Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
The principal way science advances is through the principle Einstein expressed as:
“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”
Members of the scientific community and of the public should be satisfied that the scientific process is working well when hypotheses are discarded due to nonconfirming evidence. Researchers should strive to develop evidence that rejects paradigms, and be lauded for their efforts.
The opposite took place with this 2018 commentary on two studies where the evidence didn’t confirm current biases. I curated one of these studies in DNA methylation and childhood adversity.
The commentators’ dismissive tone was set in the opening paragraph:
“Is early exposure to adversity associated with a genetic or an epigenetic signature? At first glance, two articles in this issue -..and the other from Marzi et al., who measured genome-wide DNA methylation in a prospective twin cohort assessed at age 18 – appear to say that it is not.”
The two commentators, one of whom was a coauthor of Manufacturing PTSD evidence with machine learning, went on to protect their territory. Never mind the two studies’ advancement of science that didn’t coincide with the commentators’ vested interests.
My main concern with the study was that although the children had been studied at ages 5, 7, 10, 12, and 18, the parents had never been similarly evaluated! The researchers passed up an opportunity to develop the parents as a F0 generation for understanding possible human transgenerational inherited epigenetic causes and effects.
The study focused on the children’s intergenerational epigenetic effects. However, animal studies have often demonstrated transgenerational effects that skip over the F1 generation children!
- Transgenerational pathological traits induced by prenatal immune activation found a F2 grandchild and F3 great-grandchild phenotype of impaired sociability, abnormal fear expression and behavioral despair – effects that weren’t present in the F1 children;
- A self-referencing study of transgenerational epigenetic inheritance found histone modifications in the F3 generation that weren’t found in the F1 and F2 generations; and
- A study not cited in – but completely appropriate for – The lack of oxygen’s epigenetic effects on a fetus found heart disease effects in the F1 generation that were different from the heart disease effects found in the F2 and F3 generations.
https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2018.18020156 “Considering the Genetic and Epigenetic Signature of Early Adversity Within a Biopsychosocial Framework” (not freely available)
This 2018 Korean review discussed aspects of the hypothalamus and aging:
“A majority of physiological functions that decline with aging are broadly governed by the hypothalamus, a brain region controlling development, metabolism, reproduction, circadian rhythm, and homeostasis. In addition, the hypothalamus is poised to connect the brain and the body so that the environmental information affecting aging can be transmitted through the hypothalamus to affect the systematic aging of the peripheral organs.
The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body. This review aims to assess the contribution of hypothalamic aging to the age-related decline in body functions, particularly from the perspective of:
- energy homeostasis,
- hormonal balance,
- circadian rhythm, and
and to highlight its underlying cellular mechanisms with a focus on:
- nutrient sensing
- loss of stem cell,
- loss of proteostasis, and
- epigenetic alterations.”
The reviewers didn’t consider aging to be an “unintended consequence” of development. This perspective was found in a reference to A study of DNA methylation and age:
“Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways.
Genetic programs determine developmental growth and the onset of reproduction. When these programs are completed, they are not switched off.
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.”
The epigenetic clock theory of aging cited the same author, and modified his point to say:
This review’s opposite paradigm was:
“The hypothalamus is hypothesized to be a primary regulator of the process of aging.”
Almost all of the details discussed were from rodent studies.
I favor the “unintended consequence” explanation of aging. As detailed in How to cure the ultimate causes of migraines? and its references, the hypothalamus is a brain structure that lacks feedback mechanisms for several of its activities.
This structure develops shortly after conception and has an active prenatal role. The hypothalamus plays its part in getting us developed and ready to reproduce, with several feedback loops being evolutionarily unnecessary.
The hypothalamus perfectly illustrates the point of:
“When these programs are completed, they are not switched off.”
Hypothalamic activity not winding down when its developmental role is over shouldn’t be interpreted to construe a role that has some other meaning or purpose.
https://www.sciencedirect.com/science/article/pii/S0047637418300502 “Role of hypothalamus in aging and its underlying cellular mechanisms” (not freely available)
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypic programming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing 1) the influence of the sponsor’s biases, 2) any directed narrative that ignored evidence contradicting the narrative, and 3) any storytelling.
See if you can match the meaning of the review’s last sentence (“intervene before conception” quoted above) with the meaning of any sentence in its cited reference Developmental origins of noncommunicable disease: population and public health implications.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F2 grandchild and F3 great-grandchild generations.
One omitted topic was gestational hypoxic effects of caffeine. The first paper that came up for my PubMed search of “caffeine pregnancy hypoxia” was an outstanding 2017 Florida rodent review Long-term consequences of disrupting adenosine signaling during embryonic development that had this paragraph and figure:
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational critical periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.
https://www.physiology.org/doi/abs/10.1152/physrev.00043.2017 “Gestational Hypoxia and Developmental Plasticity” (not freely available) Thanks to coauthor Dr. Xiang-Qun Hu for providing a copy.
This 2018 UK review subject was colored-hearing experiences from music:
“Music-colour synaesthesia has a broad scope encompassing not only tone-colour synaesthesia elicited on hearing individual tones, but a complex and idiosyncratic mixture of phenomenological experiences often mediated by timbre, tempo, emotion and differing musical style.
The possession of synaesthesia or absolute pitch was shown to have very little effect on the actual colours chosen for each of the musical excerpts, but it might be reasonable to expect that music that elicits a strong emotional response may be more likely to induce synaesthesia than music that does not.
The examination of eight neuroimaging studies were found to be largely inconclusive in respect of confirming the perceptual nature of music-colour synaesthesia. Neither the hyperconnectivity nor the disinhibited feedback theory currently holds as a single categorical explanation for synaesthesia.
Theories promoting the notion of ‘ideaesthesia’ have highlighted the importance of the role of concept and meaning in the understanding of synaesthesia..and a replacement definition: Synaesthesia is a phenomenon in which a mental activation of a certain concept or idea is associated consistently with a certain perception-like experience.”
Much of the review was philosophizing and casting around for clues. The review cited interesting studies and reviews, including The Merit of Synesthesia for Consciousness Research.
One relevant element missed by the underlying research and the review was critical periods of human development. A cited reference in How brains mature during critical periods was Sensitive periods in human development: Evidence from musical training (not freely available) which illuminated some aspects of the research:
“In contrast to a critical period, where a function cannot be acquired outside the specific developmental window, a sensitive period denotes a time where sensory experience has a relatively greater influence on behavioral and cortical development. Sensitive periods may also be times when exposure to specific stimuli stimulates plasticity, enhancing changes at the neuronal and behavioral levels.
The developmental window for absolute pitch may be more similar to a critical than a sensitive period.
The auditory cortex appears to have an unusually long period of developmental plasticity compared with other sensory systems; changes in its cellular organization and connectivity continue into late childhood.
The effects of musical training have been shown to impact auditory processing in the brainstem as well.”
Let’s say that a researcher wanted – as one cited study did – to examine absolute pitch, a rare trait, present in a subset of synesthetes – music-color, another rare trait. The study as designed would probably be underpowered due to an insufficient number of subjects, and it would subsequently find “very little effect.”
Let’s say another researcher focused on brain areas in the cerebrum, and like the eight cited studies, ignored the nuclei in the pons part of the brainstem which are the first brain recipients of sound and equilibrium information from the inner ear via the eighth cranial nerve. Like those studies, the researcher was also biased against including limbic brain areas that would indicate “a strong emotional response.” A study design that combined leaving out important brain-area participants in the synesthesia process with a few number of synesthetes would be unlikely to find conclusive evidence.
The reviewer viewed the lack of evidence from “eight neuroimaging studies” as indicating something about the “perceptual nature of music-colour synaesthesia.” An alternative view is that the “inconclusive” evidence had more to do with study designs that:
- Had a small number of subjects;
- Omitted brain areas relevant to the music-color synesthesia process;
- Didn’t investigate likely music-color synesthesia development periods; and
- Didn’t investigate associations of music-color synesthesia with epigenetic states.
Consider the magnitude of omitting the thalamus from synesthesia studies as one “perceptual nature” example. Just the background information of Thalamus gating and control of the limbic system and cerebrum is a form of memory indicated its relevance to synesthesia:
“Despite the fundamental differences between visual, auditory and somatosensory signals, the basic layouts of the thalamocortical systems for each modality are quite similar.
For a given stimulus, the output neural response will not be static, but will depend on recent stimulus and response history.
Sensory signals en route to the cortex undergo profound signal transformations in the thalamus. A key thalamic transformation is sensory adaptation in which neural output adjusts to the statistics and dynamics of past stimuli.”
One of this study’s researchers described ways that an individual’s “stimulus and response history” became unconscious memories with the thalamus. Including the thalamus in synesthesia studies may also have findings that involve reliving or re-experiencing a memory, possibly an emotional memory.
In such future research, it could be a design element to ask synesthetes before and after the experiment to identify feelings and memories accompanying synesthesia experiences.
It shouldn’t be a requirement, however, to insist that memories and emotions be consciously identified in order to be included in the findings. Human studies, for example, Unconscious stimuli have a pervasive effect on our brain function and behavior have found:
“Pain responses can be shaped by learning that takes place outside conscious awareness.
Our results support the notion that nonconscious stimuli have a pervasive effect on human brain function and behavior and may affect learning of complex cognitive processes such as psychologically mediated analgesic and hyperalgesic responses.”
Does an orangy twilight of aging sunflowers help you feel?
https://www.sciencedirect.com/science/article/pii/S1053810017305883 “Music-colour synaesthesia: Concept, context and qualia” (not freely available)
This 2018 Alabama rodent study investigated the epigenetic effects on developing breast cancer of timing a sulforaphane-based broccoli sprouts diet. Timing of the diet was as follows:
- Conception through weaning (postnatal day 28), named the Prenatal/maternal BSp (broccoli sprouts) treatment (what the mothers ate starting when they were adults at 12 weeks until their pups were weaned; the pups were never on a broccoli sprouts diet);
- Postnatal day 28 through the termination of the experiment, named the Postnatal early-life BSp treatment (what the offspring ate starting at 4 weeks; the mothers were never on a broccoli sprouts diet); and
- Postnatal day 56 through the termination of the experiment, named the Postnatal adult BSp treatment (what the offspring ate starting when they were adults at 8 weeks; the mothers were never on a broccoli sprouts diet).
“The experiment was terminated when the mean tumor diameter in the control mice exceeded 1.0 cm.
Our study indicates a prenatal/maternal BSp dietary treatment exhibited maximal preventive effects in inhibiting breast cancer development compared to postnatal early-life and adult BSp treatments in two transgenic mouse models that can develop breast cancer.
Postnatal early-life BSp treatment starting prior to puberty onset showed protective effects in prevention of breast cancer but was not as effective as the prenatal/maternal BSp treatment. However, adulthood-administered BSp diet did not reduce mammary tumorigenesis.
The prenatal/maternal BSp diet may:
- Primarily influence histone modification processes rather than DNA methylation processes that may contribute to its early breast cancer prevention effects;
- Exert its transplacental breast cancer chemoprevention effects through enhanced histone acetylation activator markers due to reduced HDAC1 expression and enzymatic activity.
This may be also due to the importance of a dietary intervention window that occurs during a critical oncogenic transition period, which is in early life for these two tested transgenic mouse models. Determination of a critical oncogenic transition period could be complicated in humans, which may partially explain the controversial findings of the adult BSp treatment on breast cancer development in the tested mouse models as compared the previous studies. Thus long-term consumption of BSp diet is recommended to prevent cancers in humans.”
“The dietary concentration for BSp used in the mouse studies was 26% BSp in formulated diet, which is equivalent to 266 g (~4 cups) BSp/per day for human consumption. Therefore, the concentration of BSp in this diet is physiological available and represents a practical consumption level in the human diet.
Prior to the experiment, we tested the potential influences of this prenatal/maternal BSp regimen on maternal and offspring health as well as mammary gland development in the offspring. Our results showed there was no negative effect of this dietary regimen on the above mentioned factors (data not shown) suggesting this diet is safe to use during pregnancy.”
I downgraded the study’s rating because I didn’t see where the sulforaphane active content of the diet was defined. It’s one thing to state:
“SFN as the most abundant and bioactive compound in the BSp diet has been identified as a potent HDAC inhibitor that preferably influences histone acetylation processes.”
and describe how sulforaphane may do this and may do that, and include it in the study’s title.
It’s another thing to quantify an animal study into findings that can help humans. Normal people aren’t going to eat “4 cups BSp/per day” but we may take one capsule of a sulforaphane dietary supplement when the price is $.20 a day.
The study’s food manufacturer offers dietary products to the public without quantifying all of the active contents like sulforaphane. Good for them if they can stay in business by serving customers who can’t be bothered with scientific evidence.
These researchers shouldn’t have conducted a study using the same lack of details as the food manufacturer provided, though. They should have either tasked the manufacturer to specify the sulforaphane active content, or contracted the analysis.
Regarding timing of a sulforaphane-based broccoli sprouts diet for humans, the study also didn’t provide evidence for recommending:
“Thus long-term consumption of BSp diet is recommended to prevent cancers in humans.”
http://cancerpreventionresearch.aacrjournals.org/content/early/2018/05/15/1940-6207.CAPR-17-0423.full-text.pdf “Temporal efficacy of a sulforaphane-based broccoli sprout diet in prevention of breast cancer through modulation of epigenetic mechanisms”
The first 2018 epigenetic clock human study was from Finland:
“We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems.
Maternal history of depression diagnosed before pregnancy and greater antenatal depressive symptoms were associated with child’s lower epigenetic GA. Child’s lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys.”
Listening to a podcast by one of the coauthors, although the researchers’ stated intent was to determine the etiology of the findings, I didn’t hear any efforts to study the parents in sufficient detail to be able to detect possible intergenerational and transgenerational epigenetic inheritance causes and effects. There were the usual “associated with” and “it could be this, it could be that” hedges, which were also indicators of the limited methods employed toward the study’s limited design.
Why was an opportunity missed to advance human research in this area? Are researchers satisfied with non-causal individual differences non-explanations instead of making efforts in areas that may produce etiological findings?
https://www.jaacap.org/article/S0890-8567(18)30107-2/pdf “The Epigenetic Clock at Birth: Associations With Maternal Antenatal Depression and Child Psychiatric Problems” (not freely available)
The second 2018 epigenetic clock human study was from Alabama:
“We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations.
Both DNA methylation age estimates were highly correlated with chronological age. We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated.
The Horvath age acceleration measure exhibited marginal associations with increased postprandial [after eating a meal] HDL [high-density lipoprotein], increased postprandial total cholesterol, and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL and positively associated with postprandial TG [triglyceride], interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNFα).
Overall, the observed effect sizes were small.“
https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-018-0481-4 “Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study”
The third 2018 epigenetic clock human study was a meta-analysis of cohorts from the UK, Italy, Sweden, and Scotland:
“The trajectories of Δage showed a declining trend in almost all of the cohorts with adult sample collections. This indicates that epigenetic age increases at a slower rate than chronological age, especially in the oldest population.
Some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like underlying training population for the respective clocks may also have influenced this trend. It may also be possible that there is a ceiling effect for Δage whereby epigenetic clock estimates plateau.”
https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/gly060/4944478 “Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data”