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 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.

Astaxanthin bioavailability

By request, research on astaxanthin bioavailability. I used a “astaxanthin” “bioavailability” “quinone reductase” 2021 search term, and read citing papers.

“The bioaccessibility, bioavailability, and antioxidative activities of three astaxanthin geometric isomers were investigated using an in vitro digestion model.

  • 13Z-Astaxanthin showed higher bioaccessibility than 9Z- and all-E-astaxanthins during in vitro digestion, and
  • 9Z-astaxanthin exhibited higher transport efficiency than all-E- and 13Z-astaxanthins.

These might explain why 13Z- and 9Z-astaxanthins are found at higher concentrations in human plasma than all-E-astaxanthin.

9Z- and 13Z- astaxanthins exhibited a higher protective effect than all-E-astaxanthin against oxidative stress.”

https://pubs.acs.org/doi/10.1021/acs.jafc.7b04254 “Bioaccessibility, Cellular Uptake, and Transport of Astaxanthin Isomers and their Antioxidative Effects in Human Intestinal Epithelial Caco-2 Cells” (2017, not freely available)


jf1c00087_0005

“Astaxanthin with a high proportion of Z-isomer (especially rich in 9Z- and 13Z-isomers) was prepared from (all-E)-astaxanthin by thermal treatment and solid–liquid separation. Z-isomer-rich astaxanthin diet resulted in higher levels of astaxanthin in blood and many tissues (in particular, skin, lung, prostate, and eye) compared to all-E-isomer-rich diet.

Z-isomer-rich diet enhanced the level of 13Z-isomer in blood and tissues rather than that of 9Z-isomer. (13Z)-astaxanthin would have higher bioavailability and tissue accumulation than other isomers.”

https://pubs.acs.org/doi/10.1021/acs.jafc.1c00087Z-Isomers of Astaxanthin Exhibit Greater Bioavailability and Tissue Accumulation Efficiency than the All-E-Isomer” (2021, not freely available)


“Astaxanthin is highly susceptible to light, oxygen, and heat stress degradation. In addition, poor water solubility and bioavailability limit its efficacy in vivo. Investigating novel astaxanthin delivery systems is necessary in order to solve these drawbacks.”

https://www.mdpi.com/1420-3049/24/14/2640/htm “The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective” (2019)


“Astaxanthin Z-isomers potentially have greater bioavailability and biological activity than (all-E)-astaxanthin. However, stability of Z-isomers is lower than all-E-isomer, which is a serious problem affecting its practical use.

In this study, we investigated impacts of different suspension media (oils and fats) and additives on astaxanthin isomer stability.

  • Z-isomers of astaxanthin isomerized to all-E-isomer during storage.
  • When soybean and sunflower oils were used as the suspension medium, astaxanthin isomers were hardly degraded. However the total Z-isomer ratio decreased from ~80% to ~50% during 6-week storage at 30 °C.
  • (9Z)-astaxanthin showed higher stability than 13Z- and 15Z-isomers.”

https://www.sciencedirect.com/science/article/abs/pii/S0308814621003770 “Evaluation and improvement of storage stability of astaxanthin isomers in oils and fats” (2021, not freely available)


I looked for but didn’t find a graph similar to this one that comparatively plotted astaxanthin:

OMCL2019-2716870.006

I also didn’t find recent human studies.

It seems that a special delivery system is required for taking astaxanthin as a supplement. It would require investigating manufacturers’ claims about isomer content and stability.

Eating colorful seafood is another way to get astaxanthin. Don’t know about eating raw or dried algae.

Week 56 of Changing to a youthful phenotype with sprouts

1. Per Improving healthy compounds of broccoli sprouts and Broccoli sprouts’ immune effects, this week I added mustard sprouts and red cabbage sprouts to my twice-daily routine of eating 3-day-old microwaved broccoli sprouts.

At first, I started mustard and red cabbage seeds with the same 10.7 gram weight (one tablespoon) of seeds. They grew well such that after three days, mustard sprouts weighed an average 61.2 g, and red cabbage sprouts weighed 60.3 g average. Both of these were slightly less than broccoli sprouts’ 65.5 g average.

3-day-old mustard sprouts substantially mellowed out from mustard seeds’ effects. After microwaving mustard sprouts to ≤ 60°C (140°F) and letting them sit for five minutes, I still felt constant nose burn while eating them. 3-day-old red cabbage sprouts were milder than broccoli sprouts, so no difficulties.

The main problem with doing one tablespoon seed weights of all three Brassicaceae species consistently was that 61.2 + 60.3 + 65.5 = 187 g (6.6 ounces) twice a day was too much for me. I eat a lot of low-calorie fibrous food everyday to make my gut microbiota happy. An extra 4+ oz increase at the same time as twice-daily broccoli sprouts put my stomach over the top.

I changed to make equal contents of these three Brassicaceae species be the 10.7 g (one tablespoon) that I started sprouting twice a day.

2. I haven’t seen relevant mustard and red cabbage 3-day-old sprout studies, only 7+ day microgreen and mature plant studies. Evidence is limited in determining effects of cutting my estimated 52 mg of daily sulforaphane intake from broccoli sprouts by two-thirds starting this week.

A. I’ve eaten a clinically-relevant amount of sulforaphane every day for 4+ times longer than any clinical trial. I’ve experienced many positive effects described in studies, and look forward to further improvements.

Reducing sulforaphane intake from broccoli sprouts to 17 mg is still within boundaries of measurable effects. As an example, Upgrade your brain’s switchboard with broccoli sprouts found effects from a daily sulforaphane 17.3 mg (100 µmol) intake.

B. Mustard’s main glucosinolate, sinigrin, hydrolyzes to allyl isothiocyanate, and is in the same aliphatic group as broccoli’s glucoraphanin, which hydrolyzes to sulforaphane. An example of their similar effects was in a citation of Eat broccoli sprouts for DIM:

“Isothiocyanates are both inducers and substrates for Phase II enzymes as glutathione-S-transferases, and polymorphisms of these enzymes have a significant impact.”

Mustard’s myrosinase enzyme activities over and above broccoli myrosinase were highlighted in cited studies of Does sulforaphane reach the colon? Pretty sure that mustard sprouts’ myrosinase ≤ 60°C increases broccoli sprouts’ sulforaphane.

C. Red cabbage’s main glucosinolate is also glucoraphanin. Here’s a graphic from a 2010 study RED CABBAGE, A VEGETABLE RICH IN HEALTH-RELATED GLUCOSINOLATES which compared its glucoraphanin content with white cabbage:

red cabbage glucoraphanin vs white cabbage

The seeds I received were an “Agnostic” variety. In clarification correspondence with my supplier, I received a response “It means in this use ‘Generic’ or Variety not stated. Meaning it is just whatever variety of Red cabbage we bought and we don’t know the exact specifics.” 🙄

Red cabbage anthocyanins have a larger extent than broccoli anthocyanins, which was highlighted in Colorize your diet, Red cabbage pigments and the brain, and Measuring bioavailability. Figure 5 of Lab analyses of broccoli sprout compounds had analysis of three red cabbage cultivars’ 9-day-old sprouts. Glucosinolates are on top, hydrolysis products on the bottom. Glucoraphanin is red 4MSOB in A, and sulforaphane is red 4MSOB-ITC in C:

red cabbage 9-day-old sprouts

D. In summary, I don’t think I’ve significantly reduced broccoli sprouts’ effects by substituting two-thirds weight with two other Brassicaceae species. I haven’t noticed that growth characteristics / compounds interfered with each other.

Still looking for mustard and red cabbage 3-day-old sprout studies. My current Brassicaceae species composite is tasty, and doesn’t cause mustard nose burn.

3. This Brassicaceae species composite isn’t photogenic:

PXL_20210502_214348538

Red cabbage sprouts by themselves are pretty.

PXL_20210504_212505224

4. I still eat 3-day-old oat sprouts twice a day per Sprouting hulled oats. I don’t eat them with Brassicaceae species, but wait at least an hour later with Avena nuda oats in the morning, and AGE-less chicken vegetable soup in the evening.

Measuring bioavailability

This 2017 review challenged snapshot measurements of biological availability:

“There is a general belief that anthocyanins, flavanones, and other polyphenols are poorly bioavailable with only relatively small amounts of ingested dose entering systemic circulation in the form of metabolites. When lower molecular weight phenolic and aromatic ring-fission catabolites produced primarily by colonic microbiota are taken into account, it is evident that anthocyanins and flavanones are much more bioavailable than previously envisaged.

Although plasma pharmacokinetic measurements provide a snapshot of absorbed circulating metabolites, 0–24-h urinary excretion of both metabolites absorbed in the small intestine and catabolites of distal gastrointestinal (GI) origin that are products of bacterial processing provide a more quantitative reflection of polyphenol absorption. Overall 0–48-h urinary recovery of phenolic compounds – after baseline subtraction – was 43.9 ± 8.0 μmol, which is equivalent to 15% of ingested anthocyanins.

raspberries

With orders of magnitude higher plasma/serum Cmax levels and significantly longer half-lives, evidence points toward lower molecular weight phenolic and aromatic catabolites being the primary bioavailable products of anthocyanin consumption. Gut-derived catabolites can often exert higher bioactivity than their precursor flavonoid structures.”

https://www.annualreviews.org/doi/full/10.1146/annurev-food-030216-025636 “Anthocyanins and Flavanones Are More Bioavailable than Previously Perceived: A Review of Recent Evidence” (not freely available)


Much of this review’s anthocyanin section was dedicated to a coauthor’s 9-person study where they ate a huge amount of raspberries. Its flavanone section was similarly influenced by another coauthor’s human orange juice studies.

I’d like to see stronger evidence before reviewer statements become faits accomplis, elevated through citations to become indisputable facts. Its underlying point that studies could take more and varied measurements over extended periods seems amenable to evidence.

I arrived at this review through its citations in Colorize your diet and Red cabbage pigments and the brain.

Colorize your diet

This 2020 review subject was anthocyanins in Brassicaceae species:

“Anthocyanins provide red to blue colors in Brassicaceae plants, have nutritional value, and pharmaceutical potential. This review summarizes chemical composition, stability, bioavailability, and health benefits.

Edible sprouts are good sources of anthocyanins. Even within the same species, content of anthocyanins may vary with cultivar, growing season, growth condition, and plant organ.

Acylated anthocyanins were more stable than non-acylated anthocyanins. Bioavailability is the proportion of nutrient reaching systemic circulation.

Brassicaceae anthocyanins

Large amounts of unabsorbed anthocyanins reached the large intestine, where they were extensively metabolized by microbiota, forming simple anthocyanins, which were much more bioavailable. Degradation products can also be absorbed.

When these events are taken into account, Brassicaceae anthocyanins might be more bioavailable than previously perceived.

Stability of Brassicaceae anthocyanins may be beneficial in preventing certain chemical degradation in the gastrointestinal tract. Anthocyanins reaching blood circulation may be different from original food compounds.

Brassicaceae anthocyanins possess potential:

  • Antioxidant;
  • Anti-cancer;
  • Anti-inflammatory activities;
  • Protection against hepatic andrenal damage; and
  • Cardiovascular disease.

Most evidence is based on in vitro studies. More studies are necessary to further understand health benefits, as well as levels of consumption to maximize benefits, and mechanisms involved.”

https://www.tandfonline.com/doi/abs/10.1080/10408398.2020.1852170 “Anthocyanins in Brassicaceae: composition, stability, bioavailability, and potential health benefits” (not freely available)


I found this review as a fourth-order citation of related papers.

Chew it!

This 2020 human study examined associations between food consumption and chewing difficulty:

“Masticatory function influences not only control of chewing frequency and pressure, but also quality of life through food intake. Reduced food intake caused by chewing difficulty results in loss of eating pleasure and nutritional imbalance.

Chewing difficulty (DC) has been related to brain-related diseases such as cognitive impairment, cerebrovascular disorder, and Parkinson’s disease, increase in occurrence of diseases such as muscular dystrophy, aging acceleration, stomach, and kidney dysfunction due to reduced digestive enzyme secretion, and depression.

Subjects were divided into not difficult in chewing (NDC) and DC groups, with 24.17% being classified into DC. Average age of all subjects (n = 20,959 adult subjects aged between 19 and 64 yrs plus older) was 50.67 yrs. Average age of DC (60.5 yrs) was about 13 yrs older than NDC (47.5 yrs old).

Males and females consumed 35 and 37 items less frequently than the other sex, respectively:

nrp-14-637-g001

Subjects over 65 yrs who had chewing difficulty were 45.4% whereas that of adults was 24.3%. Items known to contain relatively high dietary fiber content or a high content of connective tissues were considered as foods to avoid by those with chewing difficulty due to strong or hard texture.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683204/ “Food consumption frequency of Korean adults based on whether or not having chewing difficulty using 2013–2016 KNHANES by sex-stratified comparative analysis”


I’d like to know more about subjects who had unresolved dental problems. This study focused on age and sex, but I’ve known twenty-somethings who had problems such as false teeth and dentures.

I go to a dentist twice a year. Don’t think I’d make my gut microbiota happy with Avena nuda oats, broccoli and oat sprouts, and AGE-less chicken vegetable soup if I had dental problems.

One aspect of research on short-chain fatty acids

To further understand An overlooked gut microbiota product, a 2018 rodent study found:

“Microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, neuroimmune regulation, and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood

SCFAs are primarily derived from fermentation of dietary fibres, and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress.

Administration of SCFAs to mice undergoing psychosocial stress alleviated enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability.

experimental design

SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress.”

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP276431 “Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations”


One way researchers advance science is to relate aspects of their findings to previous studies. That approach works, but may miss items that weren’t covered in previous research.

This study fed specific quantities of three SCFAs – acetate, butyrate, and propionate – apparently due to previous research findings. If other SCFAs produced by gut microbiota were ignored – like crotonate (aka unsaturated butyrate) – how would that approach advance science?

I found this study from its citation in Harnessing endogenous defenses with broccoli sprouts.

Benefits of eating fermentable fiber

This 2021 review subject was effects of short-chain fatty acids produced by gut microbiota:

“SCFAs are the main players in the interplay between diet, microbiota, and health. SCFAs contribute to intestinal homeostasis and regulation of energy metabolism.

SCFAs regulate the blood–brain barrier and neuroimmunoendocrine functions. During gestation, SCFAs can cause epigenetic imprinting and protect against allergic airway disease.

gr3_lrg

Fiber reaching the colon is anaerobically fermented by gut bacteria, which produce SCFAs. Nondigestible polysaccharides are found in plant cell walls, and are further classified into soluble and nonsoluble dietary fibers.

A role for SCFAs in histone modification of tissues in the body was definitively shown by dietary supplementation of germ-free mice with microbially produced acetate, propionate, and butyrate. These SCFAs increased acetylation of histone H4 and H3 in a tissue-specific fashion.

Most research to date has focused on butyrate but unlike acetate and propionate, it is typically present in undetectable or very low concentrations in the body. SCFAs appear to influence health through three principal mechanisms:

  1. Altering levels of HAT [histone acetyltransferase] and HDAC [histone deacetylase] activity;
  2. Signaling by specific fatty acid-sensing GPCRs [G-protein-coupled receptors]; and
  3. Anti-inflammatory mechanisms in the periphery and tissues due to the first two mechanisms.”

https://www.cell.com/trends/microbiology/fulltext/S0966-842X(21)00035-4 “Microbial Regulation of Host Physiology by Short-chain Fatty Acids”


PXL_20210412_104327851

Several diseases, one treatment?

This 2021 review summarized three dietary supplements’ effects on psychiatric symptoms:

“Upregulation of Nrf2 has been suggested as a common therapeutic target for major neuropsychiatric disorders. In this paper, evidence is presented showing how NAC [N-acetyl-cysteine], coenzyme Q10 (CoQ), and melatonin can ameliorate many important effects of oxidative stress by upregulating Nrf2.

Given its key role in governing cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder, and schizophrenia. These are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide, and peroxynitrite.

CoQ:

  • Acts as a superoxide scavenger in neuroglial mitochondria;
  • Instigates mitohormesis;
  • Ameliorates lipid peroxidation in the inner mitochondrial membrane;
  • Activates uncoupling proteins;
  • Promotes mitochondrial biogenesis; and
  • Has positive effects on the plasma membrane redox system.

Melatonin:

  • Scavenges mitochondrial free radicals;
  • Inhibits mitochondrial nitric oxidesynthase;
  • Restores mitochondrial calcium homeostasis;
  • Deacetylates and activates mitochondrial SIRT3;
  • Ameliorates increased permeability of the blood-brain barrier and intestine; and
  • Counters neuroinflammation and glutamate excitotoxicity.”

https://www.researchgate.net/publication/348309816_Increasing_Nrf2_Activity_as_a_Treatment_Approach_in_Neuropsychiatry “Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry” (registration required)


These reviewers explored three selected supplements, citing 380 references. They overlooked something, though. There was only one mention of sulforaphane in their paper, yet four references’ titles included sulforaphane?

I take two of the three exogenous supplements discussed. The one I stopped taking over a year ago – NAC – was thoroughly discussed, but not in contexts directly related to the Nrf2 transcription factor. Why?

Switch on your Nrf2 signaling pathway pointed out:

“We use NAC in the lab all the time because it stops an Nrf2 activation. So that weak pro-oxidant signal that activates Nrf2, you switch it off by giving a dose of NAC. It’s a potent antioxidant in that right, but it’s blocking signalling. And that’s what I don’t like about its broad use.”

The current review noted that Nrf2 is activated by oxidative stress. NAC is a precursor to glutathione – our main endogenous antioxidant – and neither one activates Nrf2 pathways.

What does? Sulforaphane.

PXL_20210412_104353167

Repositioning DNA methylation

This 2021 human study found:

“We report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72. The 8-week treatment program included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients.

This is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge (2013) epigenetic aging in healthy adult males. Larger-scale and longer duration clinical trials are needed to confirm these findings, as well as investigation in other human populations.

aging-v13iundefined-202913-figure-f3

In both treatment and control groups, there was no net increase or decrease in methylation of 353 sites that compose the Horvath clock. This finding suggests that intervention did not lead to an overall increase in methylation of Horvath clock sites, but rather it prompted a repositioning of clock CpG methylation patterns consistent with a younger biological age.

One significant limitation of this pilot trial is limited statistical power due to relatively small sample size. It is not yet fully established whether interventions that slow any methylation clocks necessarily curtail risks of age-related disease.”

https://www.aging-us.com/article/202913/text “Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial”


Baffled as to why these researchers relied on 2013 research rather than at least Dr. Horvath’s improved 2018 skin and blood clock, a review of which noted:

“Although the skin-blood clock was derived from significantly less samples (~900) than Horvath’s clock (~8000 samples), it was found to more accurately predict chronological age, not only across fibroblasts and skin, but also across blood, buccal and saliva tissue. A potential factor driving this improved accuracy in blood could be related to the approximate 18-fold increase in genomic coverage afforded by using Illumina 450k/850k beadarrays.”

Which would you prefer? A 2013 flip phone, or a 2018 smartphone?

Gut microbiota topics

Here are thirty 2019 and 2020 papers related to Switch on your Nrf2 signaling pathway topics. Started gathering research on this particular theme three months ago.

There are more researchers alive today than in the sum of all history, and they’re publishing. I can’t keep up with the torrent of interesting papers.

on

2020 A prebiotic fructo-oligosaccharide promotes tight junction assembly in intestinal epithelial cells via an AMPK-dependent pathway

2019 Polyphenols and Intestinal Permeability: Rationale and Future Perspectives

2020 Prebiotic effect of dietary polyphenols: A systematic review

2019 Protease‐activated receptor signaling in intestinal permeability regulation

2020 Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

2019 Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

2020 The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals

2019 Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis

2019 Prebiotics, Probiotics, and Bacterial Infections

2020 Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

2020 Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor

2019 Involvement of Astrocytes in the Process of Metabolic Syndrome

2020 Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice (not freely available)

2019 Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1−/Δ7 mice

2020 Plasticity of Paneth cells and their ability to regulate intestinal stem cells

2020 Coagulopathy associated with COVID-19 – Perspectives & Preventive strategies using a biological response modifier Glucan

2020 Synergy between Cell Surface Glycosidases and Glycan-Binding Proteins Dictates the Utilization of Specific Beta(1,3)-Glucans by Human Gut Bacteroides

2020 Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

2020 Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

2019 Prebiotic supplementation in frail older people affects specific gut microbiota taxa but not global diversity

2020 Effectiveness of probiotics, prebiotics, and prebiotic‐like components in common functional foods

2020 Postbiotics-A Step Beyond Pre- and Probiotics

2019 Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential

2020 Postbiotics: Metabolites and mechanisms involved in microbiota-host interactions

2020 Postbiotics against Pathogens Commonly Involved in Pediatric Infectious Diseases

2019 Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis

2019 Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice

2020 Live and heat-killed cells of Lactobacillus plantarum Zhang-LL ease symptoms of chronic ulcerative colitis induced by dextran sulfate sodium in rats

2019 Health Benefits of Heat-Killed (Tyndallized) Probiotics: An Overview

2020 New Horizons in Microbiota and Metabolic Health Research (not freely available)

Oat digestibility

A reader questioned one part of Oat species comparisons of the good stuff regarding Avena nuda hull digestibility. This 2019 study partially investigated that aspect:

“We investigated effects of proteins, lipids, and β-glucan in naked oat flour on in vitro digestibility of starch. Content of rapidly digested starch increased, and content of resistant starch decreased after removing non-starch constituents.

There are three categories of starch in accordance with the rate and degree of starch digestion, namely, rapidly digested starch, slowly digested starch, and resistant starch. Resistant starch cannot be digested. Instead, it promotes growth of beneficial colonic flora.

Digestibility of starch is influenced by size and shape of starch granules, food processing method, physical and chemical modifications, viscosity, and food matrix components. Physicochemical properties of naked oat starch and naked oat flour after removing non-starch constituents were compared to study relationships between starch digestibility and intrinsic factors:


Oats contain more proteins and lipids than other common grains. Proteins can effectively reduce starch digestibility by several mechanisms:

  • Proteins can form a protection around starch granules, restricting entry of enzymes into substrates.
  • Surface proteins can block catalytic binding of enzymes on starch granule exterior.
  • α-amylase can partially bind to proteins, reducing enzyme utilization.

By contrast, effects of lipids on starch digestibility is primarily due to forming complexes with amylose, which is better able to resist amylase.

β-glucan, particularly the extracted water-soluble fraction, can lower digestion rate of starch by increasing viscosity. β-glucan can create a complex of adjacent proteins to form a robust structure that resists amylase, resulting in a decrease in starch digestibility.”

https://www.sciencedirect.com/science/article/abs/pii/S0308814619310556 “Non-starch constituents influence the in vitro digestibility of naked oat (Avena nuda L.) starch” (not freely available)


When viewing the above graphic, keep in mind that its order wasn’t sequential. So “degreased” oat flour (lipids removed, DG-NOF) wasn’t included in “deproteinized” oat flour (DP-NOF).

This in vitro study missed an opportunity to investigate human-practical aspects. Nobody eats oats without preparing them with water. But effects on digestibility from minutes and hours of soaking, boiling, microwaving, etc. weren’t analyzed.

Gut microbiota outnumber human cells. Treat them well with both Avena nuda resistant oat starch and indigestible hulls, and expect reciprocity.