People will forgive you for being wrong, but they will never forgive you for being right – especially if events prove you right while proving them wrong. Thomas Sowell
“If sexually naïve females have their formative sexually rewarding experiences paired with the same male, they will recognize that male and display mate-guarding behavior towards him in the presence of a female competitor. Female rats that display mate-guarding behavior also show enhanced activation of oxytocin and vasopressin neurons in the supraoptic and paraventricular hypothalamic nucleus.
We examined the effect of a lysine-specific demethylase-1 inhibitor to block the action of demethylase enzymes and maintain the methylation state of corresponding genes. Female rats treated with the demethylase inhibitor failed to show any measure of mate guarding, whereas females treated with vehicle displayed mate guarding behavior. Demethylase inhibitor treatment also blocked the ability of familiar male cues to activate oxytocin and vasopressin neurons, whereas vehicle-treated females showed this enhanced activation.”
General principles and their study-specific illustrations were:
“Histone modifications are a key element in gene regulation through chromatin remodeling. Histone methylation / demethylation does not have straightforward transcriptional outcomes as do other histone modifications, like acetylation, which is almost invariably associated with transcriptional activation.
What is of vital importance in regards to histone methylation / demethylation is the pattern of methylation that is established. Patterns of methylation incorporate both methylated and demethylated residues, and are what ultimately play a role in transcriptional outcomes.
In the present study, inhibiting LSD1 demethylase enzymes disrupted the ability of cells to properly establish histone methylation / demethylation patterns, thus creating a deficit in the cells’ ability to transcribe the gene products necessary for the enhanced induction of OT, AVP, and the subsequent mate-guarding behaviors we observed. This study is the first to demonstrate a definitive role of epigenetic histone modifications in a conditioned sexual response.”
A subset of memory recall–induced neurons in the DG [dentate gyrus] becomes reactivated after memory attenuation,
The degree of fear reduction positively correlates with this reactivation, and
The continued activity of memory recall–induced neurons is critical for remote fear memory attenuation.
Although other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated, these results suggest that fear attenuation at least partially occurs in memory recall–induced ensembles through updating or unlearning of the original memory trace of fear.
These data thereby provide the first evidence at an engram-specific level that fear attenuation may not be driven only by extinction learning, that is, by an inhibitory memory trace different from the original fear trace.
Rather, our findings indicate that during remote fear memory attenuation both mechanisms likely coexist, albeit with the importance of the continued activity of memory recall–induced neurons experimentally documented herein. Such activity may not only represent the capacity for a valence change in DG engram cells but also be a prerequisite for memory reconsolidation, namely, an opportunity for learning inside the original memory trace.
As such, this activity likely constitutes a physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans: the engagement, rather than the suppression, of the original trauma.”
The researchers also provided examples of human trauma:
“We dedicate this work to O.K.’s father, Mohamed Salah El-Dien, and J.G.’s mother, Wilma, who both sadly passed away during its completion.”
So, how can this study help humans? The study had disclosed and undisclosed limitations:
1. Humans aren’t lab rats. We can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments.
2. It’s a bridge too far to go from neural activity in transgenic mice to expressing unfounded opinions on:
“A physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans.”
Human exposure therapies have many drawbacks, in addition to being applied externally to the patient on someone else’s schedule. A few others were discussed in The role of DNMT3a in fear memories:
“Inability to generalize its efficacy over time,
Potential return of adverse memory in the new/novel contexts,
Context-dependent nature of extinction which is widely viewed as the biological basis of exposure therapy.”
3. Rodent neural activity also doesn’t elevate recall to become an important goal of effective human therapies. Clearly, what the rodents experienced should have been translated into human reliving/re-experiencing, not recall! Terminology used in animal studies preferentially has the same meaning with humans, since the purpose of animal studies is to help humans.
4. The researchers acknowledged that:
“Other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated.”
“The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”
The study I curated yesterday, Organ epigenetic memory, demonstrated organ memory storage. It’s hard to completely rule out that other body areas may also store traumatic memories.
The wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address the whole person, the whole body, and each individual’s entire history.
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.
It’s dawned on me that although links in blog posts are indexed by search engines, links in comments may not be. Here’s a post to elevate links in three comments that may have escaped notice.
“It is my view that all researchers have a narrow focus on what they want to research, without having an over-riding paradigm in which to fit the research and its results. Janovian Primal Therapy and theory, with its focus and understanding of the three different levels of consciousness would provide for a much needed over-arching paradigm, especially in the area of mental health.”
“You are right on. The Norcross survey, in particular, is utter crap. More than half of those “experts” surveyed were CBT therapists who knew nothing about PT and yet deemed themselves confident to judge “primal scream therapy” as “discredited.” I feel the therapy will never be understood for what it is.”
“There is of course, reversibility. Michael Meaney’s baby rats had their epigenetic changes reversed with loving maternal care. There are several compounds in development which have been shown to reverse methylation. This former physician and researcher says, “Epigenetic changes affect the level of activity of our genes. Genetic activity levels affect our emotions, beliefs, and our bodies. Exploring epigenetics and chronic illness may help us understand causes that many of us suspect have played a role in the onset and evolution of our illnesses. Furthermore, these epigenetic changes have been found to be reversible, at least some of the time, even with a seemingly indirect treatment such as psychotherapy.” Epigenetics and Chronic Illness: Why Symptoms May Be Reversible
So what gives? I suspect that your researcher is working with his/her head in the sand, hamstrung by their ideological biases. If CBT can effect epigenetic changes, imagine what primal therapy can do.”
And a seven-year anniversary repost of events that affect me every day:
This 2017 UC Irvine human review subject provided details of how fetalhypothalamic-pituitary-adrenal components and systems develop, and how they are epigenetically changed by the mother’s environment:
“The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.
Development of the fetal HPA axis is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed.
Human gestational physiology and fetal HPA axis development differ even from that of closely related nonhuman primates, thereby limiting the generalizability of animal models. This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”
1. Every time I read a prenatal study I’m in awe of all that has to go right – and at the appropriate times and sequences – for a fetus to be undamaged. Add in what needs to happen at birth, during infancy, and throughout early childhood, and it seems impossible for any human to escape epigenetic damage.
2. The reviewers referenced animal studies and human research performed with postnatal subjects, despite the disclaimer:
This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”
This led to blurring of what had been studied or not with human fetuses regarding the subject.
3. These reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. Other reviewers offer informed analysis of cited studies, as Sex-specific impacts of childhood trauma summarized with cortisol:
“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:
presence and severity of psychopathology symptomology.”
4. The paper would have been better had it stayed on topic with its title “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover animals, post-natal humans, and questionable evidence.
5. I asked the reviewers to provide a searchable file to facilitate using their work as a reference.
This 2018 US government rodent study used extreme dosages to achieve its directed goals of demonizing nicotine and extolling the biomarker paradigm:
“This study examined whether adolescent nicotine exposure alters adult hippocampus-dependent learning, involving persistent changes in hippocampal DNA methylation and if choline, a dietary methyl donor, would reverse and mitigate these alterations.
Mice were chronically treated with nicotine (12.6mg/kg/day) starting at post-natal day 23 (pre-adolescent), p38 (late adolescent), or p54 (adult) for 12 days followed by a 30-day period during which they consumed either standard chow or chow supplemented with choline (9g/kg).
Our gene expression analyses support this model and point to two particular genes involved in chromatin remodeling, Smarca2 and Bahcc1. Both Smarca2 and Bahcc1 showed a similar inverse correlation pattern between promoter methylation and gene expression.
Our findings support a role for epigenetic modification of hippocampal chromatin remodeling genes in long-term learning deficits induced by adolescent nicotine and their amelioration by dietary choline supplementation.”
Let’s use the average weight of a US adult male – published by the US Centers for Disease Control as 88.8 kg – to compare the study’s dosages with human equivalents:
Nicotine at ((“12.6mg/kg/day” x .081) x 88.8 kg) = 90.6 mg.
Neither of these dosages are even remotely connected to human realities:
The human-equivalent dosage of nicotine used in this study would probably kill an adult human before the end of 12 days.
What effects would an adult human suffer from exceeding the choline “Tolerable Upper Intake Level” BY 18 TIMES for 30 days?
Isn’t the main purpose of animal studies to help humans? What’s the justification for performing animal studies simply to promote an agenda?
A funding source of this study was National Institute on Drug Abuse (NIDA) Identification of Biomarkers for Nicotine Addiction award (T-DA-1002 MG). Has the biomarker paradigm been institutionalized to the point where research proposals that don’t have biomarkers as goals aren’t funded?
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:
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.
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.
[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!
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.”
This 2018 McGill paper reviewed findings from animal and human studies on the relationships between drug-seeking behavior and epigenetic DNA methylation:
“Although there is an increasing line of evidence from preclinical models of addiction, there are only a few human studies that systematically assessed DNA methylation in addiction. Most of the studies were done on small cohorts and focused on one or a few candidate genes, except in the case of alcohol use where larger studies have been carried out.
A long line of evidence suggests that abnormal patterns of gene expression occur in brain regions related to drug addiction such as the nucleus accumbens, prefrontal cortex, amygdala, and the ventral tegmental area.
Using the “incubation of craving” model in rats trained to self-administer cocaine, and treated with either SAM or RG108, the genome-wide DNA methylation and gene expression landscape in the nucleus accumbens after short (1 day) and long (30 days) abstinence periods and the effects of epigenetic treatments were delineated. The main findings are:
A long incubation period results in robust changes in methylation;
Direct accumbal infusion of SAM that is paired with a “cue” after long incubation times increases drug-seeking behavior,
Whereas a single treatment with RG108 decreases this behavior.
Importantly, the effects of these single administrations of a DNA methylation inhibitor remain stable for 30 more days. These data suggest that DNA methylation might be mediating the impact of “incubation” on the craving phenotype and that this phenotype could be reprogrammed by a DNA demethylation agent.”
The review covered neither human dimensions of the impacts of unfulfilled needs nor investigations of exactly what pain may impel human drug-seeking behavior. The “Implications for Diagnostic and Therapeutics” were largely at the molecular level.
This 2018 Polish review subject was relationships between melatonin and depression:
“Although melatonin has been known about and referred to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment.
Melatonin has an antidepressant effect by:
Maintaining the body’s circadian rhythm;
Regulating the pattern of expression of clock genes in the suprachiasmatic nucleus (SCN); and
Modifying key genes of serotoninergic neurotransmission that are linked with a depressive mood.
Light input causes release of γ-aminobutyric acid (GABA) by the SCN, and the inhibitory signal is transmitted to the pineal gland to inhibit melatonin production.
Melatonin is produced via metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors.
Both melatonin and serotonin are synthesized from the same amino acid, tryptophan. People on a high tryptophan diet (>10 mg/kg body weight per day) have a significantly lower level of depressive symptoms, irritation, and anxiety than people on a low tryptophan diet (<5 mg/kg body weight per day).
To our knowledge, there are only 2 studies in the literature that characterize mRNA expression of ASMT in the peripheral blood of recurrent depressive disorders. They demonstrated reduced mRNA expression of ASMT in patients with depression and cognitive impairment. Surprisingly, these studies, despite promising results, have not been replicated. Moreover, no analysis of other melatonin related-genes as potential biomarkers of depression has been provided.
The main monoamine hypothesis of pathophysiology of depression indicates that depression is induced by a change in levels of ≥1 monoamines such as serotonin, noradrenaline, and dopamine. Evidence for the serotonergic theory is an observation that antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and noradrenaline reuptake inhibitors increase the level of serotonin in the brain.
We focus on serotonin as a neurotransmitter which is a precursor of melatonin synthesis. In a depressed patient, serotonin synthesis is impaired, and poor precursor availability may prevent formation of an adequate amount of melatonin. However, only a few studies have analyzed the relationship between serotonin and melatonin levels and the correlation with blood serum.”
At eight cents a day ($.04 for women), melatonin is a cheap and effective supplement.
I hadn’t considered possible antidepressant effects until reading this review. More human studies are needed.
This 2017 Massachusetts human review described one example of psychological research continuing to misinterpret measurements for hypotheses that have been rejected for physiological research:
“The current paper is a case study examining what happens to psychological research when its foundational biological context is invalidated or superseded. The example we use is heart rate variability (HRV) as a purported measure of cardiac sympathetic outflow.
The hypotheses in question are of direct relevance to fields including biological psychology, psychophysiology, and social neuroscience that use physiological measurements to answer applied questions with broader social scientific relevance. A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.
These were important and popular metrics, they attracted appropriate scrutiny, and were subsequently discarded. The above reflects well on the scientific process within basic research. The present ensuing period of ‘life after death’ within applied research does not.
It has been widely used as a dependent variable in studies of emotion, panic, stress, attentional state, health status in psychological science.
If the criteria for publishing a scientific article is simply that the measured results resolve to be statistically significant, an unstable measurement of an unstable phenomenon is an excellent vehicle for engineering differences between groups, especially considering the substantial flexibility in modern publication practices.”
Factors facilitating the misinterpretation of heart rate variability include:
Measurements are convenient and inexpensive (like salivary cortisol):
“HRV measurement lacks barriers to collection – measurement is possible during movement and activities of daily living, is easily capable of taking multiple sequential measurements without participant fatigue, and is suitable for long-term recordings. It is also inexpensive, due to multiple commercially available hardware platforms and free software analysis programs.”
The experimental concept is easily explained to sponsors.
https://psyarxiv.com/637ym “Dead Science in Live Psychology: A Case Study from Heart Rate Variability (HRV)”
This 2018 Korean review discussed aspects of the hypothalamus and aging:
“A majority of physiological functions that decline with aging are broadly governed by the hypothalamus, a brain region controlling development, metabolism, reproduction, circadian rhythm, and homeostasis. In addition, the hypothalamus is poised to connect the brain and the body so that the environmental information affecting aging can be transmitted through the hypothalamus to affect the systematic aging of the peripheral organs.
The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body. This review aims to assess the contribution of hypothalamic aging to the age-related decline in body functions, particularly from the perspective of:
energy homeostasis,
hormonal balance,
circadian rhythm, and
reproduction,
and to highlight its underlying cellular mechanisms with a focus on:
The reviewers didn’t consider aging to be an “unintended consequence” of development. This perspective was found in a reference to A study of DNA methylation and age:
“Aging is not programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways.
Genetic programs determine developmental growth and the onset of reproduction. When these programs are completed, they are not switched off.
Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”
“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes.”
“The hypothalamus is hypothesized to be a primary regulator of the process of aging.”
Almost all of the details discussed were from rodent studies.
As detailed in How to cure the ultimate causes of migraines? and its references, the hypothalamus is a brain structure that lacks feedback mechanisms for several of its activities. This structure develops shortly after conception and has an active prenatal role.
The hypothalamus plays its part in getting us developed and ready to reproduce, with certain feedback loops being evolutionarily unnecessary. The hypothalamus perfectly illustrates the point of:
“When these programs are completed, they are not switched off.”
Evolutionarily unnecessary feedback for aspects of hypothalamic activity may result in it not winding down when its developmental role is over. This activity shouldn’t be interpreted to construe a role that has some other meaning or purpose.
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypicprogramming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing 1) the influence of the sponsor’s biases, 2) any directed narrative that ignored evidence contradicting the narrative, and 3) any storytelling.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F3 great-grandchild generation.
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
The timing of in utero caffeine treatment leads to differences in adult cardiac function, gene expression, and phenotype. Exposure to caffeine from E6.5–9.5 leads the F1 generation to develop dilated cardiomyopathy with decrease % FS and increased Myh7 expression. In utero caffeine exposure from E10.5–13.5 leads to a hypertrophic cardiomyopathy in the F2 generation along with increased % FS and decreased Myh7 expression
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational critical periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.
This 2018 Nevada rodent study was on acetyl-L-carnitine’s action in the brainstem:
“We examined age-related changes in the efficiency of synaptic transmission at the calyx of Held, from juvenile adults (1-month old) and late middle-age (18- to 21-month old) mice. The calyx of Held synapse has been exploited as a model for understanding excitation-secretion coupling in central glutamatergic neurons, and is specialized for high-frequency transmission as part of a timing circuit for sound localization.
Our observations suggest that during aging, there is neuronal cell loss in the MNTB [Medial nucleus of the trapezoid body, a collection of brainstem nuclei in an area that’s the first recipient of sound and equilibrium information], similar to previous reports. In remaining synapses of the MNTB, we observed severe impairments in transmission timing and SV [synaptic vesicle] recycling, resulting in timing errors and increased synaptic depression in the calyx of Held synapse. These defects reduce the efficacy of this synapse to encode temporally sensitive information and are likely to result in diminished sound localization.
We orally administered ALCAR for 1 month and found that it reversed transmission defects at the calyx of Held synapse in the older mice.
These results support the concept that facilitators of mitochondrial metabolism and antioxidants may be an extremely effective therapy to increase synaptic function and restore short-term plasticity in aged brains, and provide for the first time a clear mechanism of action for ALCAR on activity-dependent synaptic transmission.“
Human brainstem research is neglected, as noted by Advance science by including emotion in research. Evidence from such research doesn’t play well with beliefs in the popular models and memes of human cerebral dominance.
Do you know any “late middle-age” people who have obvious auditory and synaptic deficits? What if some of the neurobiological causes of what’s wrong in their brains could be “reversed by ALCAR?”
Before using this study as a guide, however, I asked the study’s researchers about the “daily dose of ~2.9 g/kg/d.” An equivalent for a 70 kg human is (2.9 g x 70) x .081 = 16 grams daily, compared with the 500 mg to 1 g dietary supplement dose of acetyl-L-carnitine.
The study’s corresponding coauthor replied:
“This is indeed much larger than that normally consumed by humans via dietary supplementation. We are currently working to determine the effective ‘minimal’ dose of ALCAR and alpha lipoic acid, to better assist guidelines for human application of this supplement.”
Surface Your Real Self 