Year: 2016

Gene therapy by DNA methylation using CRISPR-Cas9

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system ,

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

gettingwell4 0-1 star Wasted resources, Cortisol, Epigenetics, Neurochemicals, Stress ,

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.

2015年12月22日-陆炎模式图单独导出-v2

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

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Brain development, Brainstem, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Neurochemicals, Oxytocin, Serotonin, Stress, Telomeres, Testosterone, Thalamus, Vasopressin , , , , ,

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

gettingwell4 2-3 stars Required further work, Cortisol, Epigenetics, Immune system, Neurochemicals, Stress ,

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

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

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

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals, Stress , , , , ,

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

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Telomeres ,

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”

Using an epigenetic clock with children

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , ,

This 2015 UK human study by many of the coauthors of What’s the origin of the problem of being fat? applied the Horvath epigenetic clock method to the same UK mother-child pairs and a Danish cohort:

“There has been no investigation on prenatal and antenatal factors that affect AA [age acceleration] in children. It is possible that the detrimental consequences of a higher AA may accrue over time, initiating in childhood. Conversely, it could be postulated that having a positive AA during early life and childhood is developmentally advantageous. To reflect this, we could refer to AA as an epigenetic measure of development in children.

We found associations between AA and sex, birth weight, caesarean section delivery and several maternal characteristics, namely smoking in pregnancy, weight, BMI, selenium and cholesterol level.

Offspring of non-drinkers had higher AA on average at birth, but this appeared to resolve during childhood. Offspring of smokers had higher AA on average and this difference became larger during childhood and adolescence.

The lack of correlation between AA and several clinical variables may also indicate that AA reflects an ‘intrinsic’ aging rate that is independent of various aging factors.

The observation that the estimated genetic component of AA increased in older study participants may indicate that the AA measure is more biologically meaningful in adults rather than children, though alternatively it could be a reflection of a decreasing environmental influence on DNA methylation patterns over time.

This accords with our finding of strengthening within subject correlation over time, which suggests the period of rapid early life changes in methylation affects epigenetic age during development to a greater extent than adulthood changes in methylation.”

The heritability of age acceleration was analyzed:

“The heritability estimate from our study (h = 0.37) is lower than that reported Horvath (h = 1.0), which was based on a small number of cord blood samples from twin pairs. Both of these heritability estimates were based on relatively few samples. Future large scale studies will be needed to arrive at precise estimates of the heritability of AA in newborns and minors.

While our heritability estimate may seem low, empirical evidence has suggested that fitness related traits tend to have lower heritability than morphological traits because selection acts to purify deleterious genetic variation, and one might consider age accelerated residuals in the former category.”

Like the coauthors’ follow-on study, causality couldn’t be definitively determined:

“Assessing the causal relationship between exposures and AA (through Mendelian randomization) is underpowered in our current data.”

Epigenetic age acceleration at birth seemed to be overall “developmentally advantageous” for offspring of non-drinking mothers. That age acceleration continued for the offspring of smokers at the second and third measurement times (ages 7 and 15-17) seemed to have “detrimental consequences.” I’d guess that the methylation state of specific CpG sites would be more informative than the overall rate in these cases.

The point about “AA..is independent of various aging factors” was similar to one made in Using an epigenetic clock to distinguish cellular aging from senescence:

“Cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

The study was a step toward establishing the Horvath epigenetic clock for widespread usage. The Hannum method was also compared and contrasted.

http://hmg.oxfordjournals.org/content/25/1/191.full “Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies”

What’s the origin of the problem of being fat?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , , ,

This 2016 UK human study attempted to replicate the DNA methylation and adiposity associations found by studies on a long-term longitudinal UK cohort:

“We tested for replication of associations between previously identified CpG sites at HIF3A [the hypoxia inducible factor 3 alpha subunit gene] and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children.”

The researchers had sufficient data to test the unidirectional and causal findings of previous studies:

“Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality.”

The analyses didn’t replicate the previous studies’ findings, and a new finding was indicated:

“Our results were discordant with those expected if HIF3A methylation has a causal effect on BMI [body mass index, derived from height and weight] and provided more evidence for causality in the reverse direction i.e. an effect of BMI on HIF3A methylation.

These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation.

Our results also highlight an apparent long-lasting inter-generational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own [offspring] adiposity and HIF3A methylation.”

A person’s parents contributed all of their genetic material and the prenatal environment, and usually almost all of their postnatal and childhood development environment. If a person has a health problem that may have genetic and developmental origins, this is where to look for causes and preventive actions.

That these distant causes can no longer be addressed is a hidden assumption of research and treatment of effects of health problems. Aren’t such assumptions testable here in the current year?

http://diabetes.diabetesjournals.org/content/early/2016/02/01/db15-0996.long (pdf) “DNA methylation and body mass index: investigating identified methylation sites at HIF3A in a causal framework”

Epigenetic effects of diet, and reversing DNA methylation

gettingwell4 2-3 stars Required further work, Acetylcholine, Brain development, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Limbic system, Lower brain, Neurochemicals, Stress , , , , , ,

This 2015 French review focused on:

“The role of maternal health and nutrition in the initiation and progression of metabolic and other disorders.

The effects of various in utero exposures and maternal nutritional status may have different effects on the epigenome. However, critical windows of exposure that seem to exist during development need to be better defined.

The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course.”

The reviewer used the term “transgenerational” to refer to effects that were more appropriately termed parental or intergenerational. Per the definition in A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply there needed to be evidence in at least the next 2 male and/or 3 female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

The review had separate sections for animal and human studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663595/ “Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood”

I arrived at the above review as a result of it citing the 2014 Harvard Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. I’ll quote a few items from that review’s informative “Role of DNA demethylation in neural development” section:

“Distinct parts of mammalian brains, including frontal cortex, hippocampus, and cerebellum, all exhibit age-dependent acquisition of 5hmC [an oxidized derivative of 5mC [methylation of the fifth position of cytosine]].

In fact, the genome of mature neurons in adult central nervous system contains the highest level of 5hmC of any mammalian cell-type (~40% as abundant as 5mC in Purkinje neurons in cerebellum). These observations indicate that 5mC oxidation and potentially DNA demethylation may be functionally important for neuronal differentiation and maturation processes.

A comprehensive base-resolution analyses of 5mC and 5hmC in mammalian frontal cortex in both fetal and adult stages indicate that non-CpG methylation (mCH) and CpG hydroxymethylation (hCG) drastically build up in cortical neurons after birth, coinciding with the peak of synaptogenesis and synaptic pruning in the cortex. This study demonstrated that mCH could become a dominant form of cytosine modifications in adult brains, accounting for 53% in adult human cortical neuronal genome.

In mature neurons, intragenic mCH is preferentially enriched at inactive non-neuronal lineage-specific genes, indicating a role in negative regulation of the associated transcripts. By contrast, genic hCG is positively correlated with gene expression levels.”

The link between scientific value and content is broken at PNAS.org

gettingwell4 < 0 Detracted from science, Neurochemicals, Oxytocin, Telomeres

Should we expect content posted on the Proceedings of the National Academy of Sciences of the United States of America to have scientific value?

This 2016 Singapore study was a “PNAS Direct Submission” that claimed:

“This paper makes a singular contribution to understanding the association between biological aging indexed by leukocyte telomeres length (LTL) and delay discounting measured in an incentivized behavioral economic task.

LTL is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient.”

1. Whether measured at the level of a human or of a blood cell, in 2016 there wasn’t incontrovertible evidence to support:

  • “Biological aging indexed by leukocyte telomeres length
  • LTL is an emerging marker of aging at the cellular level”

Using an epigenetic clock to distinguish cellular aging from senescence found:

“Cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

If that study was too recent, the researchers and reviewer knew or should have known of studies such as this 2009 study that found the correlation between a person’s chronological age and blood cell telomere length was r = −0.51 in women and r = −0.55 in men.

2. A study of biological aging in young adults with limited findings was cited for evidence that “the seeds of biological aging are widely thought to be planted early in life.” That study didn’t elucidate the point, however, as it didn’t fully link its measurements of 38-year-old subjects with measurements taken during the subjects’ early lives.

F2.large

3. Problematic research with telomere length was cited for evidence that “other factors, such as the early family environment, lifestyle, and stress, also have considerable impact on cellular aging.” The researchers had to be willing to overlook that study’s multiple questionable practices in order to cite it as evidence for anything.

4. Deliberately overlooking abundant disconfirming evidence, the current study used a one-to-one correspondence of telomere length and cellular aging.

The researchers went on to speciously model a relationship between telomere length and the behavioral trait “poor decision making that often entails being overly impatient.” That overreach was further stretched to the breaking point:

“We then asked if genes possibly modulate the effect of impatient behavior on LTL.

The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor β gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females.”

The “significantly mitigate” finding was “fun with numbers” that produced false effects rather than solid evidence. Consider that:

  1. The study’s model disregarded the probability that “Cellular ageing is independent of telomere length.”
  2. The researchers provided no mechanisms that plausibly linked performance “in an incentivized behavioral economic task” with telomere length.
  3. The researchers didn’t demonstrate any causal mechanisms whereby two gene variants plausibly affected the task performance’s purported effect on telomere length.

What’s the real reason this poor-quality paper’s reviewer forwarded it to PNAS.org?

http://www.pnas.org/content/113/10/2780.full “Delay discounting, genetic sensitivity, and leukocyte telomere length”

What’s a good substitute for feeling loved?

gettingwell4 0-1 star Wasted resources, Memory, Primal Therapy , ,

A friend of mine sent a link to this TED talk yesterday. The speaker inspired my friend to change their life along the speaker’s guidelines:

“The very act of doing the thing that scared me undid the fear.

That feeling, you can’t help but strive for greatness at any cost.

The more I work to be successful, the more I need to work.”

I wasn’t similarly inspired.

For one thing, a fear memory isn’t undone by behavior that covers it over and tamps it down. Fear extinction is the learned inhibition of retrieval of previously acquired responses provided evidence for what happens with a fear memory.

What I saw expressed in the TED talk was an exhausting pursuit of substitutes for feeling loved.

This February 18, 2016 blog post by Dr Arthur Janov framed the TED talk in the context that I understood the speaker:

“Most of us thought that once we choose a profession and follow it and succeed at it, becoming an expert and well known, that would be fulfilling. We would feel like a success.

Success is not a feeling, loved is.

Fame is other people’s idea of success; it is in a way their feeling…admiration, humbling, important, etc.

And why does the person, even most accomplished, never feel satisfied nor fulfilled?”

What do you feel is the appropriate context of the TED talk?

What do you think are likely outcomes of a person following the speaker’s guidelines?

Using an epigenetic clock to distinguish cellular aging from senescence

gettingwell4 5+ stars Premium, Epigenetics, Telomeres

The 2016 UK/UCLA human study found:

“Induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway, highlighting the independence of senescence from cellular ageing.

We used primary endothelial cells (ECs) that were derived from the human coronary artery of a 19 year old male.

The fact that maintenance of telomere length by telomerase did not prevent cellular ageing defines the singular role of telomeres as that of a means by which cells restrict their proliferation to a certain number; which was the function originally ascribed to it. Cellular ageing on the other hand proceeds regardless of telomere length.

Collectively, our results reveal that cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

The following was the closest the study came to a Limitations statement:

“Although the characteristics of cellular ageing are still not well known, the remarkable precision with which the epigenetic clock can measure it and correlate it to biological ageing remove any doubt of its existence, distinctiveness and importance. This inevitably raises the question of what is the nature of this cellular ageing, and what are its eventual physical consequences.

Admittedly, the observations above do not purport to provide the answer, but they have however, cleared the path to its discovery by unshackling cellular ageing from senescence, telomeres and DNA damage response, hence inviting fresh perspectives into its possible mechanism.”

The epigenetic clock method was the same used by:

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7383&path[]=21162 “Epigenetic clock analyses of cellular senescence and ageing”

What’s the underlying question for every brain study to answer?

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Beliefs, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Testosterone, Thalamus , , , , , ,

Is the underlying question for every brain study to answer:

  • How do our brains internally represent the external world?

Is it:

  • How did we learn what we know?
  • How do we forget or disregard what we’ve learned?
  • What keeps us from acquiring and learning newer or better information?

How about:

  • What affects how we pay attention to our environments?
  • How do our various biochemical states affect our perceptions, learning, experiences, and behavior?
  • How do these factors in turn affect our biology?

Or maybe:

  • Why do we do what we do?
  • How is our behavior affected by our experiences?
  • How did we become attracted and motivated toward what we like?
  • How do we develop expectations?
  • Why do we avoid certain situations?

Not to lose sight of:

  • How do the contexts affect all of the above?
  • What happens over time to affect all of the above?

This 2015 UCLA paper reviewed the above questions from the perspective of Pavlovian conditioning:

“The common definition of Pavlovian conditioning, that via repeated pairings of a neutral stimulus with a stimulus that elicits a reflex the neutral stimulus acquires the ability to elicit that the reflex, is neither accurate nor reflective of the richness of Pavlovian conditioning. Rather, Pavlovian conditioning is the way we learn about dependent relationships between stimuli.

Pavlovian conditioning is one of the few areas in biology in which there is direct experimental evidence of biological fitness.”

The most important question unanswered by the review was:

  • How can its information be used to help humans?

How can Pavlovian conditioning answer: What can a human do about the thoughts, feelings, behavior, epigenetic effects – the person – the phenotype – that they’ve been shaped into?

One example of the unanswered question: the review pointed out in a section about fear extinction that this process doesn’t involve unlearning. Fear extinction instead inhibits the symptoms of fear response. The fear memory is still intact, awaiting some other context to be reactivated and expressed.

How can this information be used to help humans?

  • Is inhibiting the symptoms and leaving the fear memory in place costless with humans?
  • Or does this practice have both potential and realized adverse effects?
  • Where’s the human research on methods that may directly address a painful emotional memory?

One relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is that a person continues to be their conditioned self until they address the sources of their pain. A corollary is that efforts to relieve symptoms seldom address causes.

How could it be otherwise? A problem isn’t cured by ameliorating its effects.

http://cshperspectives.cshlp.org/content/8/1/a021717.full “The Origins and Organization of Vertebrate Pavlovian Conditioning”

Use it or lose it: the interplay of new brain cells, age, and activity

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres, Testosterone , , , ,

This 2015 German review was of aging and activity in the context of adult neurogenesis:

“Adult neurogenesis might be of profound functional significance because it occurs at a strategic bottleneck location in the hippocampus.

Age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis, because adult neurogenesis is neuronal development under the conditions of the adult brain.

The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes (e.g., in cell or synapse numbers), but emerge on a systems level and above when an organism ages. With respect to adult neurogenesis, only one multilevel experiment including morphology and behavior has been conducted, and, even in that study, only three time points were investigated.

In old age, adult neurogenesis occurs at only a small fraction of the level in early adulthood. The decline does not seem to be ‘regulated’ but rather the by-product of many age-related changes of other sorts.

From a behavioral level down to a synaptic level, activity increases adult neurogenesis. This regulation does not seem to occur in an all-or-nothing fashion but rather influences different stages of neuronal development differently. Both cell proliferation and survival are influenced by or even depend on activity.

The effects of exercise and environmental enrichment are additive, which indicates that increasing the potential for neurogenesis is sufficient to increase the actual use of the recruitable cells in the case of cognitive stimulation. Physical activity would not by itself provide specific hippocampus-relevant stimuli that induce net neurogenesis but be associated with a greater chance to encounter specific relevant stimuli.

Adult hippocampal neurogenesis might contribute to a structural or neural reserve that if appropriately trained early in life might provide a compensatory buffer of brain plasticity in the face of increasing neurodegeneration or nonpathological age-related functional losses. There is still only limited information on the activity-dependent parameters that help to prevent the age-dependent decrease in adult neurogenesis and maintain cellular plasticity.

The big question is what the functional contribution of so few new neurons over so long periods can be. Any comprehensive concept has to bring together the acute functional contributions of newly generated, highly plastic neurons and the more-or-less lasting changes they introduce to the network.”

I’ve quoted quite a lot, but there are more details that await your reading. A few items from the study referenced in the first paragraph above:

“The hippocampus represents a bottleneck in processing..adult hippocampal neurogenesis occurs at exactly the narrowest spot.

We have derived the theory that the function of adult hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty..a mechanism for preparing the hippocampus for processing greater levels of complexity.”

The role of the hippocampus in emotion was ignored as it so often is. The way to address many of the gaps mentioned by the author may be to Advance science by including emotion in research.

For example, from the author’s The mystery of humans’ evolved capability for adults to grow new brain cells:

“Adult neurogenesis is already effective early in life, actually very well before true adulthood, and is at very high levels when sexual maturity has been reached. Behavioral advantages associated with adult neurogenesis must be relevant during the reproductive period.”

When human studies are designed to research how “behavioral advantages associated with adult neurogenesis must be relevant” what purpose does it serve to exclude emotional content?

http://cshperspectives.cshlp.org/content/7/11/a018929.full “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”