Stopping Ageing and Age-Related Degenerative Ailments by Balancing Methylation

Sly Nedic supplies a complete look into the method of methylation, its relationship with the ageing course of, and find out how to defend in opposition to hostile components

Methylation, also called one-carbon metabolism, is a biochemical course of that takes place repeatedly in each cell in our physique and includes the addition of a methyl group to a molecule. By persistently offering methyl teams with quite a few methyltransferase reactions through the ever present methyl donor, S-adenosyl methionine (SAMe), the method turns into susceptible to destabilization resulting in both hypo or hypermethylation.

Unbalanced methylation is a cornerstone of untimely ageing and a number of age-related degenerative ailments. Moreover, epigenetic phenomena and epigenetic vitamin, as a novelty intervention in modifying gene expression and subsequently altering ageing and age-related degenerative problems, are primarily DNA methylation pushed. Quite a few research undertaken on this subject show conclusive proof that has enabled physicians to make use of evolving intervention approaches for balancing methylation, a technique not extensively accepted by typical medication.

Methylation is concerned in a number of organic processes and several other important capabilities within the physique in an intricate method that can’t simply be recognizable when unbalanced. These processes are listed as follows:

Synthesis of DNA and RNA and biosynthesis of purine nucleotides

The method is impacted by persistent methyl donor deficiency, resembling Folate (Vitamin B9), resulting in DNA strand brakes, apoptosis, and carcinogenesis. By utilizing a delicate in vitro mannequin system (comprised of mouse prostate transgenic adenoma simulating a prostate most cancers) the outcomes have emphasised the importance of Folate restriction for genetic, epigenetic and phenotypic modifications1,2.

Gene expression and silencing

DNA methylation is among the well-known epigenetic mechanisms that instantly regulates gene expression and phenotypes. In wholesome cells, it ensures the right regulation of gene expression (with out altering DNA sequence) and steady gene silencing.

Methylation of DNA happens at so-called CpG websites (the place cytosine lies subsequent to guanine). The CpG websites within the areas close to the promoters of genes are generally known as CpG islands. Latest research have proven that DNA methylation of CpG islands, deacetylation of histone, and methylation of histone results in gene silencing. Beneath regular circumstances, the vast majority of CpG dinucleotides are methylated, however aberrations in gene expression attributable to epigenetic promoter hypermethylation of CpG islands can result in carcinogenesis (inappropriate silencing)3,4.

Metabolism of neurotransmitters

Metabolism of biogenic amine neurotransmitters (serotonin, epinephrine, norepinephrine, dopamine, and melatonin) is extremely depending on balanced methylation. COMT (Catechol-O-Methyl Transferase) is a methylation enzyme that repeatedly inactivates catecholamines. COMT transfers a methyl group from SAMe to the catechol group of the neurotransmitter that’s being processed, altering its chemical construction and properties, and clearing it from the system. Unbalanced methylation results in the buildup of the neurotransmitters primarily epinephrine and norepinephrine that can’t be sufficiently utilized throughout extended stress. Balanced methylation additionally supplies BH4 (tetrahydrobiopterin) wanted to generate neurotransmitters. BH4 delivers the co-factors crucial to show tryptophan and tyrosine into their respective neurotransmitters serotonin and dopamine5.

Metabolism of estrogen

COMT methylates catechol estrogens to the anti-cancer molecules of methoxy-estrogens. As the extent of catechol estrogens will increase, the extent of methoxy estrogen metabolites additionally will increase with COMT exercise. Conversely, with growing ranges of SAH (S-adenosylhomocysteine) that takes place in ‘clogged’ methylation, there’s a decreased manufacturing of protecting methoxy metabolites and an elevated amount of damaging catechol–estrogens that may oxidize into DNA damaging quinones and semiquinones. A well-documented examine outlines the hyperlinks between low COMT exercise, elevated homocysteine with low SAMe:SAH ratio, and an elevated danger of reproductive organ malignancy and breast most cancers6.

Immune system regulation

The differentiation of immune cells, significantly T-cells; boosting the killing exercise of cytotoxic T and NK cells; and Th2 cytokine regulation are all extremely depending on balanced DNA methylation. T-cells are required to assist management B-cells and stability TH1 and TH2 responses which are usually affected when in a state of hypomethylation7,8.

Manufacturing of phosphatidylcholine

The cell membrane has a phospholipid bilayer, and 50% of these phospholipids are phosphatidylcholine (PC), which is used as a constructing block for membrane construction, bile and the transportation of fat. Research level out that the CDP-choline pathway synthesized solely two or three main varieties of PC; whereas, the PEMT methylation pathway generates at the least eight main varieties of PC with vital effectivity. PEMT methylation pathway provides PC in case of dietary deficiency of choline. This course of is extremely depending on balanced methylation because it consumes three methyl teams to synthesize PC from phosphatidylethanolamine9,10.

Power manufacturing

The methylation pathway is critical for the synthesis of CoQ10, which, in flip, is essential for its perform in ATP manufacturing within the mitochondrial respiratory chain. Carnitine is one other nutrient concerned in mitochondrial power meeting; its synthesis begins with the methylation of the amino acid L-lysine by SAMe. Mitochondrial fatty acid oxidation is the first power supply for coronary heart and skeletal muscle. Carnitine is concerned within the transport of those fatty acids into the mitochondrial matrix11.

Biotransformation and antioxidant exercise

Methylation is required for the elimination of environmental toxins from the physique. This course of includes conjugating methyl teams to the toxins earlier than elimination and supporting the manufacturing of glutathione, taurine, sulfate, and cysteine. Inside direct conjugation, it detoxifies xenobiotics and carcinogens together with heavy metals, resembling mercury, lead and arsenic. Glutathione is a sulfated protein concerned in inflammatory management and discount reactions, catalyzed by glutathione S-transferase. It’s a major endogenous antioxidant produced by the cells, contributing reliably to the neutralization of free radicals and reactive oxygen species, in addition to sustaining exogenous antioxidants (vitamin C and E) of their decreased types.

Myelination of nerve cells

Nerve myelination is a course of depending on methylation, with analysis exhibiting a decreased quantity of S-adenosyl methionine within the cerebrovascular fluid in a person the place demyelination is current12.

Methylation is essential for early CNS improvement (neural tube defect attributable to maternal low folate consumption) histamine metabolism, ammonia clearing, pathology of autism and extra, that are associated to components aside from ageing and age-related ailments.

Methylation physiology

The first objective of the methylation cycle is to repeatedly present the common methyl donor, S-adenosylmethionine (for all mobile methyltransferase reactions), for the balanced functioning of the methionine cycle.

The methionine cycle is an intricate course of that includes the regeneration of methionine from homocysteine within the methionine synthase response through the vitamin B-12–dependent switch of a methyl group from 5-MTHF (5-methyltetrahydrofolate). Methionine types S-adenosylmethionine (SAMe) through methionine adenosyltransferase exercise. The elimination of the methyl group from SAMe to the completely different ‘methyl dependent molecules’ ends within the formation of S-adenosylhomocysteine (SAH). The SAH will get reversibly hydrolyzed to homocysteine and adenosine through SAH hydrolase (SAHH) exercise.

Homocysteine is then repeatedly used to regenerate methionine. This course of runs easily offered all methylation parts can be found (e.g. proteins and enzyme cofactors), there are not any genetic SNPs creating misbalance, environmental toxin interference, or greater demand for glutathione manufacturing.

The method of homocysteine being both re-methylated to methionine or irreversibly faraway from the methionine cycle to kind cysteine, glutathione, and taurine is a steady balancing act. Two basic issues of methionine cycle turnover blockage are the decreased synthesis of SAMe and diminished synthesis of glutathione as an antioxidant grasp (Determine 1).

Methylation and ageing

Quite a few research have concluded that a methylation deficit and unbalanced methylation may very well be a reason behind accelerated ageing (together with grey hair), heart problems, and untimely arteriosclerosis, diabetes, dementia, Alzheimer’s, Parkinson’s, neurotransmitter imbalances and psychiatric problems, persistent irritation, irregular immunity and autoimmunity, varied cancers, insomnia, first presentation of bronchial asthma in aged and chemical sensitivities, thyroid illness, and extra13–20.

A number of research have particularly validated that modifications in DNA methylation patterns are related to organic ageing and have an effect on human lifespan. Research discovered that DNA methylation modifications attributable to an epigenetic drift are basic to the ageing course of. Each hypermethylation and hypomethylation have been related to the progressive accumulation of epigenetic harm attributable to environmental components. This phenomenon demonstrates that the epigenetic similarities between younger people are misplaced over time resulting in completely different phenotypic expression and ageing-associated DNA methylation modifications within the aged (research on an identical twins). Moreover, with ageing, methylation capability decreases by 20–30% even with none obvious illness21,22.

Unbalanced methylation

Each hypermethylation or hypomethylation can have an effect on an individual’s well being. International DNA hypomethylation is a possible consider lowering genome stability and growing chromosomal aberrations. Particular DNA hypomethylation might be seen in lots of ailments, resembling autoimmunity. Website-specific hypermethylation of promoter areas is present in each ageing and tumour genesis.

Components contributing to
unbalanced methylation
Single nucleotide polymorphism (SNPs)

A very powerful genes governing methylation are MTHFR A1298C and C677T, COMT V158M and H62H, AHCY, MTR, MTRR, GST, MAO-A R297R, NOS D298E, SHMT, PEMT, VDR/Taq and VDR/ Fokl, and CBS. The significance of MTHFR  in domineering methylation has been supported by quite a few research23,24.

The primary position of MTHFR is to generate 5-methyltetrahydrofolate, which is then utilized by MTR (methionine synthase) to re-methylate homocysteine again into methionine for the renewal of SAMe. When MTHFR SNPs are current, homocysteine can’t be re-methylated, SAMe decreases and the methyl cycle subsequently failS inflicting untimely ageing and age-related neurodegenerative problems (Parkinson’s, arteriosclerosis, ischemic stroke, cancers, diabetes) normally with a excessive homocysteine degree25,26.

MTHFR C677T constructive people have bother utilizing dietary folic acid to re-methylate homocysteine as they can not effectively convert dietary folic acid into the 5-MTHF kind.

The presence of assorted methylation SNPs concomitantly has the cumulative impact of inflicting well being issues. For instance, the presence of MTRR /66/AG/GG and /H595Y/ will increase the chance of breast, prostate, and pancreatic most cancers, in addition to gastric most cancers in Asian populations alongside weight problems. Nonetheless, if current with MTHFR C677T, CBS, and MTR, MTRR can enhance the chance of different unbalanced methylation well being dangers attributable to a collective impact27.

Describing all SNPs is past the aim of this text, however understanding that their presence will impression methylation, particularly along with environmental components, is important in figuring out methylation functionality.

Dietary components

Dietary components required for methylation can have an effect on the methylation fee and consequence if poor. These are methionine, choline, glycine, glutamine, cysteine, betaine, phosphatidylcholine, and nutritional vitamins in addition to cofactors, resembling riboflavin, pyridoxalphosphate, B12, folate, niacin, zinc, magnesium, molybdenum, vitamin C, and vitamin D. It’s well-known how folic acid fortification within the USA and routine prescription of folic acid in pregnant ladies worldwide decreased neural tube defect by manipulating the methylation dietary enter. Through the years, folic acid fortification has turn into extreme, and it now adversely impacts methylation because of the excessive ranges of folic acid present in meals. Dietary folate from leafy greens will get hydrolyzed within the intestines as a way to enter the folate cycle as THF (tetrahydrofolate). Folic acid, in artificial kind, alternatively, must be decreased within the liver twice by the a lot slower DHFR enzyme earlier than it may enter the folate cycle as THF (Determine 2). Extra importantly, non-metabolised artificial folic acid blocks DHFR, which is required for its discount but in addition prevents MTHFR exercise (some of the essential enzymes for the SAMe manufacturing.) Including 5-MTHF as a substitute of artificial folic acid can overcome all of the above-related blockages, with research demonstrating that the folate standing undeniably improved after such intervention28,29.

Nonetheless, including methyl donors will not be at all times a straightforward and easy activity as methylation dynamic will depend on different members and interplays. We typically witness methyl donors over-sensitivity after supplying 5-MTHF or SAMe particularly in people affected by co‑existent irritation, excessive free radical formation and stress (‘clogged’ methylation).

Many co-factors essential for balanced methylation can not merely be added on the belief that their impact will trigger elevated methylation. For instance, riboflavin that’s basic for MTHFR exercise might be affected by an under-active thyroid, and its impression can then be compromised. Merely including riboflavin with out checking thyroid perform will end in a attainable failure to stability methylation. Due to this fact, an integrative method whereas understanding the interplay between all methylation members is essential. Equally, including sure co-factors after comprehensively investigating methylation can create vital rapid enchancment in some sufferers. For instance, including molybdenum and ceasing dairy product ingestion (containing xanthine oxidase, which makes use of up molybdenum) in sufferers with excessive sulfite, instantly improved signs.

Environmental toxicity

Environmental toxicity can have an effect on DNA methylation (epigenetic impact) and metabolic methylation, predominantly through the use of methyl donors for cleansing processes (Determine 3). A few of these toxins can block particular methylation enzymes (mycotoxins stopping glutathione manufacturing from cysteine) diminishing the worldwide methylation course of. Numerous research have confirmed the hostile impact of heavy metals, resembling mercury, cadmium, arsenic, and lead in addition to the impact of persistent natural pollution, resembling phthalates, bisphenol A, benzene jet gas, mould, and pesticides30. A number of epigenetic mechanisms, resembling DNA methylation, histone modifications, and microRNA expression can change genome capabilities when uncovered to environmental toxins. For instance, smoking has pro-ageing results by inducing DNA methylation modifications to genes concerned in age-related ailments, resembling heart problems and most cancers. Latest proof means that arsenic elevated the toxicity of particular methylated intermediate metabolites, and that cadmium publicity has been related to hypermethylation-dependent silencing of DNA restore31. In depth investigation has proven that plastics, resembling bisphenol A (BPA) and phthalates which are extensively utilized in day by day merchandise negatively have an effect on human well being. The epigenetic impression of BPA and phthalates (hypomethylation) was demonstrated in yellow mice and was prevented by maternal dietary supplementation with a methyl donor like folic acid (Determine 4)32.

Methylation disruptors

A side not usually thought-about in typical medication that considerably impacts methylation is the impression of treatment. Their use is accompanied by substantial ignorance, maybe serving to with some issues however blocking methylation within the course of. It’s nicely documented how methotrexate impacts methylation by inhibiting DHFR (folate metabolism) and affecting B12 malabsorption (GI toxicity, hepatotoxicity and alopecia in MTHFR constructive sufferers)33. Many different medicine intervene with folate metabolism: carbamazepine and phenytoin are folate antagonists; antimalarial medicine, TMP-sulfamethoxazole, triamterene, and sulfasalazine are DHFR inhibitors; and oral contraception enhance folate necessities. Antacids, PPI, and cholestyramine alter B12 absorption that’s crucial for methionine recycling, and nitrous oxide inhibits methionine synthase and might be very harmful in folks with MTHFR SNP that have already got compromised methylation. Niacin and theophylline restrict pyridoxal kinase that prompts vitamin B6 crucial for methylation. Niacin additionally depletes SAMe in a fashion much like alcohol, however typically this may be useful; for instance, in circumstances of oversensitivity with methyl donors, the quickest approach of lowering this situation can be through using excessive doses of niacin.

Inner methylation interaction: SAMe competitors and metabolic priorities

Methylation is an exceptionally advanced course of with an inside interaction, the place aggressive wants for SAMe, environmental components, present well being state, and methylation ‘gamers’ repeatedly impression the method. Understanding methylation dynamics is subsequently important when making an attempt to stability methylation.

The inner interaction refers to particular interactions that exist throughout the methylation course of and these at all times comply with the identical rule.

Excessive SAH (S–Adenosylhomocysteine) that get created when SAMe is spend as a methyl donor has a damaging impression on COMT (Catechol-O-Methyltransferase). This assumes impaired Catecholamine metabolism results in overstimulation of adrenoreceptor mediated physiological responses in CNS and CVS. It additionally damages vascular endothelial cells and catechol-containing neurons by the manufacturing of extreme semiquinones. An identical impression happens in estrogen metabolism the place a excessive formation of semiquinones and DNA damaging quinones enhance the chance of breast most cancers34. SAH construct up additionally inhibits SAMe dependant DNA methyltransferases (DNMTs) resulting in accelerated ageing and malignancies whereas contributing to a number of degenerative ailments, resembling Alzheimer’s35. It’s clear that a low SAMe:SAH ratio is undesirable when assessing methylation capability.

Extreme SAMe inhibits MTHFR and slows down methylation, which results in different damaging penalties. Extreme homocysteine inhibits the enzyme that hydrolyzes SAH to homocysteine defending it from an extra enhance in homocysteine but in addition growing SAH construct up36.

SAMe competitors is an ongoing course of that’s distinctive to every particular person and repeatedly adapts relying on rapid calls for. Examples of those calls for are: environmental toxicity, excessive catecholamine requirement throughout stress, estrogen dominant states, sure medicines, excessive histamine clearance demand but in addition elevated want for power manufacturing, and phosphatidylcholine that makes use of extra SAMe molecule then others. Balancing methylation is the one approach to maintain these necessities happy. Often including or eradicating a few of these burdens can spare SAMe and be sure that it’s used for important capabilities.

Methylation dynamics generally adapts and modifies to the physique’s ongoing necessities and metabolic priorities. Extreme oxidative harm, irritation, bodily and psychological stress, intestine and microbiome points, insulin resistance usually have an effect on methylation stability. Irritation distresses methylation through inflammation-signalling molecules that intervene with DNA methylation and, not directly, by altering insulin signalling and growing oxidative stress that use homocysteine by way of transsulfuration, quite than recycling it again for SAMe manufacturing. It’s a problem to stability methylation under-activation and up-regulation of NFKb and excessive ROS manufacturing as bodily ‘perception’ focuses methylation in the direction of overcoming it. It also needs to be a precedence for a doctor to make clear this earlier than making an attempt to stability methylation37.

Methylation evaluation

From the above dialogue, we are able to assume that assessing methylation requires an integrative and holistic analysis of the physique capabilities that may doubtlessly have an effect on methylation. Moreover, there is no such thing as a typical marker for evaluating unbalanced methylation, which makes the evaluation much more difficult. There are a number of exams that may be carried out to estimate methylation capability, resembling homocysteine degree; SAMe:SAH ratio; serum folate and nutritional vitamins B6, B12, and B2; natural acids, evaluating irritation ranges, oxidative stress, adrenal and insulin perform, estrogen degree, thyroid exercise, heavy steel intoxication, intestine and microbiome points, use of treatment, and alcohol and environmental toxicity, are all important in assessing methylation.

Symptom questionnaires might help determine issues in methylation nicely earlier than unbalanced methylation results in obvious illness. Methylation SNPs that govern susceptibilities are important to find as a way to modify methylation issues previous to illness or ageing setting-in.

Quite a few research have demonstrated the position of homocysteine in ageing and age-related ailments. There’s a vital affiliation between excessive homocysteine and heart problems, together with arteriosclerosis, coronary heart assaults, and cerebrovascular insult. It’s supposed that hyperhomocysteinemia causes endothelial cell harm and a discount of blood vessel plasticity. This course of is mediated by a number of mechanisms, resembling oxidative stress, inhibition of endothelial nitric oxide (eNOS), NFkb activation, and irritation.

Moreover, there was a attainable suggestion that hyperhomocysteinemia has a job within the pathophysiology of CNS neurodegenerative problems. A number of research confirmed that homocysteine might set off neuronal harm through oxidative stress, stimulation of irritation, DNA harm and activation of pro-apoptotic components. These could also be related to modifications in psychological well being resembling dementia, Alzheimer’s, and Parkinson’s illness and despair. There are indications that hyperhomocysteinemia might be chargeable for a worldwide DNA hypomethylation. Low homocysteine can be a pathological signal like in CBS up-regulation that’s usually seen in fibromyalgia and chemical sensitivities.  Homocysteine is among the markers of methylation that has been accepted by typical medication and is extensively used. Nonetheless, for improved analysis of methylation stability, SAMe:SAH ratio is advisable because it defines the methylation potential of the cell (Determine 5)38–42.

Methylation balancing interventions

The main problem of the balancing act is to handle the methylation act with out inducing hypo or hypermethylation as these are dangerous to well being. Step one with out making an attempt so as to add, right or manipulate any a part of methylation is to clear underlying issues. The clearing course of includes all interventions to take away something that’s not considerably supporting methylation (however quite blocking it), resembling irritation, oxidative stress, environmental toxicity, heavy metals, mycotoxins and stress, which is commonly ample to rebalance methylation.

Earlier than making an attempt so as to add methyl donors, evaluation of signs of unbalanced methylation and co-factors deficiencies must be carried out. Low zinc or magnesium are frequent findings in addition to the low exercise of riboflavin in such a prevalent hypothyroid state. These corrections come with out danger of inducing hyper or hypomethylation.

Use of methyl donors particularly 5-MTHF has turn into very fashionable amongst integrative medication physicians, particularly in MTHFR constructive people. Important enhancements have been noticed in transmethylation metabolites and glutathione redox standing after remedy with methylcobalamin and folinic acid in some kids with autism. Many research urged that folate supplementation could also be essential for methylation upkeep in people with MTHFR polymorphisms. Novel experiments researching maternal methyl donor supplementation in utero demonstrated the impression of early vitamin in influencing the epigenome. Utilizing folate and B12 in delicate cognitive decline sufferers with excessive homocysteine confirmed an enchancment in comparison with people with regular homocysteine. Previously decade, conflicting proof has emerged suggesting that excessively supplementing methyl donors particularly 5-MTHF can have an hostile impact on DNA methylation (e.g., DNA hypermethylation) and its impression is extra sophisticated than beforehand understood43–45. Nonetheless, supplementing folate and different methylation vitamins from entire meals have by no means been proven in research to hurt DNA methylation; actually, it demonstrated the identical impact on reducing homocysteine ranges as 5-MTHFR and had a constructive impact on DNA methylation. Methylation weight-reduction plan is a novelty method in safely modifying and balancing methylation in line with a genetic and scientific evaluation of methylation47. In a simplified portrayal, a methylation weight-reduction plan ought to embrace meals that’s toxin, hormone, antibiotic, GMO and heavy metals free. Weight-reduction plan must be wealthy in plant-based parts ideally ‘rainbow-colored’ that’s enhanced with deferent phytonutrients and cruciferous greens, ample protein consumption and fats consumption (fish, olive oil, avocado, and so forth.)46,47.

Along with weight-reduction plan, way of life interventions resembling bodily exercise, caloric restriction, and excessive antioxidant consumption might counteract DNA methylation modifications contributing to ageing48–51.

One other protected method can be through an intervention to spare and thereby make out there SAMe to donate ample methyl teams; for instance, by including phosphatidylcholine.

As epigenetic applied sciences and nutri-epigenetics proceed to emerge, incorporating vitamin and DNA methylation turns into important in creating epigenetically- centered therapeutic and preventative methods in combating ageing. A number of research demonstrated an epigenetic impact of particular vitamins and bioactive meals parts on the regulation of DNA methylation through SAMe and instantly on DNA methyltransferases expression. These bioactive meals parts, resembling EGCG, resveratrol, curcumin, and isoflavone genistein at the moment are acknowledged as methylation balancing components and can be utilized in stopping ageing and age-related degenerative ailments.  For instance, curcumin-mediated DNA methylation modifications are acknowledged as most cancers chemo-prevention (colon most cancers research), and EGCG demonstrated in research sure hypermethylated genes in most cancers and ageing underwent re-expression underneath its affect48–50.

Conclusion

Methylation is a posh course of influenced by multifactorial inside and exterior components that require an in-depth and encompassing holistic evaluation. Just by including methylation vitamins, co-factors and donors is not going to essentially positively drive methylation as anticipated and should bear hypermethylation, for instance. The final word objective is to realize balanced methylation which is attainable by going again to fundamentals:  through using methylation supporting weight-reduction plan and way of life interventions. And certainly epigenetic clock evaluation on weight-reduction plan and way of life components has confirmed that our way of life influences our epigenetic age51.

Acknowledgements

  Declaration of curiosity None

  Opening picture © Christoph Bock, Max Planck Institute for Informatics

Figures 1 © Sly Nedic, 2  Tailored from Fan BJ, Chen T, Grosskreutz C et al. Lack of affiliation of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma. Molecular Imaginative and prescient 2008; 14:2484-249; Three Tailored from Baccarelli A, Bollati V. Epigenetics and environmental chemical substances. Curr Opin Pediatr. 2009; 21(2):243-51; Four Tailored from Singh S, Shoei-Lung Li S. Epigenetic Results of Environmental Chemical substances Bisphenol A and Phthalates. Int J Mol Sci. 2012; 13(8): 10143–10153; 5 Sly Nedic

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