Anti-Age Your Brain – The Glutathione Breakthrough

Keep Oxidants Down

Your brain has 400 miles of blood vessels. Keeping oxidants down is perhaps the single most important thing you can do for vascular health. Vascular dementia, for example, is strongly associated with oxidation – antioxidantAntioxidants are substances that protect cells within the body from damage caused by free radicals. They help to strengthen the body’s ability to fight infection… intake from fruit and vegetables on the one side and smoking and pollution on the other.

Those in the top quarter of Total Antioxidant Capacity (TAC) in their diet have halve the risk, in study on 2,716 people over age 60.^[i]

Critical Antioxidants

Critical antioxidants such as vitamin CWhat it does: Strengthens immune system – fights infections. Makes collagen, keeping bones, skin and joints firm and strong. Antioxidant, detoxifying pollutants and protecting against… and vitamin EWhat it does: Acts as an antioxidant, protecting cells from damage, including against cancer. Helps body use oxygen, preventing blood clots, thrombosis, atherosclerosis. Improves wound…, if supplemented together, reduced the risk of developing Alzheimer’s by as much as two-thirds. Taking either cut risk by a quarter in a study of 4,740 elderly residents of Cache County, Utah .[ii] A study of all studies to date show, that ‘either a high vitamin E or C intake showed a trend of attenuating risk by about 26 per cent’ according to China’s leading prevention expert Professor Jin Tai Yu of Fudan University in Shanghai, making these nutrients ‘grade 1’ top level prevention factors.[iii]

Vitamin C, which is water based and protects you against smoke and pollution, and vitamin E, which is fatThere are many different types of fats; polyunsaturated, monounsaturated, hydrogenated, saturated and trans fat. The body requires good fats (polyunsaturated and monounsaturated) in order to… based and protects you from burnt and fried fats, including sunburn, are in the bloodstream outside of cells. Inside cells, especially brain cells, is the most potent antioxidant of all – glutathione.

Glutathione is the Master Intracellular Antioxidant

Nutritionists have been measuring red cell glutathione (GSH) for decades as an indicator of a person’s antioxidant capacity. GSH is the most important antioxidant and free radical scavenger that is found to be decreased in the brains of people with a wide range of mental and neurological illnesses from schizophrenia[iv] to dementia[v] ^[vi].

The problem with just measuring glutathione is, however, two fold. Firstly, since it so rapidly oxidises it has to be immediately ‘fixed’ to avoid any degradation to its oxidised form GSSG. It is therefore usually dependent on going to a lab who draw the blood and must immediately test it or fix it to limit its oxidation. In reality, the reliability of glutathione measurements, unless done under strictly controlled conditions, may be questionable due to its rapid oxidation once blood is taken.

The Glutathione Index (GSH/GSSG) is the best measure of antioxidant status

Also, it is the amount of ‘spent’ or oxidised glutathione (GSSG) that reflects to extent of oxidative stress a person is under. Think of glutathione as the water in the fire engine. It gets rapidly used up keeping your brain protected. The ‘spent’ or oxidised glutathione (GSSG), much like steam, then has to be cooled to reload the fire engine. This recycling is done by vitamin C and an enzyme called Glutathione Reductase (GR), returning Glutathione back to its fully loaded ‘reduced’ form. Another enzyme, Glutathione Peroxidase (GP), is involved. GR is riboflavin (vitamin B2), dependent and GP is seleniumWhat it does: Antioxidant properties help to protect against free radicals and carcinogens, reduces inflammation, stimulates immune system to fight infections, promotes a healthy heart,… dependent.

Dr Konrad Kowalski, Food for the Brain’s analytic chemist, explains: “Reductions in GR enzyme levels in patients with dementia are well established. GR levels alone are therefore a good biomarker of dementia. But the mere presence of the enzyme does not guarantee its high activity. GR needs to consume NADP molecules to function properly.  As shown by Irene Martinez de Toda et al 2019 data, patients with dementia have a reduction in both the enzymes (GR and GP) that recycle glutathione.  Thus, in general it can be said that the glutathione metabolismMetabolism is a term that is used to describe the chemical reactions that take place within the body’s cells. The body gets the energy it… (recycling) loop in those with dementia ‘spins’ much slower than in healthy patients.

“The advantage of our measurement of the Glutathione Index (GSH/GSSG) is therefore that it shows changes in GR activity not only due to higher/lower GR gene activity but also due to the absence of the reaction cofactor NADP.

“As a result, dementia patients have a lower potential to dynamically fight free radicalsFree radicals are molecules produced when the body breaks down food or by environmental exposure to things like cigarette smoke, pollution and radiation. Free radicals… and will have a worse GSH/GSSG, which we call the Glutathione Index.[vii] The worse the ratio the worse a person’s cognitive function is likely to be. It’s a bit like having a direct measure of how fast your brain is ageing. Patients with dementia have a reduction in glutathione and its ability to be recycled.^[viii] This ratio, the Glutathione Index, is a biomarker for many diseases, including both type 1 and 2 diabetes, liver cirrhosis, multiple sclerosis and Alzheimer’s disease.” says Dr Konrad Kowalski, the analytic chemist in the brain team who has developed this test for foodforthebrain.org. “It’s too early to know the perfect number but it is looking like a Glutathione Index of 500 means your brain can roll with the punches, while below 200 a person definitely needs to be both changing their diet and supplementing antioxidants. Having a way to measure brain ageing with a home test kit from a pin prick of blood, means we can realistically see what the impact of specific diet changes and antioxidant supplements might be.”

Testing Challenges

One of the biggest challenges in developing the Glutathione Index, which is a home test kit involving a pin prick of blood dripped onto a dry blood spot card, is that the conventional DBS cards didn’t provide enough stability for the rapidly oxidising GSH. So we developed a method that instantly ‘fixes’ the sample for a guaranteed 12 week stability from taking the sample.

The red arrows indicate reduced or increased activity in dementia patients

Food for the Brain Tests

At foodforthebrain.org we want people to both measure their Glutathione Index and complete our validated Cognitive Function Test and the follow-on Dementia Risk Index questionnaire, which calculates an ‘antioxidant’ domain score, to track these against the person’s blood level of Glutathione Index. This will help us establish what an optimal level is. This means those boundaries, which we show in colours from green(good), yellow(OK), orange (not good), red (bad) will evolve and become more accurate thanks to you and people like you. This is unique and vital research funded by the people – Citizen Scientists.

How Glutathione and vitamin C recycle each other

Vitamin C helps ‘reload’ glutathione and glutathione helps reload vitamin C as you’ll see in the figures below. This glutathione-vitamin C cycle is one of the hottest discoveries in anti-ageing science. You’ll see that NADPH, derived from niacin (vitamin B3) and its cousin NAD are involved. Co-enzyme Q10 it is reduced form ubiquinol is also involved, although not shown in this diagram, and low levels are found in those with Alzheimer’s.[ix]

Raising glutathione – the role of NAC

Nutritional therapists have been measuring red cell glutathione and supplementing glutathione or its precursor N-Acetyl-Cysteine (NAC) for decades. However oral GSH supplementation has poor bioavailability[x] largely because it is so rapidly oxidised to GSSG as it disarms free radicals. N-Acetyl Cysteine (NAC), a precursor of glutathione, is therefore often used instead and has been shown to successfully raise plasma glutathione levels, for example, in those with schizophrenia.[xi] Anthocyandins also recycle glutathione thus sparing it if supplemented together.[xii]

NAC has plenty of evidence to support its use as a promoter of glutathione and mental health, thus reducing the brain’s oxidative stress. The latest 2022 review states: “N-acetyl-L-cysteine (NAC) is a compound of increasing interest in the treatment of psychiatric disorders. Primarily through its antioxidant, anti-inflammatory, and glutamate modulation activity, NAC has been investigated in the treatment of neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, anxiety disorders, obsessive compulsive-related disorders, substance-use disorders, neurocognitive disorders, and chronic pain. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders.”[xiii] For example a large RCT of 140 participants observed significant improvements on global symptomatology, and general and negative symptoms of schizophrenia in the NAC supplementation (2 g/d; in addition to anti-psychotic medication) group in comparison to the placebo group over a 24 week period.[xiv]

According to Dr Chris Palmer, assistant professor at Harvard Medical School, “Glutathione (GSH), the brain’s primary antioxidant, plays a crucial role in maintaining redox balance. Magnetic resonance studies studies have provided mixed results regarding GSH levels in schizophrenia patients, with some studies indicating decreased levels in chronic schizophrenia, while others found no significant differences. However, these inconsistencies may be due to variations in disease chronicity, age, and symptom severity among study participants. The findings from these studies suggest several potential therapeutic targets for schizophrenia. Addressing mitochondrial dysfunction, redox imbalance, and impaired energy metabolism could lead to more effective treatments. For instance, N-acetylcysteine (NAC), a precursor to GSH, has shown promise in increasing brain GSH levels and improving symptoms in first episode psychosis patients.”

NAC is so medically effective that it has been classified a medicine, hence not a food, and is no longer available over the counter in the US.

Next Steps

Foodforthebrain.org have a Glutathione Index test which is also part of their 5-in-1 DRIfT test also measuring HomocysteineHomocysteine is an amino acid found in the blood. Elevated levels of homocysteine have been associated with narrowing and hardening of the arteries, an increased…, HbA1c, vitamin DWhat it does: Helps maintain strong and healthy bones by retaining calcium. Deficiency Signs: Joint pain or stiffness, backache, tooth decay, muscle cramps, hair loss…. and Omega-3 Index.

To take part in their research visit foodforthebrain.org/antiage

HOLFORDirect supply a 7 nutrient anti-oxidant supplement Age Antioxidant which contains Glutathione and Vitamin E, designed to be taken with ImmuneC.

References

[i] Peng, M., et al. Dietary Total Antioxidant Capacity and Cognitive Function in Older Adults. J Nutr Health Aging (2023).

[ii] Basambombo LL, Carmichael PH, Côté S, Laurin D. Use of Vitamin E and C Supplements for the Prevention of Cognitive Decline. Ann Pharmacother. 2017 Feb;51(2):118-124. doi: 10.1177/1060028016673072. Epub 2016 Oct 5. PMID: 27708183.

[iii] Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-1209. doi: 10.1136/jnnp-2019-321913. Epub 2020 Jul 20. PMID: 32690803; PMCID: PMC7569385.

[iv] Yao JK, Leonard S, Reddy R: Altered glutathione redox state in schizophrenia. Dis Markers 2006, 22(1):83–93 ; see also Gawryluk JW, Wang J-F, Andreazza AC, Shao L, Young LT: Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 2011, 14(01):123–130.

[v] Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM, Moreira WL, Loureiro AP, de Souza-Talarico JN, Smid J, Porto CS, Bottino CM, Nitrini R, Barros SB, Camarini R, Marcourakis T. Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2011;26(1):59-68. doi: 10.3233/JAD-2011-110284. PMID: 21593563

[vi] Park SA, Byeon G, Jhoo JH, Kim HC, Lim MN, Jang JW, Bae JB, Han JW, Kim TH, Kwak KP, Kim BJ, Kim SG, Kim JL, Moon SW, Park JH, Ryu SH, Youn JC, Lee DW, Lee SB, Lee JJ, Lee DY, Kim KW. A Preliminary Study on the Potential Protective Role of the Antioxidative Stress Markers of Cognitive Impairment: Glutathione and Glutathione Reductase. Clin Psychopharmacol Neurosci. 2023 Nov 30;21(4):758-768. doi: 10.9758/cpn.23.1053. Epub 2023 Jul 14. PMID: 37859449; PMCID: PMC10591176.

[vii] Park SA, Byeon G, Jhoo JH, Kim HC, Lim MN, Jang JW, Bae JB, Han JW, Kim TH, Kwak KP, Kim BJ, Kim SG, Kim JL, Moon SW, Park JH, Ryu SH, Youn JC, Lee DW, Lee SB, Lee JJ, Lee DY, Kim KW. A Preliminary Study on the Potential Protective Role of the Antioxidative Stress Markers of Cognitive Impairment: Glutathione and Glutathione Reductase. Clin Psychopharmacol Neurosci. 2023 Nov 30;21(4):758-768. doi: 10.9758/cpn.23.1053. Epub 2023 Jul 14. PMID: 37859449; PMCID: PMC10591176.

[viii] Martínez de Toda I, Miguélez L, Vida C, Carro E, De la Fuente M. Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease. J Alzheimers Dis. 2019;71(1):153-163. doi: 10.3233/JAD-190198. PMID: 31356205.

[ix] J. Frontiñán-Rubio et al. Molecular and Cellular Neuroscience 92 (2018)

[x]  Witschi A, Reddy S, Stofer B, Lauterburg B: The systemic availability of oral glutathione. Eur J Clin Pharmacol 1992, 43(6):667–669.

[xi] Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, Bovet P, Bush AI, Conus P, Copolov D, Fornari E, Meuli R, Solida A, Vianin P, Cuénod M, Buclin T, Do KQ: Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 2008, 33(9):2187–2199.

[xii] Ohlenschlager G,Treusch G, patent number: 5925620 International Classification A61K 3800 for synergistic action of anthocyanidins and glutathione

[xiii] Bradlow RCJ, Berk M, Kalivas PW, Back SE, Kanaan RA. The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders. CNS Drugs. 2022 May;36(5):451-482. doi: 10.1007/s40263-022-00907-3. Epub 2022 Mar 22. Erratum in: CNS Drugs. 2022 Apr 28;: PMID: 35316513; PMCID: PMC9095537.

[xiv] Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Busha AI: N- acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008, 64(5):361–368.