2-3 stars Required further work

Research needing further work

Telomere dynamics, stress, and aging across generations

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

This 2015 Pennsylvania/North Dakota animal and human review noted:

“The mechanisms linking stress exposure to disease progression and ageing either within individuals or across generations are still unclear, but recent work suggests that telomere dynamics (length and loss rate) may play an important role.

Parental stress may directly influence the parental germline telomeres pre-fertilization, affecting the telomere length inherited by offspring. Alternatively, parental stress may affect telomere dynamics indirectly either pre- or post-natally. The physiological mechanisms by which stress elicits changes in telomere length are also diverse.

We need more information about how these effects vary between developmental stages, among individuals, and within tissues of individuals..to mitigate the effects of early life adversity on human health.”

I was disappointed that the reviewers chose Problematic research with telomere length as a reference. Then again, maybe their statement:

“how these traits are related to one another clearly deserves more study”

is a polite way of saying that study’s methodology was flawed?

Regarding evolutionary biology:

“While most evidence suggests that the effect of parental stress exposure on offspring telomeres is negative, it is important to remember that this is just one trait that can contribute to parental and offspring fitness.

Investment in traits that increase fitness is expected to be favoured, even if they come at a cost to traits associated with longevity, such as telomere length.”

A similar point was made in a reference of A study of DNA methylation and age that:

“Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”

 

http://rsbl.royalsocietypublishing.org/content/11/11/20150396 “Telomere dynamics may link stress exposure and ageing across generations”

A review of epigenetic transgenerational inheritance of reproductive disease

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Stress , , ,

This 2015 Washington review of epigenetic transgenerational inheritance of reproductive disease defined transgenerational effects as follows:

“In considering transgenerational phenomena it is important to distinguish between direct exposure effects versus germline (sperm or egg) mediated transgenerational events.

When a gestating F0 generation female is exposed the F0 generation female, the F1 generation fetus and the germ cell (sperm or egg) that is inside the fetus and that will produce the F2 generation are all directly exposed. Any effects in the F0, F1 and F2 generations may be due to direct exposure toxicity or to environmentally induced epigenetic changes in the directly exposed cells. Examination of the F3 generation (great grand-offspring) is needed to determine if a transgenerational phenomenon has occurred, since the F3 generation has had no direct exposure effects.

In contrast, in the event an adult male or non-pregnant female is exposed, the F0 generation adult and the germ cells that will generate the F1 generation are directly exposed, such that examination of the F2 generation (grand-offspring) is required to demonstrate a transgenerational phenomenon.”

This review was an example of a government agency commissioning science that narrowly supported their view. NIEHS funded this review, and the authors interpreted “environment” in “Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease” to fit this conduit of public funds.

The problem was that this interpretation of “environment” limited the subject to the categories pictured in this Venn diagram. The authors’ tailoring of “environmentally induced” to the government agency’s interests should have similarly restricted the title.

F3 sperm epimutations

Other interpretations of “environment” were in studies such as:

and their references. Such studies demonstrated both that:

  1. Environmental factors like stress and nutrition – especially in early life – cause diseases in later life; and
  2. These diseases may be inherited by the subjects’ descendants.

The authors elsewhere referred generally and specifically (nutrition) to studies of other environmental factors.

Have you ever heard that our children and then their children could possibly inherit our diseases caused by stressful environments? Wouldn’t that research be of equal to or greater importance in our lives than pesticides’ harmful effects?

http://www.bioone.org/doi/10.1095/biolreprod.115.134817 “Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease”

A human study of changes in gene expression

gettingwell4 2-3 stars Required further work, Epigenetics ,

This 2015 international human study of genetic and epigenetic factors was the largest in its field:

“We perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age.

We further used the gene expression profiles to calculate the ‘transcriptomic age’ of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features.”

Items of interest:

  • About 1,450 of the “1,497 genes that are differentially expressed” are newly identified;
  • The subjects’ mean age was 55.81 with a pooled standard deviation of 11.59;
  • The mean difference “between transcriptomic age and chronological age” was 7.84 years; and
  • Native American, Mexican American, and African American studies were used as replication cohorts.

It was refreshing to see the peer-review influence of numerous coauthors on the study. Papers that are written by only one or two researchers don’t often have frank limitation explanations such as:

“A potential limitation of our study is that we relied on a linear regression model to identify age-associated genes. A linear model assumes constant change over age, which may not be always correct in biological processes that stretch over several decades (adulthood). A recent study demonstrated that a quadratic regression model has a higher statistical fit to cross-sectional gene expression datasets over linear model.

A limitation of our study is that we used the Illumina Infinium Human Methylation 450K Bead Chip Array for measuring methylation levels: this array queries only 1.6% of all CpGs in the genome and the CpG selection is biased towards CpG islands.

In addition, we did not examine non-CpG methylated sites, which have recently been suggested to play a role in regulating gene expression as well.

Other techniques—whole-genome bisulfite sequencing and methylC-capture (MCC) sequencing, for example—have definite technical advantages (higher resolution and no CpG island selection bias), but these have currently not been applied to a large number of samples.”

http://www.nature.com/ncomms/2015/151022/ncomms9570/full/ncomms9570.html “The transcriptional landscape of age in human peripheral blood”

The roles of DNA methylation and demethylation in forming memories

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Brain development, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals , , , ,

This 2015 Alabama combined animal and human review noted:

“Memories can last a lifetime, yet the proteins that enable synaptic plasticity, allowing for the establishment and maintenance of the memory trace, are subject to perpetual turnover.

DNA methylation may likely serve as the principle cellular information storage device capable of stably and perpetually regulating cellular phenotype.”

The authors developed a framework for understanding disparate findings of DNA methylation and demethylation concerning memory.

The dependencies expressed in the framework among the numerous factors – with their relative strengths, timings, and durations – reminded me of this video:

1) If such an error-prone framework accurately reflected the evolved architecture of our memory, we wouldn’t have the variety and number and intensity of memories that we have.

2) The framework neither accounted for prenatal memory processes nor differentiated emotional memories, although some of the referenced studies’ findings were applicable.

3) DNA methylation and demethylation aren’t the entirety of memory formation explanations. For example, they don’t explain state-dependent memories that can be instantiated, reactivated, and amnesia induced without involving “the proteins that enable synaptic plasticity” described in the authors’ framework. For completeness, the authors could have assessed the relative contributions of other memory processes, or at least enumerated them.

4) DNA methylation and demethylation explanations don’t cover all epigenetic biochemical processes. There are also placental interactions, histone/protein interactions, microRNA interactions, etc. For completeness, the authors could have placed the review’s topic within appropriate contexts of other epigenetic processes that influence memory.

This review of DNA methylation and demethylation roles in memory formation opened up a few slats in the blind covering one window. There’s more to be done to fully open that blind, and more window blinds to be opened before the workings of our memory are illuminated.

http://nro.sagepub.com/content/21/5/475.full “DNA Methylation in Memory Formation: Emerging Insights”

Identifying epigenetic DNA changes with blood tests

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

This 2015 Chinese human study found:

“With reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. This development has opened up numerous research avenues and diagnostic applications.

Our study takes advantage of the recent availability of reference methylomes of a number of tissues. It is likely that such reference databases would be continually updated to include more sample types and from more individuals.”

Up to 41% of plasma DNA in pregnant women was from the placenta. However, I didn’t understand why the non-pregnant women in the control group had measurable placental DNA of up to 2.9%. Maybe it was leftover from a prior pregnancy?

http://www.pnas.org/content/112/40/E5503.full “Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments”

Countering the epigenetic effects of obese mothers on their fetuses

gettingwell4 2-3 stars Required further work, Epigenetics

This 2015 Colorado rodent study found:

“Maternal ADN [adiponectin, a hormone produced by fat cells, that regulates fat and glucose metabolism] supplementation reversed the adverse effects of maternal obesity on placental function and fetal growth.

Babies of mothers with obesity and/or gestational diabetes mellitus (GDM) are often large at birth and have increased adiposity, which predisposes them to the development of metabolic disease later in life.

Maternal ADN infusion in obese dams from E14.5 to E18.5 [the last 4 days of pregnancy, a period that accounts for 70% of the total fetal growth] normalized maternal insulin sensitivity, placental insulin/mTORC1 and PPARα signaling, nutrient transport, and fetal growth without affecting maternal fat mass.”

As the study may apply to humans:

“This hormone or a similar agent could feasibly do the same thing for humans that it did for mice,” Jansson said.

Jansson said more work needs to be done to track the long-term effects of the hormone treatment on the mice.”

The study focused on epigenetic effects of the mothers’ environment on fetuses, and didn’t assess possible genetic contributions.

As alternatives to adiponectin supplementation:

http://www.pnas.org/content/112/41/12858.full “Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth”

Inflexible behavior may be a byproduct of stress

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

This 2015 German human study found:

“15-mo-old infants exposed to stress thereafter kept performing a previously effective action, even after the action suddenly became ineffective.

Infants in a no-stress control group flexibly adjusted their behavior by disengaging from the newly ineffective action in favor of exploring an alternative action.

This finding demonstrates that stress impairs infants’ ability to adjust their behavior to changing circumstances.”

The primary measurement of stress levels was cortisol. Stressful conditions were:

  • A stranger sat down next to them;
  • A dancing robot played loud music and moved around;
  • The infant’s caregivers left the room for up to four minutes.

News coverage stated that the study’s design was an adaptation of experiments that produced the same findings in adults. But would adult humans be stressed by being left alone for four minutes?

It’s likely that animal studies were the basis for some of this study’s experiments, as in the If research provides evidence for the causes of stress-related disorders, why only focus on treating the symptoms? study:

“Maternal separation in rodents is a useful model of early-life stress that results in enduring physiological and behavioral changes that persist into adulthood.”

A study limitation was that it involved just 26 infants.

http://www.pnas.org/content/112/41/12882.full “Stress impairs cognitive flexibility in infants”

A hippocampal protein that increases when stress increases

gettingwell4 2-3 stars Required further work, Epigenetics, Hippocampus, Limbic system, Stress

This 2015 Michigan human/rodent study found:

“Gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD).

We show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2.”

The researchers went down the evolutionary scale from human findings to replicate many of the findings with rodents:

“We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression.

Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders.”

http://www.pnas.org/content/112/38/11953.full “Fibroblast growth factor 9 is a novel modulator of negative affect”

Adverse effects of inflammation and stress on hippocampal synapses

gettingwell4 2-3 stars Required further work, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , ,

This dense and highly-jargoned 2015 rodent study found:

“The suppression of BDNF [brain-derived neurotrophic factor] signaling, LTP [long-term potentiation], and memory may be driven by an increased sensitivity to IL-1β [the proinflammatory cytokine interleukin 1β] that occurs directly at synapses.”

The researchers reversed the adverse effects of IL-1β after they induced stress and inflammation. Blocking IL-1β when there wasn’t stress or inflammation, however, also caused adverse effects:

“Interestingly, administration of AS1 [the compound that blocked the proinflammatory responses] in the absence of LPS [the bacterial compound used to stress the subjects’ immune systems] treatment also impaired OLM [the object location memory test where control group rodents exhibited a preference for a novel location over a familiar location].

This finding is consistent with the notion that endogenous IL-1β at physiologically low levels may be essential for hippocampal memory function.”

The researchers asserted:

“Our data reveal a previously unidentified mechanism that explains the age-related vulnerability of hippocampal function to impairment by inflammation.”

Instead of couching their findings with a non-causal “age-related” term, could the researchers have specifically identified causes?

“IL-1β activates different pathways via AcP (proinflammatory) or AcPb (prosurvival) IL-1 receptor subunits.

This study demonstrates that the IL-1 receptor subunit system undergoes an age-dependent reconfiguration in hippocampal synapses.

This previously undescribed reconfiguration, characterized by an increase in the AcP/AcPb ratio, is responsible for potentiating impairments of synaptic plasticity and memory by IL-1β.”

What were the underlying causes for the relatively increased AcP activation over AcPb activation? The researchers didn’t say. Their explanations were left hanging at a correlated-but-not-causal “age-dependent” level rather than a “mechanism that explains.”

http://www.pnas.org/content/112/36/E5078.full “Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus”

We first recognize familiar faces with our limbic system

gettingwell4 2-3 stars Required further work, Amygdala, Hippocampus, Limbic system, Memory

This 2015 Belgian human study found:

“Medial temporal lobe structures (perirhinal cortex, amygdala, hippocampus) and anterior inferior temporal cortex responded abruptly when sufficient information for familiar face recognition was accumulated.

Activation in ventral occipitotemporal face-preferential regions increased with visual information, independently of long-term face familiarity.

[The researchers] isolated the discriminative neural responses to unfamiliar and familiar faces by slowly increasing visual information (i.e., high-spatial frequencies) to progressively reveal faces of unfamiliar or personally familiar individuals.”

A limitation of the study was, however:

“Behavioral data were acquired from only 11 subjects because of a technical error.”

http://www.pnas.org/content/112/35/E4835.full “Neural microgenesis of personally familiar face recognition”

Who’s responsible for your physical and emotional health?

gettingwell4 2-3 stars Required further work, Cortisol, Glutamate, Neurochemicals, Stress, Testosterone , ,

This 2015 Houston human study measured 575 metabolites in 72 biochemical pathways. The researchers used “nontargeted metabolomics” with next-generation gene sequencing to:

“Take account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy.”

The 80 subjects were 45 men and 35 women, average age of 54, in “normal health with complete medical records and three-generation pedigrees.” The subjects all had college degrees, and were members or spouses of members of an upper-level socioeconomic organization.

The study’s range of 575 metabolites certainly cast a shadow over studies such as Running a marathon, cortisol, depression, causes, effects, and agendas that singled out 1 metabolite and tortured its data until it confessed a relationship that supported the preferred agenda.

Limitations of this study that weren’t mentioned by the researchers included:

  1. There were no specific target levels for each metabolite, which could lead to a misinterpretation that a “healthy” blood plasma level of a metabolite would always be the norm of the 80 subjects. This interpretation of each metabolite’s ideal level could be reinforced by the study calculating z-scores and P values of each individual’s measurement’s position within the cohort. The researchers stated:

    “The identification of abnormal metabolic signatures was restricted by the relatively small number of subjects in the cohort.”

    but that limitation wasn’t the flip side of omitted optimal levels.

  2. The metabolite measurements were mainly a one-time event although a series of measurements may have been more appropriate. Many of these metabolite levels vary with the time of day, what each individual had recently eaten, what each individual’s recent stress levels were, etc. This limitation may have been one of the sources for what the researchers noted:

    “Statistical analysis revealed a considerable range of variation and potential metabolic abnormalities across the individuals in this cohort.”

  3. There was no assessment of the relative contributions of epigenetic and genetic factors when discussing possible genetic impacts.

Regarding 1. above:

  • It may be interesting to compare an individual to their peers and to other sources of information. However, when it comes time for “individualized therapy” because of a metabolic measurement that’s an outlier compared to these other sources, an individual’s history also matters.
  • Each individual’s history could be used as a guide for optimal levels of some metabolites. For example, an optimal goal for “individualized therapy” for low testosterone levels of each of the 54-year old male subjects could be each individual’s previous higher levels of three decades earlier. It wouldn’t make sense for a 54-year old male to start testosterone therapy with a goal of raising his low levels to the non-therapeutic, low-level norm of other 54-year old males.

Regarding 2. above:

Regarding 3. above:

  • As an example of unconsidered epigenetic factors, there was a discussion of acetaminophen metabolites because:

    “The identification of at-risk populations could improve therapeutic options for individual patients and prevent adverse clinical outcomes.”

    The researchers specifically compared and contrasted two subjects with the highest levels of acetaminophen metabolites, and concluded:

    “These observations may suggest that volunteer 3976 was sensitive to acetaminophen-induced liver injury, whereas volunteer 3958 could tolerate acetaminophen well. This difference may relate to their cellular capability to maintain GSH [reduced glutathione] levels in response to acetaminophen. We searched for a genetic basis of this variation in acetaminophen degradation/toxic metabolism without success.”

  • The researchers shouldn’t have left the discussion hanging at this point. There’s no reason in 2015 for researchers to not investigate the contribution of epigenetic factors to:

    “Take account of human individuality in genes, environment, and lifestyle.”

I was put off by the researchers statement:

“The volunteer’s cardiologist was informed of this observation to monitor possible drug interaction or toxicity.”

It appeared that the researchers bypassed one subject and informed the subject’s doctor directly when the subject was doing something the researchers considered detrimental to the subject’s health. I don’t know if the subject gave prior consent to be bypassed, though, because I didn’t see either study’s consent terms in the below linked material.

A few concluding questions:

  • If it’s alright for personal health information to be transmitted without the consent of highly-educated, upper-level socioeconomic subjects, what can the rest of the population expect?
  • Is “individualized therapy” best done through individual choices, or by forcing an individual to conform to expert opinion?
  • Who is responsible for an individual’s physical and emotional health?

http://www.pnas.org/content/112/35/E4901.full “Plasma metabolomic profiles enhance precision medicine for volunteers of normal health”

http://www.pnas.org/content/110/42/16957.full “Personalized genomic disease risk of volunteers” (2013 original study with the same subjects)

DNA damage to fat cells may cause obesity and insulin resistance

gettingwell4 2-3 stars Required further work, Epigenetics, Stress ,

This 2015 Indiana rodent study found:

“DNA damage is a root cause of adipocyte senescence [fat cells that can no longer replicate], which plays a determining role in the development of obesity and insulin resistance.”

The researchers removed the capability for the subject mice to produce a protein that “plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage.” They showed that this genetic deficiency:

“Causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance.”

These researchers – in contrast with the Pulling on the chain of causes and effects with insulin resistance study – investigated causes for the various effects that included insulin resistance. However, the study’s applicability to humans wasn’t clear, since we most often develop symptoms such as insulin resistance due to causes other than genetics.

The study also demonstrated that treatment with a common dietary supplement – N-acetyl cysteine (NAC) – or metformin (Met):

“Reduce[d] adipose DNA damage.

Ameliorated cellular senescence and metabolic abnormalities.”

Body fat

High-fat and high-fructose diets caused the opposite effects in the subject genetic-deficient mice.

http://www.pnas.org/content/112/33/E4556.full “Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities”

Over 500 million people affected but no news coverage

gettingwell4 2-3 stars Required further work ,

Sometimes I wonder how research becomes newsworthy. I couldn’t find any news coverage of this 2015 Chinese rodent study which provided details of the effects of a gene for which:

“Over 500 million people worldwide carry a specific polymorphism.

Is a risk factor for liver cancer.”

1 out of every 15 people alive today has this condition, and can expect:

“Increased sensitivity to acute or chronic alcohol-induced toxicity

Higher risk for gastrointestinal cancers

Enzyme deficiency in the liver, leading to inefficient detoxification of aldehydes and accumulation of cancer-causing mutations.”

Was the lack of news coverage because 40% of East Asians are affected? Would this study become newsworthy if 40% of some other group was affected?

http://www.pnas.org/content/112/29/9088.full “ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis”

What could cause humans to have a unique sense of smell?

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

This 2015 Israeli human study found:

“Each person expresses a nearly unique set of different olfactory receptor genes, and therefore may have unique olfactory perception.”

From news coverage of the study, the researchers thought that their findings may be of use for:

“Smell-based social networks

A diagnostic tool for diseases that affect the sense of smell, such as Parkinson’s

A security biometric.”

The researchers attempted to link the subjects’ olfactory components to components of their immune systems. Since studies such as:

provided details on how our immune systems become unique, it would follow that this study’s subjects’ immune systems may have been the underlying cause for the findings.

However, in the study’s limitations paragraph, the researchers stated that this study didn’t demonstrate such causes:

“We did not directly measure genetic makeup.

Given that HLA [human leukocyte antigen genes that regulate our immune systems] captures self and olfactory fingerprints capture self, then there will be a link between HLA and olfactory fingerprints even if they are not the result of linked genes.”

Perhaps the causes for our “unique olfactory perception” will be researched in future studies.

http://www.pnas.org/content/112/28/8750.full “Individual olfactory perception reveals meaningful nonolfactory genetic information”

Interruptions to the circadian cycle negatively affect memory consolidation

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Cerebrum, Hippocampus, Limbic system, Memory, Stress

This 2015 German rodent study found:

“The control of sleep and memory consolidation may share common molecular mechanisms.”

Somewhat counter to the “Enhanced memory consolidation” in the study’s title, the researchers also found:

“Elevated IGF2 [insulin-related growth factor 2] signaling in the long term, however, has a negative impact on cognitive processing.”

The IGF2 finding was in genetically altered mice that had their circadian rhythm permanently disturbed, however. The study didn’t clearly determine the contribution of other factors that could have contributed to the cognitive decline.

The study traced fear memories induced by stress through the cerebrum to the anterior cingulate cortex and hippocampus parts of the limbic system.

Researchers have no problems studying emotional memories in these brain areas with rodents. In human memory experiments, however, emotional content is consistently excluded, as if none of our memories had anything to do with our feelings.

http://www.pnas.org/content/112/27/E3582.full “Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex”