Cerebrum

A GWAS meta-analysis of two epigenetic clocks

gettingwell4 0-1 star Wasted resources, Beliefs, Cerebrum, Epigenetics, Immune system, Telomeres , , ,

This 2019 UK human study conducted a meta-analysis of genome-wide association studies of two epigenetic clocks using 13,493 European-ancestry individuals aged between ten and 98 years:

“Horvath-EAA, described in previous publications as ‘intrinsic’ epigenetic age acceleration (IEAA), can be interpreted as a measure of cell-intrinsic ageing that exhibits preservation across multiple tissues, appears unrelated to lifestyle factors, and probably indicates a fundamental cell ageing process that is largely conserved across cell types.

In contrast, Hannum-EAA, referred to in previous studies as ‘extrinsic’ epigenetic age acceleration (EEAA), can be considered a biomarker of immune system ageing, explicitly incorporating aspects of immune system decline such as age-related changes in blood cell counts, correlating with lifestyle and health-span related characteristics, and thus yielding a stronger predictor of all-cause mortality.

The meta-analysis of Horvath-EAA identified ten independent associated SNPs [single nucleotide polymorphisms], doubling the number reported to date, and highlighted 21 genes involved in Horvath-based epigenetic ageing. Four of the ten Horvath-EAA-associated SNPs are mQTL [methylation quantitative trait loci] for CpGs used in the Horvath/Hannum epigenetic clocks. A possible interpretation of this is that the functional mechanism by which these SNPs influence the rate of biological ageing is via altering methylation levels.

Father’s age at death, a rough proxy for lifespan, was nominally significantly correlated with both EAA measures, and parents’ age at death was additionally correlated with Hannum-EAA. Aside from these, genetic correlations with age-related traits were surprisingly few: it is possible that this could reflect an overly conservative correction for the multiple tests carried out, or low statistical power, rather than a genuine lack of correlations.

Genetic correlation analysis should be restricted to GWAS with a heritability Z-score of 4 or more, on the grounds of interpretability and power, so the Horvath-based results particularly should be interpreted with caution.”

A non-apologetic way to explain the above graphic is that NONE of these 218 “health and behavioral traits” were any more associated with the studied genetic measurements than would be expected by chance!

Fervent believers in the GWAS methodology’s capability to exactly predict individual phenotypes eventually become victims of the scientific method. These GWAS researchers griped about “overly conservative correction, or low statistical power” and other predictable shortfalls, and ended a long limitations statement with:

“While we have identified a number of SNPs and genes significantly associated with EAA, including genes already known to be related to ageing, the analyses presented here fall short of providing a mechanistic explanation for how these variants and genes act to influence biological age.”

Outside of beliefs, it’s hard to understand why research money keeps pouring into the GWAS dead end. If these researchers and their employing institution and sponsors want to make a difference in human lives, they need to get busy in other areas.

These researchers were employed by the same institution that couldn’t be bothered to scrape together six more weeks of funds to study the transgenerational damaging effects of acetaminophen – an analgesic available to billions of people – in Epigenetics research that was designed to fall one step short of wonderful.

https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008104 “A meta-analysis of genome-wide association studies of epigenetic age acceleration”

Restrict information in the name of science?

gettingwell4 < 0 Detracted from science, Beliefs, Cerebrum

A Stanford researcher was annoyed that we live in the 21st century, and advocated we return to previous centuries’ information-flow check valves of wise old men. No doubt the publishers of and subscribers to the Journal of the American Medical Association applauded the same old tired prescription.

Ten instances of the word “should” in the final two paragraphs provided ample evidence of the paper’s intent. Mirroring the current political climate – projecting – accusations made of others were items the accusers were guilty of themselves, such as:

“When these scientists act as investigators in the hundreds of observational studies that they publish, or as editors and peer reviewers in evaluating submissions from others, would they tolerate publishing analyses and funding proposals that might contradict their belief system?”

https://jamanetwork.com/journals/jama/fullarticle/2753533 “Neglecting Major Health Problems and Broadcasting Minor, Uncertain Issues in Lifestyle Science”

One of the paper’s references included an informative graphic:

“A histogram of the total number of rumor cascades in our data across the seven most frequent topical categories.”

https://science.sciencemag.org/content/359/6380/1146 “The spread of true and false news online”

I’ll borrow from the curation of another Stanford paper Online dating cuts out the middlemen in conclusion:

“Are there examples where it wouldn’t potentially improve a person’s life to choose their information sources? Friends, family, and other social groups – and religious, educational, and other institutions – have had their middlemen/guarantor time, and have been found lacking.

Make your own choices for your one precious life.”

Perinatal stress and sex differences in circadian activity

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Brain development, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Stress, Testosterone , , , ,

This 2019 French/Italian rodent study used the PRS model to investigate its effects on circadian activity:

“The aim of this study was to explore the influence of PRS on the circadian oscillations of gene expression in the SCN [suprachiasmatic nucleus of the hypothalamus] and on circadian locomotor behavior, in a sex-dependent manner.

Research on transcriptional rhythms has shown that more than half of all genes in the human and rodent genome follow a circadian pattern. We focused on genes belonging to four functional classes, namely the circadian clock, HPA axis stress response regulation, signaling and glucose metabolism in male and female adult PRS rats.

Our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.”

“There was a clear-cut effect of sex on the effect of PRS on the levels of activity:

  • During the period of lower activity (light phase), both CONT and PRS females were more active than males. During the light phase, PRS increased activity in males, which reached levels of CONT females.
  • More interestingly, during the period of activity (dark phase), male PRS rats were more active than male CONT rats. In contrast, female PRS rats were less active than CONT females.
  • During the dark phase, CONT female rats were less active than CONT male rats.

The study presented evidence for sex differences in circadian activity of first generation offspring that was caused by stress experienced by the pregnant mother:

“Exposure to gestational stress and altered maternal behavior programs a life-long disruption in the reactive adaptation such as:

  •  A hyperactive response to stress and
  • A defective feedback of the hypothalamus-pituitary-adrenal (HPA) axis together with
  • Long-lasting modifications in stress/anti-stress gene expression balance in the hippocampus.”

It would advance science if these researchers carried out experiments to two more generations to investigate possible transgenerational epigenetic inheritance of effects caused by PRS. What intergenerational and transgenerational effects would they possibly find by taking a few more months and extending research efforts to F2 and F3 generations? Wouldn’t these findings likely help humans?

One aspect of the study was troubling. One of the marginally-involved coauthors was funded by the person described in How one person’s paradigms regarding stress and epigenetics impedes relevant research. Although no part of the current study was sponsored by that person, there were three gratuitous citations of their work.

All three citations were reviews. Unlike study researchers, reviewers aren’t bound to demonstrate evidence from tested hypotheses. Reviewers are free to:

  • Express their beliefs as facts;
  • Over/under emphasize study limitations; and
  • Disregard and misrepresent evidence as they see fit.

Fair or not, comparisons of reviews with Cochrane meta-analyses of the same subjects consistently show the extent of reviewers’ biases. Reviewers also aren’t obligated to make post-publication corrections for their errors and distortions.

As such, reviews can’t be cited for reliable evidence. Higher-quality studies that were more relevant and recent than a 1993 review could have elucidated points.

Sucking up to the boss and endorsing their paradigm was predictable. Since that coauthor couldn’t constrain themself to funder citations only in funder studies, it was the other coauthors’ responsibilities to edit out unnecessary citations.

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00089/full “Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle”

Would you return a lost wallet?

gettingwell4 0-1 star Wasted resources, Beliefs, Cerebrum , ,

The researchers in this 2019 Swiss/US study intentionally “lost” > 17,000 wallets under experimental conditions:

“We conducted field experiments in 40 countries to examine whether people act more dishonestly when they have a greater economic incentive to do so, and we found the opposite to be true. Citizens were more likely to return wallets that contained relatively larger amounts of money. Neither nonexperts nor professional economists were able to predict this result.

When people stand to heavily profit from engaging in dishonest behavior, the desire to cheat increases but so do the psychological costs of viewing oneself as a thief.”

The study did well in some aspects, including publicity. However:

1. The researchers admitted in the final paragraph:

“Using average reporting rates across countries, we find substantial variation in rates of civic honesty, ranging from 14 to 76%. This variation largely persists even when controlling for a country’s gross domestic product, suggesting that other factors besides a country’s wealth are also at play.”

Yet the paper’s first page contained the above graphic, which used each country’s GDP as a dependent variable! Wasn’t a behavioral economics study of honesty required to present their data honestly, and use factors that were experimentally significant?

2. “Other factors..at play” were relegated to the supplementary materials. The paper was only three-and-a-half pages long, so there was room for further explanations.

Here’s one comment on cultural differences from a Chinese PhD student:

“Biased design. In China (and Asian countries), people seldom use email, and our merit is to leave things untouched (“路不拾遗“:no one picks up lost articles in the street (idiom)).”

3. The study design had nothing to do with avoiding taxes, but three of the four sentences in the paper’s first paragraph did. This impressed as pointless.

https://science.sciencemag.org/content/365/6448/70 “Civic honesty around the globe” (not freely available)

Caloric restriction’s epigenetic effects

gettingwell4 0-1 star Wasted resources, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Oxytocin, Stress, Telomeres , ,

This 2019 US review subject was caloric restriction (CR) without malnutrition:

“Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Short- and long-term CRs produce significant changes in different tissues and across species, in some animal models even with sex-specific effects. Early CR onset may cause a different and even an opposite effect on physiological outcomes in animal models such as body weight.”

https://academic.oup.com/advances/article-abstract/10/3/520/5420411 “Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction” (not freely available)

1. The review didn’t present evidence to equate survival (left axis) with methylation drift (right axis) per the above graphic. Methylation drift should point in the opposite direction of survival, if anything.

2. No mention was made of the epigenetic clock method of measuring age acceleration, although it’s been available since 2013 and recent diet studies have used it. The sole citation of an age acceleration study was from 2001, which was unacceptable for a review published in 2019.

3. The review provided many cellular-level details about the subject. However, organism-level areas weren’t sufficiently evidenced:

A. Arguments for an effect usually include explanations for no effect as well as for opposite effects. The reviewers didn’t provide direct evidence for why, if caloric restriction extended lifespan, caloric overabundance produced shorter lifespans.

B. Caloric restriction evidence was presented as if only it was responsible for organism-level effects. Other mechanisms may have been involved.

An example of such a mechanism was demonstrated in a 2007 rodent study Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet which compared two 40%-calorie-restricted diets.

The calories and composition of both diets were identical. However, advanced glycation end product (AGE) levels were doubled in standard chow because heating temperatures were “sufficiently high to inadvertently cause standard mouse chow to be rich in oxidant AGEs.”

The study found that a diet with lower chow heating temperatures increased lifespan and health span irrespective of caloric restriction!

  • The low-AGE calorie-restricted diet group lived an average of 15% longer (>20 human equivalent years) than the CR group.
  • 40% of the low-AGE calorie-restricted diet group were still alive when the last CR group member died.
  • The CR group also had significantly more: 1) oxidative stress damage; 2) glucose and insulin metabolism problems; and 3) kidney, spleen, and liver injuries.

A drug that countered effects of a traumatizing mother

gettingwell4 2-3 stars Required further work, Acetylcholine, Amygdala, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Oxytocin, Stress, Telomeres , , , , , , , , , , ,

This 2019 US rodent study concerned transmitting poor maternal care to the next generation:

“The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. Infant experiences with a caregiver have lifelong behavioral consequences.

Maternal behavior is a complex behavior requiring the recruitment of multiple brain regions including the nucleus accumbens, bed nucleus of the stria terminalis, ventral tegmental area, prefrontal cortex, amygdala, and medial preoptic area. Dysregulation within this circuitry can lead to altered or impaired maternal responsiveness.

We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring.

  1. We replicate that dams with a history of maltreatment mistreat their own offspring.
  2. We show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring.
  3. We show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care.
  4. We show altered methylation and gene expression in maltreated dams normalized by zebularine.

These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.

Maternal behavior is an intergenerational behavior. It is important to establish the neurobiological underpinnings of aberrant maternal behavior and explore treatments that can improve maternal behavior to prevent the perpetuation of poor maternal care across generations.”

The study authors demonstrated intergenerational epigenetic effects, and missed an opportunity to also investigate transgenerational epigenetically inherited effects. They cited reference 60 for the first part of the above quotation, but the cited reviewer misused the transgenerational term by applying it to grand-offspring instead of the great-grand-offspring.

There were resources available to replicate the study authors’ previous findings, which didn’t show anything new. Why not use such resources to uncover evidence even more applicable to humans by extending experiments to great-grand-offspring that would have no potential germline exposure to the initial damaging cause?

Could a study design similar to A limited study of parental transmission of anxiety/stress-reactive traits have been integrated? That study’s thorough removal of parental behavior would be an outstanding methodology to confirm by falsifiability whether parental behavior is both an intergenerational and a transgenerational epigenetic inheritance mechanism.

Rodent great-grand-offspring can be studied in < 9 months. It takes > 50 years for human studies to reach the great-grand-offspring transgenerational generation.

  • Why not attempt to “prevent the perpetuation of poor maternal care across generations?”
  • Isn’t it a plausible hypothesis that humans “with a history of maltreatment mistreat their own offspring?”
  • Isn’t it worth the extra effort to extend animal research to investigate this unfortunate chain?

https://www.nature.com/articles/s41598-019-46539-4 “Pharmacological manipulation of DNA methylation normalizes maternal behavior, DNA methylation, and gene expression in dams with a history of maltreatment”

Wikipedia is a poor source of information on advanced glycation end products (AGEs)

gettingwell4 < 0 Detracted from science, Beliefs, Cerebrum, Epigenetics, Immune system, Stress

A link to Wikipedia is usually on the first page of search results. The Wikipedia post on AGEs lacks the evidence that a reader may infer from its text.

For example, the second paragraph of the AGEs post, Dietary Sources, contained the following text and references:

  1. “However, only low molecular weight AGEs are absorbed through diet, and vegetarians have been found to have higher concentrations of overall AGEs compared to non-vegetarians. [4]
  2. Therefore it is unclear whether dietary AGEs contribute to disease and aging, or whether only endogenous AGEs (those produced in the body) matter. [5]
  3. This does not free diet from potentially negatively influencing AGE, but implicates dietary AGE may be less important than other aspects of diet that lead to elevated blood sugar levels and formation of AGEs. [4] [5]”

[4] https://www.sciencedirect.com/science/article/pii/S0278691513004444 “Advanced glycation end products in food and their effects on health” (not freely available) 2013 Denmark.

Please note on this linked page that a German researcher took the time to correct one bias of the Danish reviewers, citing evidence from his studies that:

“The deleterious effects of food-derived AGEs in subjects with type 2 diabetes mellitus are proven.”

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257625 “Dietary Advanced Glycation End Products and Aging” 2010 US.

Both of these references were reviews.

Unlike study researchers, reviewers aren’t bound to demonstrate evidence from tested hypotheses. Reviewers are free to:

  • Express their beliefs as facts;
  • Over/under emphasize study limitations; and
  • Disregard and misrepresent evidence as they see fit.

Reviewers also aren’t obligated to make post-publication corrections for their errors and distortions. For example, the Danes didn’t correct their review with any findings the German researcher presented.

As such, reviews can’t be cited for reliable evidence.

A sample of other problems with each of the Wikipedia sentences:

1. “However, only low molecular weight AGEs are absorbed through diet, and vegetarians have been found to have higher concentrations of overall AGEs compared to non-vegetarians. [4]”

The first part of sentence 1 came from the review’s abstract:

“Only LMW AGEs..may be absorbed from the gut and contribute to the body burden of AGEs.”

But the reviewers didn’t support their abstract’s statement with direct evidence from any study!

2. “Therefore it is unclear whether dietary AGEs contribute to disease and aging, or whether only endogenous AGEs (those produced in the body) matter. [5]”

The “therefore” of sentence 2 was misplaced. Sentence 1 didn’t attempt to explain whether “dietary AGEs contribute to disease and aging” or “only endogenous AGEs matter.”

Since sentence 2 wasn’t a consequence of sentence 1, the Wikipedia contributor(s) needed to support sentence 2 with evidence. Citing an “unclear” 2010 reference [5] ignored dozens of studies that provided better clarity.

3. “This does not free diet from potentially negatively influencing AGE, but implicates dietary AGE may be less important than other aspects of diet that lead to elevated blood sugar levels and formation of AGEs. [4] [5]”

Wikipedia contributors tend to cite irrelevant references rather than get flagged with “citation needed.” The value judgment of sentence 3 was an example of this intentionally misleading masquerade.

“Dietary AGE may be less important..” wasn’t unequivocally supported by studies referenced in either review, and didn’t represent an authoritative body of evidence. Contrast those weasel words with:

“The deleterious effects of food-derived AGEs in subjects with type 2 diabetes mellitus are proven.”

Good job, Wikipedia contributors! You used lower-quality reviews to promote misunderstandings that DETRACTED from science.

Wikipedia’s premise is that since the group knows more about any subject than does any individual, everyone is entitled to contribute. The results are usually incoherent narratives that often substitute opinions for evidence.

The second paragraph of the Exogenous section of the Wikipedia glycation post provided an example:

  • Assertions of the first and third sentences needed citations. Did the contributor(s) think these would be unexamined?
  • Someone contributed a cancer reference as the fourth sentence, although it had little to do with the preceding sentences.
  • The fifth sentence was informative on exogenous glycations and AGEs. An editor would have removed “recently” and “recent” though, because the cited source was dated 2005.

Linking adult neurogenesis to Alzheimer’s disease

gettingwell4 2-3 stars Required further work, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress , , , , , ,

This 2019 Spanish human study compared DNA methylation, chromatin and histone modifications in the hippocampus of deceased Alzheimer’s disease patients with controls:

“A significant percentage of the differentially methylated genes were related to neural development and neurogenesis. It was astounding that other biological, cellular, and molecular processes generally associated with neurodegeneration such as apoptosis, autophagy, inflammation, oxidative stress, and mitochondrial or lysosomal dysfunction were not overrepresented.

The results of the present study point to neurogenesis-related genes as targets of epigenetic changes in the hippocampus affected by AD. These methylation changes might be built throughout life due to external and internal cues and would represent an example of epigenetic interaction between environmental and genetic factors in developing AD.

As an alternative explanation, these epigenetic marks might also represent the trace of DNA methylation alterations induced during early developmental stages of the hippocampus, which would remain as a fingerprint in the larger proportion of hippocampal neurons that are not exchanged. This second hypothesis would link AD to early life stages, in concordance with recent studies that revealed abnormal p-tau deposits (pre-tangles) in brains of young individuals under 30, suggesting AD pathology would start earlier in life than it was previously thought. The influence of the genetic risk for AD has also been postulated to begin in early life, and other AD risk factors may be influenced by in utero environment.”

The study cited references to adult neurogenesis:

“Though strongly related to brain development, neurogenesis is also maintained in the adult human brain, mainly in two distinct areas, i.e., the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. There is substantial neurogenesis throughout life in the human hippocampus as it is estimated that up to one third of human hippocampal neurons are subject to constant turnover.

Adult neurogenesis is linked to hippocampal-dependent learning and memory tasks and is reduced during aging. Recent evidence suggests that adult neurogenesis is altered in the neurodegenerative process of AD, but it is still controversial with some authors reporting increased neurogenesis, whereas others show reduced neurogenesis. In the human hippocampus, a sharp drop in adult neurogenesis has been observed in subjects with AD.”

One of the study’s limitations was its control group:

“There was a significant difference in age between controls [12, ages 50.7 ± 21.5] and AD patients [26, ages 81.2 ± 12.1], being the latter group older than the former group. Although we adjusted for age in the statistical differential methylation analysis, the accuracy of this correction may be limited as there is little overlap in the age ranges of both groups.”

https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-019-0672-7 “DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis”

Do delusions have therapeutic value?

gettingwell4 0-1 star Wasted resources, Beliefs, Cerebrum, Cortisol, Dopamine, Limbic system, Lower brain, Memory, Neurochemicals, Primal Therapy, Stress , , , , , , ,

This 2019 UK review discussed delusions, aka false beliefs about reality:

“Delusions are characterized by their behavioral manifestations and defined as irrational beliefs that compromise good functioning. In this overview paper, we ask whether delusions can be adaptive notwithstanding their negative features.

We consider different types of delusions and different ways in which they can be considered as adaptive: psychologically (e.g., by increasing wellbeing, purpose in life, intrapsychic coherence, or good functioning) and biologically (e.g., by enhancing genetic fitness).”

https://onlinelibrary.wiley.com/doi/full/10.1002/wcs.1502 “Are clinical delusions adaptive?”

A. Although section 4’s heading was Biological Adaptiveness of Delusions, the reviewers never got around to discussing evolved roles of brain areas and beliefs (delusions). One mention of evolutionary biology was:

“Delusions are biologically adaptive if, as a response to a crisis of some sort (anomalous perception or overwhelming distress), they enhance a person’s chances of reproductive success and survival by conferring systematic biological benefits.”

B. Although section 5’s heading was Psychological Adaptiveness of Delusions, the reviewers didn’t connect feelings and survival sensations as origins of beliefs (delusions) and behaviors. They had a few examples of feelings:

“Delusions of reference and delusions of grandeur can make the person feel important and worthy of admiration.”

and occasionally sniffed a clue:

“Some delusions (especially so‐called motivated delusions) play a defensive function, representing the world as the person would like it to be.”

where “motivated delusions” were later deemed in the Conclusion section to be a:

“Response to negative emotions that could otherwise become overwhelming.”

C. Feelings weren’t extensively discussed until section 6 Delusions in OCD and MDD, which gave readers an impression that feelings were best associated with those diseases.

D. In the Introduction, sections 4, 5, and 7 How Do We Establish and Measure Adaptiveness, the reviewers discussed feeling meaning in life, but without understanding:

  1. Feelings = meaning in life, as I quoted Dr. Arthur Janov in The pain societies instill into children:

    “Without feeling, life becomes empty and sterile. It, above all, loses its meaning.“

  2. Beliefs (delusions) defend against feelings.
  3. Consequentially, the stronger and / or more numerous beliefs (delusions) a person has, the less they feel meaning in life.

E. Where, when, why, and how do beliefs (delusions) arise? Where, when, why, and how does a person sense and feel, and what are the connections with beliefs (delusions)?

F. The word “sense” was used 29 times in contexts such as “make sense” and “sense of [anxiety, coherence, control, meaning, purpose, rational agency, reality, self, uncertainty]” but no framework connected biological sensing to delusions. Papers from other fields have detailed cause-and-effect explanations and predecessor-successor diagrams for every step of a process. Not this one.

Regarding any therapeutic value of someone else’s opinion of a patient’s delusions:

I’ll reuse this quotation from the Scientific evidence page of Dr. Janov’s 2011 book “Life Before Birth: The Hidden Script that Rules Our Lives” p.166:

“Primal Therapy differs from other forms of treatment in that the patient is himself a therapist of sorts. Equipped with the insights of his history, he learns how to access himself and how to feel.

The therapist does not heal him; the therapist is only the catalyst allowing the healing forces to take place. The patient has the power to heal himself.“

Another way Dr. Janov wrote this was on p.58 of his 2016 book Beyond Belief as quoted in Beyond Belief: The impact of merciless beatings on beliefs:

“NO ONE HAS THE ANSWER TO LIFE’S QUESTIONS BUT YOU. How you should lead your life depends on you, not outside counsel.

We do not direct patients, nor dispense wisdom upon them. We have only to put them in touch with themselves; the rest is up to them.

Everything the patient has to learn already resides inside. The patient can make herself conscious. No one else can.”

Why do we believe obvious lies?

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum

Here are two accounts of this weekend’s news from real journalists, neither of whom are fans of the current US president.

Matt Taibbi of Rolling Stone
https://taibbi.substack.com/p/russiagate-is-wmd-times-a-million
“It’s official: Russiagate is this generation’s WMD”

He cited intentional misreporting (lying) multiple times from the New York Times, Washington Post, CNN, Wall Street Journal, MSNBC, Mother Jones; and from NBC, ABC, McClatchy, New Yorker, New York Magazine, Bloomberg, BuzzFeed, Slate, Yahoo, Fortune, Guardian; and from numerous US congressmen and senators. Most of these false stories have still not yet been corrected or retracted.

  • “Recapping: the reporter who introduced Steele to the world (his September 23, 2016 story was the first to reference him as a source), who wrote a book that even he concedes was seen as “validating” the pee tape story, suddenly backtracks and says the whole thing may have been based on a Las Vegas strip act, but it doesn’t matter because Stormy Daniels, etc.
  • When explosive #Russiagate headlines go sideways, the original outlets simply ignore the new development, leaving the “retraction” process to conservative outlets that don’t reach the original audiences.
  • The Russiagate era has so degraded journalism that even once “reputable” outlets are now only about as right as politicians, which is to say barely ever, and then only by accident.
  • Authorities have been lying their faces off to reporters since before electricity! It doesn’t take much investigation to realize the main institutional sources in the Russiagate mess – the security services, mainly – have extensive records of deceiving the media.
  • As noted before, from World War I-era tales of striking union workers being German agents to the “missile gap” that wasn’t (the “gap” was leaked to the press before the Soviets had even one operational ICBM) to the Gulf of Tonkin mess to all the smears of people like Martin Luther King, it’s a wonder newspapers listen to whispers from government sources at all.”

Glenn Greenwald of The Intercept
https://twitter.com/ggreenwald

  1. “Can’t the people who got rich exploiting liberal #Resistance fears by feeding them false conspiracies at least content themselves to their bulging bank accounts from the scam they pulled off & have one day of silence where they don’t try to pretend that they were right all along?
  2. If you’re just going to let stuff like this go – unexamined, unacknowledged, and unaccounted for – don’t expect anyone to be remotely sympathetic to the fact that public trust in big media is nonexistent and politicians benefit by making journalists their enemies.
  3. And just for future reference: documenting the falsehoods, baseless conspiracies, and deceitful narratives being peddled without dissent by the major corporate media isn’t “blogging” or “media criticism.” It’s journalism. It’s reporting. And it’s vital.
  4. Nothing kills journalism worse than cowardly group-think, and it’s worse than ever since they’re congregated in the same places in Brooklyn and the West Coast and petrified of saying anything that makes them unpopular among their peers.
  5. Check every MSNBC personality, CNN law “expert,” liberal-centrist outlets and #Resistance scam artist and see if you see even an iota of self-reflection, humility or admission of massive error.
  6. I wrote this with @GGreenwald in November 2016, warning Russiagate was being used to attack, smear, and censor alternative media. Those blacklisted alternative media ended up being correct about Russiagate – while the corporate media spread actual fake news.
  7. There should be major accountability in the US media and in the intelligence community they united with to drown US political discourse for 2 years straight in unhinged conspiratorial trash, distracting from real issues. That’s what should happen as a first step. But it won’t.”

Our brains are shaped by our early environments

gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Lower brain, Memory, Neurochemicals, Oxytocin, Primal Therapy, Serotonin, Stress , , , , , , , , , , ,

This 2019 McGill paper reviewed human and animal studies on brain-shaping influences from the fetal period through childhood:

“In neonates, regions of the methylome that are highly variable across individuals are explained by the genotype alone in 25 percent of cases. The best explanation for 75 percent of variably methylated regions is the interaction of genotype with different in utero environments.

A meta-analysis including 45,821 individuals with attention-deficit/hyperactivity disorder and 9,207,363 controls suggests that conditions such as preeclampsia, Apgar score lower than 7 at 5 minutes, breech/transverse presentations, and prolapsed/nuchal cord – all of which involve some sort of poor oxygenation during delivery – are significantly associated with attention-deficit/hyperactivity disorder. The dopaminergic system seems to be one of the brain systems most affected by perinatal hypoxia-ischemia.

Exposure to childhood trauma activates the stress response systems and dysregulates serotonin transmission that can adversely impact brain development. Smaller cerebral, cerebellar, prefrontal cortex, and corpus callosum volumes were reported in maltreated young people as well as reduced hippocampal activity.

Environmental enrichment has a series of beneficial effects associated with neuroplasticity mechanisms, increasing hippocampal volume, and enhancing dorsal dentate gyrus-specific differences in gene expression. Environmental enrichment after prenatal stress decreases depressive-like behaviors and fear, and improves cognitive deficits.”

The reviewers presented strong evidence until the Possible Factors for Reversibility section, which ended with the assertion:

“All these positive environmental experiences mentioned in this section could counterbalance the detrimental effects of early life adversities, making individuals resilient to brain alterations and development of later psychopathology.”

The review’s penultimate sentence recognized that research is seldom done on direct treatments of causes:

“The cross-sectional nature of most epigenetic studies and the tissue specificity of the epigenetic changes are still challenges.”

Cross-sectional studies won’t provide definitive data on cause-and-effect relationships.

The question yet to be examined is: How can humans best address these early-life causes to ameliorate their lifelong effects?

https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14182 “Early environmental influences on the development of children’s brain structure and function” (not freely available)

A therapy to reverse cognitive decline

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Cortisol, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Telomeres, Testosterone , , , , ,

This 2018 human study presented the results of 100 patients’ personalized therapies for cognitive decline:

“The first examples of reversal of cognitive decline in Alzheimer’s disease and the pre-Alzheimer’s disease conditions MCI (Mild Cognitive Impairment) and SCI (Subjective Cognitive Impairment) have recently been published..showing sustained subjective and objective improvement in cognition, using a comprehensive, precision medicine approach that involves determining the potential contributors to the cognitive decline (e.g., activation of the innate immune system by pathogens or intestinal permeability, reduction in trophic or hormonal support, specific toxin exposure, or other contributors), using a computer-based algorithm to determine subtype and then addressing each contributor using a personalized, targeted, multi-factorial approach dubbed ReCODE for reversal of cognitive decline.

An obvious criticism of the initial studies is the small number of patients reported. Therefore, we report here 100 patients, treated by several different physicians, with documented improvement in cognition, in some cases with documentation of improvement in electrophysiology or imaging, as well.”

https://www.omicsonline.org/open-access/reversal-of-cognitive-decline-100-patients-2161-0460-1000450-105387.html “Reversal of Cognitive Decline: 100 Patients”

The lead author commented on Josh Mitteldorf’s informative post A cure for Alzheimer’s? Yes, a cure for Alzheimer’s!:

  1. “We have a paper in press, due to appear 10.22.18 (open access, JADP, I’ll send a copy as soon as available), showing 100 patients with documented improvement – some with MRI volumetrics improved, others with quantitative EEG improvements, others with evoked response improvements, and all with quantitative cognitive assessment improvement. Some are very striking – 12 point improvements in MoCA [Montreal Cognitive Assessment], for example – others less so, but all also have subjective improvement. Hopefully this will address some of the criticisms that we haven’t documented improvement in enough people.
  2. We were just turned down again for a randomized, controlled clinical trial, so on the one hand, we are told repeatedly that no one will believe that this approach works until we publish a randomized, controlled study, and on the other hand, we’ve been turned down (first in 2011/12, and now in 2018), with the complaint that we are trying to address more than one variable in the trial (as if AD is a single-variable disease!). Something of a catch-22. We are now resubmitting (unfortunately, the IRBs are not populated by functional medicine physicians, so they are used to seeing old-fashioned drug studies), and we’ll see what happens.
  3. I’ve been extending the studies to other neurodegenerative diseases, and it has been impressive how much of a programmatic response there seems to be in these ‘diseases.’
  4. I agree with you that there are many features in common with aging itself.
  5. You made a good point that APP [amyloid precursor protein] is a dependence receptor, and in fact it functions as an integrating dependence receptor, responding to numerous inputs (Kurakin and Bredesen, 2015).
  6. In the book and the publications, we don’t claim it is a “cure” since we don’t have pathological evidence that the disease process is gone. What we claim is ‘reversal of cognitive decline’ since that is what we document.
  7. As I mentioned in the book, AD is turning out to be a protective response to multiple insults, and this fits well with the finding that Abeta has an antimicrobial effect (Moir and Tanzi’s work). It is a network-downsizing, protective response, which is quite effective – some people live with the ongoing degenerative process for decades.
  8. We have seen several cases now in which a clinical trial of an anti-amyloid antibody made the person much worse in a time-dependent manner (each time there was an injection, the person would get much worse for 5-10 days, then begin to improve back toward where he/she was, but over time, marked decline occurred), and this makes sense for the idea that the amyloid is actually protecting against pathogens or toxins or some other insult.
  9. It is important to note that we’ve never claimed that all people get better – this is not what we’ve seen. People very late in the process, or who don’t follow the protocol, or who don’t address the various insults, do not improve. It is also turning out to be practitioner dependent – some are getting the vast majority of people to improve, others very few, so this is more like surgery than old-fashioned prescriptive medicine – you have to do a somewhat complicated therapeutic algorithm and get it right for best results.
  10. I’m very interested in what is needed to take the next step in people who have shown improvement but who started late in the course. For example, we have people now who have increased MoCA from 0 to 9 (or 0 to 3, etc.), with marked subjective improvement but plateauing at less than normal. These people had extensive synaptic and cellular loss prior to the program. So what do we need to raise the plateau? Stem cells? Intranasal trophic support? Something else?
  11. I haven’t yet seen a mono-etiologic theory of AD or a mono-therapeutic approach that has repeatedly positive results, so although I understand that there are many theories and treatments, there doesn’t seem to be one etiology to the disease, nor does there seem to be one simple treatment that works for most. It is much more like a network failure.”

At a specific level:

  • “There doesn’t seem to be one etiology to the disease,
  • Nor does there seem to be one simple treatment that works for most.
  • We don’t have pathological evidence that the disease process is gone.”

For general concepts, however:

  • “AD is turning out to be a protective response to multiple insults.
  • It is a network-downsizing, protective response, which is quite effective.
  • The amyloid is actually protecting against pathogens or toxins or some other insult.”

For a framework of an AD cure to be valid, each source of each insult that evoked each “protective response” should be traced.

Longitudinal studies would be preferred inside this framework. These study designs would investigate evidence of each insult’s potential modifying effect on each “protective response” that could affect the cumulative disease trajectory of each individual.

In many cases, existing study designs would be adequate if they extended their periods to the end of the subjects’ natural lifetimes. One AD-relevant example would be extending the prenatally-restraint-stressed model used in:

The framework would also encourage extending studies to at least three generations to investigate evidence for transgenerational effects, as were found in:

An hour of the epigenetic clock

gettingwell4 5+ stars Premium, Cerebrum, Epigenetics, Hypothalamus, Limbic system, Lower brain, Telomeres , , , , , ,

Starting the fifth year of this blog with a 2018 presentation by the founder of the epigenetic clock method describing the state of the art up through July 2018. The webinar was given on the release day of The epigenetic clock now includes skin study.


Segments before the half-hour mark provide an introduction to the method and several details about the concurrently-released study. The Q&A section starts a little before the hour mark.

Epigenetic causes of sexual orientation and handedness?

gettingwell4 2-3 stars Required further work, Brain development, Brain hemispheres, Cerebrum, Epigenetics, Testosterone , , , , , , ,

This 2018 Austrian human study subject was various associations of prenatal testosterone levels to fetal development:

“The available evidence suggests, albeit not conclusively, that prenatal testosterone levels may be one cause for the association of sexual orientation with handedness. Associations among women were consistent with predictions of the Geschwind–Galaburda theory (GGT), whereas those among men were consistent with predictions of the callosal hypothesis. However, research on the associations between sexual orientation and handedness appears to be compromised by various methodological and interpretational problems which need to be overcome to arrive at a clearer picture.

The GGT posits that high prenatal testosterone levels cause a delay in the fetal development of the left cerebral hemisphere which results in a right-hemisphere dominance and hence in a tendency for left-handedness. According to the GGT, high prenatal testosterone levels entail not only a masculinization of the female fetus, but also a feminization of the male fetus (contrary to neurohormonal theory). Overall, the male fetus is subjected to higher levels of intrauterine testosterone than the female fetus. The GGT is thus consistent with the higher prevalence of left-handedness among men than among women.

The callosal hypothesis applies to men only and assumes, in line with neurohormonal theory, that low prenatal testosterone levels are associated with later homosexuality. According to the CH, high prenatal testosterone enhances processes of cerebral lateralization through mechanisms of axonal pruning, thereby resulting in stronger left-hemisphere dominance and a smaller corpus callosum. Consistent with this, women have a larger corpus callosum than men.”

The study’s Limitations section included the following:

  1. “Limitations of the current study pertain to the self-report nature of our data. Behavioral data may provide differing results from those obtained here.
  2. Assessment of sexual orientation relied on a single-item measure. Utilization of rating scales (e.g., the Kinsey Sexual Orientation Scale) or of multi-item scales, and assessing different components of sexual orientation, would have allowed for a more fine-grained analysis and for a cross-validation of sexual orientation ratings with sexual attraction.
  3. Albeit both our samples were large, the proportions of bisexual and homosexual individuals were, expectedly, only small, as were effects of lateral preferences. Thus, in analysis we could not differentiate bisexual from homosexual individuals. Bisexual and homosexual individuals may differ with regard to the distribution of lateral preferences.
  4. Some effect tests in this study have been underpowered. Independent replications with even larger samples are still needed.”

The largest unstated limitation was no fetal measurements. When a fetus’ epigenetic responses and adaptations aren’t considered, not only can the two competing hypotheses not be adequately compared, but causes for the studied phenotypic programming and other later-life effects will also be missed.

https://link.springer.com/article/10.1007/s10508-018-1346-9 “Associations of Bisexuality and Homosexuality with Handedness and Footedness: A Latent Variable Analysis Approach”

Burying human transgenerational epigenetic evidence

gettingwell4 < 0 Detracted from science, Beliefs, Cerebrum, Epigenetics , ,

The poor substitutes for evidence in this 2018 US study guaranteed that human transgenerational epigenetically inherited effects wouldn’t be found in the generations that followed after prenatal diethylstilbestrol (DES) exposure:

“A synthetic, nonsteroidal estrogen, DES was administered to pregnant women under the mistaken belief it would reduce pregnancy complications and losses. From the late 1930s through the early 1970s, DES was given to nearly two million pregnant women in the US alone.

Use of DES in pregnancy was discontinued after a seminal report showed a strong association with vaginal clear cell adenocarcinoma in prenatally exposed women. A recent analysis of the US National Cancer Institute (NCI) DES Combined Cohort Follow-up Study showed elevated relative risks of twelve adverse health outcomes.

We do not have sufficient data concerning the indication for DES in the grandmother to determine whether adverse pregnancy outcomes in the third generation might resemble those of their grandmothers. Fourth generation effects of prenatal exposures in humans have not been reported.”

https://www.sciencedirect.com/science/article/pii/S0890623818304684 “Reproductive and Hormone-Related Outcomes in Women whose Mothers were Exposed in utero to Diethylstilbestrol (DES): A Report from the US National Cancer Institute DES Third Generation Study” (not freely available)

This study had many elements in common with its poor-quality reference [25] “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.

That study’s Methods section showed:

  1. Its non-statistical data was almost all unverified self-reports by a self-selected sample of the F2 grandchildren, average age 37.
  2. No detailed physical measurements or samples were taken of the F2 grandchildren, or of their F1 parents, or of their F0 grandparents, all of which are required as baselines for any transgenerational epigenetic inheritance findings.
  3. No detailed physical measurements or samples were taken of the F3 great-grandchildren, which is the generation that may provide transgenerational evidence if the previous generations also have detailed physical baselines.

That 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.”

The current study similarly used the faulty methods 1-3 above to produce results such as:

“We do not have sufficient data concerning the indication for DES in the [F0] grandmother to determine whether adverse pregnancy outcomes in the [F2] third generation might resemble those of their grandmothers.

Fourth [F3] generation effects of prenatal exposures in humans have not been reported.“

Zero studies of probably more than 10,000,000 F3 great-grandchildren of DES-exposed women just here in the US?

Who is against funding these studies? Who is afraid of what such studies may find?

One plausible hypothesis of these human studies would be of inherited effects that skipped generations! The rodent studies Epigenetic transgenerational inheritance mechanisms that lead to prostate disease and Epigenetic transgenerational inheritance of ovarian disease found inherited diseases that didn’t manifest until the F3 great-grand offspring:

The F3 generation can have disease while the F1 and F2 generations do not.

Ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.

For the current study:

  • What could be expected from a study design that didn’t include F3 women and men, which is the only generation that didn’t have direct DES exposure?
  • What a nonsensical study design to permit NON-evidence like educational level!

Human studies of possible intergenerational and transgenerational epigenetic inheritance are urgently needed. There will be abundant evidence to discover if researchers will take their fields seriously.