Transgenerational effects of early environmental insults on aging and disease

The first paper of Transgenerational epigenetic inheritance week was a 2017 Canadian/Netherlands review that’s organized as follows:

“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”

A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to the F2 grandchildren in the paternal lineage or to the F3 great-grandchildren in the maternal lineage.

The reviewers noted that the mechanisms of transgenerational programming are complex and multivariate.  The severity, timing, and type of exposure, lineage of transmission, germ cell exposure, and gender of an organism were the main factors that may determine the consequences. The mechanisms reviewed were:

  1. Parental exposure to an adverse environment;
  2. Altered maternal behavior and care of the offspring; and
  3. Experience-dependent modifications of the epigenome.

There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most of the studies were animal, but a few were human, such as those done on effects of extended power outages during the Quebec ice storm of January 1998.

One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers, but researchers could probably find enough instances to develop studies of the effectiveness of the placements in reversing a transgenerational phenotype.

The review didn’t have suggestions for reversing human transgenerational phenotypes, just  “..potential interventions to reverse negative effects of transgenerational programming.” The interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced the impact of transgenerational epigenetic effects.

The tricky wording of “..reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review is insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:

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

When reversals of human transgenerational phenotypes aren’t researched, the problems compound as they’re transmitted to the next generations. “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)


How one person’s paradigms regarding stress and epigenetics impedes relevant research

This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.

The reviewer won’t change his beliefs regarding individual differences and allostatic load since he helped to start those memes. US researchers with study ideas to develop evidence beyond such memes may have difficulties finding funding.

Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:

Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory [10] in keeping with the original definition of epigenetics [132] as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”

What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, his sphere of influence would probably steer the prospective studies’ experiments toward altering “a negative trajectory in a more positive direction” instead. An example of his influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:

“..not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I found nothing in citation [10] (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:

“..a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor”

without making any therapeutic efforts to test the permanence assumption! Never mind that researchers outside the reviewer’s sphere of influence have done exactly that. In any event, citation [10] didn’t support an “there is no such thing as reversibility” axiom.

The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate merger of behaviors are in the Conclusion section.

What may be a more promising research approach to human treatments of the epigenetic effects of stress now that it’s 2017? I pointed out in The current paradigm of child abuse limits pre-childhood causal research:

“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 the damage would also reverse the 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 human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?” “Neurobiological and Systemic Effects of Chronic Stress”

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

As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments of 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 assumption of almost all of the cited references was that these distant causes can 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 the damage would also reverse the 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 human 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 misrepresents 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 seven references the review cited for telomere length that had “is associated with” or “is linked to” child abuse findings 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.” “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

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

Is it:

  • 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 is:

  • How can its information be used to help humans?

How does Pavlov conditioning answer:

  • What can a human do about the thoughts, feelings, behavior, epigenetic effects – the person – that they’ve been shaped into?

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

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

As an example, the review pointed out in a section about fear extinction that it 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 that 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? “The Origins and Organization of Vertebrate Pavlovian Conditioning”

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

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 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? “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”

Are hormone ratios useful in explaining health? Behavior? Neurobiology? Anything?

This 2015 Zurich human review addressed:

“A remarkable lack of discussion on the meaning and interpretation of frequently used hormone ratios.

The interpretation of hormone ratios is complicated and in many cases not sufficiently supported from a theoretical point of view.

Based on the assumption that the balance between two interdependent hormones determines their eventual effects on brain and other tissues, this index has been commonly interpreted as an indicator of the balance between two endocrine systems.

The ratio is typically calculated by simply dividing the raw value of one hormone by the raw value of a second hormone. However, endocrine parameters may fluctuate considerably within individuals across short periods of time on the basis of circadian rhythms or contextual factors. Nevertheless, the ratio method has so far only rarely been applied in the context of repeated endocrine assessments.”

The researchers made a non-exhaustive list of three dozen studies that used hormone ratios among cortisol, dehydroepiandrosterone sulfate (DHEA-S), estradiol, progesterone, testosterone, triiodothyronine (T3), thyroxine (T4), etc., to explain various outcome measures such as:

  • “Health status
  • Aggressive behavior
  • Psychopathy
  • Marital violence
  • fMRI response to angry and happy faces
  • Early life adversity
  • Depression
  • Chronic stress
  • Alexithymia”

The researchers’ 2015 study on “endocrine correlates of pro-environmental behavior” was used as an illustrative example. The examined study had 229 male subjects between the ages of 19 and 77. Salivary cortisol (C) and testosterone (T) was sampled with these results:

“T/C and C/T ratios produce different means, standard deviations..and distributional properties..which significantly deviate from normality.

Height is not significantly associated with either T/C or C/T..In fact, looking at the original variables, C correlates positively with height while T shows no association.

When we include age as a covariate (assuming that it is associated with both height and hormone status)..the partial correlation between T/C and height then is significant while the association between C/T and height is non-significant, even though both ratios are based on the exact same data.

Looking at the negative association between age and T/C..the observed age-related ratio decline is mainly due to the fact that the T value in the numerator decreases with age while the C value in the denominator remains relatively constant. In this case, the analysis of the individual variables therefore offers more information and a more accurate picture of the underlying relationships.

A few previous studies have standardized the two underlying hormone distributions before calculating the ratio in order to account for the fact that two hormones often exhibit very different means and standard deviations..standardization leads to values that express each subject’s hormone concentration relative to the sample mean.

A ratio calculated on the basis of such standardized hormones takes on a different meaning. In particular, the ratio no longer merely represents the proportion of the two hormones within the individual but also incorporates how high the two hormone concentrations are with respect to the sample distributions.”

Practices to improve the use and interpretation of hormone measurements included:

“Regression techniques employed on the original variables constitute a better suited alternative devoid of the problems associated with the ratio method. Moderation analysis, in particular, is a useful approach, which often provides more detailed insight into the relationships of interest.

Ratios should either be analyzed with non-parametric techniques, or be log-transformed before parametric statistical methods are applied.”

Set points and variations in an individual’s hormone balances are usually the effects of underlying causes. Hopefully, one day researchers will pay more attention to effectively dealing with ultimate causes as the preferred methods of managing an individual’s health, behavioral, and neurobiological effects. “How to use and interpret hormone ratios”

A problematic study of testosterone’s influence on behavior and brain measurements

This 2015 US/Canadian human study of people ages 6 to 22 years found:

“Testosterone-specific associations between amygdala volume and key prefrontal areas involved in emotional regulation and impulse control:

  1. Testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC);
  2. A significant relationship between amygdala-mPFC covariance and levels of aggression; and
  3. Mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression.

These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms.

For the great majority of individuals in this sample, higher thickness of the mPFC was associated with lower aggression levels at a given amygdala volume..this effect diminished greatly and disappeared at more extreme amygdala values.”

The study provided noncausal associations among the effects (behavioral, hormonal, and brain measurements).

From the Limitations section:

“No umbilical cord or amniotic measurements were available in this study and we therefore cannot control for testosterone levels in utero, a period during which significant testosterone-related changes in brain structure are thought to occur.”

There’s evidence that too much testosterone for a female fetus and too little testosterone for a male fetus both have lifelong adverse effects. The researchers dismissed this etiologic line of inquiry with a “supporting the notion” referral to noncausal studies.

The researchers were keen to establish:

“A very specific, aggression-related structural brain phenotype.”

This putative phenotype hinged on:

  • Older subjects’ behavioral self-reports, and
  • Parental assessments of younger subjects’ behavior

exhibited during the previous six months, and within six months of their fMRI scan.

These self-reports and interested-party observations were the entire bases for the “aggressive behavior” and “anxious–depressed” associations. The researchers provided multiple references and models for the reliability of these assessments.

Experimental behavioral measurements – such as those done to measure performance in decision studies – may have been more accurate and informative than what the older subjects chose to self-report about their own behavior over the previous six months.

People of all ages have an imperative to NOT be completely honest about their own behavior. One motivation for this condition is that some of our historical realities are too painful to enter our conscious awareness and inform us about our own behavior. As a result, our feelings, thoughts, and behavior are sometimes driven by our histories without us being aware of it.

For example, would a teenager/young adult subject self-report an impulsive act, even if they didn’t fully understand why they acted that way? Maybe they would if the act could be viewed as prosocial, but what if it was antisocial?

What are the chances that the lives of these teenager/young adult subjects were NOT filled with impulsive actions during the six months before their fMRI scans? Could complete and accurate self-reports of such behaviors be expected?

Experimental behavioral measurements may have also been more accurate and informative than second-hand, interested-party observations of the younger subjects. Could someone who provided half of the genes and who was responsible for many of their child’s epigenetic changes make anything other than subjective observations of their handiwork’s behavior?

Epigenetic studies have shown that adaptations to environments are among the long-lasting causes for effects that include behavior, hormones, and brain measurements. Why, in 2015, did researchers spend public funds developing what they knew or should have known would be noncausal associations, while not investigating possible causes for these effects?

Why weren’t the researchers interested enough to gather and assess etiologic genetic and epigenetic evidence? Was it that difficult to get blood samples at the same time the subjects gave saliva samples, and perform selected genetic and DNA methylation analyses?

What did the study contribute towards advancing science? Who did the study really help? “A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood”