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:
circadian rhythm, and
and to highlight its underlying cellular mechanisms with a focus on:
“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.”
Should hypothalamic activity not winding down when its developmental role is over be interpreted to construe a role that has some other meaning or purpose as we age?
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 phenotypicprogramming 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 the influence of the sponsor’s biases, and any directed narrative that ignored evidence contradicting the narrative, and any storytelling.
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 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 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.
“Reduction of maternal behavior[nursing behavior, grooming, licking, carrying pups] was predictive of behavioral disturbances in PRS [prenatally restraint stressed] rats as well as of the impairment of the oxytocin and its receptor gene expression.
Postpartum carbetocin [an oxytocin receptor agonist unavailable in the US] corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior.
Moreover, postpartum carbetocin had an anti-stress effect on HPA[hypothalamic-pituitary-adrenal] axis activity in the adult PRS progeny and increased hippocampal mGlu5 [type 5 metabotropic glutamate] receptor expression in aging.
Early postpartum carbetocin administration to the dam enhances maternal behavior and prevents all the pathological outcomes of PRS throughout the entire lifespan of the progeny..proves that the defect in maternal care induced by gestational stress programs the development of the offspring.“
This chart from Figure 4 summarized the behavioral performance of aged adult male progeny in relation to the experimental variables of:
Stress administered to the mothers three times daily every day during the second half of pregnancy up until delivery; and
The effects on the mothers’ behavior of daily carbetocin administration during postpartum days 1 through 7.
The symbols denote which of these relationships had statistically significant effects:
“* p [Pearson’s correlation coefficient] < 0.05 PRS-Saline vs. CONT-Saline;
# p < 0.05 PRS-Carbetocin vs. the PRS-Saline group.”
There are many interesting aspects to this study. Ask the corresponding coauthor Dr. Sara Morley-Fletcher at firstname.lastname@example.org for a copy.
One place the paper referenced the researchers’ previous studies was in this context:
“Postpartum carbetocin administration reversed the same molecular and behavioral parameters in the hippocampus, as does adult chronic carbetocin treatment, i.e. it led to a correction of the HPA axis negative feedback mechanisms, stress and anti-stress gene expression, and synaptic glutamate release. The fact that postpartum carbetocin administration [to the stressed mothers in this study] had the same effect [on the PRS infants in this study] as adult carbetocin treatment [to the PRS offspring in the previous study] indicates a short-term effect of carbetocin when administered in adulthood and a reprogramming (long-term) effect lasting until an advanced age when administered in early development.”
This group’s research seems to be constrained to treatments of F0 and F1 generations. What intergenerational and transgenerational effects would they possibly find by extending research efforts to F2 and F3 generations?
As the study may apply to humans:
The study demonstrated that stresses during the second half of pregnancy had lifelong impacts on both the mothers’ and offsprings’ biology and behavior. Studies and reviews that attribute similar human biological and behavioral conditions to unknown causes, or shuffle them into the black box of individual differences, should be recognized as either disingenuous or insufficient etiological investigations.
The study showed that prevention of gestational stress was a viable strategy. The control group progeny’s biology and behavior wasn’t affected by carbetocin administration to their mothers because neither they nor their mothers had experience-dependent epigenetic deficiencies.
The study demonstrated a biological and behavioral cure for the PRS offspring by changing their stressed mothers’ behaviors during a critical period of their development. The above excerpt characterized improving the mothers’ behaviors as a long-term cure for the PRS descendants, as opposed to the short-term cure of administering carbetocin to the PRS children when they were adults.
What long-term therapies may be effective for humans who had their developmental trajectories altered by their mothers’ stresses during their gestation, or who didn’t get the parental care they needed when they needed it?
“Recent studies, primarily focused on the findings from human studies, to indicate the role of DNA methylation in the associations between childhood adversity and cardiometabolic disease in adulthood. In particular, we focused on DNA methylation modifications in genes regulating the hypothalamus-pituitary-adrenalaxis as well as the immune system.”
Recommendations in the review’s Epigenetics inheritance and preadaptation theory section included:
“Twin studies offer another promising design to explore the mediation effect of DNA methylation between child adversity and cardiometabolic outcomes..which could rule out heterogeneity due to genetic and familia[l]r environmental confounding.”
As it so happened, the below 2018 study provided some evidence.
“Tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).
Hypothesis-driven analyses of six candidate genes in the stress response (
) did not reveal predicted associations with DNA methylation.
Epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.”
One of the sad findings was that as the types of trauma inflicted by other people on the subjects increased, so did the percentage of subjects who hurt themselves by smoking. Two-thirds of teens who reported three or more of the seven adolescent trauma types also smoked by age 18. Self-harming behaviors other than smoking weren’t considered.
Another somber finding was:
“Childhood sexual victimization is associated with stable DNA methylation differences in whole blood in young adulthood.
These associations were not observed in relation to sexual victimization in adolescence.”
The researchers guided future studies regarding the proxy measurements of peripheral blood DNA methylation:
“The vast majority of subsequent human studies, including the present one, have relied on peripheral blood. This choice is expedient, but also scientifically reasonable given the aim of detecting effects on stress-related physical health systems that include peripheral circulating processes (immune, neuroendocrine).
But whole blood is heterogeneous, and although cell-type composition can be evaluated and controlled, as in the present study, it does raise the question of whether peripheral blood is a problematic surrogate tissue for research on the epigenetics of stress.
Comparisons of methylomic variation across blood and brain suggest that blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”
1. The comment on “epigenetic epidemiology” overstated the study’s findings because the epigenetic analysis, although thorough, was limited to peripheral blood DNA methylation. Other consequential epigenetic effects weren’t investigated, such as histone modifications and microRNA expression.
“A main limitation with studies using the Illumina 450 K array is that the platform only covers ~1.5 % of overall genomic CpGs, which are biased towards promoters and strongly underrepresented in distal regulatory elements, i.e., enhancers.
WGBS [whole-genome bisulfite sequencing] offers single-site resolution CpG methylation interrogation at full genomic coverage.
Another advantage of WGBS is its ability to access patterns of non-CpG methylation.”
I’d expect that in the future, researchers with larger budgets would reanalyze the study samples using other DNA methylation techniques.
4. An outstanding opportunity to advance science was missed regarding intergenerational and transgenerational epigenetic inheritance:
Wouldn’t the parents’ blood samples and histories – derived from administering the same questionnaires their twins answered at age 18 – likely provide distant causal evidence for some of the children’s observed effects?
And lay the groundwork for hypotheses about aspects of future grandchildren’s physiologies and behaviors?
This 2017 Netherlands review subject was the lasting epigenetic effects of early-life stress:
“Exposure to stress during critical periods in development can have severe long-term consequences.
One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis.
Early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood.
ELS is able to “imprint” or “program” an organism’s neuroendocrine, neural and behavioralresponses to stress. Research focuses along two complementary lines.
Firstly, ELS during critical stages in brain maturation may disrupt specific developmental processes (by altered neurotransmitter exposure, gene transcription, or neuronal differentiation), leading to aberrant neural circuit function throughout life.
Secondly, ELS may induce modifications of the epigenome which lastingly affect brain function.
These epigenetic modifications are inducible, stable, and yet reversible, constituting an important emerging mechanism by which transient environmental stimuli can induce persistent changes in gene expression and ultimately behavior.”
In early life, the lower brain and limbic system brain structures are more developed and dominant, whereas the cerebrum and other brain structures are less developed (use the above rodent graphic as a rough guide).
Stress and pain generally have a greater impact on the fetus than the infant, and on the infant than the adult.
The reviewers cited 50+ studies from years 2000-2015 in the “Early Life Stress Effects in a “Matching” Stressful Adult Environment” section to argue for the match/mismatch theory:
“Encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context.
Initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder.
Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.”
The review mainly cited evidence from rodent studies that mismatched reactions in adulthood may be consequences of early-life events. These events:
“Imprint or program an organism’s neuroendocrine, neural and behavioral responses..
Leading to aberrant neural circuit function throughout life..
Which lastingly affect brain function.”
Taking this research to a personal level:
Have you had feelings that you were unsafe, although your environment was objectively safe?
Have you felt uneasy when people are nice to you?
Have you felt anxious when someone pays attention to you, even after you’ve acted to gain their attention?
Mismatched human feelings are one form of mismatched reactions. These may be consequences of early-life experiences, and indicators of personal truths.
If researchers can let go of their biases and Advance science by including emotion in research, they may find that human subjects’ feelings produce better evidence for what actually happened during the subjects’ early lives than do standard scientific methods of:
Incorporating this evidence may bring researchers closer to backwardly predicting the major insults to an individual that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.”
The subject of this 2016 Italian/New York review was the stress response:
“The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical [HPA] axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioraladaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders.
Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations.”
The reviewers’ intentional dismissal of the role of GABA in favor of the role of glutamate was a key point:
“The changes in neuronal excitability and synaptic plasticity induced by stress are the result of an imbalance of excitatory (glutamatergic) and inhibitory (GABAergic) transmission, leading to long-lasting (mal)adaptive functional modifications. Although both glutamate and GABA transmission are critically associated with stress-induced alteration of neuronal excitability, the present review will focus on the modulation of glutamate release and transmission induced by stress and glucocorticoids.”
No particular reason was given for this bias. I inferred from the review’s final sentence that the review’s sponsors and funding prompted this decision:
“In-depth studies of changes in glutamate transmission and dendrite remodeling induced by stress in early and late life will help to elucidate the biological underpinnings of the (mal)adaptive strategies the brain adopts to cope with environmental challenges in one’s life.”
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?
“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 assumption of almost all of the cited references was that these distant causes could no longer be addressed. Aren’t such assumptions testable here in 2016?
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.”