Memory

Prenatal stress heightened adult chronic pain

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress, Thalamus , , , , , ,

This 2019 McGill rodent study found:

“Prenatal stress exacerbates pain after injury. Analysis of mRNA expression of genes related to epigenetic regulation and stress responses in the frontal cortex and hippocampus, brain structures implicated in chronic pain, showed distinct sex and region-specific patterns of dysregulation.

In general, mRNA expression was most frequently altered in the male hippocampus and effects of prenatal stress were more prevalent than effects of nerve injury. Recent studies investigating chronic pain-related pathology in the hippocampus in humans and in rodent models demonstrate functional abnormalities in the hippocampus, changes in associated behavior, and decreases in adult hippocampal neurogenesis.

The change in expression of epigenetic- and stress-related genes is not a consequence of nerve injury but rather precedes nerve injury, consistent with the hypothesis that it might play a causal role in modulating the phenotypic response to nerve injury. These findings demonstrate the impact of prenatal stress on behavioral sensitivity to a painful injury.

Decreased frontal mRNA expression of BDNF and BDNF IV in male offspring following neuropathic pain or prenatal stress respectively. Relative mRNA expression of other stress-related genes (GR17, FKBP5) and epigenetic-related genes (DNMTs, TETs, HDACs, MBDs, MeCP2) in male offspring.

A drastic decrease in expression of HDAC1 was observed in all groups compared to sham-control animals. CCI: chronic constriction injury.”

The study’s design was similar to the PRS (prenatal restraint stress) model, except that the PRS procedure covered gestational days 11 to 21 (birth):

“Prenatal stress was induced on Embryonic days 13 to 17 by restraining the pregnant dams in transparent cylinder with 5 mm water, under bright light exposure, 3 times per day for 45 min.”

None of the French, Italian, and Swiss PRS studies were cited.

The limitation section included:

  1. “Although our study shows significant changes in expression of epigenetic enzymes, it didn’t examine the impact of these changes on genes that are epigenetically regulated by this machinery or their involvement in intensifying pain responses.
  2. The current study is limited by the focus on changes in gene expression which do not necessarily correlate with changes in protein expression.
  3. Another limitation of this study is the inability to distinguish the direct effects of stress in utero vs. changes in the dam’s maternal behavior due to stress during pregnancy; cross-fostering studies are needed to address this issue.
  4. Functional experiments that involve up and down regulation of epigenetic enzymes in specific brain regions are required to establish a causal role for these processes in chronic pain.”

What do you think about possible human applicability of this study’s “effects of prenatal stress were more prevalent than effects of nerve injury” finding?

Are there any professional therapeutic frameworks that instruct trainees to recognize that if a person’s mother was stressed while pregnant, their prenatal experiences could cause more prevalent biological and behavioral effects than a recent injury?

https://www.sciencedirect.com/science/article/pii/S0166432819315219 “Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific changes in supraspinal mRNA expression of epigenetic- and stress-related genes in adulthood” (not freely available)

An epigenetic clock review by committee

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This 2019 worldwide review of epigenetic clocks was a semi-anonymous mishmash of opinions, facts, hypotheses, unwarranted extrapolations, and beliefs. Diversity of viewpoints among the 21 coauthors wasn’t evident.

1. Citations of coauthors’ works seemed excessive, and they apologized for omissions. However:

  • Challenge 5 was titled “Single-cell analysis of aging changes and disease” and
  • Table 1 “Major biological and analytic issues with epigenetic DNA methylation clocks” had single-cell analysis as the Proposed solution to five Significant issues.

Yet studies such as High-Resolution Single-Cell DNA Methylation Measurements Reveal Epigenetically Distinct Hematopoietic Stem Cell Subpopulations were unmentioned.

2. Some coauthors semi-anonymously expressed faith that using current flawed methodologies in the future – only more thoroughly, with newer equipment, etc. – would yield better results. If all 21 coauthors were asked their viewpoints of Proposed solutions to the top three Significant issues of epigenetic clocks, what would they emphasize when quoted?

3. Techniques were praised:

“Given the precision with which DNA methylation clock age can be estimated and evolving measures of biological, phenotype-, and disease-related age (e.g., PhenoAge, GrimAge)..”

Exactly why these techniques have at times produced inexplicable results wasn’t examined, though. Two examples:

  • In Reversal of aging and immunosenescent trends, Levine PhenoAge methodology estimated that the 51-65 year old subjects’ biological ages at the beginning of the study averaged 17.5 years less than their chronological age. Comparing that to Horvath average biological age of 3.95 years less raised the question: exactly why did PhenoAge show such a large difference?
  • The paper mentioned GrimAge methodology findings about “smoking-related changes.” But it didn’t explain why GrimAge methylation findings most closely associated with smoking history also accurately predicted future disease risk with non-smokers.

Eluding explanations for these types of findings didn’t help build confidence in methodologies.

4. A more readable approach to review by committee could have coauthors – in at least one section – answer discussion questions, as Reversing epigenetic T cell exhaustion did with 18 experts.

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1824-y “DNA methylation aging clocks: challenges and recommendations”

A review of fetal adverse events

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This 2019 Australian review subject was fetal adversities:

“Adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature.

These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalizing behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalizing behaviours such as anxiety. The term ‘perinatal compromise’ serves as an umbrella term for intrauterine growth restriction, maternal immune activation, prenatal stress, early life stress, premature birth, placental dysfunction, and perinatal hypoxia.

The above conditions are associated with imbalanced excitatory-inhibitory pathways resulting from reduced GABAergic signalling. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA synthesizing enzyme Glutamate Decarboxylase 1, resulting in increased levels of glutamate is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD.

The posterior cerebellum’s role in higher executive functioning is becoming well established due to its connections with the prefrontal cortex, association cortices, and limbic system. It is now suggested that disruptions to cerebellar development, which can occur due to late gestation compromises such as preterm birth, can have a major impact on the region of the brain to which it projects.

Activation of the maternal hypothalamic-pituitary adrenal (HPA) axis and placental protection. Psychological stress is perceived by the maternal HPA axis, which stimulates cortisol release from the maternal adrenal gland.

High levels of maternal cortisol are normally prevented from reaching the fetus by the 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) enzyme, which converts cortisol to the much less active cortisone. Under conditions of high maternal stress, this protective mechanism can be overwhelmed, with the gene encoding the enzyme becoming methylated, which reduces its expression allowing cortisol to cross the placenta and reach the fetus.”

The reviewers extrapolated many animal study findings to humans, although most of their own work was with guinea pigs. The “suggest” and “may” qualifiers were used often – 22 and 37 times, respectively. More frequent use of the “appears,” “hypothesize,” “propose,” and “possible” terms was justified.

As a result, many reviewed items such as the above graphic and caption should be viewed as hypothetical for humans rather than reflecting solid evidence from quality human studies.

The reviewers focused on the prenatal (before birth) period more than the perinatal (last trimester of pregnancy to one month after birth) period. There were fewer mentions of birth and early infancy adversities.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12814 “Perinatal compromise contributes to programming of GABAergic and Glutamatergic systems leading to long-term effects on offspring behaviour” (not freely available)

Organismal aging and cellular senescence

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I’ll curate this 2019 German review through its figures:

“With the discovery of beneficial aspects of cellular senescence and evidence of senescence being not limited to replicative cellular states, a redefinition of our comprehension of aging and senescence appears scientifically overdue.

Figure 1. Current determinants and relevant open questions, marking the processes of aging and senescence as discussed in the text. Aspects represented in green are considered as broadly accepted or scientifically consolidated. Novel aspects that are yet unproven, or are under debate, are highlighted in red.

SASP = senescence-associated secretory phenotype. AASP = putative aging-associated secretory phenotype as suggested in the text.

Figure 2. Theories on the causality and purpose of aging. Graphically summarized are four contrasting concepts crystallized from current evidence addressing the inductive driving force of aging. Apart from a stochastic deleteriome, there are arguments for a pseudo-programmed, programmed or at least partially programmed nature of aging.

Figure 3. Comparative representation of the aging and senescence processes highlighting different levels of interaction and putative sites of interventions.

(1) As discussed in the text, causative mechanisms of aging are still not well understood, however, multiple factors including genetic, epigenetic and stress-related effects seem to have an orchestrated role in the progression of aging. Senescence on the other hand, is seen as a programmed response to different kinds of stressors, which proceed in defined stages. Whether, in analogy, aging also follows a defined program or sequential stages is not known.

(2) Senescence involves autocrine and paracrine factors, which are responsible for a ‘seno-infection’ or bystander effect in neighboring cells. There is currently no direct evidence for a similar factor composition propagating the aging process via a kind of ‘gero-infection’.

(3) Accumulation of senescent cells has been described as a hallmark of aging; however, whether they are a causative factor or a consequence of tissue and organismal aging is still unknown. As discussed in the text, it appears possible that aging and senescence mutually influence each other through positive feedback at this level, leading to accelerated tissue damage and aging.

(4,5) Clearance of senescent or aging cells might constitute putative targets for interventional approaches aimed to reduce or reverse the impact of aging and improve cell and tissue homeostasis by inducing a ‘rejuvenation’ process.

Figure 4. Pathological and beneficial functions of aging and senescence, according to current knowledge. In red are represented pathological consequences and in green beneficial functions of aging and senescence.

The impact of aging has mainly been described at the organismal level, since a complete cellular functional profile has not yet been established. Accordingly, whether beneficial consequences of the aging process exist at the cellular level is unclear.”

The assertion of Figure 3 (2) that:

“There is currently no direct evidence for a similar factor composition propagating the aging process via a kind of ‘gero-infection.”

was shown to be false in Reevaluate findings in another paradigm:

“It was demonstrated that increased aging occurred as a result of lack of gonadotropin-releasing hormone and that increased lifespan resulted from its provision during aging.

In this manner:

  1. Aging of hypothalamic microglia leads to
  2. Aging of the hypothalamus, which leads to
  3. Aging elsewhere in the body.

So here we have a multi-level interaction:

  1. Activation of NF-κB leads to
  2. Cellular aging, leading to
  3. A diminished production of GnRH, which then
  4. Acts (through cells with a receptor for it, or indirectly as a result of changes to GnRH-receptor-possessing cells) to decrease lifespan.

So the age state of hypothalamic cells, at least with respect to NF-κB activation, is communicated to other cells via reduced output of GnRH.”

The reviewers’ position on Figure 2 was:

“In our view, recent evidence that

  • Senescence is based on an unterminated developmental growth program and the finding that
  • The concept of post-mitotic senescence requires the activation of expansion, or ‘growth’ factors as a second hit,

favor the assumption that aging underlies a grating of genetic determination similarly to what is summarized above under the pseudo-programmed causative approach.”

Their position on Figure 4’s beneficial effects of aging began with the sentence:

“If we assume that aging already starts before birth, it can be considered simply a developmental stage, required to complete the evolutionary program associated with species-intrinsic biological functions such as reproduction, survival, and selection.”

Cited studies included:

https://www.mdpi.com/2073-4409/8/11/1446 “Dissecting Aging and Senescence-Current Concepts and Open Lessons”

Epigenetic transgenerational inheritance extends to the great-great-grand offspring

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This 2019 rodent study by the Washington State University labs of Dr. Michael Skinner continued to F4 generation great-great-grand offspring, and demonstrated that epigenetic inheritance mechanisms are similar to imprinted genes:

“Epigenetic transgenerational inheritance potentially impacts disease etiology, phenotypic variation, and evolution. An increasing number of environmental factors from nutrition to toxicants have been shown to promote the epigenetic transgenerational inheritance of disease.

Imprinted genes are a special class of genes since their DNA methylation patterns are unchanged over the generation and are not affected by the methylation erasure occurring early in development. The transgenerational epigenetic alterations in the germline appear to be permanently reprogrammed like imprinted genes, and appear protected from this DNA methylation erasure and reprogramming at fertilization in the subsequent generations. Similar to imprinted genes, the epigenetic transgenerational germline epimutations appear to have a methylation erasure in the primordial germ cells involving an epigenetic molecular memory.

Comparison of the transgenerational F3 generation, with the outcross to the F4 generation through the paternal or maternal lineages, allows an assessment of parent-of-origin transmission of disease or pathology. Observations provided examples of the following:

  1. Pathology that required combined contribution of both paternal and maternal alleles to promote disease [testis and ovarian disease];
  2. Pathology that is derived from the opposite sex allele such as father to daughter [kidney disease] or mother to son [prostate disease];
  3. Pathology that is derived from either parent-of-origin alleles independently [obesity];
  4. Pathology that is transmitted within the same sex, such as maternal to daughter [mammary tumor development]; and
  5. Pathology that is observed only following a specific parent-of-origin outcross [both F4 male obesity and F4 female kidney disease in the vinclozolin lineage].”

https://www.sciencedirect.com/science/article/pii/S0012160619303471 “Epigenetic transgenerational inheritance of parent-of-origin allelic transmission of outcross pathology and sperm epimutations”

This study showed that epigenetically inherited legacies extend to the fifth generation. Do any of us know our ancestors’ medical histories back to our great-great-grandparents?

Will toxicologists take their jobs seriously, catch up to current science, and investigate possible effects in at least the F3 generation that had no direct toxicant exposure?

Reversing epigenetic T cell exhaustion

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

This 2019 worldwide discussion among 18 experts concerned T cell exhaustion:

“‘T cell exhaustion’ is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours.

Key questions remain about the potential to reverse the epigenetic programme of exhaustion and how this might affect the persistence of T cell populations.”

There were nearly a dozen viewpoints on “What do we mean by T cell exhaustion and/or dysfunction and how would you define this state?” 🙂

Answers to the question “What are the key controversies and outstanding research questions?” included:

  • “What are the cellular signalling and transcriptional pathways that drive the conversion to an exhausted T cell phenotype, and how can the chromatin and transcriptional changes of exhaustion be reversed in individual exhausted cells?
  • Whether and how we can manipulate signalling pathways to both activate and maintain T cell responses remain open questions, as does the question of whether pharmacological manipulations can reverse the epigenetic changes associated with exhaustion versus expand less-exhausted populations.
  • We need to define better the effects of the microenvironment on the induction of T cell exhaustion, the developmental trajectories of exhaustion and the point at which and extent to which exhaustion can be reversed. Understanding the consequences of unleashing T cells from exhaustion will also be crucial to designing the most effective therapeutic interventions.
  • When and how exhausted T cell populations are formed. The original view that they are terminally differentiated descendants of formerly ‘normal’ effector T cells has been challenged.
  • Whether the predysfunctional T cells themselves, or their more differentiated (and phenotypically dysfunctional) progeny, form the ultimate effector pool for control of human tumours.
  • How do the functions and states (subpopulations) of exhausted T cells change over time? Can the epigenetic state of exhaustion be reversed to form true effector or memory T cells, and is this required for improved cancer immunotherapy?
  • There is no definitive marker for exhausted T cells, although TOX may prove to be useful. Transcriptional profiles are informative, but epigenetic changes are more specific and robust. A major clinical question is whether exhausted T cells can be, or indeed need to be, reprogrammed to achieve therapeutic benefit.”

https://www.nature.com/articles/s41577-019-0221-9 “Defining ‘T cell exhaustion'” (not freely available)

Get outside today

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

This 2019 Finnish review focused on vitamin D’s immune system effects:

“The epigenome of human monocytes is at multiple levels sensitive to vitamin D. These data served as the basis for the chromatin model of vitamin D signaling, which mechanistically explains the activation of a few hundred primary vitamin D target genes.

Vitamin D and its receptor are able to antagonize the pro-inflammatory actions of the transcription factors nuclear factor activated T cells (NF-AT) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in T cells. In this way, vitamin D reduces autoimmunity, such as the onset and progression of multiple sclerosis, as well as chronic inflammation.

Population-wide recommendations do not take inter-individual variations into account, such as a different molecular response to vitamin D, which are expressed by the vitamin D response index. Instead of population-based recommendations for vitamin D3 supplementation there should be personalized recommendations in order to reach a vitamin D status that is optimized for an individual’s health protection.

Trained immunity implies that immune cells memorize challenges, to which they are exposed in their rather short lifespan, in form of changes of their epigenome leading to subtype specification. The stabilization of the epigenomes of the subtypes of monocytes, macrophages and dendritic cells by vitamin D can prevent or delay the onset of common age-related diseases.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753645/ “Vitamin D Signaling in the Context of Innate Immunity: Focus on Human Monocytes”

One of the five elements of the clinical trial Reversal of aging and immunosenescent trends was daily 3,000 IU vitamin D3 supplementation for nine months. That study’s monocyte findings included:

“Analysis of CyTOF‐defined immune cell populations revealed the most robust changes to be decreases in total and CD38‐positive monocytes and resulting increases in the lymphocyte‐to‐monocyte ratio (LMR). The changes in mean monocyte populations persisted 6 months after discontinuation of treatment, and the increase in LMR remained highly significant at 18 months as well.”

Too cheap for clinical trials

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Let’s compare and contrast a 2019 meta-analysis and a 2017 review of using acetyl-L-carnitine to treat diabetic neuropathy.

A 2019 Brazilian meta-analysis Acetyl‐L‐carnitine for the treatment of diabetic peripheral neuropathy of four previous trials stated:

  • “The risk of bias was high in both trials of different ALC doses and low in the other two trials.
  • No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief.
  • At doses greater than 1500 mg/day, ALC reduced pain more than placebo. This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.
  • The placebo-controlled studies did not measure functional impairment and disability scores.
  • No study used validated symptom scales.
  • Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.

Authors’ conclusions:

  • We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty.
  • Data on functional and sensory impairment and symptoms are lacking, or of very low certainty.
  • The evidence on adverse events is too uncertain to make any judgements on safety.”

A 2017 Italian review Effects of acetyl-L-carnitine in diabetic neuropathy and other geriatric disorders stated:

“A long history of diabetes mellitus and increasing age are associated with the onset of diabetic neuropathy, a painful and highly disabling complication with a prevalence peaking at 50% among elderly diabetic patients. The management of diabetic neuropathy is extremely difficult: in addition to the standard analgesics used for pain control, common treatments include opioids, anticonvulsants, antidepressants, and local anesthetics, alone or in combination. Such therapies still show a variable, often limited efficacy, however.

Many patients do not spontaneously report their symptoms to physicians, but, if asked, they often describe having experienced a persistent and non-abating pain for many years. The prevalence of painful symptoms is just as high in patients with mild neuropathy as in those with more advanced DPN.

Through the donation of acetyl groups, ALC exerts a positive action on mitochondrial energy metabolism. ALC has cytoprotective, antioxidant, and antiapoptotic effects in the nervous system.

ALC has also been proposed for the treatment of other neurological and psychiatric diseases, such as mood disorders and depression, dementia, Alzheimer’s disease, and Parkinson’s disease, given that synaptic energy states and mitochondrial dysfunctions are core factors in their pathogenesis. Compared to other treatments, ALC is safe and extremely well tolerated.

In nerve injury, the mGlu2 receptor overexpressed by ALC binds the glutamate, reducing its concentration in the synapses with an analgesic effect. ALC may improve nerve regeneration and damage repair after primary nerve trauma.”

Where will the money come from to realize what the 2017 review promised, as well as provide what the 2019 meta-analysis required?

Do we prefer the current “limited efficacy” treatments of “opioids, anticonvulsants, antidepressants, and local anesthetics?”

Who will initiate clinical trials of a multiple of the normal dietary supplement dose (500 mg at $.25 a day, retail)? How profitable is a product whose hypothetical effective dosage for diabetic neuropathy (3000 mg) sells for only $1.50 a day?

Perinatal stress and sex differences in circadian activity

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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”

Caloric restriction’s epigenetic effects

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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

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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”

A better method of measuring neurogenesis

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One of the references cited in Linking adult neurogenesis to Alzheimer’s disease was https://www.nature.com/articles/s41591-019-0375-9 “Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease” (not freely available).

This 2019 Spanish human study used improved techniques to find:

“Adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry. Direct evidence of AHN in humans has remained elusive. Determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential.

By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced.

These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.”

The control group was 13 neurologically healthy deceased people aged 43 to 87. The AD group was 45 deceased people, distributed among the six Braak stages of the pathology, aged 52 to 97.

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”

OCD and neural plasticity

gettingwell4 0-1 star Wasted resources, Amygdala, Brain hemispheres, Dopamine, Epigenetics, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals, Stress, Thalamus , , , ,

Update: this was retracted on February 23, 2021. The retraction note is at https://www.nature.com/articles/s41598-021-84474-5.

This 2019 New York rodent study investigated multiple avenues to uncover mechanisms of obsessive-compulsive disorder:

“Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum) may be causally linked. Numerous genetic and environmental factors may reduce striatum sensitivity and lead to maladaptive overcompensation, potentially accounting for a significant proportion of cases of pathological OCD-like behaviors.

Our results indicate that both the development and reversal of OCD-like behaviors involve neuroplasticity resulting in circuitry changes in BLA-DLS and possibly elsewhere.”

https://www.nature.com/articles/s41598-019-45325-6.pdf “Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism”

The researchers explored two genetic models of OCD, showed why these insufficiently explained observed phenomena, then followed up with epigenetic investigations. They demonstrated how and the degree to which histone modifications and DNA methylation regulated both the development and reversal of OCD symptoms.

However, the researchers also carelessly cited thirteen papers outside the specific areas of the study to support one statement in the lead paragraph:

“Novel studies propose that modulations in gene expression influenced by environmental factors, are connected to mental health disorders.”

Only one of the thirteen citations was more recent than 2011, and none of them were high-quality studies.

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.”