Epigenetics

Forcing people to learn helplessness

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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?

Week 2 of Changing an inflammatory phenotype with broccoli sprouts

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress

To follow up Changing an inflammatory phenotype with broccoli sprouts:

1. My traveling companion used a kitchen scale to measure the weight of broccoli sprouts at Day 3. She started them from one tablespoon of broccoli seeds, and they weighed 60 grams!

The model clinical trial [1] used 30 grams to produce great results:

“The intervention consisted of a 10-week period which included daily consumption of a portion (30 g) of raw, fresh broccoli sprouts. This amount is consistent with a half-serving.”

I asked the study’s corresponding coauthor for clarification of “a half-serving.” Our conversation is at Understanding a clinical trial’s broccoli sprout amount.

Eating a 60 gram “full serving” of 3-day-old broccoli sprouts yielding 27 mg of sulforaphane after microwaving [2] fits [3]‘s guidelines:

“The daily SFN [sulforaphane] dose found to achieve beneficial outcomes in most of the available clinical trials is around 20-40 mg.”

2. 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. Their temperature gets up to 57°C. YMMV.

I immediately cool down the microwaved broccoli sprouts in a colander. See Enhancing sulforaphane content for changes. Go up to the 60°C cliff but don’t fall into the 70°C 65°C canyon:

cliff

The desired range [2]:

“In the temperature range of 50–60°C, a positive correlation was observed between GLR [glucoraphanin] or SFR [sulforaphane] contents and temperature. However, these two physiochemical contents were negatively correlated with temperature when it increased to 70°C.”

3. I had several days of failed crops during Week 2. I switched over to Russian-doll glass bowls with success:

I’d guess that failures were related to excess moisture, which broccoli sprouts hate, hate, hate! Look closely at the top left Day 0 tray below:

Notice concentric raised ribs that are about 1/16″ high. Their effects may have either kept broccoli seeds too wet over a 3-day period, or promoted bacterial growth (although I ran them through a dishwasher after Day 3).

4. I started to put items on the edge of my microwave’s carousel because they don’t heat evenly when placed in the center. I thought uneven heating was a problem that was solved a long time ago, but not for the microwave I bought (Sharp model SMC1131C, which was the least expensive at Best Buy on the day I needed a carousel microwave oven.)

[1] 2018 Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects curated in How much sulforaphane is suitable for healthy people?

[2] 2020 Microwave cooking increases sulforaphane level in broccoli curated in Microwave broccoli to increase sulforaphane levels and Growing a broccoli sprouts Victory Garden

[3] 2019 Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease curated in How much sulforaphane is suitable for healthy people?

Do early experiences of hunger affect our behavior, thoughts, and feelings today?

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Reposted from five years ago.

A 2015 worldwide human study Hunger promotes acquisition of nonfood objects found that people’s current degree of hungriness affected their propensity to acquire nonfood items.

The researchers admitted that they didn’t demonstrate cause and effect with the five experiments they performed, although the findings had merit. News articles poked good-natured fun at the findings with headlines such as “Why Hungry People Want More Binder Clips.”

The research caught my eye with these statements:

“Hunger’s influence extends beyond food consumption to the acquisition of nonfood items that cannot satisfy the underlying need.

We conclude that a basic biologically based motivation can affect substantively unrelated behaviors that cannot satisfy the motivation.“

The concept of the quotes relates to a principle of Dr. Arthur Janov’s Primal Therapy – symbolic satisfaction of needs. Two fundamentals of Primal Therapy:

  1. The physiological impacts of our early unmet needs drive our behavior, thoughts, and feelings.
  2. The painful impacts of our unfulfilled needs impel us to be constantly vigilant for some way to fulfill them.

Corollary principles of Primal Therapy:

  • Our present efforts to fulfill our early unmet needs will seldom be satisfying. It’s too late.
  • We acquire substitutes now for what we really needed back then.
  • Acquiring these symbols of our early unmet needs may – at best – temporarily satisfy derivative needs.

But the symbolic satisfaction of derived needs – the symptoms – never resolves the impacts of early unfulfilled needs – the motivating causes:

  • We repeat the acquisition behavior, and get caught in a circle of acting out our feelings and impulses driven by these conditions.
  • The unconscious act-outs become sources of misery both to us and to the people around us.

As this study’s findings showed, there’s every reason for us to want researchers to provide a factual blueprint of causes for our hunger sensation effects, such as “unrelated behaviors that cannot satisfy the motivation.“

Hunger research objectives could include answering:

  • What enduring physiological changes occurred as a result of past hunger?
  • How do these changes affect the subjects’ present behaviors, thoughts, and feelings?

Hunger research causal evidence for the effect of why people acquire “items that cannot satisfy the underlying need” may include studying where to start the timelines for the impacts of hunger. The impacts potentially go back at least to infancy when we were completely dependent on our caregivers.

Infants can’t get up to go to the refrigerator to satisfy their hunger. All a hungry infant can do is call attention to their need, and feel pain from the deprivation of their need.

Is infancy far back enough, though, to understand the beginnings of potential impacts of hunger?

If people don’t stand up for their rights, their rights will be forgotten

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YouTube took down this interview and a follow-on interview It was known to everybody that the lockdown would cause a catastrophe.

Here’s an interview last week with a German epidemiologist, Professor Wittkowski, who isn’t on a government payroll:

“First of all the elderly and fragile should be separated from the population where the virus is circulating. Everyone else, especially the children, should keep going to school, because they will be the primary impetus for herd immunity.

Flattening the curve prolongs the time a virus stays in the population. People staying indoors keeps the virus healthy.

Like every other respiratory disease, without government intervention, the pandemic would already be over like it’s over in China and South Korea. Except, both in China and South Korea, social distancing started very close to the peak. By keeping the virus from running its course, they are now having a second wave of cases. It will keep on if we don’t let it complete.

There’s nothing to be scared about. This is a flu epidemic like others, maybe more severe. What’s changed is the internet. People get their information in a few seconds, rather than a week.

Tracking a respiratory disease is impossible. Even in times of social distancing. Nature has ways to make sure we survive.

The standard for AIDS reporting, i.e., the date of infection separated from the date of reporting, is not being followed.

If we had herd immunity now, we wouldn’t have a second wave in the fall. Herd immunity typically lasts for a couple of years. If we prevent herd immunity, it is certain that a second wave will occur.

Testing doesn’t stop anything. Antibody testing will give us estimates of herd immunity, which would be useful.

We don’t die of the virus. We die of pneumonia.

The downside of starting containment is that we should not believe that we are more intelligent than mother nature when we were evolving. Mother nature was pretty good at making sure we were a good match for the diseases that we happened to see virtually every year.

I think people, especially in the United States, are more docile than they should be. People should talk with their politicians, question them, ask them to explain. Because if people don’t stand up to their rights, their rights will be forgotten.”

Changing an inflammatory phenotype with broccoli sprouts

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This follow up to Growing a broccoli sprouts Victory Garden is what’s gone on during Week 1 of starting to grow broccoli sprouts for 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.

Day 0 – I’ve tried many things to cure chronic inflammation over the years, basing most of my actions on what’s proven to work for other people. These treatments have helped but haven’t completely worked for me. I’ve continued them with the hypothesis that they may have positive synergistic interactions with daily eating 60 grams of 3-day-old broccoli sprouts that yield 27 mg of sulforaphane after microwaving.

Day 0 treatments included two dozen supplements I’ve taken since turning 50, a diet low in advanced glycation end products started last year [2], and naproxen (a nonsteroidal anti-inflammatory drug). The chronically inflamed spots are the left thumb base (arthritis), tendons outside the left ankle (peroneal tendinosis), and left knee tendonitis, all probably consequences of playing golf for 40+ years.

Day 1 – The vertical farming equipment is a Deluxe Kitchen Crop 4-Tray Seed Sprouter Model VKP1200 made by VICTORIO Kitchen Products. I soak one tablespoon of organic broccoli seeds for 12 hours. Take them out of the stackable trays for a twice-daily rinsing, which is counter to directions of pouring water into the tower top. Microwave the Day 3 broccoli sprouts daily per [3]. Run its tray through the dishwasher (but no heat cycle). Put the tray back in rotation for Day 0.

Day 2 – Threw away one of my crutches, naproxen, as taking it had become more of a habit than a necessity. I’d been taking 220 mg twice daily for years until two weeks ago, when I switched to once daily.

“Sulforaphane increases several endogenous antioxidant compounds via the transcription factor Nrf2 [nuclear factor erythroid 2-related factor 2, discovered in 1994]. Of the phytochemicals with Nrf2 inducer capacity, Brassica-derived SFN [sulforaphane] is the most potent naturally occurring biomolecule known at this time.

Another transcription factor, NF-κB, which is associated with inflammatory pathways is downregulated by SFN. This dual action of SFN is especially intriguing in that Nrf2 and NF-κB interact via their own ‘cross talk’.” [4]

Day 3 – Stopped taking 2 mg of sulforaphane in the form of a broccoli sprout extract capsule, and 200 mg of a diindolylmethane (DIM) capsule daily. DIM was raised 195% from Day 0 to Day 70 after daily intake of broccoli sprouts in [1], noting:

“The anti-inflammatory effects observed with broccoli sprouts intake are likely due to the combined effects of all the hydrolysis products of glucosinolates.”

Don’t need either supplement when broccoli sprouts supply them.

The next supplement I’ll drop is N-acetyl-cysteine (NAC), the precursor to our endogenous antioxidant glutathione. I’ve taken a 600 mg capsule twice daily for fifteen years.

[4] goes on and on about sulforaphane / glutathione interactions. For example: “Several well-studied Nrf2-dependent target genes of possible relevance are those encoding synthesis of glutathione (GSH)” in Section 5.2. SFN as a Redox Modulator that included Figure 6 below, and in Section 6. SFN: Its Redox-Modulating Effects:

Day 4 – I’d seen studies of broccoli sprouts that ranged from 3-days old (the most frequent age) to 8-days old. Before [5], I hadn’t found analyses of broccoli sprout age differences in sulforaphane contents, and only a few studies of sulforaphane differences among broccoli sprout cultivated varieties.

Day 5 – I’ve eaten sprouts at 3 – 5 days old, and haven’t noticed a taste difference after microwaving per [3]. Here’s what they look like at Days 0, 1, 2, and 3:

Day 6 – Are you ready to change your phenotype?

References in order of citation:

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

[2] 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

[3] 2020 Microwave cooking increases sulforaphane level in broccoli curated in Microwave broccoli to increase sulforaphane levels and Growing a broccoli sprouts Victory Garden

[4] 2019 Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease

[5] 2020 3-day-old broccoli sprouts have the optimal yields

3-day-old broccoli sprouts have the optimal yields

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This 2020 Chinese study compared the contents of 3, 5, and 7-day-old broccoli sprouts:

“The objective of this study was:

  1. To optimize the extraction conditions of SF [sulforaphane] from seeds and sprouts at the same time to ensure the maximum SF yields from them;
  2. To compare the SF yields, total flavonoid (TF) contents, and total phenolic (TP) contents from broccoli seeds and sprouts (after 3, 5, and 7 days germination respectively) of six different cultivated varieties; and
  3. To evaluate and compare the the stability and bioaccessibility of SF, TF and TP from broccoli seeds and sprouts upon in vitro gastrointestinal digestion; total antioxidant activities of samples before and after digestion were also investigated in this section.

Most varieties obtained the maximum SF, TP and TF contents in sprouts on day 3. SF contents in sprouts were 46% – 97% of seeds, whereas TP and TF contents in sprouts were 1.12 – 3.58 times higher than seeds among varieties.

sprout ages 1B

After in vitro digestion, broccoli sprouts from MNL variety kept considerable SF, TF, and TP contents, as well as antioxidant capacities, with all values higher than seeds.

SF from seeds and sprouts both showed high bioaccessibility values of 0.91 and 1.00, respectively. The high bioaccessibility of SF in vitro experiments provide an additional evidence for its efficient utilization, as many previous researches have reported a high bioavailability of SF in vivo.”

This study provided higher measures of sulforaphane in vitro bioaccessibility compared with previous studies of in vivo bioavailability.

It was good to read a definitive study that addressed both broccoli sprout age and cultivated variety for optimizing sulforaphane. The need was there. As the study authors put it:

“From the perspective of comparison methods, broccoli varieties, and germination processes, there is still lack of a systematic comparison of SF yields and other bioactive compounds contents between broccoli seeds and sprouts.”

https://www.sciencedirect.com/science/article/pii/S0308814620300637 “Sulforaphane and its antioxidative effects in broccoli seeds and sprouts of different cultivars” (not freely available)

Growing a broccoli sprouts Victory Garden

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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 μmol / 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 of sulforaphane / 75 kg = 2.04 μmol of sulforaphane / kg, compared to the 1.36 μmol of glucoraphanin / 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 of glucoraphanin / 85.8 kg = 1.36 μmol of glucoraphanin / kg.)
    6. Don’t have a practical estimate of the amount of sulforaphane I metabolize from post-microwave glucoraphanin that would add to the calculated 153 μmol of sulforaphane. 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] that would result from 153+ μmol of sulforaphane.

I don’t have a laboratory in my kitchen 🙂 and won’t have quantified results. See Grow a broccoli sprouts Victory Garden today! for August 2020 practices.

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

fsn31493-fig-0003-m

[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 https://pubchem.ncbi.nlm.nih.gov/compound/sulforaphane 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?

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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?

These researchers didn’t give a consumer-practical answer, so 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 a clinical trial perspective:

“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 higher limits of dosing with sulforaphane, and not so much of a concern when dosing with glucoraphanin, or even with glucoraphanin-plus-myrosinase.

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; safety of broccoli sprouts has been confirmed. However, use of a phytochemical in chemoprevention engages very different biochemical processes when using the same molecule in chemotherapy; biochemical behaviour of cancer cells and normal cells is very different.”

2. Commercial products from a 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 its clinical trials table. A further investigation of Avmacol showed that its supplier for broccoli extract, TrueBroc, was cofounded by a John Hopkins coauthor! Yet the review stated:

“The authors declare no conflict of interest.”

Please disclose easily discoverable ethical and commercial conflicts without prevarication. 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 a commercial perspective.

3. Dosage from a 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 delivery of sulforaphane to study participants.

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

Dosage from a commercial perspective:

“Of 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%. 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.

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

From a commercial perspective:

“In a recent study using 30 grams of fresh broccoli sprouts incorporated daily into diet, two key inflammatory cytokines were measured at four time points in forty healthy overweight [BMI 24.9 – 29.9] people. Levels of both interleukin-6 (Il-6) and C-reactive protein (CRP) declined over the 70 days during which 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 baseline level at day 160.

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


From a clinical trial perspective, glucoraphanin dosage was “1.67 (GR) μmol/kg BW.” This wasn’t accurate, however. It was assumed into existence by:

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

117 μmol / 1.67 μmol/kg = 70 kg.

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

A clinical trial perspective included this study in Section “3.2. Clinical Studies with Broccoli-Based Preparations: Efficacy” subsection “3.2.8. Diabetes, Metabolic Syndrome, and Related Disorders.” This was somewhat misleading, as it was grouped with studies such as a 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).

A commercial perspective pointed out substantial differences between these two studies:

“Where the study described above by Lopez-Chillon et al. investigated healthy overweight people to assess 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 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 clinical trial perspective:

  • Effectively promoted one commercial product whose supplier was associated with a coauthor;
  • 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.”

But 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 a 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.”

The commercial perspective didn’t specifically mention any commercial products.

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.

The clinical trial perspective will eventually have to make practical dosage recommendations 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 those books.

Each monthly assignment was individualized so that students couldn’t undo the assignment’s purpose – to think for yourself – with parasitical collaboration. This former practice remains a good measure of intentional dumbing-down of young people, the intent of which has become clearer.

You can see from these linked testimonials that their approach was in a bygone era, back when some teachers considered a 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.”

Microwave broccoli to increase sulforaphane levels

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This 2020 Chinese/USDA study investigated effects on sulforaphane amount from heating broccoli in water and microwaving at different power settings to different temperatures:

“Microwave treatment causes a sudden collapse of cell structure due to the increase in osmotic pressure difference over vacuole membrane. Mild heating could increase SFR [sulforaphane] level, possibly explained by the increased activity of MYR [the enzyme myrosinase] which can hydrolyze GLR [glucoraphanin] into SFR at high temperature (up to 60°C).

Microwave‐cooked broccoli had higher levels of these two compounds compared to broccoli heated in water. The broccoli sample without cooking as a control showed the least amount of GLR, indicating that microwave heating did help to release more GLR from the cell.

In the temperature range of 50–60°C, a positive correlation was observed between GLR or SFR contents and temperature. However, these two physiochemical contents were negatively correlated with temperature when it increased to 70°C.

The glucoraphanin (GLR) and sulforaphane (SFR) contents (μmol/g DW) in florets of broccoli during microwaving at 40, 50, 60, and 70°C using low power level (LL) or high power level (HL). Data are reported as the mean ± SD (n = 3). Values with different letters are significantly (p < .05) different.

[For example, sulforaphane levels of the control (raw), LL40, LL70, and HL40 conditions weren’t significantly different, and the HL70 level was significantly lower than those levels]. The microwave using high level at 60°C showed the greatest SFR level (2.45 µmol/g DW).”

Table S1 from the supporting material:

Temperature

(°C)

 Time

(S)

 Power level

(W)
Heating in water 40 185 NA
50 230
60 262
70 290
Microwave (HL) 40 65 950
50 90
60 108
70 120
Microwave (LL) 40 115 475
50 148
60 178
70 200

https://onlinelibrary.wiley.com/doi/10.1002/fsn3.1493 “Microwave cooking increases sulforaphane level in broccoli”

The researchers demonstrated a more effective method of increasing sulforaphane than did the cited and widely discussed 2004 Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli (not freely available). The older study methods were difficult to implement in kitchens, and evaluated heating temperature as the only factor.

The present study added microwave power level irradiation effects as a factor, and simplified heating temperature implementation. People can use Table S1 to maximize broccoli floret sulforaphane content in their kitchens. See Week 2 of Changing an inflammatory phenotype with broccoli sprouts for changes.

The study provided an optimal sulforaphane end result of “(2.45 µmol/g DW)”. I asked a study author for additional data, and they replied:

“The control GLR and SLR amount was 2.18 and 0.22 µmol/g DW, respectively, while the HL60 GLR amount was 2.78 µmol/g DW.”

Microwaving 10 grams of broccoli florets to 60°C (140°F) increased the sulforaphane amount by 1,114% (2.45 / .22)! That also increased the glucoraphanin amount by 27% (2.78 / 2.18) for further processing into sulforaphane after eating.

I replied: That’s an exciting result, increasing sulforaphane more than 11 times, while also increasing glucoraphanin! I haven’t found similar experiments with broccoli sprouts. Would you expect similar results?

The study author responded:

“We didn’t expect this result, and think microwave irradiation might help to release more conjugated forms of glucosinolates and then get hydrolyzed by released myrosinase. Further studies are being carried out.”

The study also measured broccoli stems:

“GLR and SFR were hardly detected in stems. Less than 52% of GLR was detected in the [50/50] mixture of florets and stems compared to florets.

Microwaved at 60°C, the florets had a concentration of GLR and SFR at 2.78 and 2.45 µmol/g DW, respectively, which was significantly higher than the levels detected in mixture of florets and stems (1.21 and 0.82 µmol/g DW, respectively).”

The 50% florets / 50% stems mixture’s glucoraphanin amount of 1.21 µmol was roughly comparable with the 1.08 µmol glucoraphanin amount of mature broccoli extract in item 2 below.

Reminders from Eat broccoli sprouts today:

  1. A 1 mg sulforaphane weight equals a 5.64 μmol sulforaphane amount.
  2. “Content of glucoraphanin in extract from broccoli sprouts was 16.6 μmol per gram of fresh weight. In contrast, mature broccoli extract contained 1.08 μmol per gram of fresh weight.”
  3. The bioavailability of sulforaphane in a broccoli sprout extract with the myrosinase enzyme 100 μmol gelcap was 36.1% which weighed 6.4 mg.
  4. The question of how much sulforaphane is suitable for healthy people remains unanswered.

Eat broccoli sprouts today!

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress , , ,

This 2020 Korean letter to a journal editor cited 23 recent papers in support of sulforaphane’s positive effects, mainly in anti-cancer treatments:

“Gene expression is mediated by chromatin epigenetic changes, including DNA methylation, histone modifications, promoter-enhancer interactions, and non-coding RNA (microRNA and long non-coding RNA)-mediated regulation. Approximately 50% of all tumor suppressor genes are inactivated through epigenetic modifications, rather than by genetic mechanisms, in sporadic cancers. Accumulating evidence suggests that epigenetic modulators are important tools to improve the efficacy of disease prevention strategies.

Because sulforaphane (SFN) induces the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element pathway that induces the cellular defense against oxidative stress, SFN has received increased attention because it acts as an antioxidant, antimicrobial, anti-inflammatory, and anticancer agent.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068201/ “A recent overview on sulforaphane as a dietary epigenetic modulator”

Letters to the editor aren’t peer-reviewed, though. One of the cited papers was a 2018 Czech mini-review that included metabolism, preparation and processing evidence:

“Sulforaphane is a phytochemical that occurs in plants in the form of biological inactive precursor glucoraphanin. This precursor belongs to the group of phytochemicals – glucosinolates – that are rapidly converted to isothiocyanate by the enzyme myrosinase.

The process of transformation takes place after a disruption of plant tissues by biting, chewing, slicing, and other destruction of tissues, when myrosinase is released from plant tissues. When myrosinase is destroyed during meal preparation (during cooking, steam cooking, or microwave treatment), a likely source of isothiocyanates is microbial degradation of glucosinolates by intestinal microflora. However, hydrolysis by microflora has been reported to be not very efficient, and in humans it is very diverse and variable.

Content of glucoraphanin in extract from broccoli sprouts was 16.6 μmol per gram of fresh weight. In contrast, mature broccoli extract contained 1.08 μmol per gram of fresh weight. Total amount of glucosinolates in young broccoli sprouts is 22.7 μmol per gram of fresh weight and 3.37 μmol per gram of fresh weight for mature broccoli.

Percentage amount of sulforaphane formed from its precursor glucoraphanin in broccoli which had not been heat treated and had been lyophilized [freeze-dried] was 22.8%. Broccoli steaming (5 min) and its lyophilization decrease the amount of sulforaphane formed to 4.2%.”

https://www.liebertpub.com/doi/full/10.1089/jmf.2018.0024 “Isothiocyanate from Broccoli, Sulforaphane, and Its Properties (not freely available)

Information about 43 completed sulforaphane clinical trials is here. Among them, the 2014 Effect of Broccoli Sprouts on Nasal Response to Live Attenuated Influenza Virus in Smokers: A Randomized, Double-Blind Study was of particular interest, stating:

“Nutritional interventions aimed at boosting antioxidants may be most effective in individuals who are relatively antioxidant-deficient at baseline, a condition likely to be more prevalent in smokers.”

I didn’t notice regular supplement dosage studies. Maybe I didn’t read control group information carefully enough?

https://pubchem.ncbi.nlm.nih.gov/compound/sulforaphane lists sulforaphane’s molecular weight as 177.3 g/mol. A 1 mg sulforaphane capsule weight equals a 5.64 μmol sulforaphane amount (.001 / 177.3).

From the 2015 Sulforaphane Bioavailability from Glucoraphanin-Rich Broccoli: Control by Active Endogenous Myrosinase:

  • Figure 4 showed bioavailability of sulforaphane in a broccoli sprout extract with myrosinase 100 μmol gelcap was 36.1% which weighed 6.4 mg (36.1 / 5.64).
  • Figure 3 showed bioavailability of sulforaphane in freeze-dried broccoli sprouts in pineapple-lime juice was 40.5% in 50, 100, and 200 μmol amounts and 33.8% with 100 μmol gel caps. You do the weight math.
  • Figure 2 showed that if broccoli sprout extract didn’t have the enzyme, bioavailability of sulforaphane was 10.4% whether the amount was 69 or 230 μmol, weighing 1.27 mg (69 x .104) / 5.64 and 4.24 mg (230 x .104) / 5.64.

Bioavailability ranged from Figure 2’s 10.4% to Figure 4’s 36.1%. The question of how much sulforaphane is suitable for healthy people remains unanswered.

Humans individually evolve by..?

gettingwell4 0-1 star Wasted resources, Epigenetics, Primal Therapy , , ,

This 2020 UK evolutionary biology article was part of a “Fifty years of the Price equation” issue:

“Genetic and non-genetic inheritance usually produce a phenotype [the composite of an organism’s characteristics, including its developmental, biophysical, and behavioral traits] through a highly complex developmental process that also relies on many features of the world over which the parents have little, if any, control. As a consequence, the relationship between the phenotypes of parents and offspring, the offspring–parent distribution, can take on many forms and vary from one place or time to another.

The extension of transmission and quantitative genetic models retain the assumption that the relationship between inheritance and phenotypic variation is such that it is sufficient to focus on the transmissibility of inherited variants or additive variance rather than phenotype development.

The concept of heredity as a developmental process is a more significant departure from traditional notions of inheritance. The mechanisms of non-genetic inheritance, such as parental behaviour, do not only affect the parent–offspring resemblance, but also the generation of variation and individual fitness.

Any feature of the parents, including their DNA sequence, physiology and behaviour can carry information about the conditions that the offspring will encounter. That this information content itself must be an evolving property is perhaps most evident when heredity is viewed as a developmental process; a developmental perspective is particularly useful when the aim is to study how the evolutionary process itself is evolving.”

https://royalsocietypublishing.org/doi/full/10.1098/rstb.2019.0366 “Different perspectives on non-genetic inheritance illustrate the versatile utility of the Price equation in evolutionary biology”

This article and the “Fifty years of the Price equation” issue’s other articles had numerous mentions of individual evolution and behavior. They acknowledged “a diversity of perspectives” but I didn’t see my 2015 page’s perspective that it’s up to each individual to mold their own phenotype. In it, the Price equation prompted the question:

“How does a phenotype influence its own change?”

which I applied to a person individually evolving.

The article and the issue’s other articles tinkered with equations, and cited plant, animal, and human studies with frameworks that didn’t include investigating causes for the observed effects. These often wasted resources by providing solutions that addressed symptoms instead of addressing the uninvestigated causes.

For example, I didn’t see any mentions of how an individual’s pain may drive their phenotype. Pain induced by threats to survival are common parts of animal experiments that create and investigate phenotypes of epigenetic responses to stressors.

Regarding possible human applicability, how can a person remedy their undesirable traits and acquire desirable traits without addressing a root cause?

Unlike animals, people can therapeutically resolve underlying causes without the timing, duration, and intensity of efforts being externally determined. A human’s efforts to change their phenotype don’t have to mimic animal studies’ forcible approaches with drugs, etc., directed on someone else’s schedule. Addressing pain may be required for such efforts.

The article also promoted an outdated paradigm of epigenetic transgenerational inheritance:

“The transgenerational stability of some epigenetic states may fall within the same range as the stability of behaviours that are learnt from parents. Quantifying the environmental sensitivity and transgenerational stability of epigenetic variation has emerged as a major research focus over the past decade.”

As explained in Transgenerational epigenetic inheritance of thyroid hormone sensitivity:

“Observing the same phenotype in each generation is NOT required for transgenerational epigenetic inheritance to exist. Animal transgenerational studies have shown that epigenetic inheritance mechanisms may both express different phenotypes for each generation, and entirely skip a phenotype in one or more generations.”

Considering only “transgenerational stability of epigenetic variation” as proof will misinterpret this supporting evidence.

Aging as a disease

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Neurochemicals, Oxytocin, Telomeres ,

This 2020 interview was with UC Berkeley researchers:

“Lack of cure goes hand in hand with inability to accept that this [aging] is disease. For example, there was some resistance to accept tuberculosis as the actual disease. When there was no antibiotics or cure against it, people tended to discard it and said, oh, it’s just nerves, you need to go to a sanatorium and relax.

It used to be that, please do not diagnose that there’s bacterial meningitis, because there is no cure. Whatever else you can come up with, do it first. Now, diagnose it as fast as possible, so we can put patients on antibiotics immediately. My prediction is that the same will happen to aging.

We and others have demonstrated that you can, from the outside, either by some signal or blood therapy, parabiosis, something like that, some intervention, jump-start aged resident stem cells in tissue and get them to behave as, by whatever means you’re measuring it, young or a lot closer to young than they would normally be. Intrinsic capacity of them to act that way is there.

As we grow old, the environment of differentiated niche stem cells does not provide productive instruction. It provides counterproductive instruction, which, overall, tells them just to remain quiescent and do nothing.

It’s not a program to kill you. It’s the lack of a program to keep you young and healthy for longer than 90 years.

If your program was that whenever you’re a damaged, differentiated cell, you simply trigger apoptosis and activate stem cells to make new cells, we would live much longer and healthy. The program right now is to resist being dead and replaced as much as you can for as long as you can.

So cells produce too much TGF beta [transforming growth factor-β] because it helps them to keep functioning even when they’re damaged. That too much TGF beta, ironically, inhibits resident stem cells, so they are not replacing old cells with new ones. It’s almost like you have old bureaucrats that are running an organization and do not want to be replaced.

Our thoughts are probably different from most people, because we go to the data and the data show that they’re not really fully what authors wrote in the abstract or conclusion. When you look at that, my thought is that much more work needs to be done before it [partial cellular reprogramming] could be even thought to be commercialized.”

https://www.lifespan.io/news/apheresis-with-profs-irina-michael-conboy/ “Irina & Michael Conboy – Resetting Aged Blood to Restore Youth”

Keep in mind that although the interviewers’ organization had changed, their advocacy position as displayed in A blood plasma aging clock persisted. One of the interviewees is on the interviewers’ organization scientific advisory board, and they also have an interest in downgrading competing approaches.

Despite caveats, this interview was these researchers’ perspective in their decades-long investigations of aging. I included a graphic and below quote from Organismal aging and cellular senescence to note how their paradigm compared with other aging researchers:

“In our view, recent evidence that

  • Senescence is based on an unterminated developmental growth program and finding that
  • The concept of post-mitotic senescence requires activation of expansion, or ‘growth’ factors as a second hit,

favor the assumption that aging underlies a grating of genetic determination similarly to what is summarized above under the pseudo-programmed causative approach.”

Train your immune system every day!

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress ,

This 2019 US review subject was β-glucan:

“β-1,3-Glucans (hereafter referred to as glucan) are natural molecules able to significantly improve our health. In human studies, the tested (and suggested) daily dose remains in the range of 100–500 mg for stimulation of the immune system, whereas for a decrease in cholesterol levels a daily dose of 3 g is recommended.

Glucan does not represent essential nutrients, but it might be successfully used not only for:

  • Improvement of immune functions, but also to improve the general quality of life via
  • Improvements of immune status,
  • Lowering cholesterol,
  • Improving blood glucose levels and
  • Reduction of stress.

ClinicalTrials.gov summarizes 177 [now 207 with 110 completed] β-glucan clinical trials, mostly in cancer, gastrointestinal tract therapy, lowering cholesterol and improvements of immune reactions.

The question is not if glucans will move from food supplement to widely accepted drug, but how soon.

Reactions known to be influenced by glucan are represented in white, reactions where glucan has no confirmed effects are shown in black. The first defensive body response to infection results from formation of the anorexia cytokines (IL-1, IL-6, IL-8, and TNF-α).”

https://www.mdpi.com/1420-3049/24/7/1251/htm “Beta Glucan: Supplement or Drug? From Laboratory to Clinical Trials”

The review is also indexed at https://www.betaglucan.org/i-p/ under “Immunomodulator”

I’m curating this review on Day 12 of a self-quarantine after coming back from Milano, Italy, Monday, February 24, 2020. The previous Friday into Saturday I flew to Milano sitting with a group of elderly Italians who were returning from vacation.

On Saturday my traveling companion and I used the Milano rail and crowded subway system to go downtown. On Sunday we used their crowded rail, crowded bus, and crowded ferry systems to visit Como, Bellagio, and Menaggio.

I don’t think we could have mixed in more with people during transits, touristing, and Carnevale celebrations.

IMG_9539

After returning to our hotel Sunday evening, we heard about the coronavirus outbreak south of Milano and the closing of ten towns. We changed flights and departed for the US early Monday morning.

Neither of us have had any signature symptoms of COVID-19 (fever, shortness of breath, dry cough). Our daily diet the past few years included β-glucan from steel-cut oats (~3 g) and from a 1/3, 1/6 yeast cell wall supplement.

Coincidence?

Each of our futures will depend on what we do Now to prepare.

Take responsibility for your one precious life.

Moonrise at sunrise with Venus

An evolutionary view of transgenerational epigenetic inheritance

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

This 2020 Swiss/German review mainly cited weed, worm, and yeast studies:

“RNA interference-related mechanisms can mediate the deposition and transgenerational inheritance of specific chromatin modifications in a truly epigenetic fashion.

Epigenetics was initially defined as any heritable change in gene expression patterns without changes in the DNA sequence. Now, epigenetic phenomena are often characterized as ‘gene expression changes that are mutation independent and heritable in the absence of the triggering event’, a definition we will follow in this review. We note that this definition can be expanded to include protein only-based inheritance mechanisms that do not necessarily cause changes in gene expression.

Gene silencing can persist over multiple generations in the germline of C. elegans. Gene repression is typically maintained without the initial trigger for three to seven generations and occasionally for tens of generations. In contrast, silencing of somatically expressed genes mostly affects only the subsequent generation through nonepigenetic parental effects.

In the presence of an ‘enabling’ mutation, primary siRNAs [small interfering RNAs] can trigger an RNAe [RNA-induced epigenetic silencing] response. Secondary siRNA amplification is required for transgenerational inheritance.

The fitness of a population in a dynamic environment strongly depends on the ability of individuals to adapt to the new condition as well as to remember, inherit, and forget such adaptation:

  • (A) A well-adapted population (grey) is at its maximal density (dotted line) in a given niche until an environmental change (1st stress) creates a bottleneck. Only few individuals can adapt through mutations and repopulate the niche. After the environment changes back to the initial blue state, only individuals that acquire rare counteracting mutations survive, often leading to extinction of the population.
  • (B) Individuals of a population in the red state can gain beneficial epimutations through siRNAs and repopulate the niche. When exposed again to the blue state, the epimutations can be quickly reversed and the population rapidly reaches maximal density. After recurrence of the red state, organisms establish de novo epimutations with the same low frequency as when they first encountered this state.
  • (C) In contrast, organisms that can maintain the memory of a beneficial silencing event can quickly re-establish beneficial epimutations and grow to full density. Such memory can be maintained by phenotypically neutral epimutations, marked by the continuously high production of siRNAs without substantial reductions in the expression of a gene. A population that can adapt through phenotypically plastic epimutations is predicted to have a maximal fitness advantage in a dynamic environment.”

The Concluding Remarks section included:

“RNA-mediated epigenetic responses could contribute to adaptation.

Even though RNAe may yield significant adaptive advantages, a high induction frequency could cause silencing of multiple essential genes and therefore be detrimental. Hence, it is plausible that mechanisms would have coevolved that counteract silencing.

Similarly, if constituting a bet-hedging strategy to cope with ever-changing environments, permanent fixation of an acquired silencing response would not constitute a selective advantage and mechanisms that modify and limit the duration of RNAe would be predicted.”

https://www.sciencedirect.com/science/article/pii/S0168952519302598 “Small RNAs in the Transgenerational Inheritance of Epigenetic Information”

The review’s arguments were based on evolutionary selective advantages and less-complex organisms. It predicted that there would be an endpoint generation as in the (A) case of the above graphic.

Were the mechanisms in the (B) case necessarily transgenerational throughout? The review further explained:

“Epimutations tend to occur in hot spots (e.g., in stress-related or nutritional pathway genes) and can potentially silence several homologous genes simultaneously. Incomplete penetrance of a beneficial epimutation by stochastic loss of siRNAs [59] can result in loss of adaptation in a given environment (red state), but can be beneficial if the previous blue state is re-established. However, when the environment changes back to the red state, epimutations must initiate de novo, at the same low frequency as when the population first encountered this state.”

The study cited at 59 found:

“A feedback between siRNAs and RNAi genes determines heritable silencing duration”

but not “Incomplete penetrance of a beneficial epimutation by stochastic loss of siRNAs.” Hmm.

In any event, the review stated:

“Evidence for naturally occurring RNAe-related phenomena in other animals is scarce and we should be cautious about inferring RNAe as a widely conserved phenomenon.”

It’s encouraging to read studies that find benefits to epigenetic transgenerational inheritance, albeit in organisms that are less complex than rodents and humans.

 

The epigenetics of perinatal stress

gettingwell4 5+ stars Premium, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Vasopressin , , , , , , ,

This 2019 McGill review discussed long-lasting effects of perinatal stress:

“Epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioral phenotypes. Since these phenotypes are apparent a long time after early experience, changes in gene expression programming must be stable.

Although loss of methylation in a promoter is necessary for expression, it is not sufficient. Demethylation removes a barrier for expression, but expression might be realized at the right time or context when needed factors or signals are present.

DNA methylation anticipates future transcriptional response to triggers. Comparing steady-state expression with DNA methylation does not capture the full meaning and scope of regulatory roles of differential methylation.

A model for epigenetic programming by early life stress:

  1. Perinatal stress perceived by the brain triggers release of glucocorticoids (GC) from the adrenal in the mother prenatally or the newborn postnatally.
  2. GC activate nuclear glucocorticoid receptors across the body, which epigenetically program (demethylate) genes that are targets of GR in brain and white blood cells (WBC).
  3. Demethylation events are insufficient for activation of these genes. A brain specific factor (TF) is required for expression and will activate low expression of the gene in the brain but not in blood.
  4. During adulthood a stressful event transiently triggers a very high level of expression of the GR regulated gene specifically in the brain.

Horizontal arrow, transcription; circles, CpG sites; CH3 in circles, methylated sites; empty circles, unmethylated CpG sites; horizon[t]al curved lines, mRNA.”

Review points discussed:

  • “Epigenetic marks are laid down and maintained by enzymes that either add or remove epigenetic modifications and are therefore potentially reversible in contrast to genetic changes.
  • Response to early life stress and maternal behavior is also not limited to the brain and involves at least the immune system as well.
  • The placenta is also impacted by maternal social experience and early life stress.
  • Most studies are limited to peripheral tissues such as saliva and white blood cells, and relevance to brain physiology and pathology is uncertain.
  • Low absolute differences in methylation seen in most human behavioral EWAS raise questions about their biological significance.

  • Although post-mortem studies examine epigenetic programming in physiologically relevant tissues, they represent only a final and single stage that does not capture dynamic evolution of environments and epigenetic programming in living humans.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952743/ “The epigenetics of perinatal stress”

Other reviewers try to ignore times when we were all fetuses and newborns. For example, in the same journal issue was a Boston review of PTSD that didn’t mention anything about earliest times of human lives! Those reviewers speculated around this obvious gap on their way to being paid by NIH.

Why would researchers ignore perinatal stress events that prime humans for later-life PTSD? Stress generally has a greater impact on fetuses and newborns than on infants, and a greater impact on infants than on adults.