Aging is associated with global DNA hypomethylation and DNA hypermethylation of CpG regions

Aging as an Epigenetic Phenomenon

Vasily V Ashapkin  1 Lyudmila I Kutueva  1 Boris F Vanyushin  1 Affiliations

Abstract

Introduction: Hypermethylation of genes associated with promoter CpG islands, and hypomethylation of CpG poor genes, repeat sequences, transposable elements and intergenic genome sections occur during aging in mammals. Methylation levels of certain CpG sites display strict correlation to age and could be used as “epigenetic clock” to predict biological age. Multi-substrate deacetylases SIRT1 and SIRT6 affect aging via locus-specific modulations of chromatin structure and activity of multiple regulatory proteins involved in aging. Random errors in DNA methylation and other epigenetic marks during aging increase the transcriptional noise, and thus lead to enhanced phenotypic variation between cells of the same tissue. Such variation could cause progressive organ dysfunction observed in aged individuals. Multiple experimental data show that induction of NF-κB regulated gene sets occurs in various tissues of aged mammals. Upregulation of multiple miRNAs occurs at mid age leading to downregulation of enzymes and regulatory proteins involved in basic cellular functions, such as DNA repair, oxidative phosphorylation, intermediate metabolism, and others.p

Conclusion: Strong evidence shows that all epigenetic systems contribute to the lifespan control in various organisms. Similar to other cell systems, epigenome is prone to gradual degradation due to the genome damage, stressful agents, and other aging factors. But unlike mutations and other kinds of the genome damage, age-related epigenetic changes could be fully or partially reversed to a “young” state.

My take – Increasing activity of TET enzymes could reduce incidences of cancer, slow aging and ameliorate various mental illness, such as schizophrenia. Increasing activity of TET enzymes can be done now.

DNA (cytosine-5) methyltransferase inhibitors: a therapeutic agent for schizophrenia?

I think increasing DNA demethylation by increasing activity of TET enzymes, which demethylate DNA, would be much safer. Cancers are associated with a global hypomethylation in what are called seas as opposed to CpG islands which are hypermethylated

DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes

Marija Kundakovic  1 Ying ChenErminio CostaDennis R Grayson Affiliations

Abstract

Reelin and glutamic acid decarboxylase 67 (GAD67) mRNAs and protein levels are substantially reduced in postmortem brains of patients with schizophrenia. Increasing evidence suggests that the observed down-regulation of reelin and GAD67 gene expression may be caused by dysfunction of the epigenetic regulatory mechanisms operative in cortical GABAergic interneurons. To explore whether human reelin and GAD67 mRNAs are coordinately regulated through DNA methylation-dependent mechanisms, we studied the effects of DNA methyltransferase inhibitors on reelin and GAD67 expression in NT-2 neuronal precursor cells. Competitive reverse transcription-polymerase chain reaction with internal standards was used to quantitate mRNA levels. The data showed that reelin and GAD67 mRNAs are induced in the same dose- and time-dependent manners. We further demonstrated that the activation of these two genes correlated with a reduction in DNA methyl-transferase activity and DNA methyltransferase 1 (DNMT1) protein levels. Time course Western blot analysis showed that DNMT1 protein down-regulation occurs temporally before the reelin and GAD67 mRNA increase. In addition, chromatin immunoprecipitation assays demonstrated that the activation of the reelin gene correlates with the dissociation of DNMT1 and methyl-CpG binding protein 2 (MeCP2) from the promoter, and an increased acetylation of histones H3 in the region. Together, our data strongly imply that human reelin and GAD67 genes are coordinately regulated through epigenetic mechanisms that include the action of DNMT1. Our study also suggests that negative regulation of the reelin gene involves methylation-dependent recruitment of DNMT1, MeCP2, and certain histone deacetylases, which most likely reduce the activity of the promoter by shifting the surrounding chromatin into a more compact state.

Life expectancy among persons with schizophrenia or bipolar affective disorder

Life-expectancy was 18.7 years shorter for schizophrenic men compared to men in the general population. Corresponding numbers for schizophrenic women was 16.3 years, for bipolar men 13.6 years, and for bipolar women 12.1 years,.’ With DNA demethylating mechanisms going awry in schizophrenia, due to dysregulation of TET enzymes and JumjC domain-containing proteins, all kinds of illnesses in individuals with schizophrenia can develop shortening life spans.

Sodium-dependent transport in the gut

Sodium dependent transport in very common with the sodium-dependent multivitamin transporter only one example. Sodium is also required for the transport of vitamin C by sodium-dependent vitamin C transporter 1 and sodium dependent vitamin C transporter 2 .

Why would sodium-dependent transport in the gut be especially prone to dysregulation? Sodium-dependent transport is regulated transport. When the gut epigenome goes awry regulated transport can become dysregulated and a large part of regulated transport in the gut is sodium-dependent. With regulated transport there is an opening for DNA hypermethylation to have a large effect. Transport by passive diffusion may not be so susceptible to dysregulation when the gut epigenome goes awry.

The first order of business would be to re-regulate the gut epigenome. TET enzymes and JmjC domain proteins are vitamin C and iron dependent enzymes. Both iron and vitamin C would be required to re-regulate TET enzymes and JmjC domain proteins in the gut.

Vitamin C and iron, however, cannot be taken at the same time. Vitamin C complexes with iron which would make iron unavailable in the gut even though iron absorption can be increased by vitamin C. Iron from iron carbonyl would be taken at bedtime five or so hours after the last vitamin C dosage of the day. Vitamin C can also interfere with copper absorption so copper from copper gluconate would also be taken at bedtime. Only trace minerals that are available in the gut can be supplemented. There are some excellent chelated minerals on the market all of which must be avoided.

One of the difficulties in any epigenetic approach to illnesses is to select which hypermethylated genes are the relevant hypermethylated genes. In a range of illnesses there could be excess DNA hypermethylation of genes associated with sodium dependent transport. Given this is the case this would clearly be relevant to the etiology such illnesses..

Decreasing DNA methylation vs. increasing DNA demethylation

DNA methylation is necessary to life. Just decreasing DNA methylation by main force by decreasing levels of enzymes that methylate DNA could have unpredictable and undesirable effects. Increasing the ability of TET enzymes to demethylate DNA would seem to be a more benign approach to decreasing DNA methylation. Presumably TET enzymes are regulated and and only called into play when necessary..

TET enzymes, JMJC domain containing enzymes and the gut

I have repeatedly stressed in this blog what happens in the gut is key. TET2 is highly expressed in the gut. TET3 is also highly expressed in the gut. There are a lot of JMJC domain containing proteins and a lot of them are highly expressed in the gut. For some examples see the Human Protein Atlas.

Reprogramming the gut epigenome via immediate release vitamin vitamin C and iron from iron carbonyl taken at bedtime away from vitamin C could have a large effect on the gut and therefore have large systematic effects. Copper from copper gluceonate would be taken at bedtime too as vitamin C can decrease copper absorption. Even with normal levels of iron iron from iron carbonyl would be supplemented at bedtime. as iron must be available in the gut as well as absorbed.

Unless the epigenome can be reprogrammed one ends up playing whack a mole. Upon addressing one symptom successfully other symptoms become prominent. Address one symptom successfully and one .can still be very ill. Ameliorating .one symptom then does not feel like much of a victory. A minimal program would be vitamin C taken during the day and iron and copper taken at bedtime. Mineral levels would be checked.

Dysregulation of TET enzymes contributes to transgenerational epigenetic inheritance in mice.

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Multi and transgenerational epigenetic effects of di-(2-ethylhexyl) phthalate (DEHP) in liver

Yi Wen  1 Saniya Rattan  2 Jodi A Flaws  2 Joseph Irudayaraj  3

Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous industrial pollutant, is a known endocrine disrupter implicated in metabolic diseases. Prenatal DEHP exposure promotes epigenetic multi- and transgenerational inheritance of adult onset disease in subsequent generations (F1-F3). However, the epigenetic toxicity is less understood in the liver. In this study, CD-1 mice were prenatally exposed to 20 μg/kg/day, 200 μg/kg/day, 500 mg/kg/day, or 750 mg/kg/day DEHP from gestational day (GD) 10.5 until birth of pups. Following prenatal exposure, the multigenerational and transgenerational effects of mRNA expression of epigenetic regulators were evaluated in F1, F2, and F3 generation mouse livers at postnatal days (PNDs) 8 and 60. Results showed that DEHP exposed mice livers exhibited significant changes in global DNA methylation levels in all three generations, with the effect being different in F2 after high dosage exposure. Histopathology indicated that DEHP exposure could induce mild damage in F1 livers. The expression levels of DNA methyltransferase 1 (Dnmt1) were significantly changed in both the F1 and F2 generations at PND 8, suggesting that maintenance Dnmt1 plays a major role in the multigenerational effect that occur in the early developmental stages. Additionally, DEHP exposure caused significant changes in ten-eleven translocation methylcytosine (Tet) dioxygenases encoding Tet1 expression in all three generations and Tet2 expression in F3 at PND 60, implicating their contributions in inducing both multi- and transgenerational effects after DEHP exposure in mouse liver. Overall, our results establish that prenatal and ancestral DEHP exposure are critical for epigenetic regulation of DNA methylation in female mouse livers.

Mental illnesses – parts of a sole huge illness

Psychiatric genetics is basically a research program with no connection to treatment except for very rare high impact genetic loci.

An endophenotype refers to a characteristic that is not easily observed on the surface. Almost all mental illnesses are due to epigenetic dysregulations. The endophenotypes of psychiatric illnesses would be the sets of epigenetic marks that are associated with given mental illnesses. The variability in symptoms in given illnesses is due to variations on the basic sets of epigenetic marks associated with such illnesses.

Mental illnesses arise due to dysregulation of TET enzymes and JmnjC-domain containing .proteins with TET enzymes involved in DNA demethylation and JmnjC-domain containing proteins involved in histone demethylation. Histone acetylation which requires acetyl-coenzyme A also plays a part.

Though dysregulation of TET enzymes and JmnjC-domain proteins and dysregulation of acetyl-coenzyme A are fundamental to all mental illnesses various mental illnesses separate from each other as spatially closely associated pathways fall together. Use the pathways or lose the pathways. And as these are epigenetic dysregulations, pathways that are lost are spatially localized to various organs and/or regions of organs, for example, regions of the brain. Trying to distinguish mental illnesses by examining genes is pointless.

Trying to isolate endophenotypes so as to enhance treatments is not necessary. With basic epigenetic dysregulations addressed almost all mental illnesses. can be treated. A treatment that addresses dysregulation of TET enzymes and JmnjC-domain proteins and dysregulation of acetyl-coenzyme A could address all mental illnesses.

Any reprogramming of youthful methylation patterns in humans would require that TET enzymes be re-regulated first

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Sinclair et al. using the eye as a model CNS tissue, showed that ectopic expression of Oct4, Sox2 and Klf4 genes in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2.

However, I have been arguing in papers (see Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the transsulfuration pathway) and on this blog that TET enzymes are the very enzymes that are dysregulated in many chronic illnesses, which results in various chronic illnesses possessing a range of phenotypic expressions. Ectopic expression of OCT4, KLF4 and SOX2 alone would not work in aged humans and/or ill humans as TET enzymes are dysregulated in aged and/or ill humans.

TET enzymes are iron and 2-oxoglutarate dependent dioxyegenases. Fixing TET enzymes could be a key part of the treatment of a range of chronic illness and would be a lot simpler and safer than systematic ectopic expression of OCT4, KLF4 and SOX2 in humans. A lot of methylation changes acquired during aging must be beneficial. Systematically turning back the clock to 18 or so would not be desirable .’Just’ fixing TET enzymes would allow desirable methylations to occur but would allow DNA demethylations of undesirable DNA methyations. Clearly fixing TET enzymes would be a required first step prior to any genetic engineering of humans to restore youthfulness given that such genetic engineering was feasible and desirable.

Mutations of genes for enzymes in the TCA cycle can inhibit TET enzymes

TET enzymes, which demethylate DNA, are 2-oxoglutarate dependent enzymes. 2-oxoglutarate is synthesized by the citric acid cycle. Mutation of genes for enzymes in the citric acid cycle can inhibit TET enzymes, thereby dysregulating epigenetic mechanisms.

Iron regulates enzymes is the TCA cycle. Dysregulation of iron metabolism could dysregulate the TCA cycle resulting in epigenetic dysregulations.