DNA methylation

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”

Linking adult neurogenesis to Alzheimer’s disease

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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

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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.

Transgenerational diseases caused by great-grandmother DDT exposure

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This 2019 rodent study from the labs of Dr. Michael Skinner at Washington State University found:

“The exposure of a gestating female during fetal gonadal sex determination to DDT can promote the epigenetic transgenerational inheritance of obesity and disease.

Transgenerational pathologies (F3 generation) of late puberty, obesity, testis, prostate, and multiple disease were observed in the DDT lineage males. Obesity, ovarian, kidney, and multiple disease transgenerational pathologies (F3 generation) were observed in the DDT lineage females.

Epigenetic biomarkers or diagnostics provide preliminary evidence for preconception diagnosis of increased susceptibility to transgenerational disease in offspring.”

For those of us who thought DDT was discontinued:

“DDT was banned in the USA in 1973, but it is still recommended by the World Health Organization for indoor residual spray. India is by far the largest consumer of DDT worldwide.

India has experienced a 5-fold increase of type II diabetes over the last three decades with a predisposition to obesity already present at birth in much of the population. Although a large number of factors may contribute to this increased incidence of obesity, the potential contribution of ancestral toxicant exposures in the induction of obesity susceptibility requires further investigation.”

Where are the human studies of this subject? Why aren’t follow-on generations’ diseases traced to the likely sources?

How many F3 great-grandchildren of women exposed to DDT during pregnancy are alive today? Millions, tens of millions?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536675 “Sperm epimutation biomarkers of obesity and pathologies following DDT induced epigenetic transgenerational inheritance of disease”

Infant DNA methylation and caregiving

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This 2019 US human study attempted to replicate findings of animal studies that associated caregiver behavior with infant DNA methylation of the glucocorticoid receptor gene:

“Greater levels of maternal responsiveness and appropriate touch were related to less DNA methylation of specific regions in NR3c1 exon 1F, but only for females. There was no association with maternal responsiveness and appropriate touch or DNA methylation of NR3c1 exon 1F on prestress cortisol or cortisol reactivity. Our results are discussed in relation to programming models that implicate maternal care as an important factor in programing infant stress reactivity.”

The study had many undisclosed and a few disclosed limitations, one of which was:

“Our free-play session, while consistent with the length of free-play sessions in other studies, was short (5 min). It is unclear whether a longer length of time would have yielded significant different maternal responsiveness and appropriate touch data.”

The final sentence showed the study’s purpose was other than discovering factual evidence:

“Following replication of this work, it could ultimately be used in conjunction with early intervention, or home-visiting programs, to measure the strength of the intervention effect at the epigenetic level.”

https://onlinelibrary.wiley.com/doi/full/10.1002/imhj.21789 “DNA methylation of NR3c1 in infancy: Associations between maternal caregiving and infant sex” (not freely available)

What drives cellular aging?

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This 2019 US/UK human cell study by the founder of the epigenetic clock method investigated epigenetic aging:

“It is widely assumed that extension of lifespan is a result of retardation of ageing. While there is no counter-evidence to challenge this highly intuitive association, supporting empirical evidence to confirm it is not easy to acquire.

The scarcity of empirical evidence is due in part to the lack of a good measure of age that is not based on time. In this regard, the relatively recent development of epigenetic clocks is of great interest.

At the cellular level more is known, but from the perspective of what epigenetic ageing is not, rather than what it is. While we still do not know what cellular feature is associated with epigenetic ageing, we can now remove:

  • somatic cell differentiation

from the list of possibilities and place it with

  • cellular senescence,
  • proliferation and
  • telomere length maintenance,

which represent cellular features that are all not linked to epigenetic ageing.”

The study used several agents, including rapamycin, to investigate the hypotheses. Rapamycin isn’t a panacea, however:

“The ability of rapamycin to suppress the progression of epigenetic ageing is very encouraging for many reasons not least because it provides a valuable point-of-entry into molecular pathways that are potentially associated with it. Evidently, the target of rapamycin, the mTOR complex is of particular interest.

The convergence of the GWAS observation with the experimental system described here is a testament of the strength of the skin & blood clock in uncovering biological features that are consistent between the human level and cellular level. It lends weight to the emerging view that the mTOR pathway may be the underlying mechanism that supports epigenetic ageing.”

The limitation section ended with:

“It is important to note that it is inadvisable (actively discouraged) to directly extrapolate the studies here, especially in terms of the magnitude of age suppression, to potential effects of rapamycin on humans.”

https://www.aging-us.com/article/101976/text “Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation”

Another important transgenerational epigenetic inheritance study

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This 2019 Washington State University rodent study from Dr. Michael Skinner’s lab found:

“A cascade of epigenetic alterations initiated in PGCs [primordial germ cells of F3 males] appears to be required to alter epigenetic programming during spermatogenesis to modify the sperm epigenome involved in transgenerational epigenetic inheritance phenomenon.

Following fertilization there is a DNA methylation erasure to generate stem cells in the early embryo, which then remethylate in a cell type-specific manner. DNA methylation erasure is thought to, in part, reset deleterious epigenetics in the germline. However, imprinted gene DNA methylation sites and induced transgenerational epimutations appear to be protected from this DNA methylation erasure.

A germline with an altered epigenome has the capacity to alter the early embryo’s stem cell’s epigenome and transcriptome that can subsequently impact epigenomes and transcriptomes of all derived somatic cells. Therefore, an altered sperm epigenome has the capacity to transmit phenotypes transgenerationally. Experiments have demonstrated that epigenetic inheritance can also be transmitted through the female germline.

Previously, agricultural fungicide vinclozolin was found to promote transgenerational inheritance of sperm differential DNA methylation regions (DMRs) termed epimutations that help mediate this epigenetic inheritance. The current study was designed to investigate developmental origins of transgenerational DMRs during gametogenesis.

The current study with vinclozolin-induced transgenerational inheritance demonstrates that sperm DMRs also originate during both spermatogenesis and earlier stages of germline development, but at distinct developmental stages. Fetal exposure initiates a developmental cascade (i.e., distinct developmental origins) of aberrant epigenetic programming, and does not simply induce a specific number of DMRs that are maintained throughout development.”

https://www.tandfonline.com/doi/pdf/10.1080/15592294.2019.1614417?needAccess=true “Transgenerational sperm DNA methylation epimutation developmental origins following ancestral vinclozolin exposure”

The study’s main hypotheses were:

“Following fertilization, the hypothesis is that transgenerational epimutations modify early embryonic transcriptomes and epigenomes to re-establish the cascade for the next generation.

As the individual develops, all somatic cells have altered epigenomes and transcriptomes to promote disease susceptibility later in life.”

Researchers: adopt these hypotheses, and apply them to human studies.

1. Don’t get off track by requiring that the same phenotype must be observed in each generation for there to be transgenerational epigenetic inheritance, because:

“Fetal exposure..does not simply induce a specific number of DMRs that are maintained throughout development.”

Animal transgenerational studies have shown that epigenetic inheritance mechanisms may both express different phenotypes for each generation, and entirely skip a phenotype in one or more generations!

2. Don’t limit your study designs to F1 children as did:

3. Don’t stop at F2 grandchildren as did:

4. Continue studies on to F3 great-grandchildren who had no direct exposure to altering stimulus. Keep in the forefront of your research proposals that there are probably more than 10,000,000 F3 descendants of DES-exposed women just in the US!

The transgenerational impact of Roundup exposure

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This 2019 Washington rodent study from Dr. Michael Skinner’s lab found adverse effects in the grand-offspring and great-grand-offspring following their ancestor’s exposure during pregnancy to the world’s most commonly used herbicide:

“Using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed.

The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities:

  1. Prostate disease in approximately 30% of F3 generation glyphosate lineage males, a three-fold increase in disease rate over controls.
  2. A transgenerational (F3 generation) obese phenotype was observed in approximately 40% of the glyphosate lineage females and 42% of the glyphosate lineage males.
  3. An increased incidence of kidney disease observed in the F3 generation glyphosate lineage females affecting nearly 40% of females.
  4. A significant increase in ovarian disease observed in the F2 [48% vs. 21% for controls] and F3 [36% vs. 15% for controls] generation glyphosate lineage females.
  5. During the gestation of F2 generation mothers with the F3 generation fetuses, dramatic parturition abnormalities were observed in the glyphosate lineage. The frequency of unsuccessful parturition was 35%. To further investigate the parturition abnormalities an outcross of F3 generation glyphosate lineage males with a wildtype female was performed. There were parturition abnormalities observed with a frequency of 30%.

Classic and current toxicology studies only involve direct exposure of the individual, while impacts on future generations are not assessed. The ability of glyphosate and other environmental toxicants to impact our future generations needs to be considered, and is potentially as important as the direct exposure toxicology done today for risk assessment.”

Why isn’t coverage of this study the top story of world news organizations? Is what’s reported more important than reliable evidence of generational consequences to environmental experiences?

Current toxicology practices are a scientific disgrace:

  • What are hypotheses of practices that test only effects on somatic cells, and don’t look for generational effects on germ cells?
  • Are tests selected for their relative convenience instead of chosen for their efficacy?

Why don’t sponsors fund and researchers perform human studies of transgenerational epigenetic inheritance? For example, from Burying human transgenerational epigenetic evidence:

“From the late 1930s through the early 1970s, DES was given to nearly two million pregnant women in the US alone.

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

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

There will be abundant human evidence to discover if sponsors and researchers will take their fields seriously.

https://www.nature.com/articles/s41598-019-42860-0.pdf “Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology”

Non-emotional memories

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This 2019 US review covered memory mechanisms:

“With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding.

These levels are not isolated, but linked by shared components of feedback loops.”

Despite the review’s exhaustive discussion, the reviewers never came to the point. The word cloud I made of the review’s most frequent thirty words had little to do with why memory occurs:

  • Why do some stimuli evoke a memory in response?
  • Why are almost all of the stimuli an organism receives not remembered?

Much of the discussion was baseless because it excluded emotion. Many of the citations’ memory findings relied on emotion, though.

For example, in the subsection Roles of persistent epigenetic modifications for maintaining LTF [long-term facilitation], LTP [long-term potentiation], and LTM [long-term memory]:

  • “Histone acetylation is increased after fear conditioning in the hippocampus and amygdala.
  • Correspondingly, inhibition of histone deacetylase enhances fear conditioning and LTP.
  • Following fear conditioning, histone phosphorylation is also increased.
  • DNA methylation is also up-regulated in the hippocampus and amygdala after fear conditioning, and inhibition of DNA methylation blocks fear LTM.”

http://learnmem.cshlp.org/content/26/5/133.full “How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory”

Statistical inferences vs. biological realities

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A 2019 UCLA study introduced a derivative of the epigenetic clock named GrimAge:

“DNAm GrimAge, a linear combination of chronological age, sex, and DNAm-based surrogate biomarkers for seven plasma proteins and smoking pack-years, outperforms all other DNAm-based biomarkers, on a variety of health-related metrics.

An age-adjusted version of DNAm GrimAge, which can be regarded as a new measure of epigenetic age acceleration (AgeAccelGrim), is associated with a host of age-related conditions, lifestyle factors, and clinical biomarkers. Using large scale validation data from three ethnic groups, we demonstrate that AgeAccelGrim stands out among pre-existing epigenetic clocks in terms of its predictive ability for time-to-death, time-to-coronary heart disease, time-to-cancer, its association with computed tomography data for fatty liver/excess fat, and early age at menopause.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ “DNA methylation GrimAge strongly predicts lifespan and healthspan”

A miserable attempt at reporting the study’s findings included angles of superstition, fear-of-the-future, and suspicion-by-spurious-association:

“The research has already captured the attention of the life insurance industry. After all, a solid death date could mean real savings when it comes to pricing policies.

The hope is that if and when legitimate anti-aging drugs are developed, GrimAge could be used to test their effectiveness. In a world with functional anti-aging drugs, “doctors could test [your GrimAge number] and say, ‘You know what, you’re aging too quickly. Take this,'” Horvath said.”

https://onezero.medium.com/a-new-test-predicts-when-youll-die-give-or-take-a-few-years-2d08147c8ea6 “A New Test Predicts When You’ll Die (Give or Take a Few Years)”

A detailed blog post from Josh Mitteldorf provided scientific coverage of the study:

“Methylation sites associated with smoking history predicted how long the person would live more accurately than the smoking history itself. Even stranger, the methylation marks most closely associated with smoking were found to be a powerful indication of future health even when the sample was confined to non-smokers.

The DNAm GrimAge clock was developed in two stages, a correlation of a correlation. Curiously, the indirect computation yields the better result.

Horvath’s finding that secondary methylation indicators are more accurate than the underlying primary indicator from which they were derived is provocative, and calls out for a new understanding.”

https://joshmitteldorf.scienceblog.com/2019/03/05/dnam-grimage-the-newest-methylation-clock “DNAm GrimAge—the Newest Methylation Clock”

When there are logical disconnects in findings like the above, it’s time to examine underlying premises. As noted in Group statistics don’t necessarily describe an individual, an assumption required by statistical analyses is that each measured item in the sample is interchangeable with the next.

This presumption is often false, producing individually inapplicable results. For example, Immune memory vs. immune adaptation included this description of the adaptive immune system:

“To be effective, highly specific immune response requires huge diversity of receptors and antibodies, which is achieved by somatic rearrangement of gene segments. Recombination results in millions of TCR [T cell receptor] and antibody variants able to recognize and neutralize millions of various antigens.”

Standard statistics of millions of T cell receptor and antibody variants won’t represent their individually unique properties. But individual differences are both their purpose and benefit to us.

The GrimAge study’s overreach was most apparent in stratifying educational attainment to develop correlations. As mentioned in Does a societal mandate cause DNA methylation? such statistics are poor evidence of each individual’s biological realities.

Neither derivatives of group statistics, nor correlations of correlations, seem to be the techniques needed to understand biological causes of effects. Another commentary on the GrimAge study mentioned but glossed over this point:

“It remains a mystery why exactly the epigenetic clocks work, and whether age-related changes in DNA methylation contribute to the cause of aging or are a result of it.”

Immune memory vs. immune adaptation

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This 2019 Dutch/German/Romanian perspective aimed for a better understanding of immune systems:

“Based on molecular, immunological, and evolutionary arguments, we propose that innate immune memory is a primitive form of immune memory present in all living organisms, while adaptive immune memory is an advanced form of immune memory representing an evolutionary innovation in vertebrates.

Innate immune responses have the capacity to be trained, and thereby exert a new type of immunological memory upon reinfection. The central feature of trained innate immune cells is their ability to mount a qualitatively and quantitatively different transcriptional response when challenged with microbes or danger signals. Evidence supports convergence of multiple regulatory layers for mediating innate immune memory, including changes in chromatin organization, DNA methylation, and probably non-coding RNAs such as microRNAs and/or long non-coding RNAs.

Two properties of adaptive immune response are mediated by two fundamentally different types of mechanisms:

  1. Higher magnitude and speed of the response is mediated by epigenetic programming.
  2. Specificity of the response is insured by gene recombination of TCR [T cell receptor] and BCR [B cell receptor] and clonal expansion of specific cell subpopulations upon antigen recognition.

To be effective, highly specific immune response requires huge diversity of receptors and antibodies, which is achieved by somatic rearrangement of gene segments. Recombination results in millions of TCR and antibody variants able to recognize and neutralize millions of various antigens.“

This paper included speculations such as “Evidence supports..probably non-coding RNAs” quoted above, and the penultimate sentence:

“One can envision that vaccines that are capable of inducing both forms of immune memory at the same time would be more effective.”

100% factual evidence is preferred. Overall information can only be as accurate as the least accurate information.

This review highlighted a goal for humans to have both a functional innate immune system and a functional adaptive immune system. The lead author coauthored A dietary supplement that trains the innate immune system and a study referenced in Eat your oats.

https://www.sciencedirect.com/science/article/pii/S1931312818306334 “Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host’s Response to Pathogens” (not freely available)

Our brains are shaped by our early environments

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

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

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

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

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

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

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

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

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

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

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

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

A therapy to reverse cognitive decline

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

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

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

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

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

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

At a specific level:

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

For general concepts, however:

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

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

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

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

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

Epigenetic transgenerational inheritance mechanisms that lead to prostate disease

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This 2019 Washington State University rodent study found:

“Ancestral exposure to toxicant vinclozolin induces an epigenetic transgenerational increase in susceptibility to prostate pathology in F3 [male great-grandchildren] generation rats. These results are in agreement with previous studies which found a transgenerational increase in rates of prostatic:

  • Epithelial atrophy;
  • Cystic hyperplasia; and
  • Prostatitis

in transgenerational F3 and F4 [male great-great-grandchildren] generations after exposure of F0 [great-great-grandmother] generation pregnant rats to vinclozolin. These effects were accompanied by transgenerational changes in mRNA expression in F3 generation ventral prostate epithelial cells.

A number of previous transgenerational studies have shown no ventral prostate histopathology or disease detected. Therefore, observations suggest ancestral exposure specificity in the ability to induce transgenerational inheritance of prostate disease.

There was also no increase in prostate histopathology in directly exposed F1 [male children] or F2 [male grandchildren] generation vinclozolin lineage rats compared to controls.

prostate pathology

The mechanism by which epigenetic transgenerational inheritance affects prostate epithelium involves control of gene expression by DNA methylation and lncRNAs. It will be necessary to determine exact gene targets of these epigenetic modifications to determine further mechanisms.

Future studies need to investigate if similar mechanisms are at work in human males who have adult-onset BPH or prostate cancer. Ancestral exposures to toxicants and epigenetic transgenerational inheritance may contribute to development of prostate disease in men today.”

This study’s above bolded sentence added to evidence that epigenetic effects may skip generations. A study by the same group, Epigenetic transgenerational inheritance of ovarian disease, found in females:

There was no increase in ovarian disease in direct fetal exposed F1 or germline exposed F2 generation vinclozolin or DDT lineage rats compared to controls.

A disturbance in the paradigm of child abuse referenced other studies that found generation-skipping effects.

Researchers are closer to discovering evidence for precise mechanisms of epigenetic transgenerational inheritance. It’s well past time that other researchers performing studies like Burying human transgenerational epigenetic evidence:

  • Turn things around;
  • Take their work seriously; and
  • Truly investigate human evidence for epigenetic transgenerational inheritance.

What are more important research and funding priorities than such human studies?

https://www.nature.com/articles/s41598-019-38741-1 “Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease”

An hour of the epigenetic clock

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


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