peptides on days with no Rapa. I also developed a habit of asking GPT-4 about contraindications for supplements that I combine. Itā€™s a nice tool to use. Trying to reduce the number of supplements per day :grinning:

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#7

Just to be clear, there is no strong evidence that typical supplemental NAC doses meaningfully increase lung cancer risk.

All of the studies I looked at were of mice. NAC did not cause lung cancer it only increased its growth. Many anti-oxidants like vitamin E also do this.
Too many anti-oxidants are not a good thing.

Some strains of lab mice are more prone to develop cancers.
High cancer susceptibility strains like AKR mice develop leukemia and lung tumors spontaneously.
ā€œFor example, 50 to 90% of aged mice die of cancer3ā€“5, while in humans this number is approximately 23%ā€ ā€œMechanisms of cancer resistance in long-lived mammals - PMCā€

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#8

More than six months on 7 grams/each component, every day, divided on three takes of GlyNAC. No probs so far. Blood works OK but a BIG ā€˜butā€™: you never get used to NACs terrible taste, mostly in the morning. A possible trick: dilute both in water some 1/2hour before taking it, seems to reduce bitterness somehow.

Now in a 2 weeks pause.

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#9

ā€œyou never get used to NACs terrible tasteā€

Why are you using powder? I use 1 gram tablets so of course there is no taste.

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#10

3x2,5 grams per day of both, glycine and NAC, with meals based on the famous study on glyNAC advantages for elder ones. I am 65.

I take NAC powder because otherwise the amount of pills or capsules I should have to swallow would be unpractical. Iā€™ve tried capsules but at the end the day my throat was claiming ā€˜half a moment, pleaseā€™. Three gulps a day is OK for me.

On the other hand, the unpleasant seconds of NACs bad taste go away in a moment when you drink a bit of water after. But, undoubtely, your tongue has to pay the toll if you want to get the benefits. In my case at least.

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#11

I also go with the 1 g NOW tablets to avid the taste of NAC. I take two in the morning and two at night.

I also get the NOW 600 mg capsule with Selenium and Mo as the price is cheaper for NAC than the tablets and you get the other two trace elements for free. I only take one of those per day otherwise itā€™s too much Selenium.

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#12

or put in a capsule, itā€™s actually sort of fun to do (be sure to buy the capsules separated, not assembled!)

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#13

i read some posts said NAC dull the effect of medicine, coffee, etc. Thatā€™s why i asked should i stop taking NAC on the day of rapamycin?

#14

Those posts are incorrect as I explained above

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#15

A new hint I am using at present to sweeten the somehow NACā€™s nasty experience: three sort dashes of liquid stevia make it way, way better.

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#16

Iā€™ve been taking alot of things for some years now. Rapamycin 15mg fortnightly for 3 years plus Acarbose, AAKG, Taurine, Creatine, Fisetin, a whole heap of other vitamins, supplements, etc.

Canā€™t say that Iā€™ve noticed much significant from any of them to be honest. Iā€™ve certainly lost body fat (down to 70cm waist from 74cm) and gained muscle (72kg from 68kg), so perhaps the Rapamycin has been having an effect. My blood work is certainly looking a bit better, but in terms of feeling the effects - has been pretty subtle.

Iā€™ve also been taking Glynac for a while now too, but only 1g of each a day or less.

However, 3-4 weeks ago after reviewing the papers again I decided to up my dose to that in the recent papers - which I calculated to be 9g NAC + 7g Glycine for my weight. Split it into 2 doses - morning & night. No noticeable side-effects.

Andā€¦ wow. I thought it was perhaps co-oincidence at first, but I now think its had a really big effect.

I used to train for triathlons when I was in my 20s. I remember my muscles never seemed to run out of energy - it was always my cardiovascular fitness that limited how hard I could push, never my muscles. If I was working just under my cardio limit I could keep going for ages - my muscles would never seem to run out of energy or hit the wall.

Iā€™m 54 now and one thing thatā€™s been super noticeable is its not my cardio fitness that limits me anymore, but my muscles. Itā€™s really hard to reach my maximum heart rate as my legs or arms simply hit the wall before I get there. They just seem to reach a hard limit and start to really burn. It only takes a few mins and theyā€™ve overloaded. I donā€™t remember that when I was younger.

But the last few weeks the change has been dramatic. I go for a run, with a few sprints in the middle. I start a sprint and then wait for the burn to start after a few 100m and my legs to hit the wall andā€¦ it doesnā€™t come - Iā€™m still sprinting and my legs are fine. Instead of 250m I can go 1.5km at my sprint pace. The burn never comes. Same with cycling - instead of maintaining an intense push for perhaps 500m max I can now go for 2-3 km and still no burn - just hitting my cardio limit.

What a great feeling! That feeling of almost unlimited energy again - my legs are once again happy to do what I ask of them instead of giving up early :-).

Perhaps this makes sense if Glynac is improving mitochondrial function?

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#17

I know that the amino acid glycine is produced very easily in the body, so it is not an essential amino acid. But NAC is not produced in the body, so I wonder if results like glyNac can be achieved by just taking NAC?

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#18

Cysteine (from NAC) and Glycine are both produced in adequate amounts by your body from your food. However, as you age, the amount your body effectively utilizes drops off at 30 and becomes a real problem at around 50 and continues to rapidly get worse. Thatā€™s why you need to supplement both Glycine and Cysteine (through NAC) at higher and higher levels as you get older.

The link below talks about taurine, glycine and cysteine deficiencies.

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#19

Your report is similar to my experience when I Started to take 10 gr of Taurine on empty stomach every morning, it was transformative experience.

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#20

What did you notice from taking 10g Taurine? Iā€™ve been taking 1g Taurine, but your comment suggests perhaps I should up that big time too.

Curiously the guidence on the Taurine I bought suggests just 60mg as the recommended daily doseā€¦