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How do memories transfer?

gettingwell4 2-3 stars Required further work, Acetylcholine, Brainstem, Cerebellum, Cerebrum, Hippocampus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Thalamus , , , ,

This 2018 Chinese study electronically modeled the brain’s circuits to evaluate memory transfer mechanisms:

“During non-rapid-eye-movement (NREM) sleep, thalamo-cortical spindles and hippocampal sharp wave-ripples have been implicated in declarative memory consolidation. Evidence suggests that long-term memory consolidation is coordinated by the generation of:

  • Hierarchically nested hippocampal ripples (100-250 Hz),
  • Thalamo-cortical spindles (7-15 Hz), and
  • Cortical slow oscillations (<1 Hz)

enabling memory transfer from the hippocampus to the cortex.

Consolidation has also been demonstrated in other brain tasks, such as:

  • In the acquisition of motor skills, where there is a shift from activity in prefrontal cortex to premotor, posterior parietal, and cerebellar structures; and
  • In the transfer of conscious to unconscious tasks, where activity in initial unskilled tasks and activity in skilled performance are located in different regions, the so-called ‘scaffolding-storage’ framework.

By separating a neural circuit into a feedforward chain of gating populations and a second chain coupled to the gating chain (graded chain), graded information (i.e. information encoded in firing rate amplitudes) may be faithfully propagated and processed as it flows through the circuit. The neural populations in the gating chain generate pulses, which push populations in the graded chain above threshold, thus allowing information to flow in the graded chain.

In this paper, we will describe how a set of previously learned synapses may in turn be copied to another module with a pulse-gated transmission paradigm that operates internally to the circuit and is independent of the learning process.”

The study had neither been peer-reviewed, nor were the mechanisms tested in living beings.

https://www.biorxiv.org/content/early/2018/07/27/351114 “A Mechanism for Synaptic Copy between Neural Circuits”

Hidden hypotheses of epigenetic studies

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Stress , , , ,

This 2018 UK review discussed three pre-existing conditions of epigenetic genome-wide association studies:

“Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting ‘hypothesis-free’ examinations in relation to adversity and/or mental health problems. Results of EWAS are in fact conditional on several a priori hypotheses:

  1. EWAS coverage is sufficient for complex psychiatric problems;
  2. Peripheral tissue is meaningful for mental health problems; and
  3. The assumption that biology can be informative to the phenotype.

1. CpG sites were chosen as potentially biologically informative based on consultation with a consortium of DNA methylation experts. Selection was, in part, based on data from a number of phenotypes (some medical in nature such as cancer), and thus is not specifically targeted to brain-based, stress-related complex mental health phenotypes.

2. The assumption is often that distinct peripheral tissues are interchangeable and equally suited for biomarker detection, when in fact it is highly probable that peripheral tissues themselves correspond differently to environmental adversity and/or disease state.

3. Analyses result in general statements such as ‘neurodevelopment’ or the ‘immune system’ being involved in the aetiology of a given phenotype. Whether these broad categories play indeed a substantial role in the aetiology of the mental health problem is often hard to determine given the post hoc nature of the interpretation.”

The reviewers mentioned in item #2 the statistical flaw of assuming that measured entities are interchangeable with one another. They didn’t mention that the problem also affected item #1 methodologies of averaging CpG methylation measurements in fixed genomic bins or over defined genomic regions, as discussed in:

The reviewers offered suggestions for reducing the impacts of these three hypotheses. But will doing more of the same, only better, advance science?

Was it too much to ask of researchers whose paychecks and reputations depended on a framework’s paradigm – such as the “biomarker” mentioned a dozen and a half times – to admit the uselessness of gathering data when the framework in which the data operated wasn’t viable? They already knew or should have known this.

Changing an individual’s future behavior even before they’re born provided one example of what the GWAS/EWAS framework missed:

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

DNA methylation and childhood adversity concluded that:

“Blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”

The truth about complex traits and GWAS added another example of how this framework and many of its paradigms haven’t produced effective explanations of “the aetiology of the mental health problem”

“The most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.”

Researchers need to reevaluate their framework if they want to make a difference in their fields. Recasting GWAS as EWAS won’t make it more effective.

https://www.sciencedirect.com/science/article/pii/S2352250X18300940 “Hidden hypotheses in ‘hypothesis-free’ genome-wide epigenetic associations”

Restoration of a “normal” epigenetic landscape

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system ,

This 2018 Texas human review subject was prostate cancer epigenetics:

“We comprehensively review the up-to-date roles of epigenetics in the development and progression of prostate cancer. We especially focus on three epigenetic mechanisms: DNA methylation, histone modifications, and noncoding RNAs. We elaborate on current models/theories that explain the necessity of these epigenetic programs in driving the malignant phenotypes of prostate cancer cells.

It is now generally accepted that epigenetics contributes to the development of nearly every stage of PCa [prostate cancer]. Considering the highly heterogeneous nature of PCa, it is quite likely that [the] effect of a particular epigenetic pattern on growth of cancer cells varies from case to case and [is] context specific.

Restoration of a “normal” epigenetic landscape holds promise as a cure for prostate cancer.”

The review’s Epigenetic Therapy section explained much of what’s going on in the above graphic. Its Table 3 was instructive for up-to-date clinical trial information on epigenetic treatments of prostate cancer.

“Restoration of a “normal” epigenetic landscape” won’t guarantee a healthy outcome once diseases start. Prevention seems desirable to avoid the situation where:

“Numerous epigenetic alterations reinforce the establishment of a context-specific transcriptional profile that favors self-renewal, survival, and invasion of PCa cells.”

http://www.ajandrology.com/article.asp?issn=1008-682X;year=2019;volume=21;issue=3;spage=279;epage=290;aulast=Liao “Epigenetic regulation of prostate cancer: the theories and the clinical implications”

A book review of “Neuroepigenetics and Mental Illness”

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Stress ,

A 2018 online book “Neuroepigenetics and Mental Illness” was published at https://www.sciencedirect.com/bookseries/progress-in-molecular-biology-and-translational-science/vol/158/suppl/C (not freely available). Three chapters are reviewed here, with an emphasis on human studies:

Actually, I won’t waste my time or your time with what I planned to do. The lack of scientific integrity and ethics displayed by the book’s publisher, editor, and contributors in the below chapter spoke volumes.

How can the information in any other chapter of this book be trusted?

“Chapter Twelve: Transgenerational Epigenetics of Traumatic Stress”

This chapter continued propagating a transgenerational meme that had more to do with extending paradigms than advancing science. The meme is that there are adequately evidenced transgenerational epigenetic inheritance human results.

As noted in Epigenetic variations in metabolism, there aren’t any published human studies that provide incontrovertible evidence from the F0 great-grandparents, F1 grandparents, F2 parents, and F3 children to confirm definitive transgenerational epigenetic inheritance causes and effects. Researchers urgently need to do this human research, and stop pretending that it’s already been done.

How did the book’s editor overlook what this chapter admitted?

“Literature about the inheritance of the effects of traumatic stress in humans has slowly accumulated in the past decade. However, it remains thin and studies in humans also generally lack clear “cause and effect” association, mechanistic explanations or germline assessment.”

Were the publisher and editor determined to keep the chapter heading – and the reviewers determined to add another entry to their CVs – in the face of this weasel-wording?

“In conclusion, although less studied from a mechanistic point of view, inter- and possibly transgenerational inheritance of the effects of traumatic stress is supported by empirical evidence in humans.”

See the comments below for one example of the poor substitutes for evidence that propagators of this transgenerational meme use to pronounce human transgenerational epigenetic inheritance a fait accompli. Researchers supporting the meme and its funding pipeline most certainly know that not only this one example, but also ALL human transgenerational epigenetic inheritance studies:

“Lack clear “cause and effect” association, mechanistic explanations or germline assessment.”

Lack of scientific integrity is one reason why such human research hasn’t been undertaken with the urgency it deserves. Propagating this meme is unethical, and adversely affects anyone who values evidence-based research.

Measuring epigenetic changes at a single-cell level

gettingwell4 5+ stars Premium, Epigenetics, Immune system , , ,

This 2018 Canadian cell study described the development of a single-cell protocol to:

“Profile primitive hematopoietic cells of mouse and human origin to identify epigenetically distinct subpopulations. Deep sampling of the CpG content of individual HSCs allowed for the near complete reconstitution of regulatory states from epigenetically defined subpopulations of HSCs and revealed a high level of redundancy of CpG methylation states within these phenotypically defined hematopoietic cell types.

Hematopoietic stem cells (HSCs) are functionally defined cells that display evidence of extensive self-renewal of their ability to generate mature blood cells for the lifetime of the organism and following transplantation into myelosuppressed permissive hosts. Most of the epigenetic measurements underpinning these observations represent consensus values experimentally derived from thousands of cells partially enriched in HSCs or their progeny, thus failing to discern distinct epigenetic states within HSCs.

Current analytical strategies for single-cell DNA methylation measurements average DNA methylation in fixed genomic bins or over defined genomic regions.

However, inference across cells (as well as sequence context) assumes homogeneity across cells, which is at cross-purposes with the generation of single-cell molecular measurements through the potential to mask rare subpopulations.

We identified donor as a significant source of consistent epigenetic heterogeneity, which was reduced but not eliminated by correcting for personal genetic variants. This observation is consistent with previous reports that showed genetic diversity as related to but not accountable for all DNA methylation differences and suggests that in utero environmental differences may be encoded within the HSC compartment.”

The study advanced science not only by measuring CpG methylation within each HSC, but also by producing another data point “that in utero environmental differences may be encoded within the HSC compartment.”

The paragraph with “assumes homogeneity across cells” bold text provided another example of the statistical analysis flaw that gives individually inapplicable results per Group statistics don’t necessarily describe an individual. The above graphic of human hematopoietic phenotypes demonstrated that the researchers have potentially solved this problem by measuring individual cells.

The researchers discussed another aspect of the study that’s similar to the epigenetic clock methodology:

“Phenotype-specific methylation signatures are characterized by extensive redundancy such that distinct epigenetic states can be accurately described by only a small fraction of single-CpG methylation states. In support of such a notion, the unique components of a DNA methylation “age” signature are contained in ∼353 CpGs sites, presumably representing a random sample of a total age signature that involves many more sites not detected using the reduced representation strategies from which these signatures have been derived.”

Also, in The epigenetic clock theory of aging the originator of the epigenetic clock characterized HSCs as an effective intervention against epigenetic aging:

“In vivo, haematopoietic stem cell therapy resets the epigenetic age of blood of the recipient to that of the donor.”

https://www.cell.com/stem-cell-reports/article/S2213-6711(18)30308-4/fulltext “High-Resolution Single-Cell DNA Methylation Measurements Reveal Epigenetically Distinct Hematopoietic Stem Cell Subpopulations”

Epigenetic effects of breast cancer treatments

gettingwell4 2-3 stars Required further work, Cerebrum, Epigenetics, Immune system, Memory, Stress, Telomeres , , ,

This 2018 UC San Diego review subject was the interplay between breast cancer treatments and their effects on aging:

“Although current breast cancer treatments are largely successful in producing cancer remission and extending lifespan, there is concern that these treatments may have long lasting detrimental effects on cancer survivors, in part, through their impact on non-tumor cells. It is unclear whether breast cancer and/or its treatments are associated with an accelerated aging phenotype.

In this review, we have highlighted five of nine previously described cellular hallmarks of aging that have been described in the context of cytotoxic breast cancer treatments:

  1. Telomere attrition;
  2. Mitochondrial dysfunction;
  3. Genomic instability;
  4. Epigenetic alterations; and
  5. Cellular senescence.”

The review was full of caveats weakening the above graphic’s associations:

  1. “Telomere attrition – Blood TL [telomere length] was not associated with chemotherapy in three out of four studies;
  2. Mitochondrial dysfunction – How cancer therapies affect cellular energetics as they relate to rate of aging is unclear;
  3. Genomic instability – Potentially contributing to accelerated aging;
  4. Epigenetic alterations – Although some of the key regulators of these processes have begun to be identified, including DNA and histone methylases and demethylases, histone acetylases and de-acetylases and chromatin remodelers, how they regulate the changes in aging through alteration of global transcriptional programs, remains to be elucidated; and
  5. Cellular senescence – Dysregulated pathways can be targeted by cytotoxic chemotherapies, resulting in preferential cell death of tumor cells, but how these treatments also affect normal cells with intact pathways is unclear.”

To their credit, these reviewers at least presented some of the contrary evidence, and didn’t continue on with a directed narrative as other reviewers are prone to do.

https://www.sciencedirect.com/science/article/pii/S1879406818301176 “Breast cancer treatment and its effects on aging” (not freely available)

The originator of the epigenetic clock methodology was a coauthor of the review. Only one of his works was cited in the Epigenetic alterations subsection:

https://link.springer.com/article/10.1007%2Fs10549-017-4218-4 “DNA methylation age is elevated in breast tissue of healthy women”

This freely-available 2017 study quoted below highlighted that epigenetic clock measurements as originally designed were tissue-specific:

“To our knowledge, this is the first study to demonstrate that breast tissue epigenetic age exceeds that of blood tissue in healthy female donors. In addition to validating our earlier finding of age elevation in breast tissue, we further demonstrate that the magnitude of the difference between epigenetic age of breast and blood is highest in the youngest women in our study (age 20–30 years) and gradually diminishes with advancing age. As women approach the age of the menopausal transition, we found that the epigenetic of age of blood approaches that of the breast.”

Additional caution was justified in both interpreting age measurements and extending them into “cellular hallmarks” when the tissue contained varying cell types:

“Our studies were performed on whole breast tissue. Diverse types of cells make up whole breast tissue, with the majority of cells being adipocytes. Other types of cells include epithelial cells, cuboidal cells, myoepithelial cells, fibroblasts, inflammatory cells, vascular endothelial cells, preadipocytes, and adipose tissue macrophages.

This raises the possibility that the magnitude of the effects we observe, of breast tissue DNAm age being greater than other tissues, might be an underestimation, since it is possible that not all of the cells of the heterogenous sample have experienced this effect. Since it is difficult to extract DNA from adipose tissue, we suspect that the majority of DNA extracted from our whole breast tissues was from epithelial and myoepithelial cells.”

Allergies and epigenetic histone modifications

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory, Stress , , , ,

This 2018 German review provided short summaries of 44 studies on the contribution of histone modifications to allergies. An overall summary of their search results was:

“There are at least two levels at which the role of histone modifications is manifested.

  • One is the regulation of cells that contribute to the allergic inflammation (T cells and macrophages) and those that participate in airway remodeling.
  • The other is the direct association between histone modifications and allergic phenotypes.

Inhibitors of histone-modifying enzymes may potentially be used as anti-allergic drugs. Furthermore, epigenetic patterns may provide novel tools in the diagnosis of allergic disorders.”

This type of search is what’s expected of researchers who will perform either:

  • A meta-analysis of studies selected from the search results; or
  • Their own study.

These reviewers didn’t indicate that they were proceeding along either path.

The review was fine for the purpose of presenting current studies of the subject. But this was just the preparatory stage of research.

https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0259-4 “Histone modifications and their role in epigenetics of atopy and allergic diseases”

Epigenetic variations in metabolism

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Memory, Neurochemicals, Oxytocin, Stress , , , , , ,

This 2018 German review was comprehensive for its subject, epigenetic control of variation and stochasticity in metabolic disease. I’ll focus on one aspect, phenotypic variation:

“Phenotypic [Mendelian] variation can result both from gain- and loss-of-function mutations. Because of the extreme interconnectivity of cell regulatory networks, even at the cellular level, predicting the impact of a sequence variant is difficult as the resultant variation acts:

  • In the context of all other variants and
  • Their potential additive, synergistic and antagonistic interactions.

This phenomenon is known as epistasis.

∼98.5% of our genome is non-protein-coding: it is pervasively transcribed, and its transcripts can support regulatory function. Among the best functionally characterized non-coding RNAs (ncRNAs) arising from these sequences are microRNAs (miRNAs).

Environmental [non-Mendelian] variation or ‘stimuli’ occurring during critical windows of susceptibility can elicit lifelong alterations in an individual’s phenotype. Intergenerational metabolic reprogramming [in fruit flies] results from global alterations in chromatin state integrity, particularly from reduced H3K27me3 and H3K9me3 [histone] domains.

The broad variation of fingerprints in humans is thought to depend to a large degree on stochastic variation in mechanical forces. These clear examples of inducible multi-stable or stochastic variation highlight how little we know about the landscape of potential phenotypic variation itself.

Consensus estimates of heritability for obesity and T2D are ∼70% and ∼35% respectively. The remaining, unexplained component is known to involve gene–environment interactions as well as non-Mendelian players.”

Although the above graphic displays transgenerational inheritance for humans, the reviewers didn’t cite any human studies that adequately demonstrated causes for and effects of transgenerational epigenetic inheritance.

I’ve read the cited Swedish and Dutch studies. Their designs, methods, and “correlate with” / “was associated with” results didn’t provide incontrovertible evidence from the F0 great-grandparents, F1 grandparents, F2 parents, and F3 children. It’s necessary to thoroughly study each generation to confirm definitive transgenerational epigenetic inheritance causes and effects.

As noted in How to hijack science: Ignore its intent and focus on the 0.0001%, there aren’t any such published studies to cite. Researchers urgently need to do this human research, and stop using these poor substitutes [1] to pretend there are already adequately evidenced transgenerational epigenetic inheritance human results.

I downgraded the review for treating research of this and other subjects as faits accomplis. It’s opposite ends of the evidential spectrum to state “how little we know about the landscape of potential phenotypic variation,” and in the same review, speciously extrapolate animal experiments into putative human results.

https://www.sciencedirect.com/science/article/pii/S2212877818301984 “Epigenetic control of variation and stochasticity in metabolic disease”

[1] As an example of the poor substitutes for evidence, a researcher referred me to the 2013 “Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine” which is freely available at https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.12136 as a study finding human transgenerational epigenetic inheritance.

The Methods section showed:

  • The study’s non-statistical data was almost all unverified self-reports by a self-selected sample of the F2 generation, average age 37.
  • No detailed physical measurements or samples were taken of them, nor of the F1 generation, nor of the F0 generation, all of which are required as baselines for any transgenerational epigenetic inheritance findings.
  • No detailed physical measurements or samples were taken of the F3 generation, which is the generation that may provide transgenerational evidence if the previous generations also have detailed physical baselines.

The study’s researchers drew enough participants (360) such that their statistics package allowed them to impute and assume into existence a LOT of data. But the scientific method constrained them to make factual statements of what the evidence actually showed. They admitted:

“In conclusion, we did not find a transgenerational effect of prenatal famine exposure on the health of grandchildren in this study.”

Yet this study is somehow cited for evidence of human transgenerational epigenetically inherited causes and effects!

Group statistics don’t necessarily describe an individual

gettingwell4 2-3 stars Required further work, Primal Therapy, Stress , ,

I’m curating this 2018 UC Berkeley/Drexel/Netherlands analysis of human studies via its press coverage. The authors:

“Collaborated to analyze data on hundreds of adults – some mentally or physically sound, others suffering from various conditions such as depression, anxiety, or post-traumatic stress disorder. Participants had completed surveys about their mental health and had their heart rates monitored via electrocardiogram.

Researchers used the data to conduct six different experiments. They sought to find out whether the conclusions of each study would successfully apply to participants individually.

One study that focused on how frequently depression sufferers reported feeling worried. Results tallied from the pool of participants showed that depressed people worry a significant amount.

But when the analysis was applied individually, the results were all over the map. Some participants worried hardly at all, while others were notably beyond the group average.

Another experiment that centered around the link between fear and avoidance showed a strong correlation when measured as a group. Yet a significant number of participants who experienced fear had no issues with avoiding various activities.

Across all six experiments, the authors could not show that what was concluded for the group applied to most individuals.”


http://www.pnas.org/content/early/2018/06/15/1711978115.full “Lack of group-to-individual generalizability is a threat to human subjects research”

Other studies such as the below have addressed problems with statistical analysis techniques. These issues aren’t limited to human studies:

The current study highlighted the fact that people aren’t interchangeable. Assuming ergodicity is a statistical analysis flaw that produces individually inapplicable results for many measurements of fruit flies, cells, humans, you name the organism.

When this presumption makes a study’s statistics useless for an individual, researchers can’t cure the analysis by invoking an “individual differences” meme. Neither is the flaw fixed by spinning a tale about “This is how we can truly personalize medicine.”

The current study needed to provide evidence for its proposed solution.

Regarding worrying, Dr. Arthur Janov said it best as I quoted in How well can catastrophes be predicted?:

“Worrying is not a problem, it is the symptom of something that is occurring physiologically within the brain. What causes worrying is the problem.

Constant worry is anticipating catastrophe. But what we don’t realize is that the catastrophe already has happened; we simply have no access to it.

We are actually worried about the past, not the future.”

A study of our evolutionary remnants

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system ,

This 2018 Michigan human cell study subject was factors affecting the expression of human endogenous retroviruses:

“We provide a comprehensive genomic and epigenomic map of the more than 500,000 endogenous retroviruses (ERVs) and fragments that populate the intergenic regions of the human genome.

The repressive epigenetic marks associated with the ERVs, particularly long terminal repeats (LTRs), show a remarkable switch in silencing mechanisms, depending on the evolutionary age of the LTRs:

  • Young LTRs tend to be CpG-rich and are mainly suppressed by DNA methylation, whereas
  • Intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation.
  • The evolutionarily old LTRs are more likely inactivated by the accumulation of loss-of-function genetic mutations.

Because the expression of ERVs is potentially dangerous to the host cell, understanding the repressive mechanisms is important. Earlier studies have implicated the aberrant expression of ERVs in autoimmune disease pathogenesis. However, this “enemy within” may also play a beneficial role in cancer therapy.

The same kinds of chromatin dynamics appear to be used both by LTRs and genes.”

I wasn’t going to curate this study before I saw the above graphic of our Boreoeutherian ancestor. Evolutionary subjects seem very abstract until an artist reconstructs the data visually.

https://genome.cshlp.org/content/early/2018/07/03/gr.234229.118.full.pdf “Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses” (not freely available)

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Preventing prostate cancer with a broccoli sprouts diet

gettingwell4 0-1 star Wasted resources, Epigenetics , ,

This 2018 Oregon rodent study fed a 15% broccoli sprout diet beginning at four weeks of age to a mouse strain with a near-100% chance of developing prostate cancer:

“Broccoli sprouts reduced prostate cancer incidence and progression to invasive cancer. Broccoli sprout consumption also decreased histone H3 lysine 9 trimethylation in the ventral lobe (age 12 wk), and decreased histone H3 lysine 18 acetylation in all prostate lobes (age 28 wk).

The TRAMP model of prostate cancer was utilized because the tumors occur in the prostate epithelium and the tumor tissue histopathology closely mimics human disease. Additional advantages include that the tumors arise spontaneously and appear in ∼100% of mice.”

Like in utero prevention of breast cancer by a broccoli sprouts diet, this study had a problem measuring sulforaphane dosage. The relevant statements were:

“This 15% broccoli sprout diet had 400 mg SFN [sulforaphane]/kg diet, which was chosen because it is equivalent to 1 mg SFN/d which has been used in previous studies.

Food consumption was measured over the course of the study and no difference was found in the intake of food between the control and broccoli sprout–fed groups.”

To be “equivalent to 1 mg SFN/d” at a .4 mg sulforaphane/gram rate, the animals would eat 2.5 grams per day. That’s half of a normal intake. “Food consumption was measured” but not disclosed.

The study for the “1 mg SFN/d” dosage cited at http://cancerpreventionresearch.aacrjournals.org/content/early/2015/02/21/1940-6207.CAPR-14-0386.full-text.pdf was actually:

“4 week old male TRAMP mice were treated with PBS [phosphate-buffered saline] (control) or 1 mg SFN in PBS three times/week for 15-18 weeks.”

not “1 mg SFN/d which has been used in previous studies.”

The researchers didn’t sufficiently quantify their findings to help humans, which is the basic purpose of any animal study.

https://academic.oup.com/cdn/article/2/3/nzy002/4803105 “Broccoli Sprouts Delay Prostate Cancer Formation and Decrease Prostate Cancer Severity with a Concurrent Decrease in HDAC3 Protein Expression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice”

Starving awakens ancient parasite DNA within us

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress, Telomeres , ,

This 2018 Italian human cell study conducted a series of experiments on the effects of nutrient deprivation:

“Reduced food intake, and in particular protein or amino acid (AA) restriction, extends lifespan and healthspan.

We have previously shown that, in mammalian cells, deprivation of essential AAs (methionine/cysteine or tyrosine) leads to the transcriptional reactivation of integrated silenced transgenes by a process involving epigenetic chromatic remodeling and histone acetylation.

Here we show that the deprivation of methionine/cysteine also leads to the transcriptional upregulation of endogenous retroviruses [ERVs], suggesting that essential AA starvation affects the expression not only of exogenous non-native DNA sequences, but also of endogenous anciently-integrated and silenced parasitic elements of the genome.

ERVs, comprising 8% of the human genome, represent the remnants of past infections of germ cells by exogenous retroviruses, and are mostly unable to retrotranspose in the human genome. However, they can reactivate during physiological development, or in pathological conditions like cancer, and regulate the expression of nearby genes by their LTR elements, leading to general transcriptional reprogramming.

Dissection of the underlying mechanism ruled out a role for the main AA-deficiency sensor GCN2 and pointed to the ribosome as the possible master controller.”

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200783 “Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences”

The study found that reality is sometimes stranger than what fiction writers dream up. 🙂

The authors cited a 2016 Danish review I hadn’t previously curated:

https://www.nature.com/articles/nrendo.2016.87 “The role of diet and exercise in the transgenerational epigenetic landscape of T2DM” (not freely available)

Contrary to what’s implied by its title, though, and as I noted in How to hijack science: Ignore its intent and focus on the 0.0001%, those reviewers didn’t cite any human studies that adequately demonstrated transgenerational epigenetic inheritance causes and effects. They admitted:

“Direct evidence that epigenetic factors drive the inheritance of T2DM [type 2 diabetes mellitus] in humans is lacking.”

The Danish reviewers then continued on as if proof of human transgenerational epigenetic inheritance was a foregone conclusion! It didn’t serve any valid scientific purpose to assume such evidence into existence.

A dietary supplement that trains the innate immune system

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Immune system, Memory, Neurochemicals, Stress

This 2018 Netherlands review topic was long-term epigenetic programming of the innate immune system:

“Immunological memory has been classically described for the adaptive immune system, in which naive B and T lymphocytes develop antigen-specific, long-lasting memory cells after encountering a new antigen.

Immunological memory is not an exclusive trait of lymphocytes. The function of cells from the innate immune system, such as monocytes, macrophages, dendritic cells, and NK cells, is also influenced by contact with different stimuli, undergoing functional reprogramming.

β-glucan, the prototypical trained immunity-inducing agonist:

  • Modulates hematopoietic stem and progenitor cells, influencing behavior and responsiveness of peripheral myeloid cells;
  • Leads to a shift of cellular metabolism from oxidative phosphorylation toward aerobic glycolysis.

Analysis of transcriptional data from macrophages stimulated with β-glucan revealed that the cholesterol synthesis pathway is highly up-regulated in trained immunity. A follow-up of this study showed that activation of the cholesterol synthesis pathway, but not its synthesis itself, is crucial for innate memory. In agreement with this, inhibition of cholesterol synthesis in mice reduced induction of trained immunity by β-glucan.

β-glucan-induced changes in trimethylation of histone 3 lysine 4 (H3K4me3) and acetylation of histone 3 lysine 27 (H3K27ac) in human monocytes 7 days after the first stimulation in vitro were associated with a switch to glycolysis, suggesting a deep, long lasting reprogramming of cells.

Inducers of cellular reprogramming such as β-glucan have shown potential as a treatment or adjuvant for osteosarcoma, influenza, or skin lesions, among others.”

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1002/JLB.MR0318-104R “Long-term reprogramming of the innate immune system”

A seasonal epigenetic effect of conception on BMI

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress ,

This 2018 Swiss human/rodent study found:

“The presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring.

Adipose tissue functions as a dynamic endocrine organ, and its ‘quality’ is considered to be an important factor in the development of obesity-associated comorbidities. Adipose tissue can be divided into the functionally and morphologically distinct white adipose tissue (WAT) and BAT. The main function of BAT is energy dissipation via nonshivering thermogenesis, which is enabled by the presence of uncoupling protein (UCP1) in the inner mitochondrial membrane.

In humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

BAT variability

We performed a retrospective study of FDG-PET/CT scans from 2007–2015 that were collected from the University Hospital of Zurich (n = 8,440 individuals). Individuals with active BAT were 3.2% more likely to have been conceived in the colder period of the year, for example, between October and February (mean temperature estimate 2° C), whereas individuals without active BAT were more likely to have been conceived in the warmer months, for example, between April and September (mean temperature estimate 13° C).”

The study provided another example of how stressful experiences of parents – even those before offspring conception – affected their offspring.

Edit 8/13/2018: I substituted the authors’ corrected graphic where the calendar month started with April vs. January.

A review of this study was made in The imperative of human transgenerational studies.

https://www.nature.com/articles/s41591-018-0102-y “Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring” (not freely available)

A mid-year selection of epigenetic topics

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Beliefs, Brain development, Brainstem, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Telomeres, Testosterone, Vasopressin , , , , , , , , , , , , , , , , , ,

Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:

The pain societies instill into children

DNA methylation and childhood adversity

Epigenetic mechanisms of muscle memory

Sex-specific impacts of childhood trauma

Sleep and adult brain neurogenesis

This dietary supplement is better for depression symptoms than placebo

The epigenetic clock theory of aging

A flying human tethered to a monkey

Immune memory in the brain

The lack of oxygen’s epigenetic effects on a fetus