Exercise substitutes?

Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)

A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

  • Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.
  • Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.
  • Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.
  • It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).
  • Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”


Vitamin D and pain

This 2022 human study investigated epigenetic clock associations:

“We assessed the potential relationship of Vitamin D’s effects on pain intensity and disability through associations in epigenetic aging in individuals with and without knee osteoarthritis (KOA). We hypothesized that associations between Vitamin D levels with pain intensity and interference in persons with KOA would be significantly mediated by epigenetic aging.

As a whole, the sample had a mean Vitamin D serum level of 26.7 ng/mL (± 12.8 ng/mL). The mean AgeAccelGrim was 2.4 years (± 5.6 years). There were no significant differences in Vitamin D levels between sex, race, and study site categories.

There was a significant difference in Vitamin D levels between the pain groups, with individuals in the High Impact Pain group showing significantly lower mean levels of Vitamin D (24.01 ng/mL) compared to the Low Impact Pain (28.30 ng/mL) and No Pain (27.30 ng/mL) groups.

vitamin d and pain

Data from this study highlight the important role that Vitamin D plays within the genomic environment, as well as in relation to health outcomes including pain intensity and disability.”

https://link.springer.com/article/10.1007/s12603-022-1758-z “Accelerated Epigenetic Aging Mediates the Association between Vitamin D Levels and Knee Pain in Community-Dwelling Individuals” (not freely available)

It’s good to see a study relating biological age to nutrition status. I didn’t see much discussion of other obvious factors involved in either pain or biological age in their limitations paragraph.

Subjects’ Vitamin D 26.7 ng/mL ± 12.8 ng/mL status indicated that most didn’t spend a few cents every day for their own one precious life. And Vitamin D supplementation wasn’t an exclusion criterion.

The local fire and rescue squad came last Friday to take away a younger neighbor’s body who died overnight. Last I talked with them, they were at least 50 pounds overweight and never exercised. Expressed condolences to their spouse, but wasn’t shocked.

I don’t live in a community-dwelling situation (old people who live on their own as opposed to those taken care of in nursing homes) like this study’s subjects. My youngest neighbors are in their twenties.

Nature hasn’t cared about our lives after our early teens, because we survived long enough to reproduce. What happens in our lives after puberty is largely up to each individual.


Gut microbiota knowledge through 2021

I’ll curate this 2022 review of what’s known and unknown about our trillions of gut microbiota through its topic headings:

“Most microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases.

A. Understanding the Microbiome Composition and Factors That Shape Its Diversity
Effect of Diet Composition on the Microbiome Diversity

  • Macronutrients and Microbiome Diversity
  • Nutrient and Mineral Supplements and Microbiome Diversity



Race and Host Genetics



  • Exercise
  • Smoking
  • Urbanization

B. Understanding the Microbiome Function and Its Association With Onset and Progression of Many Diseases

Microbiome Association With Inflammatory and Metabolic Disorders

  • Chronic Inflammation in GIT and Beyond
  • Development of Malignant Tumors
  • Obesity
  • Coronary Artery Disease
  • Respiratory Diseases

Microbiome Role in Psychiatric, Behavioral, and Emotional Disorders

C. Understanding the Microbiome Function as Mediated by Secreted Molecules

D. Conclusion and Future Directions – A pioneering study aimed to computationally predict functions of microbes on earth estimates the presence of 35.5 million functions in bacteria of which only 0.02% are known. Our knowledge of its functions and how they mediate health and diseases is preliminary.”

https://www.frontiersin.org/articles/10.3389/fmicb.2022.825338 “Recent Advances in Understanding the Structure and Function of the Human Microbiome”

I took another test last month at the 14-month point of treating my gut microbiota better. Compared with the 7-month top level measurements, what stood out was an increase in relative abundance from 1% to 7% in the Verrucomicrophia phylum that pretty much exclusively comprises species Akkermansia muciniphilia in humans:

top 5 phylum 2-2022

This review termed Akkermansia muciniphilia relative increases as beneficial. Go with the Alzheimer’s Disease evidence didn’t.

Preventing human infections with dietary fibers inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But I already eat much more fiber than our human ancestors’ estimated 100 grams of fiber every day, so lack of fiber definitely didn’t cause this relative increase.

Resistant starch therapy observed:

“Relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders increase in relative abundance to a greater extent.”

I’ll wait for further evidence while taking responsibility for my own one precious life.

Didn’t agree with this review’s statements regarding microbial associations with fear. These reviewers framed such associations as if gut microbiota in the present had stronger influences on an individual’s fear responses than did any of the individual’s earlier experiences. No way.

I came across this review by it citing The microbiome: An emerging key player in aging and longevity, which was Reference 25 of Dr. Paul Clayton’s blog post What are You Thinking?

Also didn’t agree with some of the doctor’s post:

  • Heterochronic parabiosis of young and old animals is wildly different from fecal transfer. Can’t really compare them to any level of detail.
  • Using a rodent young-to-old fecal microbiota transplant study to imply the same effects would happen in humans? Humans don’t live in controlled environments, so why would a young human individual’s gut microbiota necessarily have healthier effects than an old individual’s?
  • Another example was the penultimate paragraph: “By adding a mix of prebiotic fibers to your diet and maintaining a more youthful and less inflammatory microbiome you will have less inflammation, less endotoxaemia and less inflammageing. You will therefore live healthier and longer.” I’m okay with the first sentence. Equivalating the first sentence to both healthspan and lifespan increases in the second sentence wasn’t supported by any of the 45 cited references.

Vitamin K2 and hypertension

This 2021 rodent study investigated effects of Vitamin K2 on salt-sensitive hypertension:

“Mice were supplemented with VK2 and gut bacteria were detected by 16S rRNA. Common signaling pathway-related proteins were detected to further verify signaling pathways before validation of clinical samples.

Diets for 4 weeks were:

  • Normal group diet containing 0.5% NaCl;
  • High salt group (HS) diet containing 8% NaCl;
  • High salt diet plus VK2 supplementation group (HS_VK2) diet containing 8% NaCl and additional 0.025% VK2.

VK2 supplementation protected blood pressure and aortic vessels in salt-induced mice:

mk-4 salt

VK2 treated salt-sensitive hypertension by inhibiting the renin–angiotensin system.


Possible mechanisms of VK2 for salt-sensitive hypertension.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.639467/full “Network and 16S rRNA Sequencing-Combined Approach Provides Insightal Evidence of Vitamin K2 for Salt-Sensitive Hypertension”

The form of Vitamin K2 was MK-4 per its C31H40O2 molecular formula. Data wasn’t provided to calculate a human-equivalent dose for 0.025% MK-4.

This study was part of a 2022 Gut Microbial Response to Host Metabolic Phenotypes collection which included animal studies investigating gut microbiota in contexts of β-carotene and β-sitosterol supplementation. I found this collection by it citing the 2018 rodent study GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose which was Reference 27 of Dr. Paul Clayton’s blog post Sweet Nothing.

Signaling pathways and disordered proteins

This 2022 review explored the title subject:

“Cell signaling imposes many demands on proteins that comprise these pathways, including abilities to form active and inactive states, and to engage in multiple protein interactions. Signaling often requires amplifying signals, regulating or tuning responses to signals, combining information sourced from multiple pathways, all while ensuring process fidelity.

Sensitivity, adaptability, and tunability are possible, in part, due to inclusion of intrinsically disordered regions in many proteins involved in cell signaling.  This review highlights the critical role of intrinsically disordered proteins for signaling:

  • In widely diverse organisms (animals, plants, bacteria, fungi);
  • In every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine); and
  • At each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process.

Function of the glucocorticoid receptor is regulated in part by its intrinsically disordered C-terminal tail. Prior to activation, the glucocorticoid receptor resides in cytosol:

glucocorticoid receptor

Intrinsic disorder in the glucocorticoid receptor not only enables multiple allosteric regulatory interactions to impact function, but also allows deployment of different surfaces of the protein to enable binding to many different sets of macromolecules, and regulation of these interactions via mRNA splicing and phosphorylation.

Combinations of alternative translation initiation and alternative mRNA splicing result in production of multiple glucocorticoid receptor isoforms from one gene. Various isoforms exhibit distinctive tissue distribution patterns and altered transcriptional regulatory profiles.

Greater than 90% of transcription factors either contain intrinsically disordered regions of proteins or are entirely intrinsically disordered. The many advantages conferred by disorder to cell signaling cascades means that:

  1. Understanding signaling required definition of roles disorder plays in each pathway;
  2. Many more examples of disordered proteins in cell signaling pathways are likely to be discovered; and
  3. More mechanisms by which disorder functions remain to be elucidated.”

https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00821-7 “Intrinsically disordered proteins play diverse roles in cell signaling”

Cells in vivo seldom act on their own impetus. I would have liked discussion – or at least mention – of bidirectional signals between genes / cells / tissues / organs / organism / environment. This review’s topic of cell signaling pathways excluded “interactions of complex, interconnected systems spanning hierarchical levels” as explored in An environmental signaling paradigm of aging.

Every baby needs a sugar mama

This 2021 in vitro study examined butyrate producers:

“Butyrate produced by gut microbiota has multiple beneficial effects on host health. Oligosaccharides derived from host diets, and glycans originating from host mucus, are major sources of its production.

Butyrate is the major energy source for epithelial cells in the distal colon, induces differentiation of colonic regulatory T cells, and functions as an inhibitor of host histone deacetylase. These activities are essential for documented beneficial properties of butyrate, including anti-inflammation, gut immune homeostasis, inhibition of proliferation, and induction of apoptosis of colorectal cancer cells.

FOS-type oligosaccharides (kestose, nystose, fructooligosaccharide) were metabolized by only 6 of 14 butyrate-producing strains tested:

Growth of butyrate producers

Faecalibacterium prausnitzii, which is the most abundant butyrate producer in the healthy human gut, metabolized only FOS-type oligosaccharides among tested oligosaccharides. Anaerostipes spp. exhibited a similar pattern, except that A. caccae metabolized kestose but not nystose.

Glycoside hydrolase (GH)32 enzymes exhibiting FOS degradation activities were conserved in all six strains metabolizing FOS, and in three of the eight strains that did not metabolize FOS. This suggests that GH32 enzymes in those three strains are not actively used in metabolism.

The present study highlighted that even if functional genes are present in microbes, they are sometimes unable to metabolize substrates. This should be carefully considered in metagenomic studies to understand metabolic potential of gut microbiota.”

https://www.tandfonline.com/doi/full/10.1080/19490976.2020.1869503 “Characterization of fructooligosaccharide metabolism and fructooligosaccharide-degrading enzymes in human commensal butyrate producers”

These researchers had some work to do to show that selected strains’ characteristics were representative of their species. This post’s title was excerpted from Citation 37.


Resistant starch, β-glucan, and inulin

This 2021 paper reported results of two related human clinical trials:

“Lean and prediabetic overweight/obese men were included in two randomized crossover studies. In one study, participants received supplements of either long-chain inulin+resistant starch (INU+RS), INU or maltodextrin (placebo, PLA) the day prior to a clinical investigation day. The second trial studied beta glucan+RS (BG+RS) versus BG and PLA.

1. In lean men, INU+RS increased breath hydrogen and fasting plasma butyrate, which was accompanied by increased energy expenditure, carbohydrate oxidation, and peptide YY, and decreased postprandial glucose concentrations compared to PLA.

In prediabetic men, INU+RS increased plasma acetate compared to INU or PLA, but did not affect metabolic parameters.

The three supplements were:

  • INU: 12 g long-chain inulin in combination with 5.43 g maltodextrin to make it isocaloric.
  • INU+RS: 12 g of long-chain inulin in combination with 9.39 g 80% resistant starch RS2 granular potato starch.
  • PLA: 11.43 g maltodextrin.

2. BG+RS increased plasma butyrate compared to PLA in prediabetic individuals, but did not affect other fermentation/metabolic markers in both phenotypes.

The three supplements were:

  • BG: 35.25 g 34% yeast beta glucan with 5.43 g maltodextrin to make it isocaloric.
  • BG+RS: 35.25 g 34% yeast beta glucan in combination with 9.39 g 80% RS2 granular potato starch.
  • PLA: 11.43 g maltodextrin + 13.1 g protein and 4.58 g fat, same type and amounts as in the beta glucan product.

Effects of one-day consumption with a ‘slowly fermentable’ complex INU or BG alone, or INU or BG combined with a more ‘rapidly fermentable’ RS on substrate and energy metabolism were studied. These fiber mixtures were selected based on a high distal colonic acetate and total SCFA production in a validated in vitro model of the human colon.

Further research should study whether longer-term supplementation periods are required to elicit beneficial metabolic health in prediabetic individuals.”

https://www.tandfonline.com/doi/full/10.1080/19490976.2021.2009297 “Fiber mixture-specific effect on distal colonic fermentation and metabolic health in lean but not in prediabetic men”

The Discussion section related these findings to other research. Not sure how these researchers determined a trial time period. As Reviewing clinical trials of broccoli sprouts and their compounds pointed out:

“Biomarkers of effect need more time than biomarkers of exposure to be influenced by dietary treatment.”


Eat broccoli sprouts for your workouts

This 2021 human study investigated effects of pre- and post-workout glucoraphanin intake:

“The tablet used in this study contained 30 mg of glucoraphanin, a precursor of sulforaphane (SFN), which is converted to SFN in the intestinal lumen by intestinal microflora. Subjects took one tablet of SFN supplement per meal, three times a day. Healthy men without exercise habits, smoking, or medication were included in the experiment:

eccentric exercise subjects

Pain on palpation reached its peak 1–2 days after exercise and recovered to baseline 5 days after exercise. Muscle soreness on palpation and range of motion were significantly lower 2 days after exercise in the sulforaphane group:

range of motion

Serum malondialdehyde, an indicator of exercise-induced oxidative stress, showed significantly lower levels 2 days after exercise in the sulforaphane group. SFN intake may protect the balance of antioxidant capacity and suppress excessive oxidative stress caused by exercise.

Continuation of SFN intake – from 2 weeks before and up to 4 days after eccentric exercise – suppressed exercise-induced oxidative stress and inhibited muscle soreness and muscle damage. To our knowledge, this study is the first to analyze these effects of SFN in humans.”

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15130 “Effect of a sulforaphane supplement on muscle soreness and damage induced by eccentric exercise in young adults: A pilot study”

This study found that four days wasn’t enough time for 19-to-23-year-old men to fully recover from bicep eccentric exercise, regardless of glucoraphanin treatment or control group status. What’s an appropriate exercise recovery time? found a similar result using taurine as treatment with 20-to-33-year-old recreationally fit men who didn’t fully recover from bicep eccentric exercise after three days.

These researchers referenced Autism biomarkers and sulforaphane to acknowledge that this study’s 30 mg of glucoraphanin three times daily wasn’t sufficient to fully activate Nrf2 signaling pathways:

When SFN was added to PBMCs of healthy subjects in ex vivo experiments, NQO1 expression was increased, while HO-1 was not increased at a low SFN concentration (0.5 µM). However, when 2 or 5 µM of SFN was added to PBMCs, both NQO1 and HO-1 gene expression were increased. Concentration of the SFN supplement may be a reason why the amount of supplementation used in our protocol did not increase HO-1 expression.”

I create isothiocyanates by microwaving 3-day-old broccoli / red cabbage / mustard sprouts at 1000 W to 60°C (140°F) shortly before eating them. Unlike this study, I don’t depend on metabolism after the stomach to produce isothiocyanates from glucosinolates:

  • Less dependence on these subjects’ gut microbiota for sulforaphane production would have reduced a source of dose variability. Broccoli sprout compounds and gut microbiota first paper reviewed that subject.
  • Glucoraphanin intake with nothing else an hour before and after would have also reduced chances of sulforaphane loss by reacting with food. See Week 19 item 2 for two studies that found eating protein, fats, and fiber along with broccoli sprouts lowered isothiocyanates’ bioavailability.

Still, this was a step forward in research. Have fun with New Year’s resolutions.


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.


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.


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.


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.”


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.


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.


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.


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