Gut microbiota and aging

January 16, 2021January 29, 2021 gettingwell4 4-5 stars Advanced knowledge, Brain development, Brainstem, Cerebrum, Dopamine, Epigenetics, Immune system, Lower brain, Memory, Neurochemicals, Serotonin, Stress Brain neurons, Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease

This 2020 review explored the title subject:

“The human body contains 10¹³ human cells and 10¹⁴ commensal microbiota. Gut microbiota play vital roles in human development, physiology, immunity, and nutrition.

Human lifespan was thought to be determined by the combined influence of genetic, epigenetic, and environmental factors including lifestyle-associated factors such as exercise or diet. The role of symbiotic microorganisms has been ignored.

Age-associated alterations in composition, diversity, and functional features of gut microbiota are closely correlated with an age-related decline in immune system functioning (immunosenescence) and low-grade chronic inflammation (inflammaging). Immunosenescence and inflammaging do not have a unidirectional relationship. They exist in a mutually maintained state where immunosenescence is induced by inflammaging and vice versa.

Immunosenescence changes result in both quantitative and qualitative modifications of specific cellular subpopulations such as T cells, macrophages and natural killer cells as opposed to a global deterioration of the immune system. Neutrophils and macrophages from aged hosts are less active with diminished phagocytosing capability.

Gut microbiota transform environmental signals and dietary molecules into signaling metabolites to communicate with different organs and tissues in the host, mediating inflammation. Gut microbiota modulations via dietary or probiotics are useful anti-inflammaging and immunosenescence interventions.

The presence of microbiomic clocks in the human body makes noninvasive, accurate lifespan prediction possible. Prior to occurrence of aging-related diseases [shown above], bidirectional interactions between the gut and extraenteric tissue will change.

Correction of accelerated aging-associated gut dysbiosis is beneficial, suggesting a link between aging and gut microbiota that provides a rationale for microbiota-targeted interventions against age-related diseases. However, it is still unclear whether gut microbiota alterations are the cause or consequence of aging, and when and how to modulate gut microbiota to have anti-aging effects remain to be determined.”

https://www.tandfonline.com/doi/abs/10.1080/10408398.2020.1867054 “Gut microbiota and aging” (not freely available; thanks to Dr. Zongxin Ling for providing a copy)

1. The “Stable phase” predecessor to this review’s subject deserved its own paper:

“After initial exposure and critical transitional windows within 3 years after birth, it is generally agreed that human gut microbiota develops into the typical adult structure and composition that is relatively stable in adults.

However, the Human Microbiome Project revealed that various factors such as food modernization, vaccines, antibiotics, and taking extreme hygiene measures will reduce human exposure to microbial symbionts and led to shrinkage of the core microbiome, while the reduction in microbiome biodiversity can compromise the human immune system and predispose individuals to several modern diseases.”

2. I looked for the ten germ-free references in the “How germ-free animals help elucidate the mechanisms” section of The gut microbiome: its role in brain health in this review, but didn’t find them cited. Likewise, the five germ-free references in this review weren’t cited in that paper. Good to see a variety of relevant research.

There were a few overlapping research groups with this review’s “Gut-brain axis aging” section, although it covered only AD and PD research.

3. Inflammaging is well-documented, but is chronic inflammation a condition of chronological age?

A twenty-something today who ate highly-processed food all their life could have gut microbiota roughly equivalent to their great-great grandparents’ at advanced ages. Except their ancestors’ conditions may have been byproducts of “an unintended consequence of both developmental programmes and maintenance programmes.”

Would gut microbiota be a measure of such a twenty-something’s biological age? Do we wait until they’re 60, and explain their conditions by demographics? What could they do to reset themself back to a chronological-age-appropriate phenotype?

The future of your brain is in your gut right now

January 12, 2021May 30, 2021 gettingwell4 5+ stars Premium, Acetylcholine, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Serotonin, Stress Antidepressants, Control group, Critical period, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease, Psychotropic medication, Reciprocity, Unconscious feelings, Unconscious memories

A 2020 paper by the author of Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease:

“The gut and brain communicate bidirectionally via several pathways which include:

Neural via the vagus nerve;

Endocrine via the HPA axis;

Neurotransmitters, some of which are synthesized by microbes;

Immune via cytokines; and

Metabolic via microbially generated short-chain fatty acids.

How does nature maintain the gut-microbiome-brain axis? Mechanisms to maintain homeostasis of intestinal epithelial cells and their underlying cells are a key consideration.

The symbiotic relationship that exists between microbiota and the human host is evident when considering nutrient requirements of each. The host provides food for microbes, which consume that food to produce metabolites necessary for health of the host.

Consider function of the human nervous system, not in isolation but in integration with the gastrointestinal ecosystem of the host, in expectation of a favorable impact on human health and behavior.”

https://www.sciencedirect.com/science/article/pii/B9780128205938000148 “Chapter 14 – The gut microbiome: its role in brain health” (not freely available)

Always more questions:

What did you put into your gut today?
What type of internal environment did it support?
What “favorable impact on human health and behavior” do you expect from today’s intake?
How will you feel?
Will you let evidence guide feeding your gut environment?

See Harnessing endogenous defenses with broccoli sprouts for further elaboration. See Switch on your Nrf2 signaling pathway for an interview with these papers’ author.

How will you feel?

January 8, 2021January 9, 2021 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Beliefs, Brain development, Cerebrum, Hippocampus, Hypothalamus, Immune system, Lower brain, Memory, Neurochemicals, Oxytocin, Serotonin, Stress Antidepressants, Brain neurons, Control group, Embryo development, Genetic factors, Neural plasticity, Psychotropic medication

Consider this a partial repost of Moral Fiber:

“We are all self-reproducing bioreactors. We provide an environment for trillions of microbes, most of which cannot survive for long without the food, shelter and a place to breed that we provide.

They inhabit us so thoroughly that not a single tissue in our body is sterile. Our microbiome affects our development, character, mood and health, and we affect it via our diet, medications and mood states.

The microbiome:

Affects our thinking and our mood;

Influences how we develop;

Molds our personalities;

Our sociability;

Our responses to fear and pain;

Our proneness to brain disease; and

May be as or more important in these respects than our genetic makeup.

Dysbiosis has become prevalent due to removal of prebiotic fibers from today’s ultra-processed foods. I believe that dietary shift has created a generation of humans less able to sustain or receive love.

They suffer from reduced motivation and lower impulse control. They are more anxious, more depressed, more selfish, more polarized, and therefore more susceptible to the corrosive politics of identity.“

Other recent blog posts by Dr. Paul Clayton and team include Skin in The Game and Kenosha Kids.

Image from Thomas Cole : The Consummation, The Course of the Empire (1836) Canvas Gallery Wrapped Giclee Wall Art Print (D4060)

Part 2 of Switch on your Nrf2 signaling pathway

January 3, 2021November 27, 2021 gettingwell4 5+ stars Premium, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, DNA methylation, Genetic factors

To follow up topics of Part 1‘s interview:

1. “We each have a unique microbial signature in the gut. Metabolites that you produce might not be the same ones that I produce. This makes clinical studies very difficult because you don’t have a level playing field.”

This description of inter-individual variability could inform researchers’ investigations prior to receiving experimental results such as:

Part 2 of Eat broccoli sprouts for DIM finding that 10 people eating 200 μmol glucobrassicin produced responses thousands of percent different for the highest and lowest individuals;
Microwave broccoli seeds to create sulforaphane finding that 10 people ingesting a 200 μmol sulforaphane dose produced sulforaphane and its metabolites in blood plasma for the highest and lowest individuals that were > 500% (2.032 / 0.359 μmol) apart;
Does sulforaphane reach the colon? finding that of 11 people ingesting a 102 μmol sulforaphane dose, 1 had no response, and responses of 2 were more than ten times greater than 2 others; and
Rub some broccoli sprouts on it finding that of 7 people receiving a topical 5 nM sulforaphane dose, 2 had no response at all.

Post-experimental analysis with statistical packages of these types of results is required. But it doesn’t produce meaningful explanations for such individual effects.

Analysis of individual differences in metabolism can better inform explanations, because it would investigate causes for widely-variable effects. Better predictive hypotheses could be a result.

2. Today I’m starting my 40^th week of eating a clinically-relevant amount of microwaved 3-day-old broccoli sprouts every day. To encourage sulforaphane’s main effect of Nrf2 signaling pathway activation, I won’t combine broccoli sprouts with anything else either during or an hour before or after.

I had been taking supplements at the same time. This interview got me thinking about the 616,645 possible combinations of my 19 supplements and broccoli sprouts.

That’s way too many to be adequately investigated by humans. Especially because contexts for each combination’s synergistic, antagonistic, or additive activities may be influenced by other combinations’ results.

I’ll just eat food and take supplements outside of this sulforaphane window.

I’ve taken 750 mg fructo-oligosaccharides (FOS) twice a day for sixteen years. I’ve considered it as my only prebiotic. Hadn’t thought of either of these points:

“Polyphenols are now considered to be a prebiotic food for microflora in the gut. They tend to focus on producing additional amounts of lesser known species like Akkermansia muciniphila, and have a direct prebiotic effect. Microbiota break these big, bulky molecules down into smaller metabolites, which clearly are absorbed. Some beneficial effects that come from polyphenols are not from the original molecule itself, but from a variety of metabolites produced in the gut.

We use a prebiotic, actually called an immunobiotic, which is a dead lactobacillus plantarum cell optimised for its cell wall content of lipoteichoic acid. Lipoteichoic acid attaches to toll-like receptor 2, and that sets off a whole host of immune-modulating processes, which tend to enhance infection control and downregulate inflammation and downregulate allergenicity.”

3. “Quinone reductase is critical because it is the final enzyme in the phase two detox pathway that stops DNA being mutated or prevents deformation of DNA adducts which are mutagenic. I want to look at genes that govern redox balance, inflammation, detoxification processes, cellular energetics, and methylation.”

Gene functional group classifications are apparently required in studies, to accompany meaningless statistics. When I’ve read papers attaching significance to gene functional groups, it often seemed like hypothesis-seeking efforts to overcome limited findings.

I’ll start looking closer when study findings include Nrf2 signaling pathway targets quinone reductase, DNA damage marker 8-hydroxydeoxyguanosine, and enzymes glutathione peroxidase and glutathione S-transferase.

4. I bolded “unregulated inflammation” in Part 1 because it’s a phrase I’d ask to be defined if that site enabled comments. Thinking on inflammation seems to come from:

“We focus on the intestinal epithelial cell as a key player because if you enhance function of that cell, and Nrf2 is part of that story, once you get those cells working as they should, they are modulating this whole underlying immune network.”

An environmental signaling paradigm of aging and Reevaluate findings in another paradigm have a different focus. That paradigm looks at inflammation in the context of aging:

“A link between inflammation and aging is the finding that inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that reduces production of gonadotropin-releasing hormone (GnRH) by neurons.

The case is particularly interesting when we realize that the aging phenotype can only be maintained by continuous activation of NF-κB. So here we have a multi-level interaction:

Activation of NF-κB leads to

Cellular aging, leading to

Diminished production of GnRH, which then

Acts (through cells with a receptor for it, or indirectly as a result of changes to GnRH-receptor-possessing cells) to decrease lifespan.

Cell energetics is not the solution, and will never lead to a solution because it makes the assumption that cells age. Cells take on the age-phenotype the body gives them.

Aging is not a defect – it’s a programmed progressive process, a continuation of development with the body doing more to kill itself with advancing years. Progressive life-states where each succeeding life-stage has a higher mortality (there are rare exceptions).

Cellular aging is externally controlled (cell non-autonomous). None of those remedies that slow ‘cell aging’ (basically all anti-aging medicines) can significantly extend anything but old age.

For change at the epigenomic/cellular level to travel up the biological hierarchy from cells to organ systems seems to take time. But the process can be repeated indefinitely (so far as we know).”

Switch on your Nrf2 signaling pathway

January 1, 2021January 13, 2021 gettingwell4 5+ stars Premium, Epigenetics, Immune system, Memory, Stress DNA methylation, Genetic factors

An informative interview to start this year with the author of Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease:

The Antioxidant Dilemma with Dr. Christine Houghton

“The thing about science is, the more you know, the more you realise you don’t know. And I have this enormous respect now for signalling processes that are going on within the cell, and not just signalling. The way mother nature switches on, switches off, foot on brake, foot on accelerator, continuously all of the time.

Things have changed in understanding the function of Nrf2 for a start, in controlling in many ways those cellular defences. We could then switch on Nrf2. You switch on a whole host of protective molecules all at the same time.

We use NAC [N-acetyl-cysteine] in the lab all the time because it stops an Nrf2 activation. So, that weak pro-oxidant signal that you use to activate 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 real advantage of sulforaphane is not only is it the most potent inducer of Nrf2, or activator, but it’s also highly bioavailable. It’s a very tiny, low-molecular weight, lipophilic molecule that just glides straight in through cell membranes. It’s about 80% bioavailable. Whereas big, bulky polyphenols are about 1% bioavailable just simply because of their chemical structure.

We focus on the intestinal epithelial cell as a key player because if you enhance function of that cell, and Nrf2 is part of that story, once you get those cells working as they should, they are modulating this whole underlying immune network.

I’m particularly interested in looking at core upstream factors that govern cellular defences. So, I want to look at genes that govern redox balance, inflammation, detoxification processes, cellular energetics, and methylation.

Intestinal epithelial, just like any other cell in the body, will respond to Nrf2 activation. It will respond to NF-κB downregulation. That’s going to enhance redox control. It’s going to reduce unregulated inflammation. It’s going to enhance detoxification processes. It’ll increase glutathione synthesis.

All of those core factors that any cell needs to work normally will be enhanced by activating Nrf2. And I use a high-yielding sulforaphane supplement of about 20 milligrams a day to do that. So, that’s the beginning.

Probiotics don’t typically colonise in an adult. That’s where we come back to this idea of restoring the gut ecosystem and using prebiotic foods.

In an ideal world, we’d be looking at 600 to 800 grams of non-starchy plant foods a day. In a real world, that isn’t always going to happen.

I never use the term leaky gut because it isn’t that. It’s a dynamic structure that becomes unresponsive.”

Hadn’t thought about weighing my daily AGE-less Chicken Vegetable Soup dinner (half) then tomorrow for lunch. Its total weight tonight was 2,575.5 grams.

Subtract 207.2 g wine, 985.6 g chicken broth, and 64.2 g noodles;
Add 131 g 3-day-old broccoli sprouts microwaved to ≤ 60°C (140°F) eaten earlier;
Subtract an estimated 170 g (6 oz.) chicken, didn’t measure juice squeezed from one lemon, didn’t estimate evaporation from 20 minutes cooking; and
Didn’t include either 81 g dry weight steel-cut oats which becomes 308 g for breakfast, or 103.8 g 3-day-old hulled oat sprouts.
Net 1,279.5 grams non-starchy plant foods

I’m doing alright by the “600 to 800 grams of non-starchy plant foods a day” guideline. Should exercise more, though, because I eat a lot.

Topics continued in Part 2.

Part 2 of Eat broccoli sprouts for DIM

December 30, 2020July 6, 2021 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress, Testosterone Control group

Continuing Part 1 with three DIM studies, the first of which was a 2020 chemical analysis investigating:

“Anti-estrogenic, anti-androgenic, and aryl hydrocarbon receptor (AhR) agonistic activities of indole-3-carbinol (I3C) acid condensation products.

I3C is a breakdown product [isothiocyanate] of glucobrassicin. Most biological activities attributed to I3C are believed to result from its acid condensation products, as it is expected that after ingestion of cruciferous vegetables, I3C is completely converted in the stomach before it reaches the intestine.

The reaction mixture was prepared from I3C under acidic conditions. Based on the various HPLC peaks, 9 fractions were collected and tested.

DIM (3,3-diindolylmethane) displayed clear estrogenic activity, showing an additive effect when co-exposed with low concentrations of E2 [estradiol] (below EC₅₀) [effective concentration that gives half-maximal-response of a biological pathway]. However, an anti-estrogenic activity was observed when DIM was co-exposed with higher concentrations of E2, i.e. above EC₅₀. None of the nine fractions was able to inhibit response of E2.

I3C and DIM showed clear anti-androgenic activities when co-exposed with concentrations of T [testosterone] at EC₅₀ or EC_max. DIM showed a relatively strong antagonistic activity, and was able to completely inhibit response of T.

All fractions displayed an AhR agonist activity. Poor activity of fraction 3 seems surprising, as it contains ICZ, which was shown to be a strong AhR agonist. This is a strong indication that ICZ is only present at a very low concentration.

Observed estrogenic and anti-androgenic effects of the reaction mixture are most likely due to DIM.

The present study is the first that demonstrates that DIM also possesses anti-estrogenic properties when co-administered with E2 concentrations above EC₅₀. Rather than ICZ, LTr₁ and several other compounds present in fractions 1 and 4 (CTr), and larger molecules present in fractions 7, 8 (LTe₁) and 9 seem responsible for observed AhR activity of the reaction mixture.”

https://www.sciencedirect.com/science/article/pii/S1878535220302811 “Acid condensation products of indole-3-carbinol and their in-vitro (anti)estrogenic, (anti)androgenic and aryl hydrocarbon receptor activities”

I came across this study as a result of its citation in Brassica Bioactives Could Ameliorate the Chronic Inflammatory Condition of Endometriosis.

A second 2016 study was with humans:

“Forty-five subjects consumed vegetables, a mixture of brussels sprouts and/or cabbage, at one of seven discrete dose levels of glucobrassicin ranging from 25 to 500 μmol, once daily for 2 consecutive days.

‘Blue Dynasty’ cabbage contained 33.5 ± 4.0 μmol glucobrassicin per 100 grams food weight. ‘Jade Cross’ brussels sprouts contained 206.0 ± 12.9 μmol per 100 grams.

At 50 μmol, variability in 24-hour urinary DIM levels appears to stem from both within an individual and between individuals. At 200 and 500 μmol dose levels, most variability is coming from between individuals rather than within an individual.

Inter-individual DIM variability may reflect the relative benefit an individual derives from consuming glucobrassicin from vegetables, responsive not only to how much glucobrassicin was consumed but also to variations in I3C uptake and DIM metabolism, many of which are not characterized.

Dose curve between glucobrassicin dose (25–500 μmol) [25, 50, 100, 200, 300, 400, 500] and urinary DIM. Bars represent SD. Estimated parameters in the original scale (95% CI): Maximum DIM 421.5 pmol/mL (154.7–1,148.4), minimum DIM 5.4 pmol/mL (0.7–44.3), EC₅₀ 90.2 μmol (29.1–151.3).

We conclude that urinary DIM is a reliable biomarker of glucobrassicin exposure and I3C uptake and that feeding glucobrassicin beyond 200 μmol did not consistently lead to more urinary DIM. Our data support the notion that cancer-preventive properties that might be derived from cruciferous vegetable consumption may require neither a large quantity of vegetables nor high-dose supplements.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220883/ “Harnessing the Power of Cruciferous Vegetables: Developing a Biomarker for Brassica Vegetable Consumption Using Urinary 3,3′-Diindolylmethane”

1. Most subjects had trouble eating 500 μmol / 242.72 grams of Jade Cross brussels sprouts:

“At the 500 μmol dose level, two subjects could not finish due to the taste of the raw Brussels sprouts and were reassigned to 50 μmol dose level.

Two of the remaining five subjects at the 500 μmol dose level “Did not eat all of the assigned vegetables.” 🙂 That amount of brussels sprouts may have made two more sick because one “Missed one void during 2–6 hour collection period” and another “Missed 2 voids during the 6–12 hour collection period.”

2. From its supplementary material, there were ten subjects who ate a 200 μmol glucobrassicin dose. That’s a lot of raw cabbage (179.10 g) and brussels sprouts (67.96 g).

On Day 1 at the 2-6 hour point, Subject 27’s urinary DIM measured 10.21 pmol/mL and Subject 20’s measured 991.88, > 9700% higher.
At that 2-6 hour point on Day 2, the same subjects measured 16.15 and 687.44 pmol/mL, > 4200% higher.
From Table 1, their respective Mean 24-h DIM ± SE, pmol/mL measurements were 20.7 ± 4.0 and 1105 ± 45, > 5300% higher.

The 100 μmol glucobrassicin dose was 149.25 g Blue Dynasty cabbage and 24.27 g Jade Cross brussels sprouts. Could you eat that every day?

3. There’s sufficient data to make individual DIM bioavailability calculations. Don’t know why this study didn’t do that, nor did any of its 18 citing papers.

One study came close for broccoli and radish sprouts, 2017’s Bioavailability and new biomarkers of cruciferous sprouts consumption (not freely available) by researchers in the same group as Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts. They didn’t disclose and analyze individual DIM bioavailability evidence, though:

“Broccoli and radish sprouts content in GB [glucobrassicin] were ~11.4 and ~7.7 μmol/20 g F.W, respectively. After ingestion of broccoli sprouts, 49% of GB was suitably metabolised and excreted as hydrolysis metabolites, calculated as the sum of I3C and DIM (~5.57 μmol /24 h). Following radish ingestion, the percentage of GB hydrolysed and absorbed was 38% (~2.92 μmol /24 h).

These results of bioavailability contrast with the extremely low percentage (< 1%) of GB excreted as DIM after consumption of Brussels sprouts and cabbage in a previous study (Fujioka, et al., 2014). Further studies about conversion of other indole GLS [glucosinolates] to I3C and DIM are needed to know more about bioavailability of these compounds, as there is no information in literature.”

A ten-subject study in Microwave broccoli seeds to create sulforaphane found inter-individual variability of sulforaphane and its metabolites in blood plasma for the highest and lowest individuals was > 500% (2.032 / 0.359 μmol). The urinary % of dose excreted by the same subjects was > 400% higher (86.9% and 19.5%, respectively.)

These studies present an opportunity for further discovery:

Which researchers will try to understand causal experiences in people’s lives that produced such effects?
Which researchers will produce evidence for factors that make people responsively either alive or dead to external influences on their internal environment?
Where are studies that show when an individual needs to change their responses – their phenotype – they can successfully do so?

Herding, the story of 2020

A case for carnitine supplementation

December 27, 2020December 27, 2020 gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Immune system, Memory, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Inherited disease, Neural plasticity

This 2020 review subject was carnitine, acetyl-L-carnitine, and its other molecular forms:

“Carnitine is necessary to deliver long-chain fatty acids from cytosol into mitochondria. Carnitine homeostasis is maintained by diet and renal absorption, as only a small amount (about 25%) is obtained by endogenous biosynthesis.

Defective fatty acid oxidation occurs with reduced intracellular levels of carnitine, leading to glucose consumption instead of lipid consumption, resulting in hypoglycemia. Non-metabolized lipids accumulate in tissues such as heart, skeletal muscle, and liver, resulting in myopathy and hepatic steatosis.

2000 mg/day is unlikely to provoke unwanted side effects and is safe for humans. In-depth studies are needed to identify a unique method of analysis which can guarantee efficient monitoring of supplement active component amounts.”

https://www.mdpi.com/1420-3049/25/9/2127/htm “The Nutraceutical Value of Carnitine and Its Use in Dietary Supplements”

The review listed animal studies of L-carnitine alone and in combination with:

Vitamin D3;
Coenzyme Q₁₀;
Nicotinamide riboside;
Selenium;
L-arginine;
Anti-histamine drugs cetirizine hydrochloride and chlorpheniramine maleate; and
Hypertension drug olmesartan.

Human studies of its effects included:

Muscle soreness, damage biomarkers, and cramps;
Osteoarthritis knee pain and inflammation markers;
Ischemic cerebrovascular injury;
Peripheral neuropathy;
Nonalcoholic fatty liver disease;
Insulin resistance and Type 2 diabetes;
Kidney diseases;
Inherited diseases phenylketonuria and maple syrup urine;
Stress, depression, and anxiety;
Male infertility; and
Hepatitis C.

Week 37 of Changing to a youthful phenotype with broccoli sprouts

December 20, 2020March 19, 2021 gettingwell4 4-5 stars Advanced knowledge, Beliefs, Cerebrum, Cortisol, Dopamine, Glutamate, Limbic system, Lower brain, Memory, Neurochemicals, Primal Therapy, Stress Conscious awareness, Control group, Genetic factors, Happiness, Levels of consciousness, Neurodegenerative disease, Unconscious feelings, Unconscious memories

1. Been wrong about a few things this past week:

A. I thought in Week 28 that extrapolating A rejuvenation therapy and sulforaphane results to humans would produce personal results by this week. An 8-day rat treatment period ≈ 258 human days, and 258 / 7 ≈ 37 weeks.

There are just too many unknowns to say why that didn’t happen. So I’ll patiently continue eating a clinically relevant 65.5 gram dose of microwaved broccoli sprouts twice every day.

The study’s lead researcher answered:

“Depends, it might take 37 weeks or more for some aspects of ‘youthening’ to become obvious. It might even take years for others.

Who really cares if you are growing younger every day?

For change at the epigenomic/cellular level to travel up the biological hierarchy from cells to organ systems seems to take time. But the process can be repeated indefinitely (so far as we know) so by the second rejuvenation you’re already starting at ‘young’. (That would be every eight to ten years I believe.)”

His framework is in An environmental signaling paradigm of aging.

B. I thought that adding 2% mustard seed powder to microwaved broccoli sprouts per Does sulforaphane reach the colon? would work. Maybe it would, maybe it wouldn’t, but my stomach and gut said that wasn’t for me.

C. I thought I could easily add Sprouting whole oats to my routine. I ran another trial Sprouting hulled oats using oat seeds from a different company and Degree of oat sprouting as a model.

2. Oat sprouts analysis paired studies were very informative, don’t you think? One study produced evidence over 18 germination-parameter combinations (hulled / dehulled seeds of two varieties, for 1-to-9 days, at 12-to-20°C).

Those researchers evaluated what mix of germination parameters would simultaneously maximize four parameters (β-glucan, free phenolic compounds, protease activity, and antioxidant capacity) while minimizing two (enzymes α-amylase and lipase). Then they followed with a study that characterized oat seeds sprouted under these optimal conditions.

I doubted PubMed’s “oat sprout” 20 search results for research 1977 to the present. Don’t know why they didn’t pick up both of these 2020 studies, but I’m sure that .gov obvious hindrances to obtaining relevant information like this won’t be fixed. What other search terms won’t return adequate PubMed results?

3. The blog post readers viewed this week that I made even better was Do delusions have therapeutic value? from May 2019. Sometimes I’ve done good posts describing why papers are poorly researched.

4. I’ve often changed my Week 4 recipe for an AGE-less Chicken Vegetable Soup dinner (half) then the next day for lunch. The biggest change brought about by 33 weeks of behavioral contagion is that I now care more about whether vegetables are available than whether or not they’re organic. Coincidentally, I’ve developed a Costco addiction that may require intervention.

1/2 lemon
4 Roma tomatoes
4 large carrots
6 stalks organic celery
6 mushrooms
6 cloves garlic
6 oz. organic chicken breast fillet
1 yellow squash, alternated with 1 zucchini
1 cup sauvignon blanc
32 oz. “unsalted” chicken broth, which still contains 24% of the sodium RDA

Pour wine into a 6-quart Instant Pot; cut and strain squeezed lemon; cut chicken into 1/4″ cubes and add; start mixture on Sauté. Wash and cut celery and stir in. Wash and cut carrots and stir in.

When pot boils around 8 minutes, add chicken broth and stir. Wash mushrooms, slicing into spoon sizes.

Wash and slice yellow squash / zucchini. Crush and peel garlic, tear but don’t slice. Turn off pot when it boils again around 15 minutes.

Wait 2-3 minutes for boiling to subside, then add yellow squash / zucchini, mushrooms, garlic, whole tomatoes. Let set for 20 minutes; stir bottom-to-top 5 and 15 minutes after turning off, and again before serving.

AGE-less Chicken Vegetable Soup is tasty enough to not need seasoning.

An oats β-glucan clinical trial

December 13, 2020March 27, 2021 gettingwell4 5+ stars Premium, Epigenetics, Immune system, Memory, Stress Control group

This 2020 human study investigated effects of processing β-glucan:

“Nutritional advantages of oats compared to many other grains include gluten-free nature, high content of polyunsaturated fatty acids, protein composition which complements that of pulses, and substantiated health effects of fibers, specifically oat β-glucan. Novel oat products, which are often semi-solid or liquid, generally need alterations of the physicochemical properties of oats.

The hypothesis in this study [Clinical trial NCT02764931] was that bioprocessing of oat bran with enzyme treatment, causing depolymerization of β-glucan, affects nutritional properties of bran and functional properties of β-glucan in human gastrointestinal tract.

The study meal consisted of oat bran concentrate treated with a commercial food-grade cell wall degrading enzyme preparation at 1 or 50 nkat β-glucanase g^-1 dm^-1. A control sample was prepared in the same way without added enzymes. Average MW [molecular weight] of β-glucan in:

Control oat bran concentrate was >1000 kDa [weight in kilodaltons] (High MW);

1 nkat g^-1 dm^-1-treated 524 kDa (Medium MW); and

50 nkat g^-1 dm^-1-treated 82 kDa (Low MW).

Results of this study supported the hypothesis that alteration of oat β-glucan MW with enzymatic treatment affects nutritional properties of oat bran and functional properties of β-glucan in the human gastrointestinal tract:

A High MW β-glucan meal resulted in the highest excretion of fecal bile acids, and the lowest excretion of phenolic compounds in urine.

A Low MW β-glucan meal resulted in the lowest excretion of fecal bile acids, but the highest excretion of phenolic compounds, especially ferulic acid, in urine.

Medium MW β-glucan was similar to High MW β-glucan in that it resulted in high excretion of fecal bile acids and low excretion of phenolic compounds to urine, but mean pressure in the duodenum was closer to Low MW than to High MW meal.

Perceived gut well-being after consumption of each meal did not differ between meals, but varied between genders, which should be further investigated.”

https://www.sciencedirect.com/science/article/abs/pii/S0308814620320811 “Effect of oat β-glucan of different molecular weights on fecal bile acids, urine metabolites and pressure in the digestive tract – A human cross over trial” (not freely available)

I eat 81 grams of steel-cut oats every morning, which is represented by this study’s high-molecular-weight control. Take responsibility for your one precious life.

No β-glucan for dolphins or seagulls

Part 2 of The transgenerational impact of Roundup exposure

December 11, 2020December 13, 2020 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Stress Control group, DNA methylation, Embryo development, Inherited disease

This 2020 study followed up The transgenerational impact of Roundup exposure using the Washington State Unversity research group’s most recent methodology in DEET and permethrin cause transgenerational diseases:

“The herbicide glyphosate has been shown to promote epigenetic transgenerational inheritance of pathology and disease in subsequent great-grand offspring (F₃ generation). The current study was designed to identify epigenetic biomarkers for glyphosate-induced transgenerational diseases using an epigenome-wide association study.

Pathologies investigated included prostate disease [13 of 44 subjects], kidney disease [11 of 44], obesity [19 of 45], and presence of multiple disease [10 of 45]. Sperm were collected from F₃ glyphosate lineage males and used to identify specific differential DNA methylation regions (DMRs) and differential histone retention sites (DHRs).

The number of DHRs were less than the number of DMRs, and DHRs were found to have disease specificity. The combination of DMRs and DHRs is anticipated to facilitate pathology diagnosis.

Low sample number is a limitation in the current analysis. Potential higher variability in data needs to be considered.

This is one of the first observations of DHRs as potential biomarkers for disease. The current study used glyphosate induction of transgenerational disease as a proof of concept such environmental biomarkers can be identified and potentially used as diagnostics for disease susceptibility in the future.”

https://www.tandfonline.com/doi/full/10.1080/15592294.2020.1853319 “Epigenome-wide association study for glyphosate induced transgenerational sperm DNA methylation and histone retention epigenetic biomarkers for disease”

Reverberations, harmonics, history

December 10, 2020December 10, 2020 gettingwell4 2-3 stars Required further work, Beliefs, Memory Reputations

Catching up with Martin Armstrong from 2012:

“Corruption within the Roman Republic was certainly at its peak during the first century BC. There was a brewing debt crisis in Rome and the oligarchy was determined to keep power at any cost. Corruption was so widespread that interest rates doubled from 4% to 8% for the elections of 54 BC because there was so much bribery going on to gain votes.

Caesar was clearly a Popularis, a man of the people who stood against the corruption of the Republic. Like today, we have no real voting control over the fate of the nation. Those who are in charge of the political machine control the real political state.

Caesar knew who his enemies truly were. He clung to his belief that if the majority of the Senate were free of the Oligarchy of Cato and Cicero, they would surely see the light. To persuade them, Caesar wrote his seven books on his truly remarkable conquest of Gaul.

Cato and his Oligarchy were so intensely anti-Caesar that they were willing to do anything to anybody. But this was a moment in time where the corruption had simply gone too far.

By September 29th, 51 BC, Caesar ran out of civilized options. Crossing the Rubicon became the only option.

Janus was the symbol of a cyclical change, the departing of one era and the birth of another. His shrine consisted of two doorways that traditionally were left open in time of war and kept closed when Rome was at peace. Leaving the doors open in time of war symbolized the new era that was possible.

Property values were collapsing. Debts were excessive. Those who held mortgages refused to accept just the property back.

Caesar dealt with this major extraordinary situation in a truly astonishing manner, realizing that assets and money are in a union of opposing forces, yet bound together. Value of property is not a constant relationship for money itself is not like a ruler.

Money is more akin to a rubber band even when it may be gold or silver. Money is like everything else – subject to the whims of supply and demand.

The economy is a dynamic relationship between everything with no real constant. We are at a tremendous disadvantage because we have grown up thinking in a flat linear world that does not exist. We limit ourselves by thinking in money,

Caesar explained that he had to borrow to fund the war and it was unethical for him to cancel all debts since he himself would benefit. Generals come and go, but true economic reformers of the state to save the nation are rare indeed. Caesar paid for his economic reform with his life.

There can be no greater example of political corruption that required desperate reform than the calendar. Caesar replaced the typical lunar year and introduced his new calendar based on 365¼ solar days on January 1st, 45 BC.

Sulla [138 – 78 BC] was a highly original, gifted and skillful general, never losing a battle. His rival described Sulla as having the cunning of a fox and the courage of a lion – but that it was the former attribute that was by far the most dangerous. This mixture was later referred to by Machiavelli in his description of the ideal characteristics of a ruler.

Sulla was more interested in retaining institutes of government while eliminating people occupying them whereas Caesar was far more compelled to act to restore institutions and to spare people, even his more threatening enemies. These are not actions of a man interested in personal power, but a man interested in saving his country.

You live in an oligarchy no different today than what Caesar faced back then. One maxim always holds true; Absolute power, corrupts absolutely!”

It appears that only Julius Caeser ever understood

100-44 BC

A normal distribution

Eat oats today!

December 6, 2020December 6, 2020 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress Brain neurons, Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

This 2020 food chemistry review provided phenolic-compound reasons to eat oats:

“Phenolamides result from the conjugation of hydroxycinnamic acids with amines. These products contain a variety of metabolic, chemical, and functional capabilities due to the large number of possible combinations among the parent compounds.

Of the currently known phenolamides, the most common are avenanthramides (AVAs), which are unique in oats. AVAs possess anti-inflammatory, anti-itch, anti-atherosclerosis, antioxidant, anti-cancer, anti-obesity, anti-fungal, anti-microbial, and neuroprotective properties.

Twenty-nine C-type AVAs have been identified in oats, and twenty-six A-type AVAs.

C-type AVAs in commercially available oat products range from 36.49-61.77 mg/kg (fresh weight).

A-type AVAs represent approximately 22.5% of total AVA levels in regular oats and 24.7-33.0% in commercial sprouted oats.

Steeping raw groats increased AVA concentrations.”

These reviews were referenced:

“Since publication of these two reviews, a few new studies reported AVAs’ beneficial health effects, mainly related to their anti-inflammatory and anti-cancer activities. AVAs can:

Significantly decrease IL-6, IL-8, and MCP-1 in endothelial cells;

Inhibit IL-1β- and TNF-α-induced NF-κB activation; as well as

Expression of adhesion molecules; and

Adhesion of monocytes to endothelial cell monolayer.

In 2020, the first evaluation of anti-inflammation effects of A-type AVAs was published from our own group. Fifteen A-type AVAs from commercial sprouted oat products interacted with lipopolysaccharide-induced nitric oxide production and iNOS expression.

Colloidal oatmeal’s natural components, AVAs, help to restore and maintain skin barrier function. AVAs are safe, well tolerated, and can be effective as adjuvant treatment in atopic dermatitis.

In one mouse model, a C-type AVA was able to mitigate many adverse effects of Alzheimer’s Disease. It restored hippocampal long-term potentiation and synaptic function, enhanced memory function, suppressed pro-inflammatory cytokines TNF-α and IL-6 levels, reduced caspase-3 levels, and increased pS9GSK-3β and IL-10 levels.

AVAs downregulated expression of hTERT and MDR1, pro-survival genes for cancer cells, and COX-2 mRNA and PGE2 levels, known pro-inflammatory markers. AVAs induced apoptosis by activating caspases 8, 3, and 2.”

https://pubs.acs.org/doi/10.1021/acs.jafc.0c02605 “The Chemistry and Health Benefits of Dietary Phenolamides” (not freely available)

Hadn’t thought about sprouting oats before this paper.

Clearing out the 2020 queue of interesting papers

December 1, 2020December 1, 2020 gettingwell4 2-3 stars Required further work, Acetylcholine, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Serotonin, Stress Antidepressants, Brain neurons, Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Infants, Inherited disease, Neural plasticity, Neurodegenerative disease, Prefrontal cortex, Psychotropic medication

I’ve partially read these 39 studies and reviews, but haven’t taken time to curate them.

Early Life

Epigenetic clocks

Epigenetics

Aging

Broccoli sprouts

Does reprogramming signaling pathways create memories?

November 29, 2020February 10, 2023 gettingwell4 0-1 star Wasted resources, Epigenetics, Immune system, Memory, Stress

This 2020 study investigated genes and signaling pathways for inflammatory memory:

“Fibroblast-like synoviocytes (FLS) play a critical role in pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment.

Sustained activated genes established pro-inflammatory signaling components known to act at multiple levels of NF-κB, STAT and AP-1 signaling cascades. Sustained repressed genes included critical mediators and targets of the BMP [bone morphogenic protein] signaling pathway.

We identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation.

FLS are synovial tissue-resident and specialized mesenchymal cells critical for homeostasis. Key features of these cells during homeostasis include the production of extracellular matrix components and providing nutrients to the synovial fluid. Healthy synovium is composed of multiple layers of FLS, which forms the synovial lining and sublining through cell–cell contacts.

Inflammatory and pro-resolving mediators are tightly regulated to maintain normal synovium functioning. However, in inflammatory and autoimmune diseases such as rheumatoid arthritis, an imbalance between these signals causes homeostasis disruption leading to synovial tissue damage, cartilage destruction and bone degeneration.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679373/ “Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory”

These researchers described a positive feedback loop that kept rheumatoid arthritis in place. No feedback diagram or explanation of what sustained a disease condition other than to say:

“Gene expression changes induced by short-term tumor necrosis factor-alpha (TNF-α) treatment were largely sustained in the FLS exposed to chronic inflammation.”

Okay – then what upstream signals sustained TNF-α? What would it take to interrupt that feedback loop? What initiated it?

Studies usually substantiate effects by also developing evidence for causes of opposite effects and of no effects. This study investigated neither reversibility nor no effect, and instead stated:

“Multiple signaling networks are irreversibly modified due to TNF-α-mediated long-term epigenetic and transcriptomic reprogramming. We speculate that sustained repression of BMP signaling may be critically required to ensure the persistently transformed phenotype of RA FLS.”

No evidence was offered for “irreversibly modified.” Anyway, that didn’t fit with:

“We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.”

Enduring epigenetic memories? Or continuous toxic stimulation? provided another perspective: “Enduring epigenetic effects may be symptoms rather than causes when toxic conditions persist.”

Been on a Steely Dan kick lately. Probably due to this year’s Royal Scam:

Zinc and broccoli sprouts – a winning combination

November 29, 2020August 7, 2021 gettingwell4 5+ stars Premium, Epigenetics, Immune system, Memory, Stress Control group

This 2019 study deserved better coverage than a one sentence mention in Reversal of aging and immunosenescent trends with sulforaphane:

“Obstructive sleep apnea syndrome is one of the most common breathing disorders in sleep, with a high prevalence of 3–7% and severe consequences. It is characterized by intermittent hypoxia (IH) due to recurrent episodes of partial or complete collapse of the upper airway during sleep, leading to blood hypoxemia, hypercapnia, sleep fragmentation, augmented respiratory efforts, and increased sympathetic activity.

Our study is the first investigation of the combination of BSE [broccoli sprout extract] and Zn [zinc] – Nrf2 and MT [metallothionein] inducers – to protect against IH-induced cardiomyopathy. By effectively activating Nrf2, its downstream targets, and MT, this combination can ameliorate defects associated with IH-induced cardiomyopathy more effectively than monotherapies.

Mice were administered with BSE (equivalent to SFN [sulforaphane] 2 mg/kg) and/or Zn sulfate heptahydrate (5 mg/kg) by gavage from 8 weeks of age at a frequency of once every other day for 8 weeks. Doses used in this study are safe to convert to human doses. [2 mg x .081 x 70 kg = 11 mg sulforaphane; 5 mg x .081 x 70 kg = 28 mg zinc]

Heart mass was significantly lower in the IH-BSE/Zn group than in IH and IH-BSE groups. Heart mass / tibia length ratio was significantly lower in the IH-BSE/Zn group than in IH and monotherapy groups.

Treatment with BSE and/or Zn can ameliorate myocardial fibrosis associated with IH, to a certain extent, and combination therapy had the best antifibrotic effect among treatments.

BSE or Zn can significantly ameliorate myocardial inflammation induced by IH, but the combination provided a better anti-inflammatory effect.

We used 3-NT as an indicator of the severity of oxidative stress. 3-NT protein levels were significantly reduced in IH mice for all treatment groups, and reduction was greater in the combination treatment group.

Combination was more effective than monotherapies to activate Nrf2-mediated antioxidant function.

In Zn-treated and combination treatment groups, MT protein expression was significantly higher than in the IH group, and there was only a slight increase in the IH-BSE group.”

Combination of Broccoli Sprout Extract and Zinc Provides Better Protection Against Intermittent Hypoxia-Induced Cardiomyopathy Than Monotherapy in Mice

One way to improve broccoli sprout compounds’ effects is to eat them with zinc. One way to improve zinc’s actions is to take it with broccoli sprouts.