Forcing people to learn helplessness

Learned helplessness is a proven animal model. Its reliably-created phenotype is often the result of applying chronic unpredictable stress.

As we’re finding out worldwide, forcing humans to learn helplessness works in much the same way, with governments imposing what amounts to martial law. Never mind that related phenotypes and symptoms include:

  • “Social defeat
  • Social avoidance behavior
  • Irritable bowel syndrome
  • Depression
  • Anxiety
  • Anhedonia
  • Increased hypothalamic-pituitary-adrenal (HPA)-axis sensitivity
  • Visceral hypersensitivity” [1]

Helplessness is both a learned behavior and a cumulative set of experiences. Animal models demonstrate that these phenotypes usually continue on throughout the subjects’ entire lifespans.

Will the problems caused in humans by humans be treated by removing the causes? Or will the responses be approaches such as drugs to treat the symptoms?

A major difference between our current situation and the situation depicted below is that during communism, most people didn’t really trust or believe what the authorities, newspapers, television, and radio said:

Image from Prague’s Memorial to the Victims of Communism

[1] 2014 GABAB(1) receptor subunit isoforms differentially regulate stress resilience curated in If research provides evidence for the causes of stress-related disorders, why only focus on treating the symptoms?

Growing a broccoli sprouts Victory Garden

To follow up How much sulforaphane is suitable for healthy people? I’ve started growing broccoli sprouts, and a 30 60 grams of fresh broccoli sprouts incorporated daily into the diet” [1] program. See Week 2 of Changing an inflammatory phenotype with broccoli sprouts for changes.

I loosely follow [2]‘s sprouting guidelines. One preparation difference is microwaving per [3]‘s findings as follows:

My current microwaving time for 60 grams of 3-day-old broccoli sprouts in 100 ml of water with a 1000 W microwave on full power is 35 seconds. The temperature gets up to 57°C. See Enhancing sulforaphane content for changes. I immediately dump the broccoli sprouts into a colander and spray with cold water to stop heating at the desired temperature.

The first batch of broccoli sprouts was a mild, cabbage-tasting side dish to the home-style chicken soup on page 238 of [4].

The a priori hypotheses:

    1. 30 grams of fresh broccoli sprouts will not have “51 mg (117 μmol)” of glucoraphanin [1] because they “Used the elicitor methyl jasmonate (MeJA) by priming the seeds as well as by spraying daily. MeJA at concentrations of 156 μM act as stressor in the plant and enhances the biosynthesis of the phytochemicals glucosinolates. Compared to control plants without MeJA treatment, the content of compounds as the aliphatic glucosinolate glucoraphanin was enhanced up to 70%.” 117 μmol / 1.70 = 69 μmol is the expected glucoraphanin amount in 30 grams weight of fresh broccoli sprouts. 69 x 2 = 138 μmol in 60 grams.
    2. One measurement [5] of how much sulforaphane is present in fresh broccoli sprouts before microwaving is 100 μmol / 111 g = .9 μmol / g. (.9 x 30 g) = 27 μmol is the expected sulforaphane amount in 30 grams of fresh broccoli sprouts. Changed assumption to 0 μmol sulforaphane due to 2013 Sulforaphane: translational research from laboratory bench to clinic “Broccoli sprouts are correctly described as releasing, generating, or yielding but not containing SFN [sulforaphane].”
    3. Last week a [3] coauthor agreed to make the data available to facilitate calculations. While I’m waiting…The study said the Figure 3 HL60 sulforaphane amount was 2.45 μmol / g. Eyeball estimate of the below Figure 3 control (raw broccoli florets) is a glucoraphanin amount of ~2.2 μmol / g. I assume that the broccoli florets and sprouts conversion would be the same at a 2.45 μmol / 2.2 μmol ≈ 1.11 ratio. I expect that microwaving the raw broccoli sprouts to 60°C will convert the 138 μmol of glucoraphanin to a 153 μmol amount of sulforaphane at this assumed 1.11 conversion ratio.
    4. The estimated sulforaphane weight per [6] would be (153 / 5.64) = 27 mg which is comparable to clinical trial dosages listed in [7] and [8].
    5. I’ve been sitting around a lot since returning from Milano, Italy, on February 24, 2020, and probably weigh around 75 kg. The estimated dosage represents 153 μmol / 75 kg = 2.04 μmol / kg, compared to the 1.36 μmol / kg average of [1]. (The study provided the subjects’ mean weight in Table 1 as “85.8 ± 16.7 kg.” The average dosage per kg body weight was 117 μmol / 85.8 kg = 1.36 μmol / kg.)
    6. Don’t have a practical estimate of the amount of sulforaphane I metabolize from post-microwave glucoraphanin. Both [7] and [8] cited a 2012 study that found: “Some conversion of GRN [glucoraphanin] to SFN can occur in response to metabolism by the gut microflora; however, the response is inefficient, having been shown to vary ‘from about 1% to more than 40% of the dose.’”
    7. Don’t have a practical estimate of the “internal dose.” [8]

I don’t have a laboratory in my kitchen 🙂 and won’t have quantified results.

References in order of citation:

[1] 2018 Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects

[2] 2017 You Need Sulforaphane – How and Why to Grow Broccoli Sprouts

[3] 2020 Microwave cooking increases sulforaphane level in broccoli curated in Microwave broccoli to increase sulforaphane levels


[4] 2016 Dr. Vlassara’s AGE-Less Diet: How a Chemical in the Foods We Eat Promotes Disease, Obesity, and Aging and the Steps We Can Take to Stop It

[5] 2016 Effect of Broccoli Sprouts and Live Attenuated Influenza Virus on Peripheral Blood Natural Killer Cells: A Randomized, Double-Blind Study

[6] 2020 lists sulforaphane’s molecular weight as 177.3 g / mol. A 1 mg weight of sulforaphane equals a 5.64 μmol sulforaphane amount (.001 / 177.3).

[7] 2019 Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease

[8] 2019 Broccoli or Sulforaphane: Is It the Source or Dose That Matters? Note that a coauthor didn’t disclose their business’ conflict of interest for an effectively promoted commercial product.

How much sulforaphane is suitable for healthy people?

This post compares and contrasts two perspectives on how much sulforaphane is suitable for healthy people. One perspective was an October 2019 review from John Hopkins researchers who specialize in sulforaphane clinical trials:

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

Since these researchers didn’t give a consumer-practical answer, I’ve presented a concurrent commercial perspective to the same body of evidence via an October 2019 review from the Australian founder of a company that offers sulforaphane products:

Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease

1. Taste from the clinical trial perspective:

“The harsh taste (a.k.a. back-of-the-throat burning sensation) that is noticed by most people who consume higher doses of sulforaphane, must be acknowledged and anticipated by investigators. This is particularly so at the higher limits of dosing with sulforaphane, and not so much of a concern when dosing with glucoraphanin, or even with glucoraphanin-plus-myrosinase.

The presence and/or enzymatic production of levels of sulforaphane in oral doses ranging above about 100 µmol, creates a burning taste that most consumers notice in the back of their throats rather than on the tongue. Higher doses of sulforaphane lead to an increased number of adverse event reports, primarily nausea, heartburn, or other gastrointestinal discomfort.”

Taste wasn’t mentioned in the commercial review. Adverse effects were mentioned in this context:

“Because SFN is derived from a commonly consumed vegetable, it is generally considered to lack adverse effects; the safety of broccoli sprouts has been confirmed. However, the use of a phytochemical in chemoprevention engages very different biochemical processes when using the same molecule in chemotherapy; the biochemical behaviour of cancer cells and normal cells is very different.”

2. Commercial products from the clinical trial perspective:

“Using a dietary supplement formulation of glucoraphanin plus myrosinase (Avmacol®) in tablet form, we observed a median 20% bioavailability with greatly dampened inter-individual variability. Fahey et al. have observed approximately 35% bioavailability with this supplement in a different population.”

Avmacol appeared to be the John Hopkins product of choice, as it was mentioned 15 times in the clinical trials table. A further investigation of Avmacol showed that its supplier for broccoli extract, TrueBroc, was cofounded and is still run by a John Hopkins coauthor! Yet the review stated:

“The authors declare no conflict of interest.”

Other products were downgraded with statements such as:

“5 or 10 g/d of BroccoPhane powder (BSP), reported to be rich in SF, daily x 4 wks (we have assayed previously and found this not to be the case).”

They also disclaimed:

“We have indicated clinical studies in which label results have been used rather than making dose measurements prior to or during intervention.”

No commercial products, not even the author’s own company’s, were directly mentioned in the commercial perspective.

3. Dosage from the clinical trial perspective:

“Reporting of administered dose of glucoraphanin and/or sulforaphane is a poor measure of the bioavailable / bioactive dose of sulforaphane. As a consequence, we propose that the excreted amount of sulforaphane metabolites (sulforaphane + sulforaphane cysteine-glycine + sulforaphane cysteine + sulforaphane N-acetylcysteine) in urine over 24 h (2–3 half-lives), which is a measure of “internal dose”, provides a more revealing and likely consistent view of the delivery of sulforaphane to study participants.

Only recently have there been attempts to define minimally effective doses in humans – an outcome made possible by the development of consistently formulated, stable, bioavailable broccoli-derived preparations.”

Dosage from the commercial perspective:

“Of the available SFN clinical trials associated with genes induced via Nrf2 activation, many demonstrate a linear dose-response. More recently, it has become apparent that SFN can behave hormetically with different effects responsive to different doses. This is in addition to its varying effects on different cell types and consequent to widely varying intracellular concentrations.

A 2017 clinical pilot study examined the effect of an oral dose of 100 μmol (17.3 mg) encapsulated SFN on GSH [reduced glutathione] induction in humans over 7 days. Pre- and postmeasurement of GSH in blood cells that included T cells, B cells, and NK cells showed an increase of 32%. The researchers found that in the pilot group of nine participants, age, sex, and race did not influence the outcome.

Clinical outcomes are achievable in conditions such as asthma with daily SFN doses of around 18 mg daily and from 27 to 40 mg in type 2 diabetes. The daily SFN dose found to achieve beneficial outcomes in most of the available clinical trials is around 20-40 mg.”

The author’s sulforaphane products are available in 100, 250, and 700 mg capsules of enzyme-active broccoli sprout powder. From Eat broccoli sprouts today:

“The bioavailability of sulforaphane in a broccoli sprout extract with the myrosinase enzyme 100 μmol gelcap was 36.1% which weighed 6.4 mg.”

The author’s products convert to 36, 90, and 253 mg sulforaphane dosages. Since only the first is in the review’s recommended “20-40 mg” range, I don’t see a readily apparent conflict.

4. Let’s see how the perspectives treated a 2018 Spanish clinical trial published as Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects.

From the commercial perspective:

“In a recent study using 30 grams of fresh broccoli sprouts incorporated daily into the diet, two key inflammatory cytokines were measured at four time points in forty healthy overweight [BMI 24.9 – 29.9] people. The levels of both interleukin-6 (Il-6) and C-reactive protein (CRP) declined over the 70 days during which the sprouts were ingested.

These biomarkers were measured again at day 90, wherein it was found that Il-6 continued to decline, whereas CRP climbed again. When the final measurement was taken at day 160, CRP, although climbing, had not returned to its baseline value. Il-6 remained significantly below the baseline level at day 160.

The sprouts contained approximately 51 mg (117 μmol) GRN, and plasma and urinary SFN metabolites were measured to confirm that SFN had been produced when the sprouts were ingested.”

The clinical trial perspective added that the study dosage was “1.67 (GR) μmol/kg BW.” This wasn’t accurate, however. It was assumed into existence by:

“In cases where the authors did not indicate dosage in μmol/kg body weight (BW), we have made those calculations using the a priori assumption of a 70 kg BW.”

117 μmol / 1.67 μmol/kg = 70 kg.

The study provided the subjects’ mean weight in Table 1 as “85.8 ± 16.7 kg.” So the study’s actual average dosage per kg body weight was 117 μmol / 85.8 kg = 1.36 μmol/kg. Was making an accurate calculation too difficult?

The clinical trial review included the study in the informative Section “3.2. Clinical Studies with Broccoli-Based Preparations: Efficacy” subsection “3.2.8. Diabetes, Metabolic Syndrome, and Related Disorders.” However, this was somewhat misleading, as it was grouped with studies such as the 2012 Iranian Effects of broccoli sprout with high sulforaphane concentration on inflammatory markers in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial (not freely available).

The commercial perspective pointed out substantial differences between the two studies:

“Where the study described above by Lopez-Chillon et al. investigated healthy overweight people to assess the effects of SFN-yielding broccoli sprout homogenate on biomarkers of inflammation, Mirmiran et al. in 2012 had used a SFN-yielding supplement in T2DM patients. Although the data are not directly comparable, the latter study using the powdered supplement resulted in significant lowering of Il-6, hs-CRP, and TNF-α over just 4 weeks.

It is not possible to further compare the two studies due to the vastly different time periods over which each was conducted.”

The commercial perspective impressed as more balanced than the clinical trial perspective. The clinical trial perspective also had an undisclosed conflict of interest!

A. The commercial perspective didn’t specifically mention any commercial products. The clinical trial perspective:

– Effectively promoted one commercial product whose supplier was a coauthor’s company;

– Downgraded several other commercial products; and

– Tried to shift responsibility for the lack of “minimally effective doses in humans” to commercial products with:

“Only recently have there been attempts to define minimally effective doses in humans – an outcome made possible by the development of consistently formulated, stable, bioavailable broccoli-derived preparations.”

Unless four years previous is “recently,” using commercial products to excuse slow research progress can be dismissed. A coauthor of the clinical trial perspective was John Hopkins’ lead researcher for the November 2015 Sulforaphane Bioavailability from Glucoraphanin-Rich Broccoli: Control by Active Endogenous Myrosinase, which commended “high quality, commercially available broccoli supplements” per:

“We have now discontinued making BSE [broccoli sprout extract], because there are several high quality, commercially available broccoli supplements on the market.”

B. The commercial perspective didn’t address taste, which may be a consumer acceptance problem.

C. The commercial perspective provided practical dosage recommendations, reflecting their consumer orientation. These recommendations didn’t address how much sulforaphane is suitable for healthy people, though.

Practical dosage recommendations are what the clinical trial perspective will eventually have do after they stop dodging their audience – which includes clinicians trying to apply clinical trial data – with unhelpful statements such as:

“Reporting of administered dose of glucoraphanin and/or sulforaphane is a poor measure of the bioavailable / bioactive dose of sulforaphane.”

How practical was their “internal dose” recommendation for non-researcher readers?

Here’s what I’m doing to answer how much sulforaphane is suitable for healthy people.

I’d like to posthumously credit my high school literature teachers Dorothy Jasiecki and Martin Obrentz for this post’s compare-and-contrast approach. They both required their students to read at least two books monthly, then minimally handwrite a 3-page (single-spaced) paper comparing and contrasting the two books.

You can see from their linked testimonials that their approach was in a bygone era, back when some teachers considered the desired outcome of public education to be that each individual learned to think for themself. My younger brother contributed:

“I can still remember everything Mr. Obrentz ever assigned for me to read. He was the epitome of what a teacher should be.”

Clearing out the 2019 queue of interesting papers

I’m clearing out the below queue of 27 studies and reviews I’ve partially read this year but haven’t taken the time to curate. I have a pesky full-time job that demands my presence elsewhere during the day. :-\

Should I add any of these back in? Let’s be ready for the next decade!

Early life “Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid” (not freely available) “Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex” (not freely available) “Intergenerational transmission of depression: clinical observations and molecular mechanisms” (not freely available)

mother “Epigenomics and Transcriptomics in the Prediction and Diagnosis of Childhood Asthma: Are We There Yet?” epigenetic clocks: estimating gestational age using placental DNA methylation levels” “Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study” “Environmental influences on placental programming and offspring outcomes following maternal immune activation” “5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns” (not freely available) “Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice” “Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress” (not freely available) “Genome-wide DNA methylation data from adult brain following prenatal immune activation and dietary intervention” in depression vulnerability and resilience: novel targets for preventive strategies”

Later life “Effect of Flywheel Resistance Training on Balance Performance in Older Adults. A Randomized Controlled Trial” “Eccentric Overload Flywheel Training in Older Adults” “Epigenetic regulation of the innate immune response to infection” (not freely available) “Hair Cell Regeneration” (not freely available) Modifications as an Intersection Between Diet and Longevity” “Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair” (not freely available) “Frailty biomarkers in humans and rodents: Current approaches and future advances” (not freely available) “Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses “In Search of Panacea—Review of Recent Studies Concerning Nature-Derived Anticancer Agents” “Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus” (not freely available) “Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis” “The Beige Adipocyte as a Therapy for Metabolic Diseases” “Bone adaptation: safety factors and load predictability in shaping skeletal form” (not freely available) “Successful treatment of post-traumatic stress disorder reverses DNA methylation marks” (not freely available) “Editing the Epigenome to Tackle Brain Disorders” (not freely available)

Do genes or maternal environments shape fetal brains?

This 2019 Singapore human study used Diffusion Tensor Imaging on 5-to-17-day old infants to find:

“Our findings showed evidence for region-specific effects of genotype and GxE on individual differences in human fetal development of the hippocampus and amygdala. Gene x Environment models outcompeted models containing genotype or environment only, to best explain the majority of measures but some, especially of the amygdaloid microstructure, were best explained by genotype only.

Models including DNA methylation measured in the neonate umbilical cords outcompeted the Gene and Gene x Environment models for the majority of amygdaloid measures and minority of hippocampal measures. The fact that methylation models outcompeted gene x environment models in many instances is compatible with the idea that DNA methylation is a product of GxE.

A genome-wide association study of SNP [single nucleotide polymorphism] interactions with the prenatal environments (GxE) yielded genome wide significance for 13 gene x environment models. The majority (10) explained hippocampal measures in interaction with prenatal maternal mental health and SES [socioeconomic status]. The three genome-wide significant models predicting amygdaloid measures, explained right amygdala volume in interaction with maternal depression.

The transcription factor CUX1 was implicated in the genotypic variation interaction with prenatal maternal health to shape the amygdala. It was also a central node in the subnetworks formed by genes mapping to the CpGs in neonatal umbilical cord DNA methylation data associating with both amygdala and hippocampus structure and substructure.

Our results implicated the glucocorticoid receptor (NR3C1) in population variance of neonatal amygdala structure and microstructure.

Estrogen in the hippocampus affects learning, memory, neurogenesis, synapse density and plasticity. In the brain testosterone is commonly aromatized to estradiol and thus the estrogen receptor mediates not only the effects of estrogen, but also that of testosterone.” “Neonatal amygdalae and hippocampi are influenced by genotype and prenatal environment, and reflected in the neonatal DNA methylome” (not freely available)

Too cheap for clinical trials

Let’s compare and contrast a 2019 meta-analysis and a 2017 review of using acetyl-L-carnitine to treat diabetic neuropathy.

A 2019 Brazilian meta-analysis Acetyl‐L‐carnitine for the treatment of diabetic peripheral neuropathy of four previous trials stated:

  • “The risk of bias was high in both trials of different ALC doses and low in the other two trials.
  • No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief.
  • At doses greater than 1500 mg/day, ALC reduced pain more than placebo. This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.
  • The placebo-controlled studies did not measure functional impairment and disability scores.
  • No study used validated symptom scales.
  • Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.

Authors’ conclusions:

  • We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty.
  • Data on functional and sensory impairment and symptoms are lacking, or of very low certainty.
  • The evidence on adverse events is too uncertain to make any judgements on safety.”

A 2017 Italian review Effects of acetyl-L-carnitine in diabetic neuropathy and other geriatric disorders stated:

“A long history of diabetes mellitus and increasing age are associated with the onset of diabetic neuropathy, a painful and highly disabling complication with a prevalence peaking at 50% among elderly diabetic patients. The management of diabetic neuropathy is extremely difficult: in addition to the standard analgesics used for pain control, common treatments include opioids, anticonvulsants, antidepressants, and local anesthetics, alone or in combination. Such therapies still show a variable, often limited efficacy, however.

Many patients do not spontaneously report their symptoms to physicians, but, if asked, they often describe having experienced a persistent and non-abating pain for many years. The prevalence of painful symptoms is just as high in patients with mild neuropathy as in those with more advanced DPN.

Through the donation of acetyl groups, ALC exerts a positive action on mitochondrial energy metabolism. ALC has cytoprotective, antioxidant, and antiapoptotic effects in the nervous system.

ALC has also been proposed for the treatment of other neurological and psychiatric diseases, such as mood disorders and depression, dementia, Alzheimer’s disease, and Parkinson’s disease, given that synaptic energy states and mitochondrial dysfunctions are core factors in their pathogenesis. Compared to other treatments, ALC is safe and extremely well tolerated.”

“In nerve injury, the mGlu2 receptor overexpressed by ALC binds the glutamate, reducing its concentration in the synapses with an analgesic effect. ALC may improve nerve regeneration and damage repair after primary nerve trauma.”

Where will the money come from to realize what the 2017 review promised, as well as provide what the 2019 meta-analysis required?

Do we prefer the current “limited efficacy” treatments of “opioids, anticonvulsants, antidepressants, and local anesthetics?”

Who will initiate clinical trials of a multiple of the normal dietary supplement dose (500 mg at $.25 a day, retail)? How profitable is a product whose hypothetical effective dosage for diabetic neuropathy (3000 mg) sells for only $1.50 a day?

A book review of “Neuroepigenetics and Mental Illness”

A 2018 online book “Neuroepigenetics and Mental Illness” was published at (not freely available). Three chapters are reviewed here, with an emphasis on human studies:

Actually, I won’t waste my time or your time with what I planned to do. The lack of scientific integrity and ethics displayed by the book’s publisher, editor, and contributors in the below chapter spoke volumes.

How can the information in any other chapter of this book be trusted?

“Chapter Twelve: Transgenerational Epigenetics of Traumatic Stress”

This chapter continued propagating a transgenerational meme that had more to do with extending paradigms than advancing science. The meme is that there are adequately evidenced transgenerational epigenetic inheritance human results.

As noted in Epigenetic variations in metabolism, there aren’t any published human studies that provide incontrovertible evidence from the F0 great-grandparents, F1 grandparents, F2 parents, and F3 children to confirm definitive transgenerational epigenetic inheritance causes and effects. Researchers urgently need to do this human research, and stop pretending that it’s already been done.

How did the book’s editor overlook what this chapter admitted?

“Literature about the inheritance of the effects of traumatic stress in humans has slowly accumulated in the past decade. However, it remains thin and studies in humans also generally lack clear “cause and effect” association, mechanistic explanations or germline assessment.”

Were the publisher and editor determined to keep the chapter heading – and the reviewers determined to add another entry to their CVs – in the face of this weasel-wording?

“In conclusion, although less studied from a mechanistic point of view, inter- and possibly transgenerational inheritance of the effects of traumatic stress is supported by empirical evidence in humans.”

See the comments below for one example of the poor substitutes for evidence that propagators of this transgenerational meme use to pronounce human transgenerational epigenetic inheritance a fait accompli. Researchers supporting the meme and its funding pipeline most certainly know that not only this one example, but also ALL human transgenerational epigenetic inheritance studies:

“Lack clear “cause and effect” association, mechanistic explanations or germline assessment.”

Lack of scientific integrity is one reason why such human research hasn’t been undertaken with the urgency it deserves. Propagating this meme is unethical, and adversely affects anyone who values evidence-based research.

A mid-year selection of epigenetic topics

Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:

The pain societies instill into children

DNA methylation and childhood adversity

Epigenetic mechanisms of muscle memory

Sex-specific impacts of childhood trauma

Sleep and adult brain neurogenesis

This dietary supplement is better for depression symptoms than placebo

The epigenetic clock theory of aging

A flying human tethered to a monkey

Immune memory in the brain

The lack of oxygen’s epigenetic effects on a fetus

Melatonin and depression

This 2018 Polish review subject was the relationship between melatonin and depression:

“Although melatonin has been known about and referred to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about the genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment.

Melatonin has an antidepressant effect by:

  • Maintaining the body’s circadian rhythm,
  • Regulating the pattern of expression of the clock genes in the suprachiasmatic nucleus (SCN) and
  • Modifying the key genes of serotoninergic neurotransmission that are linked with a depressive mood.

Light input causes the release of γ-aminobutyric acid (GABA) by the SCN, and the inhibitory signal is transmitted to the pineal gland to inhibit melatonin production.

Melatonin is produced via the metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors.

Both melatonin and serotonin are synthesized from the same amino acid, tryptophan. People on a high tryptophan diet (>10 mg/kg body weight per day) have a significantly lower level of depressive symptoms, irritation, and anxiety than people on a low tryptophan diet (<5 mg/kg body weight per day).

To our knowledge, there are only 2 studies in the literature that characterize mRNA expression of ASMT in the peripheral blood of recurrent DD [depressive disorders]. [They] have demonstrated the reduced mRNA expression of ASMT in patients with depression and cognitive impairment. Surprisingly, these studies, despite promising results, have not been replicated. Moreover, no analysis of other melatonin related-genes as potential biomarkers of depression has been provided.

The main monoamine hypothesis of the pathophysiology of depression indicates that depression is induced by a change in the level of ≥1 monoamines such as serotonin, noradrenaline, and dopamine. The evidence for the serotonergic theory is an observation that antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and noradrenaline reuptake inhibitors increase the level of serotonin in the brain.

We focus on serotonin as a neurotransmitter which is a precursor of melatonin synthesis. In a depressed patient, serotonin synthesis is impaired and the poor precursor availability may prevent the formation of an adequate amount of melatonin. However, only a few studies have analyzed the relationship between serotonin and melatonin levels and the correlation with the blood serum.”

At eight cents a day ($.04 for women) melatonin is a cheap and effective supplement.

I hadn’t considered possible antidepressant effects until reading this review. More human studies are needed. “Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status” (not freely available)

A trio of epigenetic clock studies

We’ll start with a 2018 epigenetic clock human study 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? “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. “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.” “Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data”