4-5 stars Advanced knowledge

Advanced knowledge

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

Addictive behavior and epigenetic DNA methylation

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Cerebrum, Dopamine, Epigenetics, Immune system, Limbic system, Neurochemicals , , , , , ,

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 subject has a large scope, and a narrow aspect was presented in this paper. Rodent research by one of the coauthors that was cited, Chronic pain causes epigenetic changes in the brain and immune system, provided some relevant details.

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.

https://www.sciencedirect.com/science/article/pii/S1877117318300164 “The Role of DNA Methylation in Drug Addiction: Implications for Diagnostic and Therapeutics” (not freely available)

Transgenerational epigenetic effects of maternal obesity during pregnancy

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

This 2018 Belgian review subject was in part the transgenerational epigenetic effects of maternal obesity during pregnancy. The subject was tailored for the journal in which it appeared, Atherosclerosis, so other transgenerationally inherited epigenetic effects weren’t reviewed:

“The transgenerational impact of these alterations in methylation patterns are only shown in animal studies with HFD [high-fat diet] animals. In this respect the paternal influence also comes forward.

Alterations in methylation at the spermatozoa of male rats fed with a HFD were shown in combination with transgenerational metabolic effects, mainly on the female offspring. Methylation alterations in spermatozoa were also found in the male offspring of dams fed with HFD during their pregnancy. Consequent effects on the phenotype were again only shown in female offspring (until third generation).

A transgenerational inheritance through the female germline by mitochondrial inheritance has been suggested. A recent, small study in humans found altered mitochondrial functioning in the male offspring of overweight woman. A finding that has been confirmed in mice studies with a persistence of this transfer of aberrant oocyte mitochondria into the third generation.

The identification of a number of alterations in active cardiovascular microRNA species in the offspring of animals with obesity offer promising perspectives for the future.”

Evidence for transgenerational aspects of in utero programming included two studies I hadn’t previously curated:

  1. https://www.cell.com/cell-reports/fulltext/S2211-1247(16)30663-5 “Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations” (2016)
  2. https://www.sciencedirect.com/science/article/pii/S221287781500232X “High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring” (2016)

https://www.atherosclerosis-journal.com/article/S0021-9150(18)30328-9/fulltext “In utero programming and early detection of cardiovascular disease in the offspring of mothers with obesity”

A protein involved in fasting’s epigenetic effects

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

This 2018 Illinois rodent study conducted a series of experiments on a protein that’s activated by fasting:

“Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3. JMJD3 has what we believe to be a novel metabolic role and epigenetically regulates mitochondrial β-oxidation.

Epigenetic modifications play a critical role in linking environmental signals, such as changes in nutrient and hormonal levels and the circadian rhythm, to regulate genes to maintain homeostasis. Epigenetics is particularly relevant to metabolic regulation.

In response to fasting, the interaction of JMJD3 with both SIRT1 and PPARα is induced, which leads to epigenetic activation of their own genes and of β-oxidation network genes. Downregulation of hepatic JMJD3 leads to intrinsic defects in β-oxidation, which results in liver steatosis as well as glucose and insulin intolerance.

JMJD3 was required for the beneficial effects mediated by expression of SIRT1 in obese mice and vice versa. Restoration of JMJD3 to normal levels in HFD [high-fat diet]-fed obese mice leads to improved fatty acid β-oxidation and ameliorates metabolic symptoms of obesity and these beneficial effects are largely dependent on SIRT1.”

Have to hand it to the researchers who named this protein to coincidentally rhyme with a children’s book and movie. It certainly provokes more interest than other ways of naming discoveries, such as after what it resembles and/or the discoverer’s name.

https://www.jci.org/articles/view/97736 “Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation”

Melatonin and depression

gettingwell4 4-5 stars Advanced knowledge, Dopamine, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Serotonin , , ,

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.

https://www.karger.com/Article/Pdf/489470 “Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status” (not freely available)

Dead physiological science zombified by psychological research

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Cerebrum, Cortisol, Neurochemicals, Stress

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:

  • A 30-year chain of citations similar to what Using citations to develop beliefs instead of evidence found.
  • 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)”

Common features of autoimmune diseases

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

This 2018 French review subject was mechanisms of autoimmunity:

“Autoimmune diseases (AIDs) encompass more than 80 distinct chronic disorders characterized by inflammatory reactions that can either be systemic or organ specific. In all cases, the disease development is the consequence of the effects of environmental factors in predisposed individuals.

Most of the genes identified by genome-wide association studies (GWAS) on AIDs are related to immunity. However, functional immune parameters that are commonly dysregulated in AIDs do not necessarily stem from these genetic variants. Rather than performing even larger GWAS, understanding complex traits, such as human diseases, may require meticulous analysis or cell-specific gene networks and take into account not only core genes but also seemingly irrelevant genes that may overall have an impact on the disease.

Treg cell defects have been considered a primary cause of AIDs. However, one could ask whether the Treg cell dysfunction exists before the onset of the disease or is provoked by the inflammatory event induced by the triggering components. The defect of Treg cells generally coexists with the inflammatory processes, suggesting several hypotheses:

  1. The inflammation might develop because of a poor regulation of the immune system,
  2. The Treg cells could become inefficient because of the inflammatory environment, or
  3. A common factor concomitantly leads to both effects.

It is likely that autoimmunity results from a chronic imbalance involving both environmental and intrinsic factors. It is now clear that polygenic explanations did not fulfill expectations and that more efforts are needed to understand how the interplay of environmental clues may have a phenotypic impact.”

https://nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/nyas.13560 “Pathophysiological mechanisms of autoimmunity” (not freely available) Thanks to Dr. Julien Verdier for providing a copy.

A dietary supplement that reversed age-related hearing problems in the brainstem

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Brainstem, Cerebrum, Epigenetics, Glutamate, Lower brain, Memory, Neurochemicals , , , , ,

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.”

https://www.researchgate.net/publication/323941877_Age-related_defects_in_short-term_plasticity_are_reversed_by_acetyl-L-carnitine_at_the_mouse_calyx_of_Held “Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held”

Immune memory in the brain

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

This 2018 German rodent study was a proof-of-principle for immune epigenetic memory in the brain:

“Innate immune memory is a vital mechanism of myeloid [bone marrow] cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses.

Two types of immunological imprinting can be distinguished – training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively.

Certain immune stimuli train blood monocytes to generate enhanced immune responses to subsequent immune insults. By contrast, other stimuli induce immune tolerance – suppression of inflammatory responses to subsequent stimuli.

Microglia (brain-resident macrophages) are very long-lived cells. This makes them particularly interesting for studying immune memory, as virtually permanent modification of their molecular profile appears possible. Immune memory in the brain is predominantly mediated by microglia.

In a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

Immune memory in the brain could conceivably affect the severity of any neurological disease that presents with an inflammatory component, but this will need to be studied for each individual condition.”

The researchers performed multiple experiments to test different hypotheses about how immune-response experiences are remembered. Modifications to histone methylation and acetylation were targeted.

The stimulus dosage needed to produce immune tolerance – “suppression of inflammatory responses to subsequent stimuli” – was usually four times the dosage used for immune training – “enhanced immune responses to subsequent immune insults.”

https://www.nature.com/articles/s41586-018-0023-4 “Innate immune memory in the brain shapes neurological disease hallmarks” (not freely available)

The epigenetic clock theory of aging

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Brain development, Cerebellum, Cerebrum, Epigenetics, Lower brain, Memory, Stress, Telomeres , , , , , , ,

My 400th curation is a 2018 US/UK paper by coauthors of Using an epigenetic clock to distinguish cellular aging from senescence. They reviewed the current state of epigenetic clock research, and proposed a new theory of aging:

“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes, the molecular footprints of which give rise to DNAm [DNA methylation] age estimators.

It is best to interpret epigenetic age estimates as a higher-order property of a large number of CpGs much in the same way that the temperature of a gas is a higher-order property that reflects the average kinetic energy of the underlying molecules. This interpretation does not imply that DNAm age simply measures entropy across the entire genome.

To date, the most effective in vitro intervention against epigenetic ageing is achieved through expression of Yamanaka factors, which convert somatic cells into pluripotent stem cells, thereby completely resetting the epigenetic clock. In vivo, haematopoietic stem cell therapy resets the epigenetic age of blood of the recipient to that of the donor.

Future epidemiological studies should consider other sources of DNA (for example, buccal cells), because more powerful estimates of organismal age can be obtained by evaluating multiple tissues. Other types of epigenetic modifications such as adenine methylation or histone modifications may lend themselves for developing epigenetic age estimators.”


https://www.nature.com/articles/s41576-018-0004-3 “DNA methylation-based biomarkers and the epigenetic clock theory of ageing” (not freely available)

I curated four other papers cited in this review:

Do you want your quality of life to be under or over this curve?

What are you doing to reverse epigenetic processes and realize what you want?

  • Do you have ideas and/or behaviors that interfere with taking constructive actions to change your phenotype?
  • If you aren’t doing anything, are you honest with yourself about feelings of helplessness?
  • Do your beliefs in fate, or in technology, or in divine interventions justify inactions?

The lifelong impact of maternal postpartum behavior

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Oxytocin, Stress, Vasopressin , , , , , ,

This 2018 French/Italian/Swiss rodent study was an extension of the work done by the group of researchers who performed Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies and Treating prenatal stress-related disorders with an oxytocin receptor agonist:

“Reduction of maternal behavior [nursing behavior, grooming, licking, carrying pups] was predictive of behavioral disturbances in PRS [prenatally restraint stressed] rats as well as of the impairment of the oxytocin and its receptor gene expression.

Postpartum carbetocin [an oxytocin receptor agonist unavailable in the US] corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior.

Moreover, postpartum carbetocin had an anti-stress effect on HPA [hypothalamic-pituitary-adrenal] axis activity in the adult PRS progeny and increased hippocampal mGlu5 [type 5 metabotropic glutamate] receptor expression in aging.

Early postpartum carbetocin administration to the dam enhances maternal behavior and prevents all the pathological outcomes of PRS throughout the entire lifespan of the progeny..proves that the defect in maternal care induced by gestational stress programs the development of the offspring.“


This chart from Figure 4 summarized the behavioral performance of aged adult male progeny in relation to the experimental variables of:

  1. Stress administered to the mothers three times daily every day during the second half of pregnancy up until delivery; and
  2. The effects on the mothers’ behavior of daily carbetocin administration during postpartum days 1 through 7.

The symbols denote which of these relationships had statistically significant effects:

  • “* p [Pearson’s correlation coefficient] < 0.05 PRS-Saline vs. CONT-Saline;
  • # p < 0.05 PRS-Carbetocin vs. the PRS-Saline group.”

There are many interesting aspects to this study. Ask the corresponding coauthor Dr. Sara Morley-Fletcher at sara.morley-fletcher@univ-lille1.fr for a copy.

One place the paper referenced the researchers’ previous studies was in this context:

“Postpartum carbetocin administration reversed the same molecular and behavioral parameters in the hippocampus, as does adult chronic carbetocin treatment, i.e. it led to a correction of the HPA axis negative feedback mechanisms, stress and anti-stress gene expression, and synaptic glutamate release. The fact that postpartum carbetocin administration [to the stressed mothers in this study] had the same effect [on the PRS infants in this study] as adult carbetocin treatment [to the PRS offspring in the previous study] indicates a short-term effect of carbetocin when administered in adulthood and a reprogramming (long-term) effect lasting until an advanced age when administered in early development.”

This group’s research seems to be constrained to treatments of F0 and F1 generations. What intergenerational and transgenerational effects would they possibly find by extending research efforts to F2 and F3 generations?

As the study may apply to humans:

The study demonstrated that stresses during the second half of pregnancy had lifelong impacts on both the mothers’ and offsprings’ biology and behavior. Studies and reviews that attribute similar human biological and behavioral conditions to unknown causes, or shuffle them into the black box of individual differences, should be recognized as either disingenuous or insufficient etiological investigations.

The study showed that prevention of gestational stress was a viable strategy. The control group progeny’s biology and behavior wasn’t affected by carbetocin administration to their mothers because neither they nor their mothers had experience-dependent epigenetic deficiencies.

The study demonstrated a biological and behavioral cure for the PRS offspring by changing their stressed mothers’ behaviors during a critical period of their development. The above excerpt characterized improving the mothers’ behaviors as a long-term cure for the PRS descendants, as opposed to the short-term cure of administering carbetocin to the PRS children when they were adults.

What long-term therapies may be effective for humans who had their developmental trajectories altered by their mothers’ stresses during their gestation, or who didn’t get the parental care they needed when they needed it?

https://www.sciencedirect.com/science/article/pii/S0161813X18301062 “Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance” (not freely available)

Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies

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

This 2018 French/Italian/Swiss rodent study used a prenatally restraint stressed (PRS) model to create problems that could be resolved by various chemicals:

“S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties.

Most of studies examining the antidepressant effects of new molecules are carried out using behavioral tests performed in unstressed animals.

Corticosterone-treated mice and rats exposed to chronic stress are models that do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period. The PRS rat model is characterized by a prolonged corticosterone response to stress and by abnormal behavior.

All the behavioral alterations induced by PRS were corrected by chronic S 47445 administration at both doses.”

The paper included a section comparing S 47445 to ketamine:

“Ketamine, however, causes severe cognitive impairment and psychotomimetic [mimics the symptoms of psychosis, reference not freely available] effects that are direct consequences of the prolonged inhibition of NMDA receptors in cortical and hippocampal interneurons, and seriously limit the chronic administration of the drug in the clinical setting. [reference not freely available]

S 47445 by inducing a direct activation of AMPARs displayed an antidepressant activity without the adverse effect of ketamine. Indeed, contrary to ketamine, S 47445 presented no psychotomimetic effects and induced no occurrence of spontaneous epileptic seizures. [reference freely available] Moreover, S 47445 also presented pro-cognitive properties.”

Compare the above with this April 2018 Chicago Tribune story that had opinions with no linked references:

“ketamine, an anesthetic used to sedate both people and animals before surgery. It’s also a notorious street drug, abused by clubgoers seeking a trancelike, hallucinatory high. But in recent years, numerous studies have found that ketamine can be an effective and speedy treatment for people with depression.”

Which coverage better informed us?

Treating prenatal stress-related disorders with an oxytocin receptor agonist was performed by several of this paper’s coauthors. One references to it was:

“We have already reported that depolarization-evoked glutamate release in the ventral hippocampus is negatively correlated with risk-taking behavior of PRS rats, and that such correlation can be corrected by chronic treatment with monoaminergic/ melatoninergic antidepressants or oxytocin receptor agonist. Thus, an impairment of glutamatergic transmission in the ventral hippocampus lies at the core of the pathological phenotype of PRS rats.”

Looking at the above graphic of the experimental design, I’m not sure why the term perinatal (occurring during or pertaining to the phase surrounding the time of birth) was used in the paper’s title and content to describe the stress period. The pregnant females were stressed three times every day during the second half of pregnancy up until delivery, so the prenatal (previous to birth) term was more applicable.

So, how does this study help humans?

One takeaway is to avoid stressing pregnant mothers-to-be if her children will be expected to become adults without cognitive, emotional, and behavioral problems.

The study demonstrated one way prenatal events cause lifelong effects. The PRS model provides another example of why it’s useless to ask adult humans to self-report causes of epigenetic problems in their lives when these originated before birth, during infancy, or in early childhood, well before humans develop sufficient cognitive capability to recognize such situations. It’s incomprehensible that this unreliable paradigm is still given significant weight in stress studies, especially when experimental designs:

“Do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period.”

Also, a relevant difference between humans and PRS rats is that we can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments such as those mentioned above.

https://www.sciencedirect.com/science/article/pii/S0028390818301291 “The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats” (not freely available) Thanks to coauthors Stefania Maccari and Dr. Jerome Mairesse for providing a copy.