A time to speak

“To every thing there is a season, and a time to every purpose under heaven:
A time to break down, and a time to build up;
A time to mourn, and a time to dance;
A time to embrace, and a time to refrain from embracing;
A time to keep silent, and a time to speak.”


A review from 2017:

“Few, if any, other drugs can rival ivermectin for its beneficial impact on human health and welfare. Perhaps more than any other drug, ivermectin is a drug for the world’s poor. For most of this century, some 250 million people have been taking it.

The following are an indication of disease-fighting potential that has been identified for ivermectin thus far:

  • Antiviral – Ivermectin has been found to potently inhibit replication of yellow fever virus, with EC50 values in the sub-nanomolar range. It inhibits replication in several other flaviviruses, including dengue, Japanese encephalitis, and tick-borne encephalitis. Ivermectin interrupts virus replication. It demonstrates antiviral activity against several RNA viruses by blocking nuclear trafficking of viral proteins. It has been shown to have potent antiviral action against HIV-1.
  • Asthma – Ivermectin suppressed mucus hypersecretion by goblet cells, establishing that ivermectin can effectively curb inflammation, such that it may be useful in treating allergic asthma and other inflammatory airway diseases.
  • Bedbugs – Ivermectin is highly effective against bedbugs, capable of eradicating or preventing bedbug infestations.
  • Disease vector control – Ivermectin is highly effective in killing a broad range of insects. Comprehensive testing against 84 species of insects showed that avermectins were toxic to almost all insects tested. At sub-lethal doses, ivermectin inhibits feeding and disrupts mating behavior, oviposition, egg hatching, and development.
  • Malaria – Mosquitoes that transmit Plasmodium falciparum, the most dangerous malaria-causing parasite, can be killed by ivermectin present in the human bloodstream after a standard oral dose.
  • Myiasis – Myiasis is an infestation of fly larvae that grow inside the host. Oral myiasis has been successfully treated with ivermectin, which has also been effective as a non-invasive treatment for orbital myiasis, a rare and preventable ocular morbidity.
  • Schistosomiasis – Schistosoma species are the causative agent of schistosomiasis, a disease afflicting more than 200 million people worldwide. Ivermectin helps control one of the world’s major neglected tropical diseases.
  • Trichinosis – Globally, approximately 11 million individuals are infected with Trichinella roundworms. Ivermectin kills Trichinella spiralis, the species responsible for most of these infections.”

https://www.nature.com/articles/ja201711 “Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations”


59 citations in CrossRef. Didn’t see citing 2020-2021 papers that noted any safety concerns when administered at proper doses.

Train your immune system every day, because:

“Rapid clearance following ivermectin dosing, results not from direct impact of the drug, but via suppression of a parasite’s ability to evade the host’s natural immune defense mechanisms.”

It’s safe, and it’s effective. Ivermectin’s main difficulty is that its patent expired in 1997.

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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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Take acetyl-L-carnitine for early-life trauma

This 2021 rodent study traumatized female mice during their last 20% of pregnancy, with effects that included:

  • Prenatally stressed pups raised by stressed mothers had normal cognitive function, but depressive-like behavior and social impairment;
  • Prenatally stressed pups raised by control mothers did not reverse behavioral deficits; and
  • Control pups raised by stressed mothers displayed prenatally stressed pups’ behavioral phenotypes.

Acetyl-L-carnitine (ALCAR) protected against and reversed depressive-like behavior induced by prenatal trauma:

alcar regime

ALCAR was supplemented in drinking water of s → S mice either from weaning to adulthood (3–8 weeks), or for one week in adulthood (7–8 weeks). ALCAR supplementation from weaning rendered s → S mice resistant to developing depressive-like behavior.

ALCAR supplementation for 1 week during adulthood rescued depressive-like behavior. One week after ALCAR cessation, however, the anti-depressant effect of ALCAR was diminished.

Intergenerational trauma induces social deficits and depressive-like behavior through divergent and convergent mechanisms of both in utero and early-life parenting environments:

  • We establish 2-HG [2-hydroxyglutaric acid, a hypoxia and mitochondrial dysfunction marker, and an epigenetic modifier] as an early predictive biomarker for trauma-induced behavioral deficits; and
  • Demonstrate that early pharmacological correction of mitochondria metabolism dysfunction by ALCAR can permanently reverse behavioral deficits.”

https://www.nature.com/articles/s42003-021-02255-2 “Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction”


Previously curated studies cited were:

This study had an effusive endorsement of acetyl-L-carnitine in its Discussion section, ending with:

“This has the potential to change lives of millions of people who suffer from major depression or have risk of developing this disabling disorder, particularly those in which depression arose from prenatal traumatic stress.”

I take a gram daily. Don’t know about prenatal trauma, but I’m certain what happened during my early childhood.

I asked both these researchers and those of Reference 70 for their estimates of a human equivalent to “0.3% ALCAR in drinking water.” Will update with their replies.


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Week 63 of Changing to a youthful phenotype with sprouts

Finally got around to getting an annual physical this morning. Two indicators so far, with more expected in five days. They came in early, so here’s Part 2.

1. HbA1C – glycated hemoglobin – was 4.8 on a scale of 4.8 to 5.6%. That’s down from 5.1 in June 2020. HbA1C shows a two-month average blood glucose level.

I’ve eaten advanced glycation end product (AGE)-less chicken vegetable soup almost every day since July 2019. Upcoming instantaneous blood glucose measurements may be informative, but it seems that with what I’m doing, there’s little impetus to glycate that glucose. Which satisfies my intention to avoid glycative stress.

2. BMI for a normal weight is 18.5-24.9 kg/m2. Measurements over the past two years:

  • June 2019 24.8, 0.1 below range high;
  • June 2020 22.4, 2.5 below range high and 3.9 above low; and
  • June 2021 21.0, 3.9 below range high and 2.5 above low.

Annual BMI trend is going in the right direction, but it’s too squishy to be a biomarker. I usually don’t curate studies that rely on BMI.

I eat a lot of food every day! Not going to turn my kitchen into a laboratory to quantify, though. See Switch on your Nrf2 signaling pathway for what intake was on 1/1/2021.

Once or twice a week lately I’ve backed off and skipped one of a daily two (fresh and leftovers) AGE-less chicken vegetable meals when it’s been too much food. Haven’t skipped:

  • Twice-daily combined broccoli-red cabbage-mustard sprouts; or
  • Twice-daily Avena sativa oat sprouts; or
  • My Avena nuda whole oats breakfast.

Lost 11 lbs. over 12 months without trying to lose weight. Maximal food intake didn’t result in weight gain when much of its purpose was to:

  • Reduce inflammation; and
  • Make my gut microbiota happy.

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Broccoli sprouts positively influence Sestrin proteins

Four papers on Sestrin, with the first a 2021 review:

“Sestrin 2 (Sesn2) is a member of the evolutionarily conserved and stress-inducible sestrin family. In mammals, this family is composed of Sesn1–3, and Sesn2 is the main member that responds to oxidative stress.

Sesn2 inhibits mammalian target of rapamycin (mTOR)-mediated cell over-proliferation by activating adenosine monophosphate-activated protein kinase (AMPK) and its kinase activity. Sesn2 also regulates redox balance by directly exerting antioxidant enzyme activity and regulating antioxidant signaling.

Inflammation, which is not regulated by oxidative stress, also plays an important role in cardiovascular diseases (CVDs). Sesn2 is involved in inflammation and immune regulation in many systems.

There is a positive feedback loop between Sesn2 and Nrf2:

sestrin2 nrf2

Sesn2 and p62 are expressed under oxidative stress. Sesn2 binds to ULK1 and p62 to form a functional complex, which promotes p62 phosphorylation, promoting p62-dependent autophagy degradation of Keap1.

Consequently, Nrf2 accumulates in cells, transfers to the nucleus, and promotes transcriptional activation of genes controlled by antioxidant response elements (ARE).

Circulating Sesn2 levels are elevated in a variety of CVDs, such as coronary heart disease, heart failure and atrial fibrillation, which indicates that Sesn2 is induced and plays a protective role in CVDs.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584920316270 “Sestrin 2, a potential star of antioxidant stress in cardiovascular diseases” (not freely available)


A second paper was also a 2021 review:

“Sestrin2 acts as an antioxidant protein that diminishes accumulation of ROS and inhibits mTORC1 signaling. Both accumulation of ROS and activation of mTORC1 are associated with aging and age-related diseases.

Since plasma sestrin2 levels in patients with CAD and those with carotid atherosclerosis were shown to be high, it remains unclear whether or not an exogenous administration of sestrin2 could be beneficial for prevention of atherosclerotic disease.”

https://www.mdpi.com/1422-0067/22/3/1200/htm “The Protective Role of Sestrin2 in Atherosclerotic and Cardiac Diseases”


A third paper was a 2020 human study:

“Sesn 1 and Sesn 2 levels were significantly reduced in sarcopenic compared to non-sarcopenic subjects. It can be concluded that sarcopenia can be diagnosed at the early stage by using serum sestrin as one potential biomarker.”

https://link.springer.com/article/10.1007/s40520-020-01642-9 “Serum sestrins: potential predictive molecule in human sarcopenia” (not freely available)


A fourth paper was a 2020 rodent study:

“Sulforaphane (SFN) alleviated hematological variations, oxidative stress, heart dysfunction and structure disorder, and cardiomyocyte apoptosis induced by potassium dichromate. Moreover, SFN:

  • Reduced p53;
  • Cleaved caspase-3, Bcl2-associated X protein, nuclear factor kappa-B, and interleukin-1β levels; and
  • Increased Sesn2, Nrf2, heme oxygenase-1, NAD(P)H quinone oxidoreductase-1; and
  • Phosphorylated AMPK levels.

This study demonstrated that SFN ameliorates Cr(VI)-induced cardiotoxicity via activation of the Sesn2/AMPK/Nrf2 signaling pathway.”

https://pubs.rsc.org/en/content/articlelanding/2020/mt/d0mt00124 “Sulforaphane attenuates hexavalent chromium-induced cardiotoxicity via the activation of the Sesn2/AMPK/Nrf2 signaling pathway” (not freely available)


I found these studies as well as the previous post Cow milk causes disease from their citing a 2015 study The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1 (not freely available).

Basal cognition

To follow up Electroceuticals, a 2021 article by Dr. Michael Levin:

“A key philosophical idea, borrowed from computer science, is substrate independence. Components of a living system can carry out appropriate, clearly specified cognitive functions.

Cognitive processes in embryogenesis and regeneration:

rstb20200458f01

    • (a) An egg will reliably give rise to a species-specific anatomical outcome.
    • (b) This process is usually described as a feed-forward system where activity of gene-regulatory networks (GRNs) within cells results in expression of effector proteins that, via structural properties of proteins and physical forces, will result in the emergence of complex shape. This class of models (bottom-up process driven by self-organization and parallel activity of large numbers of local agents) is difficult to apply to several biological phenomena. Regulative development can alter subsequent steps to reach the correct anatomical goal state despite drastic deviations of the starting state.
    • (c) For example, mammalian embryos can be divided in half, giving rise to perfectly normal monozygotic twins, each of which has regenerated the missing cell mass.
    • (d) Mammalian embryos can also be combined, giving rise to a normal embryo in which no parts are duplicated.
    • (e) Such capabilities suggest that pattern control is fundamentally a homeostatic process—a closed-loop system using feedback to minimize error (distance) between a current shape and a target morphology. Although these kinds of decision-making models are commonplace in engineering, they are only recently beginning to be employed in biology. This kind of pattern-homeostatic process must store a setpoint that serves as a stop condition; however, as with most types of memory, it can be specifically modified by experience.
    • (f) In the phenomenon of trophic memory, damage created at a specific point on the branched structure of deer antlers is recalled as ectopic branch points in subsequent years’ antler regeneration. This reveals ability of cells at the scalp to remember spatial location of specific damage events and alter cell behaviour to adjust the resulting pattern appropriately—a pattern memory that stretches across months of time and considerable spatial distance and is able to modify low-level (cellular) growth rules to construct a pre-determined stored pattern that differs from genome-default for this species.
    • (g) A similar capability was recently shown in a molecularly tractable model system, in which genetically normal planarian flatworms were bioelectrically reprogrammed to regenerate two-headed animals when cut in subsequent rounds of asexual reproduction in plain water.
    • (h) The decision making revealed by cells, tissues and organs in these examples of dynamic remodelling toward specific target states could be implemented by cybernetic processes at various positions along a scale of proto-cognitive complexity.

A challenge for the field of basal cognition is to reveal gradualism of cellular properties underwriting this critical biological function to leverage an understanding of clear phase transitions observed in cognitive capacities. The origin and development of nervous systems is so far the most dramatic example.”

https://royalsocietypublishing.org/doi/10.1098/rstb.2020.0458 “Uncovering cognitive similarities and differences, conservation and innovation”


Why aren’t more resources being directed toward these research efforts? Glad to see that at least one co-founder of Microsoft, Paul Allen, posthumously used his billions to sponsor science for human good.

Eat broccoli sprouts for your hearing

Two 2021 papers, both of which I found by each citing a 2009 Molecular mechanisms underlying cochlear degeneration in the tubby mouse and the therapeutic effect of sulforaphane (not freely available). First was a review:

“Hair cell damage and loss mediated by oxidative stress are important causes of hearing loss. Sensorineural hearing loss is the most common type of hearing loss, including noise induced hearing loss (NIHL), age-related hearing loss (ARHL), and ototoxic hearing loss.

Nrf2 reduces cell damage caused by oxidative stress, and maintains the dynamic balance of systematic redox by inducing and regulating expression of various antioxidant factors. This review summarizes correlation studies of Nrf2 in hearing loss, providing ideas for prevention and treatment of hearing loss with Nrf2 as the target.

fphar-12-620921-g002

There is positive feedback between p62-mediated autophagy and Nrf2. p62 promotes accumulation of Nrf2 and nuclear translocation. Concurrently, increased Nrf2 promotes p62 expression.

How Nrf2 regulates ROS changes in hair cells, and the upstream and downstream regulatory network of Nrf2 in hair cells, are still not fully understood. Studies on early prevention and treatment of hearing loss through the Keap1-Nrf2-ARE [antioxidant response element] signaling axis are still at the exploratory stage.”

https://www.frontiersin.org/articles/10.3389/fphar.2021.620921/full “The Role of Nrf2 in Hearing Loss”


Second paper was a rodent study:

“We examined oxidative stress and antioxidant response of the p62-Keap1-Nrf2 pathway in cochleae during age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL). We elucidated the function of full-length and variant p62/Sqstm1 (referred to here as p62) in regulation of Nrf2 activation.

Cochlear damage was assessed by analyzing auditory brainstem response (ABR) and by counting hair cells (HCs). Malondialdehyde (MDA, a lipid peroxidation product) levels were measured in young and old mice to determine whether oxidative stress contributed to ARHL.

auditory brainstem response

  • (A) Audiometric threshold (dB) determined from click and pure tone evoked ABRs. Thresholds were each significantly different (P < 0.001) between young mice and old mice.
  • (B) HC loss percentage in basal cochlear turns. Significant differences (P < 0.001) were observed between young and old mice.
  • (C) MDA levels in the cochleae of old mice were significantly higher (P = 0.034) than those of young mice.

ROS accumulation is closely related to ARHL and NIHL. The inability of ROS accumulation to activate the Nrf2 antioxidant stress pathway under physiological conditions may be related to alternative splicing of p62 mRNA in cochleae.

However, the agonist of the Nrf2 pathway enhanced Nrf2 nuclear translocation. This suggests a mechanism in which the antioxidant pathway was difficult to be activated in the context of accumulation of ROS.”

https://www.researchsquare.com/article/rs-535219/v1 “New Target of Oxidative Stress Regulation in Cochleae:Alternative Splicing of the p62/Sqstm1 gene”


The study’s two-month-old mice were equivalent to a 20-year-old human. Its 13-to-14-month-old mice were equivalent to humans in their 60s to 70s.

I expected preconditioning to be mentioned in both papers. Maybe these researchers thought it was too obvious and didn’t need to be stated that:

  • Repeated use of a Nrf2 activator produces transient mild stress;
  • Which elicits a stronger response; and
  • Preconditions cells for future stress?

Sulforaphane in the Goldilocks zone and its cited papers exhaustively emphasized preconditioning’s importance. The main thing I’m trying to do with isothiocyanates is to send a weak pro-inflammatory signal to my endogenous ARE system to exercise natural defenses.

Twice-daily drills make me more proficient at responding to actual emergencies. Post-drill, my body recycles material to be ready to respond the next time.

I do the same thing once a day with β-glucan 1,3/1,6 to train my innate immune system. Microphages in my gut are the first responders. Like the very reactive isothiocyanates, I don’t take anything with, or an hour before or after β-glucan 1,3/1,6.

Why tolerate “the antioxidant pathway was difficult to be activated in the context of accumulation of ROS” when a sulforaphane “agonist of the Nrf2 pathway enhanced Nrf2 nuclear translocation”? For all we know, diminished natural defenses and hearing loss may exist to turn old mammals into prey.

Continued in Part 2.

Electroceuticals

To follow up A top-down view of biological goal-directed mechanisms, 2020 and 2021 presentations by Dr. Michael Levin of Tufts University:

“We want to able to design a living form at the level of anatomy, and have the system compile it down into a set of low level instructions that you would have to give to the cellular collective to make it do this. What we would like to do is to offload all that complexity onto cells, and control this  whole thing with inputs, experiences, or stimuli.

What evolution does is to exploit bioelectricity to implement networks that store these patterns, patterns that serve as memories and goal states.”


electroceuticals


Appreciate Dr. Levin sticking with his findings for three decades now. Credit my son for refreshing my memory.

The amino acid ergothioneine

A trio of papers on ergothioneine starts with a 2019 human study. 3,236 people without cardiovascular disease and diabetes mellitus ages 57.4±6.0 were measured for 112 metabolites, then followed-up after 20+ years:

“We identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.

overall mortality and ergothioneine

Ergothioneine exists in many dietary sources and has especially high levels in mushrooms, tempeh, and garlic. Ergothioneine has previously been associated with a higher intake of vegetables, seafood and with a lower intake of solid fats and added sugar as well as associated with healthy food patterns.”

https://heart.bmj.com/content/106/9/691 “Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease”


I came across this study by its citation in a 2021 review:

“The body has evolved to rely on highly abundant low molecular weight thiols such as glutathione to maintain redox homeostasis but also play other important roles including xenobiotic detoxification and signalling. Some of these thiols may also be derived from diet, such as the trimethyl-betaine derivative of histidine, ergothioneine (ET).

image description

ET can be found in most (if not all) tissues, with differential rates of accumulation, owing to differing expression of the transporter. High expression of the transporter, and hence high levels of ET, is observed in certain cells (e.g. blood cells, bone marrow, ocular tissues, brain) that are likely predisposed to oxidative stress, although other tissues can accumulate high levels of ET with sustained administration. This has been suggested to be an adaptive physiological response to elevate ET in the damaged tissue and thereby limit further injury.”

https://www.sciencedirect.com/science/article/pii/S2213231721000161 “Ergothioneine, recent developments”


The coauthors of this review were also coauthors of a 2018 review:

“Ergothioneine is avidly taken up from the diet by humans and other animals through a transporter, OCTN1. Ergothioneine is not rapidly metabolised, or excreted in urine, and has powerful antioxidant and cytoprotective properties.

ergothioneine in foods

Effects of dietary ET supplementation on oxidative damage in young healthy adults found a trend to a decrease in oxidative damage, as detected in plasma and urine using several established biomarkers of oxidative damage, but no major decreases. This could arguably be a useful property of ET: not interfering with important roles of ROS/RNS in healthy tissues, but coming into play when oxidative damage becomes excessive due to tissue injury, toxin exposure or disease, and ET is then accumulated.”

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13123 “Ergothioneine – a diet-derived antioxidant with therapeutic potential”


I’m upping a half-pound of mushrooms every day to 3/4 lb. (340 g). Don’t think I could eat more garlic than the current six cloves.

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I came across this subject in today’s video:

The next phase of reversing aging and immunosenescent trends

Dr. Greg Fahy earlier this week provided an update on the November 2020 TRIIM-X follow-on to the September 2019 TRIIM curated in Reversal of aging and immunosenescent trends. Emphasis was on reproducibility:

23:45 Dr. Steve Horvath reanalyzed TRIIM for the plasma portion of Levine’s PhenoAge epigenetic clock. Results were congruent with four other epigenetic clocks showing a 2.5 year reduction of biological age.

39:20 TRIIM-X preliminary results started with C-Reactive protein.

43:05 No backsliding in epigenetic age deceleration between TRIIM and TRIIM-X!

continued epigenetic age deceleration

55:07 Q & A session starts with how TRIIM-X controls for supplements. Answers for resveratrol and calorie restriction, emphasizing that CR doesn’t reverse aging.

1:10 TRIIM-X took photos of subjects’ hair at baseline!


Great update! The last 20 minutes emphasized a need for capital in aging research. TRIIM-X has another 1.5 years to go, and other aging research projects needing funding were mentioned.

Don’t know what happened to the unmentioned 3000 IU vitamin D and 50 mg zinc recommendations of TRIIM. So I asked. Dr. Fahy replied:

“They are still there! Just not mentioned!”

Thought briefly about enrolling in TRIIM-X, but there’s no way anyone but me gets to experiment with my body.

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 instead of antibiotics

This 2020 cell study investigated antibiotic effects of broccoli sprout compounds:

“In this work, we asked whether isothiocyanates (ITCs) could act synergistically with each other to increase antibacterial effect. A set of aliphatic ITCs, such as iberin, iberverin, alyssin, erucin, sulforaphen, erysolin, and cheirolin was tested in combination with sulforaphane against E. coli.

All tested ITCs exhibit strong antimicrobial effect individually. Synergistic action observed for iberin, iberverin, and alyssin led to minimal inhibitory concentration necessary for antibacterial effect four- to eight-fold lower than for individual ITCs.

Effectiveness of antimicrobial effect is correlated with both type of ITC used and bacterial growth conditions. Antimicrobial action of sulforaphane analogs was impaired by specific amino acids.

The combination of several fold lower concentration of ITCs gives a similar effect as much higher amounts of individual ITCs. Antibacterial effect of ITC treatment is related to stringent response induction, which is triggered by amino acid starvation.

The use of ITCs as antibacterial agents can be advantageous, as there are very few examples of bacterial resistance to these compounds.”

https://www.frontiersin.org/articles/10.3389/fmicb.2020.591802/full “Induction of the Stringent Response Underlies the Antimicrobial Action of Aliphatic Isothiocyanates”


One of this study’s references was the 2016 Relationship between Chemical Structure and Antimicrobial Activities of Isothiocyanates from Cruciferous Vegetables against Oral Pathogens which found that broccoli and red cabbage compound indole-3-carbinol and mustard compound benzyl isothiocyanate were even more potent antibiotics than half of the aliphatic isothiocyanates in this study:

antibiotic isothiocyanates

I’m not concerned about countering antibiotic effects with “impaired by specific amino acids” supplementation like taurine, glycine, glutamine, etc. Since our ancesters evolved to deal with everyday bacteria, viruses, and other pathogens, I’m already well-equipped.

Not sure about the current virus developed to herd humans into an agenda. Train your immune system every day! disclosed that I was in Milan, Italy on the same February 22-23, 2020 weekend that ten towns were closed south of Milan. That virus bounces off of me, as I’ve never experienced any symptoms.

One factor in immune response was that fifteen years previous, I’d taken daily steps to guard against the phenotypical immune system collapse of old age. Another factor was that I’d ridden the filthy Washington DC Metro twice a day to-and-from work for years, and had already been exposed to who knows what.

Treat your gut microbiota well. Give them what they want – including cruciferous sprouts – instead of prescription antibiotics, and expect reciprocity.

Eat oats and regain cognitive normalcy

This 2020 rodent study investigated effects of different diets:

“The present study aimed to evaluate effects of β-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD). After long-term supplementation for 15 weeks, β-glucan prevented HFFD-induced cognitive impairment, assessed behaviorally by object location, novel object recognition, and nesting building tests:

  • Long-term β-glucan supplementation suppressed microglia activation and inflammation in hippocampus of HFFD-fed mice;
  • β-glucan attenuated deleterious engulfment of synapses by activation of microglia seen in HFFD mice;
  • β-glucan significantly prevented upregulation of TNF-α, IL-1β, and IL-6 mRNA expression in hippocampus; and
  • A broad-spectrum antibiotic intervention abrogated β-glucan-induced improvement in cognitive function, highlighting the essential role of gut microbiota to mediate cognitive function and behavior.

We found that short-term β-glucan supplementation did not change cognitive behavior in HFFD fed mice. HFFD feeding for 7 days dramatically changed gut microbial profile, with β-glucan-fed mice clustered apart from HFFD-fed mice sample, suggesting:

  • Quick changes in gut microbiota are induced by short-term β-glucan consumption and
  • Possible causality of gut microbiota profile on cognition.

7% β-glucan 7% nondigestible fiber

β-glucan supplementation increased place discrimination ratio in object location test compared with HFFD mice; however, there was no significant difference in total exploration time with objects during test phases between the two groups. Higher place discrimination index in β-glucan supplementation group was not due to better general performance, but increased recognition memory.

Results provide consistent evidence linking increased β-glucan intake to improved:

  • Gut microbiota profile;
  • Intestinal barrier function;
  • Reduced endotoxemia; and
  • Enhanced cognitive function via more optimized synaptic and signaling pathways in critical brain areas.

It is speculative that β-glucan improvement of gut microbiota composition, but not necessarily diversity per se, may be most critical for improved cognition. Enhanced consumption of β-glucan-rich foods is an easily implementable nutritional strategy to attenuate diet-induced cognitive decline.

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-020-00920-y “β-glucan attenuates cognitive impairment via the gut-brain axis in diet-induced obese mice”


This study did well by elaborating It’s the fiber, not the fat and Eat oats to prevent diabetes related findings. How many humans eat themselves into essentially the same situation as this HFFD group with no gut-microbiota-friendly dietary fiber?

Experiments were with β-glucan 1,3/1,4 found in oats. β-glucan 1,3/1,6 has separate effects, especially on innate immunity.

It’s a coin toss on whether observed cognitive improvement was due to 7% β-glucan soluble fiber, 7% indigestible fiber, or both. I do both, beginning with Avena nuda oats for breakfast.