Human agency vs. brain dysfunction

This 2021 human study used epigenetic clock technology to assess chronic inflammation as a driver of cognitive decline through its effects on brain structure:

“An epigenetic measure of C-reactive protein (DNAm CRP) was assembled for each participant. We found that higher inflammatory burden, indexed by DNAm CRP scores, associated with poor cognitive and neuroimaging brain health outcomes.

inflammation vs cognitive ability

DNAm CRP exhibited significantly larger associations with brain structural MRI metrics (including global grey and white matter atrophy, poorer white matter microstructure, and increased white matter hyperintensity burden) than serum CRP. Given that the 7 CpGs which make up DNAm CRP score reside in inflammation and vascular-related genes, these DNAm CRP-brain MRI associations may be capturing the impact of upstream inflammatory activity above and beyond that of serum CRP levels.

Our results indicate that some cognitive domains (processing speed) may be more mediated by brain structural consequences of chronic inflammation than others (verbal memory, visuospatial ability).

Our results add to the evidence base that DNAm-based predictors of inflammation may act as a quantifiable archive of longitudinal effects of these exposures – and other unaccounted for health and genetic profiles – that serum CRP levels fail to capture. By utilising an epigenetic inflammation measure, which integrates information from multiple immune-related CpG sites, we may provide a more reliable measure of chronic inflammation and thus a more comprehensive overview of consequences of chronic inflammation on brain structure and function.”

https://n.neurology.org/content/early/2021/11/17/WNL.0000000000012997.long “DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging”


These researchers essentially negated many of their findings by acknowledging:

“Although we endeavoured to remove participants with cognition-related pathology, these were screened via self-reported diagnoses, and we may be missing undiagnosed or subclinical incident neurodegenerative pathology.”

It wasn’t sufficient to claim in the Abstract section “Participants (N = 521) were cognitively normal, around 73 years of age” then include in the Discussion section a one-sentence limitation of relying on self-reports. Everyone defends themself against current and past realities and experiences.

Hard to imagine that objective measures such as the three comprising cognitive ability weren’t better screens. But then too many 73-year-old subjects may not have been “cognitively normal” and this study wouldn’t be adequately powered?

Can humans counteract inflammation? Non-communicable diseases? Smoking? Immune system degradation? Yes. No personal-agency actions were mentioned.

Also note this study’s social norming. The above-pictured 30-year-old female was busy at work, and subsequently hoisted a cat instead of a child in later years.

Take responsibility for your own one precious life.

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Epigenetic clocks vs. individual choices

This 2021 human twin study used four epigenetic clocks:

“We examined the mediating role of lifestyle factors on the association between sex and biological aging in younger and older adults. The Finnish Twin Cohort (FTC) includes three large cohort studies:

  1. The older FTC includes twins born before 1958;
  2. Finntwin16 includes twins born in 1975-1979; and
  3. Finntwin12 includes twins born in 1983-1987.

In comparison to women, men were biologically older and, in general, they had unhealthier life habits. The effect of sex on biological aging was partly mediated by body mass index and, in older twins, by smoking. Sex was directly associated with biological aging, and the association was stronger in older twins.

over 50 twins

Declining smoking prevalence among men is a plausible explanation for narrowing of the difference in life expectancy between sexes. Data generated by epigenetic clocks may help in estimating effects of lifestyle and environmental factors on aging and in predicting aging in future generations.”

https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/glab337/6424421 “Do epigenetic clocks provide explanations for sex differences in lifespan? A cross-sectional twin study”


It was too much to ask of epigenetic clocks to ferret out preclinical symptoms of lifestyles and environments accelerating aging in younger twins. Levine’s Phenotypic Age clinical measurements could assess accelerated aging trajectories, but may not have been available for this study. People who are busy abusing their bodies into non-communicable diseases have plenty of other warning signs, like abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein.

Preclinical symptoms may be reversible by individual choices that influence lifestyle and/or environment. Effective healthspan and lifespan changes measurable by epigenetic clocks are usually limited once clinical symptoms emerge, though.

Consider this rodent study’s graphic from Part 2 of Eat broccoli sprouts for your eyes:

retina function

This chart demonstrated that preventing diabetes’ negative effects on retinal function (i.e. controls) was measurably better than trying to fix subjects’ vision after onset of diabetes.

I would have liked this study to address a morbidity phase, where healthspan stops increasing but lifespan increases. That seems possible in twin studies, where one twin’s choices cause a healthspan halt compared to the other twin’s choices.

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Endless shingles

This 2021 review subject was the follow-on condition of chicken pox:

“Varicella-zoster virus (VZV) is a pathogenic human alpha herpes virus which is a significant cause of morbidity. VZV causes a primary infection, usually in children, called varicella (chicken pox), following which it establishes ganglionic latency in neurons. Latency is established in ganglia throughout the entire neuroaxis including dorsal root ganglia, trigeminal ganglia, and also autonomic ganglia including enteric ganglia.

After a variable period, which can span several decades, VZV may reactivate to cause the well-recognised syndrome of herpes zoster (shingles), which is an extremely painful vesicular rash. While viral reactivation may occur spontaneously, it can also follow one or more triggering factors such as diminished cell-mediated immunity to the virus as occurs with older age or immunosuppression due to drug treatment or disease, X-ray irradiation, infection, trauma, or malignancy.

The disease spectrum caused by VZV reactivation is much wider than previously thought. A possible diagnosis of VZV reactivation-induced neurological disease should be considered in all cases of undiagnosed acute, subacute or chronic brain or spinal cord syndromes, particularly if there is an accompanying cerebrospinal fluid (CSF) pleocytosis.

Virus latency and reactivation is associated with specific modifications of bound histones. Consensus is that CpG island methylation is not involved.

Precise immune cells and immune mediators required for protective immunity in primary infection versus reactivation have not been clarified. Individual contributions from different cell types, including lymphocytes, macrophages, plasmacytoid dendritic cells, and epithelial and endothelial cells, which are all present in human ganglia, remains insufficiently understood and explored.

Immunological evaluation revealed the presence of VZV DNA as well as an immunological cell infiltrate composed of CD4 T cells, CD8 T cells, and CD20 B cells. This provided somewhat surprising evidence of an ongoing immunological reaction and inflammation years after the reactivation of VZV from latency.

Latency is characterized by maintenance of the virus genome in an endless (episomal) configuration. Since alpha human herpes virus latency is established so early in life, it is unlikely that viral latency can be completely prevented.”

https://www.mdpi.com/1999-4915/13/10/2018/htm “Recent Issues in Varicella-Zoster Virus Latency”


More investigation was needed in working backwards from recent reports of shingles outbreaks to activation causes. Common lab tests easily provide evidence of immune cell populations.

So what happened to cause removal of immune protective mechanisms that prevented varicella-zoster virus reactivation? It wasn’t the X-ray etc. reasons listed above.

Recent shingles outbreaks are telling an important story. Who is looking into it?

These and other researchers won’t find evidence if they don’t get out of their labs and look at people’s cases. They’ll also need to report findings regardless of the political climate.

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Broccoli sprout compounds and gut microbiota

Two 2021 reviews from one institution, with this first focused on aliphatic glucosinolates’ (GLS) metabolism to isothiocyanates (ITCs) like sulforaphane:

“Human clinical trials examining efficacy of whole food interventions on cancer prevention targets have shown high levels of inter-individual variation in both absorption and excretion of ITCs. We discuss how consumption of cruciferous vegetables may alter the microbiome, and in turn, influence ITC absorption.

Bioavailability of ITCs from GLS has been shown to be greatly impacted by processing before ingestion. When ITCs are given preformed, they possess the greatest level of bioavailability and are readily absorbed by humans.

Studies have indicated that without plant-derived myrosinase, the gut microbiome is essential for conversion of GLS to ITCs. Without conversion to ITCs, GLS are biologically inert.

There are two different intervals in time when GLS metabolism occurs in the large intestine:

  1. Metabolism of GLS directly following consumption when GLS are not absorbed in the small intestine; and
  2. When GLS are absorbed in the small intestine and go through enterohepatic circulation, returning as GLS in the gut where factors influencing microbial metabolism (such as food matrix, pH, and other compounds present) may be different from the first interval.

This list of bacterial genera altered by cruciferous vegetable consumption focuses on studies completed in healthy individuals and animal models:

Metabolic Fate of Dietary Glucosinolates and Their Metabolites:

Clinical trials have shown that consumption of a diet rich in cruciferous vegetables, compared to a cruciferous vegetable devoid diet, significantly alters composition of the gut microbiome. Each individual responded uniquely to cruciferous vegetable consumption, suggesting that basal microbiome composition may impact outcome.

Understanding the gut microbiome’s role in GLS metabolism, specifically GLS conversion to ITCs, is important to understanding drivers of inter-individual variation . Translating chemopreventative properties of cruciferous vegetables from the lab bench to the clinic requires addressing factors that drive high variability in ITC absorption and excretion observed in clinical trials.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.748433/full “Metabolic Fate of Dietary Glucosinolates and Their Metabolites: A Role for the Microbiome”


Discussion of indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) was passed over to this second review:

“Hydrolysis of glucobrassicin GLS by plant or bacterial myrosinase produces multiple indoles, predominantly I3C. Yield of I3C from glucobrassicin is about 20%.

In the stomach, I3C undergoes extensive condensation to yield predominately DIM. Ingestion of I3C results in 20–40% conversion to DIM.

DIM has multiple mechanisms of action, the most well-characterized is modulation of aryl hydrocarbon receptor (AHR) signaling. The DIM-intestinal AHR-microbiome axis is an important component for future development of a personalized nutraceutical approach to achieving optimal health.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.734334/full “Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3′-Diindolylmethane”


DIM estimates in this second review were too high with respect to clinical trial findings of Eat broccoli sprouts for DIM. Using the trial’s 21.61 μmol of average glucobrassicin intake, this review’s 20% I3C yield would be 4.32 μmol. This review’s lowest 20% DIM yield from I3C would be 0.86 μmol, representing a 4.0% DIM bioavailability from glucobrassicin intake.

The trial’s lowest average DIM (in postmenopausal women) after 35 days of eating broccoli sprouts measured 0.5544 μmol, representing an average 2.57% DIM bioavailability from glucobrassicin intake. One of the trial’s coauthors officially reviewed this second review, but he didn’t insist on better human in vivo estimates, although 4.0 / 2.57 is more than 50% too high for the review’s lowest DIM estimate.

The trial and its parent trial also weren’t cited by either review. Aren’t human clinical trials measuring sulforaphane, sulforaphane metabolites, and DIM bioavailability relevant to “Metabolic Fate of Dietary Glucosinolates and Their Metabolites” and “Indoles Derived From Glucobrassicin”?

Something else was missing from both papers. They had academic suggestions for future studies, but neither one continued on to say “and here’s what we’re sponsored to do to fill these gaps.”

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Reinforce your immune memory every day

Three papers on trained immunity, with the first a 2021 review:

“Trained immunity is realized by epigenetic reprogramming of cells, primarily monocytes/macrophages and natural killer cells, and is less specific than adaptive immunity. It may cross-protect against other infectious agents.

Various actions of trained innate immunity on precursor cells have a strong potential for therapeutic use, particularly in infected and myelosuppressed individuals. Improvements of effects of some vaccines offer other potential use of β-glucan as an inductor of trained immunity, suggesting novel uses of a traditional therapeutic.”

https://www.mdpi.com/1422-0067/22/19/10684/htm “Trained Immunity as an Adaptive Branch of Innate Immunity”


Became tired of this review’s pedantic repetitions, that cells have a finite existence, as do cell attributes such as one-time trained immunity. Readers get it.

While belaboring the obvious, this paper missed two points:

  • As An environmental signaling paradigm of aging theorized, then demonstrated in A rejuvenation therapy and sulforaphane, and continues in current studies, cells take on phenotypes the body gives them. Focusing on cell attributes missed many signals elsewhere in cells’ environmental milieu, which make a difference in cell, organ, and body functioning.
  • Trained immunity protocol also matters. I’ve trained my immune system with yeast cell wall β-glucan every day for 17 years, recently taking nothing else an hour before or an hour after. That “no effects were found after 20 days” of only one in vitro dose isn’t relevant to my immune responses. I always have cells with one day of training, cells with (pick a number) days / weeks / months / years of training, and millions of primed cells in between.

This first paper cited a 2020 in vitro study:

“(1, 3)/(1, 6)-β-glucan can induce potent trained immunity, however, immunoregulatory activity of oat (1, 3)/(1, 4)-β-glucan has been neglected. Most studies have focused on its metabolic regulatory activity in diseases such as obesity and diabetes.

This study confirmed that β-glucan from oat dietary fiber can modulate responsiveness of innate immune cells through metabolic reprogramming. Proposed mechanism of oat β-glucan for trained immunity induction in monocytes/macrophages:

oat beta glucan trained immunity

This study showed that trained immunity induced by oat (1, 3)/(1, 4)-β-glucan was dependent on glycolysis or SDH/IRG axis in TCA cycle. These findings demonstrated that oat dietary fiber could strengthen and maintain long-term responsiveness of the innate immune system.”

https://doi.org/10.1007/s10753-020-01211-2 “Oat-Derived β-Glucans Induced Trained Immunity Through Metabolic Reprogramming” (not freely available)


A 2021 rodent study cited this second paper:

“Oat beta-glucans can stimulate secretion of anti-inflammatory cytokines, and simultaneously inhibit secretion of pro-inflammatory cytokines. The immunostimulatory effect of beta-glucan intake occurs due to its ability to activate intestinal mucosa immune cells, which results from binding of these polysaccharides to specific membrane TLR and/or Dectin-1 receptors.

We analyzed effects of oat beta-glucans at two time points, 3 and 7 days after TNBS administration:

  • High molecular mass beta-glucan forms a protective coating on the internal intestinal wall, which improves tissue recovery potential and reduces the risk of secondary microbial infection.
  • Low molar mass beta-glucan forms light solutions where short chains are well distributed and dispersed, and due to low viscosity, beta-glucan is accessible for receptors to be reached. Once reaching and complementing the receptor, bonded beta-glucan short polymeric chain induces transmission on metabolic pathways.

ijms-22-04485-g005-550

Consumption of oat beta-glucans reduced levels of inflammatory markers, and recovered signaling pathways and histological changes, with stronger effects of low molar mass beta-glucan after 7 days of colitis. Dietary oat beta-glucans can reduce colitis at the molecular and organ level, and accelerate Crohn’s disease remission.”

https://www.mdpi.com/1422-0067/22/9/4485/htm “Anti-Inflammatory Activity of Oat Beta-Glucans in a Crohn’s Disease Model: Time- and Molar Mass-Dependent Effects”


I’d seen this second study’s abstract several times, but glossed over it. I curated another 2021 rodent study from the same institution as this third paper in Oat β-glucan effects on colitis.

None of these studies investigated gut microbiota. Pretty sure our hosted microorganisms had roles in their findings.

All papers called for human studies of their findings. But it would be difficult for drug companies to make money from a research area that’s cheap and readily accessible. Take responsibility for your own one precious life.

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Eat oats for β-glucan and resistant starch

This 2021 review highlighted effects of processing oat products:

“Starch contents in oats ranges from 51% to 65%. Resistant starch (RS) accounts for 29.31% of starch content in raw granular form of oat starch.

RS in raw oat starch is RS2 starch, where its slow digestion is mainly due to the compact nature of starch granules making starch less accessible to enzymes. Since amylose–lipid complex is resistant to enzymatic breakdown, high lipid content in oats (3–7%) may be another reason why oat has a relatively high level of RS starch. This type of RS is called RS5.

Although RS2 occurs naturally, most starch needs to be cooked for consumption. RS3 that is formed due to recrystallization of gelatinized starch is more commonly consumed by processing via gelatinization and retrogradation.

β-glucans are found in cell walls of endosperm and aleurone layers of oats, accounting for 1.73-5.70% of oat grains dry basis. Oat β-glucans are not digested in the upper gastric tract, but instead can be consumed by gut microbiota in the colon. This kind of prebiotic can be fermented by colonic microbiota, resulting in production of short chain fatty acids (SCFA) metabolites.

From field to table, oats are processed into various foods for consumption, and these foods exhibit high variability of GI values:

  • β-glucan dose and molecular weight are crucial determinants affecting viscosity and gastric emptying rate; and
  • Higher content of protein in oats is an important factor that deserves attention.”

https://www.mdpi.com/2304-8158/10/6/1304/htm “Oat-Based Foods: Chemical Constituents, Glycemic Index, and the Effect of Processing”


Didn’t care for this focus on one dimension of health, glycemic index. Why not focus on healthy individuals’ behaviors? See An oats β-glucan clinical trial for more human in vivo evidence regarding β-glucan molecular weight.

I eat oats three times a day, and it’s worked out alright.

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An IBD trigger?

Three papers on interactions of the virus and inflammatory bowel disease, beginning with a 2021 review:

“Analysis signaling pathways of innate and adaptive immunity components during SARS-CoV-2 infection in IBD (inflammatory bowel disease) patients through a putative alternative route – the gastrointestinal tract, with virus attachment to ACE2 (angiotensin-converting enzyme 2) expressed on IECs (intestinal enterocytes) – allows identifying some molecular pathways and establishing possible mechanisms of immune response formation.

In general, any virus infecting intestinal tissues and/or entering the host’s body through receptors located on intestinal IECs, may be a trigger for the onset of IBD in individuals.”

https://link.springer.com/article/10.1007%2Fs11033-021-06565-w “Pathogenesis of the inflammatory bowel disease in context of SARS-COV-2 infection”


A second 2021 review continued:

“Patients with COVID-19 may develop various gastrointestinal symptoms, which may be pre-existing or not accompanied by respiratory symptoms. Positive detection of SARS-CoV-2 in stool specimens was a breakthrough because it demonstrated that the virus could replicate and exist in the digestive tract. Duration of viral nucleic acid in feces is longer than that in respiratory specimens, and the peak of viral load is later.

COVID-19 induces an acute inflammatory response which accelerates consumption of nutrients. Gastrointestinal symptoms caused by SARS-CoV-2 further impacted nutrition absorption and exacerbated malnutrition. Patients’ anxiety and poor appetite were also potential contributors to malnutrition.”

https://www.wjgnet.com/1007-9327/full/v27/i24/3502.htm “COVID-19 and its effects on the digestive system”


I found the above two papers by their citing a 2020 review:

“Based on data on over 1400 patients with IBD from an international registry, compared with TNF monotherapy, thiopurine monotherapy and combination thiopurines with TNF antagonists are associated with significantly increased risk of severe COVID-19. Mesalamine/sulfasalazine may be associated with an increased risk, particularly when compared with TNF antagonists. There are no significant differences between biological classes (TNF, interleukin-12/23 and integrin antagonists) on the risk of severe COVID-19.”

https://gut.bmj.com/content/70/4/725 “Effect of IBD medications on COVID-19 outcomes: results from an international registry”


I rated these three papers as requiring more work because they didn’t address an individual’s preparation for originating causes. Managing symptoms isn’t an appropriate response for what all of us face.

Instead, take personal responsibility for your own one precious life.

Looking forward, looking back

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Don’t count on broccoli compounds bailing out a high-fat diet’s effects on gut microbiota

Two rodent studies of mature broccoli and broccoli sprouts’ effects on a high-fat diet, with the first from 2021 investigating broccoli florets and stalks:

“Addition of broccoli florets to a HFD ameliorated insulin sensitivity. Florets further promoted gut microbiota diversity and low-grade inflammatory-associated strains.

Stalk supplementation also altered gut microbiota, leading to increased Bacteroidetes/Firmicutes ratio and levels of communities that preserve mucus layer and gut integrity while simultaneously decreasing levels of potentially harmful species.

Addition of broccoli to a HFD did not ameliorate body and tissues weight gain or food intake. Both broccoli stalks and florets did not affect fat accumulation, carbohydrate, or lipid metabolism-related parameters.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.680241/full “Broccoli Florets Supplementation Improves Insulin Sensitivity and Alters Gut Microbiome Population – A Steatosis Mice Model Induced by High-Fat Diet”


A 2020 study cited by this first study investigated compounds extracted from 1-day-old broccoli sprouts:

Bioaccessibility of aliphatic glucosinolates was shown to 76.2 ± 0.6%:

aliphatic glucosinolate bioavailability

Glucoraphanin was the predominant glucosinolate with the highest bioaccessibility in broccoli, and could effectively prevent HFD-induced body weight gain in mice, especially increases in liver weight and the accumulation of lipids in adipocytes. Furthermore, supplementation with glucoraphanin reduced the level of oxidative stress, regulated genes of FAS, PPARα, CPT1 and ACOX associated with lipid metabolism, and might be associated with changes in composition of gut microbiota.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.680241/full “Effect of glucoraphanin from broccoli seeds on lipid levels and gut microbiota in high-fat diet-fed mice”

This study’s title was “Effect of glucoraphanin from broccoli seeds..” although its Materials and methods section disclosed:

“1 day after germination from broccoli seeds, sprouts were boiled in water for 30 min. The resulting aqueous extract was processed by liquid solid separation and condensation and was subsequently spray-dried to yield an extract powder containing 249 mg glucoraphanin.”


Eat broccoli sprouts every day and its predecessor study demonstrated that broccoli intake every day had beneficial effects during shorter periods than either of these studies.

Both studies had many “may”, “could”, and “might” statements. Not sure that broccoli compounds / gut microbiota relationships are adequately investigated by choosing a few out of tens of thousands of gut microbiota species as both studies attempted to do.

There are too many additive / antagonistic / synergistic combinations to analyze even before reaching twenty gut microbiota species. But researchers aren’t often sponsored for studies unless they conform to existing research.


I haven’t made headway in understanding my top 10 of 42,156 gut microbiota species’ exact causes, effects, and interactions. The top three by themselves are considered beneficial:

top 1-10 species

Uncertainty is fine for now, though, with a 40-hour work week interfering. Finding out what my gut microbiota generally want and giving that to them has been a productive approach this year.

If you aren’t where you want to be, change yourself

This 2021 human study evaluated associations among epigenetic clocks and socioeconomic status:

“We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighbourhood environment, and childhood SES) and eight epigenetic clocks in two well-powered US ageing studies:

  • The Multi-Ethnic Study of Atherosclerosis (MESA); and
  • The Health and Retirement Study (HRS).

We found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm [Dunedin New Zealand (P)lace (o)f (A)ging (m)ethylation clock)] clocks. In the HRS, significant associations with the Levine and Yang clocks were also evident.

These associations were only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviours alone cannot explain the SES gradient in epigenetic ageing in older adults. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic ageing, SES, and the Levine clock, indicating that genetic risk and social disadvantage may contribute additively to faster biological aging.”

https://www.medrxiv.org/content/medrxiv/early/2021/03/02/2021.03.01.21252660.full.pdf “The Socioeconomic Gradient in Epigenetic Ageing Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study”


This study had a lot of squishy data. Didn’t see peer review comments, but I’d require evidence for several of these categorizations and subsequent findings.

For example, I quit smoking on February 5, 1985, the day I left my third submarine. This study would have categorized me 36 years later as a former smoker.

This categorization defied human cell turnover, with exceptions of our:

  • Cerebrum and cerebellum neurons;
  • Eye inner lens cells; and
  • Heart muscle cells.

Neither these cells nor other cells are associated with current status and quitting smoking four decades earlier. Consider that “associated” relationships don’t necessarily have any causal origins.

Another example from this study. My parents’ educational achievements of Masters degrees were during the 1950s. Pretty sure they weren’t causal to my degrees during the 1980s when I focused on advancing in the U.S. Navy.

Your responses to life events and subsequent behaviors are up to you, when and where you need them to be.

Do you feel a need to be consciously aware of who you really are? If not, unconsciously move along with the herd.


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PTSD susceptibility?

This 2021 rodent study investigated post-traumatic stress disorder (PTSD) susceptibility:

“PTSD is an incapacitating trauma-related disorder, with no reliable therapy. We show distinct DNA methylation profiles of PTSD susceptibility in the nucleus accumbens (NAc). Data analysis revealed overall hypomethylation of different genomic CpG sites in susceptible animals.

Is it possible to treat PTSD by targeting epigenetic processes? Such an approach might reverse genomic underpinning of PTSD and serve as a cure.

To test plausibility of such an approach, a reliable animal (rat) model with high construct validity is needed. Previously, we reported one such model, which uses predator-associated trauma, and cue reminders to evoke recurring trauma. This simulates clinical PTSD symptoms including re-experiencing, avoidance, and hyperarousal.

Individual PTSD-like (susceptible) behavior is analyzed, enabling identification of susceptible animals separately from those that are non-PTSD-like (resilient). This model captures salient features of this disorder in humans, in which only a fraction of trauma victims develop PTSD, while others are resilient.

experimental model

Sprague–Dawley rats were exposed to trauma and to three subsequent trauma-associated reminders. Freezing behavior was measured under conditions of:

  • Exploration;
  • Social interaction (with a companion); and
  • Hyperarousal.

Controls were exposed to identical conditions except for the traumatic event.

PTSD-like behavior of each animal was compared with baseline and with the population. Two unambiguous sub-populations were identified, resilient and susceptible.

After exposure to trauma and its reminders, susceptible animals showed an increase from baseline in freezing behavior, and over time in all three behavioral tests, as opposed to resilient and control groups.

DMRs

Differentially methylated sites in susceptible and resilient animals compared to control group.

Although we focused in this study on DNA methylation changes that associate with susceptibility, we also report unique changes in DNA methylation that occur in resilient animals. Inhibition of critical genes that are downregulated in susceptible animals convert resilient animals to become susceptible.”

https://www.researchgate.net/publication/353192082_Reduction_of_DNMT3a_and_RORA_in_the_nucleus_accumbens_plays_a_causal_role_in_post-traumatic_stress_disorder-like_behavior_reversal_by_combinatorial_epigenetic_therapy “Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy” (registration required)


Rodents with the same genetics and environment displayed individual differences in their responses to traumatic events. Please provide evidence for that before venturing elsewhere.

Not sure why it took 3+ years for this study received in November 2017 to finally be published in July 2021. Sites other than https://doi.org/10.1038/s41380-021-01178-y are more transparent about their peer review and publication processes.

No causes for PTSD susceptibility were investigated. PTSD effects and symptoms aren’t causes, notwithstanding this study’s finding that:

“Our results support a causal role for the NAc as a critical brain region for expression of PTSD-like behaviors, and a role for programming genes by DNA methylation in the NAc in development of PTSD-like behaviors.”

Can’t say that I understand more about causes for PTSD susceptibility now than before I read this study. Researchers attaching significance to gene functional groups seemed like hypothesis-seeking efforts to overcome limited findings.

Will this study’s combination of a methyl donor with a Vitamin A metabolite address PTSD causes in humans? If it only temporarily alleviates symptoms, what lasting value will it have?


Several brain and body areas that store traumatic memories other than the nucleus accumbens were mentioned in The role of recall neurons in traumatic memories. A wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address each individual, their whole body, and their entire history.

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Osprey breakfast

Gut and brain health

This 2021 human review subject was interactions of gut health and disease with brain health and disease:

“Actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids (SCFAs), tryptophan, and bile acid metabolites / pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour.

Dietary fibres, proteins, and fats ingested by the host contain components which are metabolized by microbiota. SCFAs are produced from fermentation of fibres, and tryptophan-kynurenine (TRP-KYN) metabolites from dietary proteins. Primary bile acids derived from liver metabolism aid in lipid digestion, but can be deconjugated and bio-transformed into secondary bile acids.

1-s2.0-S0149763421001032-gr1

One of the greatest challenges with human microbiota studies is making inferences about composition of colonic microbiota from faeces. There are known differences between faecal and caecal microbiota composition in humans along with spatial variation across the gastrointestinal tract.

It is difficult to interpret microbiome-host associations without identifying the driving influence in such an interaction. Large cohort studies may require thousands of participants on order to reach 20 % explanatory power for a certain host-trait with specific microbiota-associated metrics (Shannon diversity, relative microbial abundance). Collection of metadata is important to allow for a better comparison between studies, and to identify differentially abundant microbes arising from confounding variables.”

https://www.sciencedirect.com/science/article/pii/S0149763421001032 “Mining Microbes for Mental Health: Determining the Role of Microbial Metabolic Pathways in Human Brain Health and Disease”


Don’t understand why these researchers handcuffed themselves by only using PubMed searches. For example, two papers were cited for:

“Conjugated and unconjugated bile acids, as well as taurine or glycine alone, are potential neuroactive ligands in humans.”

Compare scientific coverage of PubMed with Scopus:

  • 2017 paper: PubMed citations 39; Scopus citations 69.
  • 2019 paper: PubMed citations 69; Scopus citations 102.

Large numbers of papers intentionally missing from PubMed probably influenced this review’s findings, such as:

  1. “There are too few fibromyalgia and migraine microbiome-related studies to make definitive conclusions. However, one fibromyalgia study found altered microbial species associated with SCFA and tryptophan metabolism, as well as changes in serum levels of SCFAs. Similarly, the sole migraine-microbiota study reported an increased abundance of the kynurenine synthesis GBM (gut-brain module).
  2. Due to heterogeneity of stroke and vascular disease conditions, it is difficult to make substantial comparisons between studies. There is convincing evidence for involvement of specific microbial genera / species and a neurovascular condition in humans. However, taxa were linked to LPS biosynthesis rather than SCFA production.
  3. Several studies suggest lasting microbial changes in response to prenatal or postnatal stress, though these do not provide evidence for involvement of SCFA, tryptophan, or bile-acid modifying bacteria. Similar to stress, there are very few studies assessing impact of post-traumatic stress disorder on microbiota.”

These researchers took on a difficult task. Their study design could have been better.


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Wildlife

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Eat mushrooms for a longer life?

Two papers, starting with a 2021 meta-analysis of mushroom intake:

“Mushroom consumption was associated with a lower risk of total mortality in this nationally representative sample of US adults.

median mushroom intake

15,546 participants were included, mean age 44.3 years. During a mean follow-up duration of 19.5 years, a total of 5,826 deaths were documented.

Participants who reported consuming mushrooms had lower risk of all-cause mortality compared with those without mushroom intake after adjusting for demographic, major lifestyle factors, overall diet quality, and other dietary factors including total energy.”

https://nutritionj.biomedcentral.com/articles/10.1186/s12937-021-00691-8 “Association of mushroom consumption with all-cause and cause-specific mortality among American adults: prospective cohort study findings from NHANES III”


A 2019 review with two of the same coauthors:

“Mushrooms are inherently, or can easily be made to be, excellent dietary sources of 4 important bioactive compounds that decrease in humans as they age:

  • Selenium;
  • Vitamin D2;
  • Glutathione; and
  • Ergothioneine (Ergo).

All of these except for Ergo can be found in significant amounts in other foods, and mushrooms are by far the best human dietary source.

Humans produce a highly specific transport protein for Ergo that makes it highly bioavailable and avidly retained. Such specific transporters are rarely present for nonnutrient bioactive compounds.

mushroom ergothioneine glutathione

Mushrooms are a valuable source of protein, fiber, B vitamins, phenolic compounds, potassium, and β-glucans. An Ergo increase of 3 mg/d can be accomplished by consumption of about 100 g of fresh button mushrooms per day, or around 25 g of fresh specialty mushrooms such as shiitake, oyster, or maitake mushrooms.

One potential way to add fresh button mushrooms to the diet would be to embrace the meat-blend approach in which about 30% to 40% ground, fresh button mushrooms are blended with 60% to 70% ground beef to replace pure ground beef in burgers or other common commonly consumed dishes. Another approach could be to use small amounts of Ergo-rich specialty mushroom dried powder as a new food ingredient into current or new food products.”

https://journals.lww.com/nutritiontodayonline/Abstract/2019/01000/Micronutrients_and_Bioactive_Compounds_in.5.aspx# “Micronutrients and Bioactive Compounds in Mushrooms: A Recipe for Healthy Aging?” (not freely available)


I doubt that mushroom intake was a cause of more than a third of this meta-analysis’ participants dying before they reached age 64. The first study of The amino acid ergothioneine had better methodological approaches that related mushroom intake to mortality.

I’ve eaten more than triple the first graphic’s 72 grams for over a year, not because I knew of health effects, but because I like mushrooms. The second graphic is nice to know, but probably won’t go out of my way for ergothioneine content.

Does sulforaphane treat autism?

A 2021 human study investigated sulforaphane treatments of autistic 3-to-12-year-olds:

“Sulforaphane (SF) led to non-statistically significant changes in the total and all subscale scores of the primary outcome measure. Several effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures.

13229_2021_447_Fig1

Clinical response to SF was associated with changes in mitochondrial function, and large intrasubject variability in this study was linked to underlying biological responses. The increase in ATP [adenosine triphosphate]-Linked Respiration associated with improvement in ABC [Aberrant Behavior Checklist] scores suggests that those individuals who showed improvements in behavior also had improved mitochondrial capacity to produce ATP.

Individuals who showed an improvement in ABC scores also showed a decrease in Proton Leak Respiration, suggesting that their mitochondria were better able to regulate oxidative stress. It is also possible that the increase in ATP production was related to improvement in the ability of mitochondria to handle oxidative stress.

SF had significant positive effects on oxidative stress, cytoprotective markers and cytokines, as well as mitochondrial function. These were promising findings that require further investigation of both clinical effects and mechanisms of action of SF.”

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-021-00447-5 “Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder”


Differences between this clinical trial and its pilot study curated in Autism biomarkers and sulforaphane included:

“HO-1 [heme oxygenase 1] functions to couple activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. It was initially increased in the pilot study, then paradoxically decreased in the main study, on continued treatment for longer periods with SF.

Increased HO-1 is consistent with decreases in proinflammatory cytokines we observed initially in IL-6, IL-1β and TNF-α. Decreased levels of cytokines continued after HO-1 returned to baseline with longer duration of treatment and suggest a decreased inflammatory state.

These cytokines are usually elevated in children with ASD, but were decreased on treatment with SF: IL-6 and TNF-α at 15 (but not 30) weeks.”

This study made a good effort with autistic children. Its insignificant effects of sulforaphane treatments pointed toward an understanding that human experiences when we are fetuses can override many subsequent events, treatments, and life experiences.

Your bones influence your brain

This 2020 review subject was brain-bone crosstalk:

“Multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis. Skeletal diseases display impaired brain development and function.

Along with brain and bone pathologies, trauma events highlight strong interaction of both organs. While brain-derived molecules affecting bone include central regulators – transmitters of the sympathetic, parasympathetic and sensory nervous system – bone-derived mediators altering brain function are released from bone cells and marrow.

ijms-21-04946-g001

Osteoblast-derived hormone osteocalcin (OCN) exerts neuroprotective effects. Studies revealed a bidirectional dependence of brain and bone through bone cell-derived modulators that directly affect behavioral and cognitive function.

The main bone-derived mediator affecting the brain is OCN, which is exclusively synthesized by osteoblasts. OCN was recently discovered to transverse the BBB to enter the CNS, where it promotes spatial learning and memory while preventing anxiety-like behavior or even depression.

Cognitive function and circulating levels of OCN are proposed to inversely correlate with age. Maternal osteocalcin regulates embryonic brain development by enhancing monoamine neurotransmitters and their synthesis.

Clinical observations provide key evidence for a bidirectional communication between brain and bone tissue, which is strongly supported by experimental studies that unraveled underlying mechanistic pathways and identified molecular mediators involved in this crosstalk.”

https://www.mdpi.com/1422-0067/21/14/4946/htm “Crosstalk of Brain and Bone-Clinical Observations and Their Molecular Bases”


The first paper of Vitamin K2 – What can it do? said:

Osteocalcin γ-carboxylation is the main mechanism of action through which Vitamin K2 improves bone health.”

This paper didn’t mention Matrix Gla Protein (MGP) carboxylation, and said a contrary:

“Undercarboxylated, bioactive OCN, initially considered as an inhibitor of bone mineralization, participates in systemic body regulation and homeostasis.”

The 2019 paper cited was Osteocalcin‑GPRC6A: An update of its clinical and biological multi‑organic interactions (Review):

“Osteocalcin is a small protein present in two forms: Carboxylated (cOC) and undercarboxylated (ucOC). Only ucOC can signal as a hormone while cOC cannot.”

It went on to downplay cOC, and also didn’t mention MGP carboxylation.

I think it’s a question of balance. cOC stays in your bones. Carboxylated MGP influences calcium to go into your bones instead of your blood vessel walls. Two good things.

Eat broccoli sprouts daily, and manage weight

This 2018 human study found:

“The objective of this study was to determine whether daily broccoli consumption alters absorption and metabolism of isothiocyanates derived from broccoli glucosinolates. We conducted a randomised cross-over human study (n = 18) balanced for BMI and glutathione S-transferase μ 1 (GSTM1) genotype in which subjects consumed a control diet with no broccoli (NB) for 16 d or the same diet with 200 g of cooked broccoli and 20 g of raw daikon radish daily for 15 d (daily broccoli, DB) and 100 g of broccoli and 10 g of daikon radish on day 16.

On day 17, all subjects consumed a meal of 200 g of broccoli and 20 g of daikon radish. Plasma and urine were collected for 24 h and analysed for sulphoraphane (SF) and metabolites of SF and erucin (ER). (a) BMI < 26 (b) BMI > 26.

sulforaphane and erucin metabolites

db-nb

Plasma AUC [area under the curve] and urinary excretion rates were higher on DB diet than on NB diet. Daily consumption of broccoli interacted with BMI to affect plasma concentrations and urinary excretion of glucosinolate-derived compounds.

Plasma and urinary levels of SF and mercapturic acid pathway products of SF and ER following a broccoli challenge meal were altered when preceded by 16 d of daily broccoli ingestion, and the effect depended on BMI.”

https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/absorption-and-metabolism-of-isothiocyanates-formed-from-broccoli-glucosinolates-effects-of-bmi-and-daily-consumption-in-a-randomised-clinical-trial/ “Absorption and metabolism of isothiocyanates formed from broccoli glucosinolates: effects of BMI and daily consumption in a randomised clinical trial”


Humans are the same, yet we’re each individually unique. These researchers could have explored individual differences, but that wasn’t part of this study’s design.

So we’re left with BMI as a discriminator. I don’t think that’s evidentiarily sufficient.

Eat broccoli sprouts every day. You’ll figure it out.