What is epigenetic inheritance?

This 2016 review by Eric Nestler, a well-known and well-funded researcher, entitled Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction? concluded:

“Further work is needed to understand whether and to what extent true epigenetic inheritance of stress vulnerability adds to the well-established and powerful influence of genetics and environmental exposures in determining an individual’s susceptibility versus resilience to stress throughout life.

There is growing evidence for at least some contribution of epigenetic regulation – perhaps achieved by miRNAs – in mediating part of the ability of parental behavioral experience to influence stress vulnerability in their offspring.”

The reviewer applied the terms involved to exclude behavioral inheritance mechanisms. The extent of what is “epigenetic inheritance” seemed to be lost in the process.

For example, his own 2011 research Paternal Transmission of Stressed-Induced Pathologies was cited for evidence that:

“Adult male mice subjected to chronic social defeat stress generate offspring that are more vulnerable to a range of stressful stimuli than the offspring of control mice.”

Yet that finding was dismissed in the review and in that study as behavioral:

“While epigenetic changes in sperm might be a small factor in transgenerational transmission of stress vulnerability, a large portion of the observed transmission may be behavioral.

The fact that most of the transgenerational transmission of stress vulnerability observed in our experiments was not seen with IVF argues against the preponderance of epigenetic mechanisms. Rather, our data would suggest that the bulk of the vulnerabilities are passed on to subsequent generations behaviorally.”

A few questions:

  1. If the experimental subjects had no more control over their behavioral stress-response effects than they had over their DNA methylation, histone modification, or microRNA stress-response effects, then why was such behavior not included in the “epigenetic mechanisms” term?
  2. How do behavioral inheritance mechanisms fall outside the “true epigenetic inheritance” term when behavioral stress-response effects are shown to be reliably transmitted generation after generation?
  3. Wouldn’t the cessation of behavioral inheritance mechanisms confirm their status by falsifiability? This was done with studies such as the 1995 Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress.


I ain’t got a heart of stone
I’m hurting more now than I’ve ever known
If you mean the things you said
I’m gonna wind up out of my head

Can’t sleep alone at night
I just can’t seem to get it right
Damned if I do
Damned if I don’t
But I love you

I don’t wanna tie you down
Don’t need a reason to have you around
But each time you walk away
Don’t be surprised if I ask you to stay

Can’t sleep alone at night
I just can’t seem to get it right
Damned if I do and I’m damned if I don’t
But I love you
I said I’m damned if I do and I’m damned if I don’t
But I love you

I ain’t got a heart of stone
You haven’t left me a mind of my own
But it’s got such a hold on me
I don’t think I could ever be free

How can I survive?
I’m fighting to keep myself alive
I’m damned if I do
Damned if I don’t
But I love you

Can’t seem to see the light
I’ve done everything but I can’t get it right
Damned if I do
Damned if I don’t
But I love you

A followup study of DNA methylation and age

This 2016 Finnish human study was a followup to A study of DNA methylation and age:

“At the 2.55-year follow-up, we identified 19 mortality-associated CpG sites that mapped to genes functionally clustering around the nuclear factor kappa B (NF-κB) complex. None of the mortality-associated CpG sites overlapped with the established aging-associated DNAm sites.

Our results are in line with previous findings on the role of NF-κB in controlling animal life spans and demonstrate the role of this complex in human longevity.”

I was again impressed with the researchers’ frankness in the Discussion section:

“Our data do not provide a mechanistic link between the hypomethylation of these CpG sites and the risk of mortality.

Our data do not allow us to determine whether disrupted regulation of chromatin permissiveness underlies the increased mortality risk.

None of our top 250 mortality-associated methylomic sites were among the 525 common age-associated CpG sites that have been observed in more than one study.”

Regarding the lack of confirmation at the 4-year followup:

“The number of mortality-associated CpG sites was markedly reduced from the 2.55-years follow-up to the 4-years follow-up.

A substantial part of the genomic CpG sites might be constantly remodeled, and during 4 years, their methylation levels are likely to change to an extent that their predictive ability in our population is reduced. The longer follow-up time also allows more time for stochastic mortality determinants, such as trauma, to operate, which may thus weaken the role of the genomic predictors.”

The epigenetic clock method was investigated:

“The DNAm age has also been recently demonstrated to predict all-cause mortality in four different cohorts of elderly individuals and in Danish twins. However, the DNAm age was not predictive of mortality in our study.

One reason for the negative finding might be that individuals in our cohort were all very old at baseline (90 years), and death at this age likely has different underpinnings than at younger old ages and when assessed in cohorts with wider age spectra.”

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=8278&path[]=24504 “Methylomic predictors demonstrate the role of NF-κB in old-age mortality and are unrelated to the aging-associated epigenetic drift”

A study of how genetic factors determined diet-induced epigenetic changes

This 2016 California rodent study found:

“HF [high fat] diet leads to persistent alterations of chromatin accessibility that are partially mediated by transcription factors and histone post-translational modifications. These chromatin alterations are furthermore strain specific, indicating a genetic component to the response.

These results suggest that persistent epigenetic modifications induced by HF diet have the potential to impact the long-term risk for metabolic diseases.”

The experimental procedure was that 7-8 week old subjects of two mice strains “were placed on three diet regimens:

  1. control diet for sixteen weeks,
  2. HF diet for sixteen weeks, or
  3. HF diet for an initial eight weeks followed by control diet for eight weeks (diet reversal).”

On diet regimen 3, one of the mouse strains wasn’t able to reverse the epigenetic changes caused by eight weeks of a high-fat diet. The symptoms included:

  • Elevated lipid accumulation and triglyceride levels
  • 15% of chromatin sites were more accessible, with the HNF4α transcription factor implicated
  • 6% of chromatin sites were less accessible due to H3K9 methylation
  • Persistently up-regulated genes were more likely to be in the vicinity of a persistently accessible site
  • A set of persistently up-regulated genes enriched for mitochondrial genes was present only with diet regimen 3 subjects.

A second mouse strain “known to display differences in metabolic dysfunction under HF diet” compared to the first strain didn’t experience the same symptoms on diet regimen 3:

  • Lipid accumulation and triglyceride levels weren’t elevated
  • The majority of diet-induced chromatin remodeling [was] reversible
  • Little overlap with the first strain in the set of genes that changed expression.

The study didn’t suggest any specific human applicability.

http://www.jbc.org/content/early/2016/03/22/jbc.M115.711028.long (pdf) “Persistent chromatin modifications induced by high fat diet”


A skin study that could have benefited from preregistration

This 2016 German human skin study found:

“An age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks.”

The study could have benefited from preregistration using an approach such as Registered Reports. As it was, the study gave the impression of a fishing expedition.

For example, the initial subjects were 24 women ages 18-27 and 24 women ages 61-78. The barbell shape of the subjects’ age distribution wouldn’t make sense if the researchers knew they were going to later use the epigenetic clock method.

The researchers did so, although the method’s instructive study noted:

“The standard deviation of age has a strong relationship with age correlation”

and provided further details in “The age correlation in a data set is determined by the standard deviation of age” section.

A second round of subjects were recruited, 60 women aged 20-79, “that also included intermediate ages.” No discrete numbers were provided, but from eyeballing Figure S1 in the supplementary material, the ages of the second group appeared to be evenly distributed.

The subject groups were lumped together to make findings such as:

“We observed a significant age-related hypermethylation of CpG island-associated probes. This effect was strongly enriched during two specific age windows, at 40–45 and 50–55 years.

Considering that our samples were exclusively derived from female volunteers, it seems reasonable to link the latter window to menopause, which is also known to distinctly accelerate skin aging.”

The study didn’t state that the second group of subjects were screened for menopause, or for use of hormone therapies or skin creams.

If the ages of the second group of subjects were evenly distributed, 6 of the 108 subjects would be ages 50-55. It wasn’t “reasonable to link” a small number of subjects to conditions for which they hadn’t been screened.

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12470/ “Reduced DNA methylation patterning and transcriptional connectivity define human skin aging”

Mechanisms of stress memories in plants

This 2016 Australian review’s subject was plant memory mechanisms:

“Plants are adept at rapidly acclimating to stressful conditions and are able to further fortify their defenses by retaining memories of stress to enable stronger or more rapid responses should an environmental perturbation recur.

The recovery process entails a balancing act between resetting and memory formation. During recovery, RNA metabolism, posttranscriptional gene silencing, and RNA-directed DNA methylation have the potential to play key roles in resetting the epigenome and transcriptome and in altering memory.”

Many of the principles applied to animals, and several animal studies were cited for illustration. Here’s one of the graphics:


I disagreed with the Summary statement:

“Memory, in particular epigenetic memory, is likely a relatively rare event.”

The reviewers cited a 2015 Australian study Stress induced gene expression drives transient DNA methylation changes at adjacent repetitive elements which found the opposite conclusion with rice:

“Despite 21 days of starvation, resupplying phosphate for just 1 day reversed expression of 40% of induced genes, further increasing to 80% after 3 days and corresponding with a reestablished internal root phosphate concentration. Interestingly though, 80 genes remained differentially regulated even after 31 days of resupply.”

The cited study’s researchers attributed their epigenetic memory finding to several factors, including their study design:

“The majority of DNA methylation analyses performed in plants to date have focused on Arabidopsis, despite being relatively depleted of TEs [transposable elements] (15–20% of the genome) and being poorly methylated compared to other plant genomes.

To date, only a limited number of studies have comprehensively investigated the involvement of DNA methylation in response to adverse environmental conditions. Several studies have reported that changes in the environment can affect the methylation status of some regions of the genome, using low resolution and non-quantitative techniques. These studies have lacked the resolution to provide the specific context and genomic location of the changes in DNA methylation, thus offering limited insights into the potential role of stress-induced changes in DNA methylation.”

So, the current review judging “memory, in particular epigenetic memory” to be “a relatively rare event” probably had more to do with study designs rather than what actually occurs in nature. See one of the coauthor’s response below.

http://advances.sciencemag.org/content/2/2/e1501340.full “Reconsidering plant memory: Intersections between stress recovery, RNA turnover, and epigenetics”

Oxytocin research null findings come out of the file drawer

In 2016 Belgian researchers released their previously unpublished studies:

“Is there a file drawer problem in intranasal oxytocin research?

We submitted several studies yielding null-findings to different journals but they were rejected time and time again.

The aggregated effect size was not reliably different from zero [including all of the researchers’ previously unpublished intranasal oxytocin studies].”

Neuroskeptic comments:

“By publishing these results, Lane et al. have ensured that future meta-analysts will be able to include the full dataset in their calculations.”

http://blogs.discovermagazine.com/neuroskeptic/2016/03/17/open-the-file-drawer/ “Psychologists Throw Open the File Drawer”

See Testing the null hypothesis of oxytocin’s effects in humans for more on the topic.


The epigenetic influence of obese parents at conception

This 2016 German rodent study found:

“Using in vitro fertilization to ensure exclusive inheritance via the gametes, we show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin–specific mode.”

It would have benefited the researchers to have made the full study freely available. As it is, an interested reader has to ferret out information such as the basic study design (provided in a graphic) which had in the caption that both the parental and offspring diets were normal until:

  • “Between 9 [young adult] and 15 weeks of age.
  • This experiment was replicated at least three times for each F1 cohort, using sperm and oocytes from independent donors.”

Compare that information with the description provided by the study’s most thorough news coverage:

“Researchers raised genetically similar mice for six weeks [beginning at 9 weeks of age] on one of three diets: standard mouse chow [13.5% fat], a low-fat diet [11% fat], or a high-fat [60% fat], high-calorie diet. The latter became obese and developed severe glucose intolerance (a precursor to type 2 diabetes), while the other mice stayed slim.

Harvesting the eggs and sperm from mice in each of the diet groups, the researchers then used in vitro fertilization to make specific, controlled crosses. All of the embryos were transferred to healthy, skinny [actually, the foster mothers were on the standard mouse chow diet] foster mothers. To see if the diet of their biological parents affected their metabolism, all of the pups [actually, young adults at age 9 weeks] were challenged with a high-fat, high-calorie diet [beginning at 9 weeks of age].

Unsurprisingly, the female pups with two obese parents had a high degree of insulin resistance and gained at least 20 percent more weight than the offspring of parents on standard or low-fat diets. Female pups with only one obese parent, either the mother or the father, also gained more weight than the control groups—but only between 8 and 14 percent. The result suggests that the metabolic influence of each parent may be additive.

But in a puzzling finding, the male pups didn’t have the same pattern. The male pups of obese parents did tend to be a bit heavier than those from the control groups, but the difference wasn’t statistically significant, the authors report. They did, however, also have a high degree of insulin resistance.

Examining the glucose intolerance more closely, the researchers noted that offspring (both male and female) tended to have more severe glucose intolerance if their mothers were obese. This backs up epidemiological data in humans that suggests a stronger maternal influence over type 2 diabetes development.”

The study didn’t determine causal biological mechanisms for the observed epigenetic effects. No measurements of DNA methylation, histone modifications, or microRNAs were taken.

I look forward to further research into epigenetic contributions at conception to adulthood symptoms.

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3527.html “Epigenetic germline inheritance of diet-induced obesity and insulin resistance” Thanks to the lead author Peter Huypens for providing a copy of the full study

Gene therapy by DNA methylation using CRISPR-Cas9

This 2016 Croatian human cell study was a proof-of-concept to induce specific DNA methylation of two genes:

“In this work we have created and characterized a novel CRISPR-Cas9-based epigenome editing tool, the dCas9-DNMT3A, which enabled targeted and specific CpG methylation at the promoter of two loci, the BACH2 and the IL6ST.

We have demonstrated the ability of the dCas9-DNMT3A construct to silence gene expression.

The BACH2 and IL6ST loci were previously associated with IgG glycosylation and inflammatory as well as autoimmune diseases.”

A few limitations:

“CpG methylation achieved using the active dCas9-DNMT3A construct was not stable in cultured cells. We found a ‘window’ of high methylation activity between days 5 and 15.

The relatively higher number of sgRNA [short complementary single guide RNA] targets in the BACH2 promoter compared to the IL6ST promoter (8 versus 4, respectively) might account for the higher statistical significance of gene silencing with inactive construct in the case of BACH2.”

http://nar.oxfordjournals.org/content/early/2016/03/10/nar.gkw159.full “Repurposing the CRISPR-Cas9 system for targeted DNA methylation”

Problematic research into epigenetic effects of paternal stress on male offspring

This 2016 Chinese rodent study and its accompanying commentary Don’t stress dad — it’s bad for your kids’ health were caught up in an agenda.

The first problem I noticed was that the hyperglycemic effects found only in the male offspring weren’t consistently labelled as sex-specific. Try to find that fact in the paywalled commentary with its intentionally misleading headline, or in the news coverage with headlines such as “Stressed mouse dads give their offspring high blood sugar.”

That the effects were male-only was briefly noted in the study, yet “male” was absent from the “stress-F1 mice” label used after the initial mention.


The researchers provided no mechanisms that plausibly linked the effects to offspring sex. There was plenty of time between the May 3, 2015 submission and the February 18, 2016 publication to clarify this and other items. I wonder what the reviewer noted.

The second problem was that the highest number of male “stress-F1 mice” tested was only six. I didn’t see any disclosures of what led to the scarcity of subjects, or of the likely impact of using so few.

A related limitation was that the male “stress-F1 mice” were killed as young adults. Whether or not the hyperglycemic effects carried through to old age or to another generation wasn’t determined.

I’m leery of studies like this one that didn’t have a Limitations section, and especially so when the news coverage overlooked obvious limitations. It was difficult to place the findings in a context other than promoting that a male’s stress may also adversely affect their offspring.

One of the problems that research caught up in an agenda create is that non-headline findings are overlooked. Other than sex-specific effects, the study found that the putative preconception cause of hyperglycemia didn’t cause other symptoms:

  • “No significant growth defects were observed in male offspring from stress-F0 fathers (stress-F1 mice) during their early lives.
  • Insulin sensitivity was not changed in stress-F1 mice.
  • Serum glucagon, leptin, and pro-inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-6 [IL-6]) were unaffected.
  • Body weight, food intake, locomotor activity, CO2 production, O2 consumption, and respiratory exchange ratios also remained unchanged.
  • Liver weight, liver weight/body weight ratios, hepatic triglyceride content, and the histological phenotypes were also comparable.
  • The methylation pattern and expression of microRNAs were not affected in the fetal brains of stress-F1 mice.”

The handling of the study reminded me of Transgenerational epigenetic programming with stress and microRNA where most of the news coverage similarly focused on it being a male’s stress, not a female’s, that affected the developing embryo. The important part lost from news coverage of that study was it demonstrated how a damaging influence can begin immediately after conception, but the symptoms didn’t present until adulthood!

http://www.sciencedirect.com/science/article/pii/S1550413116300067 “Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring”

The current paradigm of child abuse limits pre-childhood causal research

As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments for causes of your symptoms?

Such information wasn’t available in this 2016 Miami review of the effects of child abuse. The review laid out the current paradigm mentioned in Grokking an Adverse Childhood Experiences (ACE) score, one that limits research into pre-childhood causes for later-life symptoms.

The review’s goal was to describe:

“How numerous clinical and basic studies have contributed to establish the now widely accepted idea that adverse early life experiences can elicit profound effects on the development and function of the nervous system.”

The hidden assumptions of almost all of the cited references were that these distant causes could no longer be addressed. Aren’t such assumptions testable today?

As an example, the Discussion section posed the top nine “most pressing unanswered questions related to the neurobiological effects of early life trauma.” In line with the current paradigm, the reviewer assigned “Are the biological consequences of ELS [early life stress] reversible?” into the sixth position.

If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of damage would also reverse damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

The review also demonstrated how the current paradigm of child abuse misrepresented items like telomere length and oxytocin. Researchers on the bandwagon tend to forget about the principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

That single experiment for telomere length arrived in 2016 with Using an epigenetic clock to distinguish cellular aging from senescence. The review’s seven citations for telomere length that all had findings “associated with” or “linked to” child abuse should now be viewed in a different light.

The same light shone on oxytocin with Testing the null hypothesis of oxytocin’s effects in humans and Oxytocin research null findings come out of the file drawer. See their references, and decide for yourself whether or not:

“Claimed research findings may often be simply accurate measures of the prevailing bias.”

http://www.cell.com/neuron/fulltext/S0896-6273%2816%2900020-9 “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Epigenetic regulation of natural killer cells

This 2016 German review focused on how epigenetic processes affected the natural killer cell part of the immune system:

“Natural killer (NK) cells recognize and eliminate tumor- and virus-infected cells, parasites as well as certain types of bacteria. NK cell activity is related to a complex interaction of activating and inhibiting receptors on the NK cell surface.

During the development of HPCs [hemopoietic progenitor cells] to mature NK cells, the DNA demethylation of KIR [killer cell immunoglobin-like receptors] genes leads to KIR expression. But DNA methylation does not just determine which KIR gene is expressed, it also determines which allele expresses the KIR gene. KIR genes are also regulated by microRNA.

KIR genes exhibit highly similar histone acetylation signatures, which are typically found in expressed genes. This fact puts the KIR genes into a state of readiness for transcription which is depending on the DNA methylation as critical epigenetic modification in the regulation of KIR gene expression.

Epigenetic modifications have been reported to be involved in the expression of NKG2D, which is one the most important activating NK cell receptor.”

The reviewers included a section on NK cell activity and external stimuli. They summarized:

“The significance of the described findings is limited by study designs. Although human NK cells were frequently used, in most cases treatment took place in ex vivo experiments.”

The reviewers also provided a good three-paragraph explanation of general epigenetic mechanisms.

http://www.mdpi.com/1422-0067/17/3/326/htm “Natural Killer Cells—An Epigenetic Perspective of Development and Regulation”

Beneficial epigenetic effects of mild stress with social support during puberty

This 2016 Pennsylvania rodent study found:

“Stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase resilience to age-related cognitive decline in females.

These findings are actually consistent with previous studies showing that some amount of adversity, or adversity under more favorable circumstances such as social support or a protective gene polymorphism, provides a measure of ‘grit’ in coping with later life challenges.

Our findings provide a unique perspective on this relationship, as they highlight the important link between experience during the pubertal window and cognitive health during aging.”

These researchers made efforts to further investigate causes of unexpected results, such as:

“Peripubertal stress alone did not significantly alter Barnes maze performance in aging compared to aged Controls. Mice that had experienced stress with concurrent social support (CVS + SI) actually performed better than Control aged mice, specifically in learning the reversal task faster.

Peripubertal stress had no effect on corticosterone levels in response to an acute restraint stress or in sensorimotor gating and baseline startle reactivity.”

Their investigations led to epigenetic findings:

“Consistent with our behavioral findings, stress in the context of social interaction resulted in long-term reprogramming of gene expression in the PFC [prefrontal cortex]. While there were no differentially expressed genes between Control and CVS females, there were 88 genes that were significantly different between Control and CVS + SI groups. Of genes that were downregulated, a large portion (23 genes; 35%) were microRNAs.

We found that the PFC transcriptome of CVS + SI aged females was significantly enriched for predicted targets of the 23 microRNAs that were downregulated in the PFC in these mice. This suggests that microRNAs represent a mode of regulation capable of enacting far-reaching programmatic effects, and are a critical epigenetic gene expression regulatory mechanism.”

Applicability to humans was suggested by associations such as:

“A single microRNA can target more than a hundred different mRNA targets, and more than 45,000 conserved microRNA binding sites have been annotated in the 3′ UTR of 60% of human genes.”

A few limitations were noted:

“Given that mice at this age (1 year) are commonly compared to ‘late middle aged’ humans, later aging time points may yield differences in this group. Alternatively, it is possible that there was an effect of peripubertal stress that was not long-lasting due to the mild nature of our chronic stress model.

To include early neglect as a part of the stressor experience, CVS females were weaned one week earlier (PN21) than Control and CVS + SI mice. Addition of stress of this earlier weaning likely poses a significant contribution to programming of the PFC.”

One of the study coauthors was also a coauthor of:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870871/ “Peripubertal stress with social support promotes resilience in the face of aging”

A review that inadvertently showed how memory paradigms prevented relevant research

This 2016 Swiss review of enduring memories demonstrated what happens when scientists’ reputations and paychecks interfered with them recognizing new research and evidence in their area but outside their paradigm: “A framework containing the basic assumptions, ways of thinking, and methodology that are commonly accepted by members of a scientific community.”

A. Most of the cited references were from decades ago that established these paradigms of enduring memories. Fine, but the research these paradigms excluded was also significant.

B. All of the newer references were continuations of established paradigms. For example, a 2014 study led by one of the reviewers found:

“Successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones.

Recalling remote memories fails to induce histone acetylation-mediated plasticity.”

The researchers elected to pursue a workaround of the memory reconsolidation paradigm when the need for a new paradigm of enduring memories directly confronted them!

C. None of the reviewers’ calls for further investigations challenged existing paradigms. For example, when the reviewers suggested research into epigenetic regulation of enduring memories, they somehow found it best to return to 1984, a time when dedicated epigenetics research had barely begun:

“Whether memories might indeed be ‘coded in particular stretches of chromosomal DNA’ as originally proposed by Crick [in 1984] and if so what the enzymatic machinery behind such changes might be remain unclear. In this regard, cell population-specific studies are highly warranted.”

Two examples of relevant research the review failed to consider:

1. A study that provided evidence for basic principles of Primal Therapy went outside existing paradigms to research state-dependent memories:

“If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again.

It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories.”

What impressed me about that study was the obvious nature of its straightforward experimental methods. Why hadn’t other researchers used the same methods decades ago? Doing so could have resulted in dozens of informative follow-on study variations by now, which is my point in Item A. above.

2. A relevant but ignored 2015 French study What can cause memories that are accessible only when returning to the original brain state? which supported state-dependent memories:

“Posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval.”

The review also showed the extent to which historical memory paradigms depend on the subjects’ emotional memories. When it comes to human studies, though, designs almost always avoid studying emotional memories.

It’s clearly past time to Advance science by including emotion in research.

http://www.hindawi.com/journals/np/2016/3425908/ “Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories”

Using an epigenetic clock with older adults

This 2016 German human study found:

“Epigenetic age acceleration is correlated with clinically relevant aging-related phenotypes through pathways unrelated to cellular senescence as assessed by telomere length.

The current work employed the frailty index, a multi-dimensional approach that combines [34] parameters of multiple physiological systems and functional capacities. The present findings were based on [1,820] study participants aged 50 to 75 years.

Innovative approaches like Mendelian randomization will be needed to elucidate whether epigenetic age acceleration indeed plays a causal role for the development of clinical phenotypes.”

The study had an informative “Age acceleration and telomere length are not correlated” section with references. It was another step toward establishing the Horvath epigenetic clock for widespread usage.

http://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0186-5 “Frailty is associated with the epigenetic clock but not with telomere length in a German cohort”