Immune system

All about walnuts’ effects

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Telomeres , , , ,

Five 2022 papers focusing on walnuts, starting with a comparison of eight tree nuts:

“The aim of the present study was to examine 8 different popular nuts – pecan, pine, hazelnuts, pistachio, almonds, cashew, walnuts, and macadamia. Total content of phenolic compounds in nuts ranged from 5.9 (pistachio) to 432.9 (walnuts) mg/100 g.

Walnuts had the highest content of polymeric procyanidins, which are of great interest as important compounds in nutrition and biological activity, as they exhibit antioxidant, anti-inflammatory, antimicrobial, cardio- and neuroprotective action. Walnuts are good sources of fatty acids, especially omega-3 and omega-6.”

https://www.sciencedirect.com/science/article/pii/S2590157522002164 “Nuts as functional foods: Variation of nutritional and phytochemical profiles and their in vitro bioactive properties”

A second study compared the same eight tree nuts plus Brazil nuts and peanuts:

“The highest total content of all analyzed flavonoids was determined in walnuts (114.861 µg/g) with epicatechin the most abundant, while the lowest was in almonds (1.717 µg/g). Epicatechin has antioxidant, anti-inflammatory, antitumor, and anti-diabetic properties. Epicatechin has beneficial effects on the nervous system, enhances muscle performance, and improves cardiac function.”

https://www.mdpi.com/1420-3049/27/14/4326/htm “The Content of Phenolic Compounds and Mineral Elements in Edible Nuts”

Next, two systematic reviews and meta-analyses of human studies:

“We carried out a systematic review of cohort studies and randomized controlled trials (RCTs) investigating walnut consumption, compared with no or lower walnut consumption, including those with subjects from within the general population and those with existing health conditions, published from 2017 to 5 May 2021.

  • Evidence published since 2017 is consistent with previous research suggesting that walnut consumption improves lipid profiles and is associated with reduced CVD risk.
  • Evidence pointing to effects on blood pressure, inflammation, hemostatic markers, and glucose metabolism remains conflicting.
  • Evidence from human studies showing that walnut consumption may benefit cognitive health, which is needed to corroborate findings from animal studies, is now beginning to accumulate.”

https://academic.oup.com/nutritionreviews/advance-article/doi/10.1093/nutrit/nuac040/6651942 “Walnut consumption and health outcomes with public health relevance – a systematic review of cohort studies and randomized controlled trials published from 2017 to present”

“We aimed to perform a systematic review and meta-analysis of RCTs to thoroughly assess data concerning effects of walnut intake on selected markers of inflammation and metabolic syndrome in mature adults. Our findings showed that:

  • Walnut-enriched diets significantly decreased TG, TC, and LDL-C concentrations, while HDL-C levels were not significantly affected.
  • No significant changes were noticed on anthropometric, cardiometabolic, and glycemic indices after higher walnut consumption.
  • Inflammatory biomarkers did not record statistically significant results.”

https://www.mdpi.com/2076-3921/11/7/1412/htm “Walnut Intake Interventions Targeting Biomarkers of Metabolic Syndrome and Inflammation in Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials”

Finishing with a rodent study that gave subjects diabetes with a high-fat diet, then mixed two concentrations of walnut extract in with the treatment groups’ chow:

“This study was conducted to evaluate the protective effect of Gimcheon 1ho cultivar walnut (GC) on cerebral disorder by insulin resistance, oxidative stress, and inflammation in HFD-induced diabetic disorder mice. After HFD feed was supplied for 12 weeks, samples were orally ingested for 4 weeks to GC20 and GC50 groups (20 and 50 mg/kg of body weight, respectively).

  • Administration of GC improved mitochondrial membrane potential function, and suppressed oxidative stress in the brain.
  • GC inhibited hepatic and cerebral lipid peroxidation and the formation of serum AGEs, and increased serum antioxidant activity to improve HFD-induced oxidative stress.
  • The HFD group showed significant memory impairment in behavioral tests. On the other hand, administration of GC showed improvement in spatial learning and memory function.

walnut brain effects

Based on these physiological activities, GC showed protective effects against HFD-induced diabetic dysfunctions through complex and diverse pathways.”

https://www.mdpi.com/1420-3049/27/16/5316/htm “Walnut Prevents Cognitive Impairment by Regulating the Synaptic and Mitochondrial Dysfunction via JNK Signaling and Apoptosis Pathway in High-Fat Diet-Induced C57BL/6 Mice”

How do you like my sand art?PXL_20221016_154923750

Measuring epigenetic DNA causes

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This 2022 human cell study investigated DNA methylation and aging:

“Models based on DNA methylation can be used to predict the age of biological samples, but their interpretability is limited due to the lack of causal inferences. Neither existing epigenetic clocks nor DNA methylation changes are enriched in causal CpG sites. Causal CpGs include similar numbers of sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits.

One general approach for developing anti-aging interventions is to identify molecular changes during aging and use these changes as targets to modulate the aging process. A similar idea has also been applied to evaluate potential longevity interventions. However, this logic is intrinsically flawed, as correlation does not imply causation, and age-related changes are not necessarily causal to age-associated declines.

We developed a framework for integrating causal knowledge into epigenetic clock models and constructed DamAge and AdaptAge that measure age-related damaging and adaptive changes, respectively. DamAge acceleration is associated with various adverse conditions (e.g., mortality risk), whereas AdaptAge acceleration is related to beneficial adaptations.

causality clocks

We found that transcription factor (TF)-binding sites of BRD4 and CREB1 are enriched with CpG sites whose methylation levels promote healthy longevity, and TF-binding sites for HDAC1 are enriched with CpG sites whose methylation levels decrease healthy longevity.

  • BRD4 contributes to cell senescence and promotes inflammation, and higher DNA methylation at BRD4 binding sites may inhibit the downstream effects of BRD4 and promote healthy longevity.
  • CREB1 is related to type II diabetes and neurodegeneration, and mediates the effect of calorie restriction. Our data suggest that higher methylation at CREB1-binding sites may support its longevity effects.
  • HDAC1 is a histone deacetylase, and its activity increases with aging and may promote age-related phenotypes. Increased DNA methylation at HDAC1 binding sites may causally inhibit healthy longevity.

Our causality-informed clock models provide novel insights into the aging mechanisms and testing interventions that delay aging and reverse biological age.”

https://www.biorxiv.org/content/10.1101/2022.10.07.511382v1 “Causal Epigenetic Age Uncouples Damage and Adaptation”

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How to measure biological age?

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress, Telomeres ,

As mentioned in Week 127, I had biological age measured earlier this month, and received five reports two days ago on Sunday. Part of the company’s process is to follow up their reports (intrinsic aging, immune aging, pace of aging, telomere length, weight loss) with a consulting session to review and interpret, which lasted an hour yesterday.

Part of our conversation revolved around comparing my measurements with other customers. These people are a different population than people usually sampled for aging and other biomarkers, because people who pay to get their biological age measured probably actionably want to improve it.

We’ll see which items I asked the consultant to pass on to the company produce responses, and which interfere with their business or they’re too busy to get back to me. I offered more than a half-dozen specifics, but held back on items I didn’t think the consultant would adequately communicate.

I didn’t argue with the consultant’s recommendations for quercetin supplementation (at 4% bioavailability?) as part of a treatment for senescence (not measured in any of the reports?). I didn’t offer to follow-up with studies demonstrating yeast cell wall β-glucan (new to the consultant) effects on immune report findings here in my 19th year of taking it every day.

I did argue with their recommendation to take DHEA-S. I changed my mind about taking it a year and a half ago, but left blog posts up such as Take responsibility for your one precious life – DHEA for evidence that I’m learning.

Epigenetic clocks per The epigenetic clock theory of aging generally view biological aging as “an unintended consequence of both developmental programmes and maintenance programmes, the molecular footprints of which give rise to DNAm [DNA methylation] age estimators.”

So what would be appropriate anti-aging actions for customers to take? Should customers try to emulate youthful biological markers, and supplement DHEA-S to impact serum levels of insulin-like growth factor 1?

I don’t think so. Our bodies never evolved feedback mechanisms to determine “Time to stop the growth programs, you’ve survived to reproduction age.” Older people achieving teenagers’ DHEA-S levels and activating IGF-1 pathways, pretty much guarantees further biological aging as “an unintended consequence of both developmental programmes and maintenance programmes.”

It’s too early to recommend these biological aging measurements. We’ll see where it goes.

One good thing is the company wants their customers to tell them everything about what they’re doing. I exercise at least a half hour every day, eat Avena nuda oats for breakfast and AGE-less chicken vegetable soup for dinner, and take the following:

Before breakfast
– 3-day-old microwaved broccoli / red cabbage / mustard sprouts started from 10.7 grams of seeds, with nothing else an hour before or after
– Yeast cell wall β-glucan (Glucan 300), 1500 mg, with nothing else an hour before or after

Breakfast, lunch, and dinner
– Hyaluronic acid, Nature’s Lab, 1 serving total
– Boron, Swanson Triple Boron Complex, 9 mg total

Breakfast and dinner
– Acetyl-L-carnitine, 1 g total
– Balance oil, which blends linoleic acid 1400 mg with linolenic acid 350 mg, 2 times
– Betaine anhydrous, 3 g total
– Glucosamine hydroxychloride 1.5 g total, with chondroitin sulfate 1.2 g total
– Taurine, 2 g total
– 3-day-old Avena sativa oat sprouts started from 20 g seeds, 2 times

Breakfast only
– Minerals and vitamins, RDA mainly, Kirkland Signature Daily Multi
– D3 25 mcg
– Calcium alpha-ketoglutarate 1 g

Lunch only
– Vitamin K2 MK-7 600 mcg

Dinner only
– D3 50 mcg
– Zinc monomethionine 30 mg with 0.3 mg copper
– Lutein 25 mg with 5 mg zeaxanthin

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Week 127 of Changing to a youthful phenotype with sprouts

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress ,

1. My third gut microbiome test results came in this week. I submitted a sample earlier this month to follow methods in the second paper of Improving dietary fiber research in a continuing effort to treat my gut microbiota well.

But that study’s vendor was unable to ship an EU-approved product from The Netherlands to the US because it wasn’t FDA-approved. Our US pets can eat dried chicory root products every day, but we can’t? I haven’t received any positive responses from US vendors of dried chicory root products, so I’ll keep taking up to 10 grams of EU-manufactured inulin daily.

I also followed Dr. Horvath’s suggestion in Epigenetic clocks so far in 2022 to “measure epigenetic age because there’s always an opportunity to make a discovery” and submitted a blood test. Will link to those results when they arrive – How to measure biological age?

2. These gut microbiome test results highlight a 16S ribosomal RNA technology flaw that Resistant starch therapy pointed out:

“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.”

Here are my top two relative abundance results, genus Faecalibacterium and genus Bacteroides:

relative abundance2

  • 25.330% (46,844 total count) of my gut microbiota being a butyrate producer is relatively higher than 22.567% (42,156 total count) 14 months ago. Here’s a review of butyrate’s effects.
  • 25% cross-feeder genus Faecalibacterium didn’t relatively crowd out a primary degrader, genus Ruminococcus, which comparatively stayed at 6%. It may have relatively reduced secondary degrader genus Eubacterium abundance from 6% to 5%.

I don’t assign importance per the above graphic that other people achieve 12% relative abundance of a butyrate producer but I have 25%. Our 10,000+ microbiota species perform many overlapping functions.

Conversely, why should I care that other people host an average 25% genus Bacteroides and I relatively have 17% as I did 14 months ago? It’s similar to irrelevant comparisons of clinical biomarkers in Week 120 of Changing to a youthful phenotype with sprouts.

3. So what are appropriate gut microbiome measurements? They aren’t fine-grained relative measurements of my current gut microbiome, either vs. my previous measurements or vs. other people.

I could make a p < .05 finding out of 25.330% vs. 22.567%. But would those numbers be an adequate proxy for understanding truth?

I think science and industry will affordably catch up to these discrepancies as it has with epigenetic clocks. Haven’t come across well-designed gut microbiota studies that use technologically preferable shotgun metagenomic sequencing with absolute measures of both form and function. I’ve read plenty that are stuck in a relative abundance paradigm.

In the meantime, I’m alright, but have to toughen up quickly so that I can transition later this month from summer weather on my sunrise walk every day to a freezing destination.

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Gut microbiota, SCFAs, and hypertension

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Two 2022 rodent studies from the same research group on short-chain fatty acid effects, beginning with butyrate:

“Maternal nutrition, gut microbiome composition, and metabolites derived from gut microbiota are closely related to development of hypertension in offspring. A plethora of metabolites generated from diverse tryptophan metabolic pathways show both beneficial and harmful effects.

Butyrate, one of the short-chain fatty acids (SCFAs), has shown vasodilation effects. We examined whether sodium butyrate administration in pregnancy and lactation can prevent hypertension induced by a maternal tryptophan-free diet in adult progeny, and explored protective mechanisms.

Decreased tryptophan metabolites indole-3-acetamide and indoleacetic acid observed in offspring born to dams that received the trytophan-free (TF) diet coincided with hypertension. This suggested that gut microbiota-derived tryptophan metabolites might be an offsetting mechanism, but not a cause of TF-induced hypertension. Considering that TF intervention reduced abundance of Romboutsia and Akkermansia, and many species are able to metabolize tryptophan, further studies linking abundance of bacterial species and concentrations of tryptophan metabolites are still required to identify main tryptophan metabolite producers.

Sodium butyrate treatment during pregnancy and lactation offset effects of maternal tryptophan-deficiency-induced offspring hypertension, mainly related to shaping gut microbiome, mediating SCFA receptor GPR41 and GPE109A, and restoring the renin–angiotensin system. A better understanding of mechanisms behind tryptophan metabolism implicated in programming of hypertension is critical for developing gut microbiota-targeted therapies to halt hypertension.”

https://www.sciencedirect.com/science/article/abs/pii/S0955286322001619 “Sodium butyrate modulates blood pressure and gut microbiota in maternal tryptophan-free diet-induced hypertension rat offspring” (not freely available) Thanks to Dr. You-Lin Tain for providing a copy.

A second study was on propionate effects:

“Early-life disturbance of gut microbiota has an impact on adult disease in later life. Propionate, one of predominant SCFAs, has been shown to have antihypertensive property.

We examined whether perinatal propionate supplementation can prevent offspring hypertension induced by maternal chronic kidney disease (CKD). CKD is closely linked to adverse maternal and fetal outcomes, and is reported to affect at least 3%-4% women of childbearing age.

Male offspring were divided into four groups: control, CKD, control+propionate (CP), and CKD+propionate (CKDP).

nutrients-14-03435-g001

Perinatal propionate supplementation:

  • Prevented offspring hypertension;
  • Shaped gut microbiota with increases in species richness and evenness;
  • Increased plasma propionate level; and
  • Upregulated renal GPR41 expression.

Results reveal the feasibility of manipulating gut microbiota by altering their metabolites with early-life use of propionate to prevent offspring hypertension in later life.”

https://www.mdpi.com/2072-6643/14/16/3435/htm “Perinatal Propionate Supplementation Protects Adult Male Offspring from Maternal Chronic Kidney Disease-Induced Hypertension”

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An inflammation clock

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Here are six 2022 papers that either cited the second study of Variable aging measurements, or provided further evidence for its findings. Let’s start with a citing study:

“This study aimed to investigate expression patterns and prognostic values of the inflammatory aging clock (iAge) in glioblastoma (GBM), and its relations with stem cells. Similar to epigenetic clocks and transcriptomic clocks, iAge could track multifaceted aging phenotypes and have clinical significance in translation medicine.

iAge was positively correlated with chronological age, and highly associated with immune cells and inflammatory activities. iAge could serve as a prognostic biomarker for overall survival, and could precisely predict GBM stem cells stemness.

We identified the physiological importance and function of iAge in GBM, and provided novel insights into how iAge is a critical event for development of GBM.”

https://www.frontiersin.org/articles/10.3389/fgene.2022.925469/full “Inflammatory aging clock: A cancer clock to characterize the patients’ subtypes and predict the overall survival in glioblastoma”

Beginning with a human osteoporosis study, five papers investigated cytokine CXCL9, which the iAge study found to be “clearly actionable as shown by our experiments in CXCL9 where we can reverse aging phenotypes.”

“We assessed whether levels of CXCL9 and CXCL10 were elevated in human serum samples of older adults who had incident hip fractures. Our findings revealed higher serum levels of CXCL9 in pre-fracture blood samples of men with subsequent hip fractures, compared with their non-fracture controls. There was no such difference in CXCL9 serum levels between cases and controls in women.

Serum CXCL9 improved the prediction of osteoporotic hip fracture in men. The association between CXCL10 and hip fracture risk was not statistically significant in either sex.

While our epidemiologic findings are supported by experimental data providing the mechanistic pathway for CXCL9 in regulating osteoclast recruitment, further studies are needed to confirm validity of our findings and determine their generalizability to other study populations. Underlying biological mechanisms that limit our findings to men but not women require further investigation.”

https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.4646 “CXCL9 Predicts the Risk of Osteoporotic Hip Fracture in a Prospective Cohort of Chinese Men—A Matched Case–Control Study”

Two immune-mediated skin diseases, with a vitiligo review:

“Current findings emphasize the critical role of immune cells and their mediators in the immunopathogenesis of vitiligo. IFN-γ [interferon gamma] is the primary cytokine mediator that activates the JAK/STAT pathway, causing keratinocytes to produce the key chemokines CXCL9 and CXCL10.

Interactions between immune and non-immune cells finally result in apoptosis of melanocytes. Additional investigations of these pathways may provide an opportunity for finding possible therapeutic targets, as there are currently no targeted biological drugs available for treatment of vitiligo.”

https://www.mdpi.com/2227-9059/10/7/1639/htm “Current Concepts of Vitiligo Immunopathogenesis”

and a study of psoriasis:

“CXCL9 is an important chemokine involved in T cell recruitment, and is up-regulated in plasma of patients with psoriasis. Increased CXCL9 expression can aggravate the progression of psoriasis.

cxcl9 expression

IL-1β and CXCL9 were up-regulated and CLDN8 was down-regulated in psoriasis with statistically significant differences. Identification of potential key molecular markers and signaling pathways provides potential research directions for further understanding molecular mechanisms of psoriasis.”

https://www.wjgnet.com/2307-8960/full/v10/i18/5965.htm “Identification of potential key molecules and signaling pathways for psoriasis based on weighted gene co-expression network analysis”

Two lung-related studies, first, an editorial for a human lung transplant study that isn’t freely available:

“CXCL9 and CXCL10 are chemokines that bind to the shared receptor CXCR3, potentiating T cells, mononuclear cells, and natural killer (NK) cells. Previous studies demonstrated that presence of these chemokines in bronchoalveolar lavage samples preceded development of chronic lung allograft dysfunction (CLAD).

Acute rejection and acute lung injury are known risk factors to the development of CLAD, yet this study found that increased risk was dependent on the presence of CXCL9/CXCL10 plasma elevation. Early identification of patients at risk, possibly during the active inflammatory phase, rather than once abnormal wound healing pathways dominate resulting in irreversible injury, provides an attractive opportunity for intervention.”

https://onlinelibrary.wiley.com/doi/10.1111/ajt.17135 “CXCL9 and CXCL10 plasma levels: Potential keys to unlocking CLAD risk”

and a study of smoking effects:

“We collected blood samples from 78 healthy male volunteers aged 18–60, including non-smokers (n = 30), current smokers (n = 30), and ex-smokers (n = 18). Expression levels of CXCL9/MIG [monokine induced by IFN-γ] and sIL-6R significantly increased after smoking, and continued to increase after quitting smoking.

cxcl9 smoking

Changes in related cytokines after smoking cessation are mainly restorative, while some cytokines further strengthen the trend of smoking-related changes.”

https://www.mdpi.com/1420-3049/27/12/3715/htm “Effects of Smoking on Inflammatory-Related Cytokine Levels in Human Serum”

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Natural sulforaphane effects

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This 2022 rodent cell study used the natural form of sulforaphane to replicate experiments performed with mixtures of its natural and unnatural forms:

“Natural sulforaphane (SFN) exists as a single enantiomer with a RS absolute configuration. Most studies focusing on its biological activities, in particular its anti-inflammatory and antioxidant activities, have been conducted using its racemic (rac) form. rac-SFN has shown these effects in several in vitro and in vivo models.

(R)-sulforaphane

These findings demonstrate that (R)-SFN was able to:

  • Modulate inflammatory response and oxidative stress induced by LPS stimulation in murine peritoneal macrophages;
  • Reduce pro-inflammatory enzyme expression (iNOS, COX-2 and mPGES-1) and cytokine production (IL-1β, IL-6, IL-17, IL-18 and TNF-α);
  • Inhibit MAPK, JAK2/STAT-3, and canonical and non-canonical inflammasome signaling pathways;
  • Reduce NO and ROS levels and up-regulate the Nrf-2/HO-1 axis; and
  • Modulate epigenetic changes through histone methylation (H3K9me3) and deacetylation (H3K18ac).

(R)-SFN could be a new epinutraceutical compound useful for management of several immunoinflammatory diseases.”

https://www.mdpi.com/1424-8247/15/8/966/htm “Immunomodulatory Effects of (R)-Sulforaphane on LPS-Activated Murine Immune Cells: Molecular Signaling Pathways and Epigenetic Changes in Histone Markers”

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Epigenetic effects of plasma concentrate

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“We use data from a safety study (n = 18, mean age 74) to investigate whether human umbilical cord plasma concentrate (hereinafter Plasma Concentrate) injected weekly (1 ml intramuscular) into elderly human subjects over a 10-week period affects different biomarkers, including epigenetic age measures, standard clinical biomarkers of organ dysfunction, mitochondrial DNA copy number (mtDNA-CN), and leukocyte telomere length.

More than 20 clinical biomarkers were significantly and beneficially altered. Telomere length and mtDNA-CN were not significantly affected by treatment.

An increase in entropy means that the methylome becomes noisier. We found that entropy was significantly decreased after treatment. Decreased entropy may implicate rejuvenation of the epigenetic landscape after plasma concentrate treatments.

changes in methylation entropy

Treatment reduced DNA methylation-based GrimAge by an average of 0.82 years, suggesting a reduction in morbidity and mortality risk. By contrast, no significant results could be observed for epigenetic clocks that estimate chronological age.

Our study lends credence to the notion that there are youth-promoting factors in the secretome of umbilical cord plasma. This conclusion has also been reached by other researchers that have provided treatment with stem cells, which do not work by plasma dilution but primarily by providing humoral factors and changing the microenvironment of cells and tissues. While there may be youth-promoting microvesicles or humoral factors that are at work, we do not want to rule out the possibility that it is ‘young and undamaged’ albumin that leads to the improvements noted, especially in light of recent evidence for such a mechanism.

This first human epigenetic clock study of plasma concentrate treatments revealed age-reversal effects according to a well-established DNA methylation-based estimator of morbidity and mortality risk. Future placebo-controlled replication studies are warranted with a larger number of participants over a longer study period, which our laboratory has undertaken to pursue.”

https://onlinelibrary.wiley.com/doi/10.1111/acel.13696 “Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers”

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Improving dietary fiber research

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system

Two 2022 papers on aspects of dietary fiber research, starting with a review:

“Considerable attention has been given to unraveling the interaction between fiber type and gut microbiota utilization, focusing mainly on single, purified fibers. Studying these fibers in isolation might give us insights into specific fiber effects, but neglects how dietary fibers are consumed daily and impact our digestive tract: as intrinsic structures that include the cell matrix and content of plant tissues.

Food processing per se is not health-detrimental. Certain foods are barely digestible without any processing, and for specific populations, e.g. those suffering from malnutrition or diseases, food processing is crucial. However, increased digestibility has resulted in negative health outcomes related to obesity and welfare diseases.

whole grain

Intrinsic structural features of plant cells likely slow down fiber fermentation, inducing a lag phase, but do not necessarily reduce the absolute amount of short-chain fatty acids (SCFA) produced. Consequently, there is a gradual release of SFCA, which means that SCFA production is not restricted to the proximal colon but spread throughout the whole colon, including its distal parts, benefiting local, mucosal health.

This translates into beneficial, systemic, peripheral effects as distal SCFA infusion in vivo has shown to induce more pronounced effects on biomarkers than proximal. Delayed fermentation of intrinsic fibers presents a highly relevant feature that isolated, single fibers do not have.

Instead of further processing our already extensively processed foods to create new products, we should minimize this processing, and exploit health benefits associated with the original cell matrix of plant tissues.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.954845/full “Intrinsic dietary fibers and the gut microbiome: Rediscovering the benefits of the plant cell matrix for human health”

Reference 115 was a human study by the same researchers:

“We investigated the impact of dried chicory root in a randomised, placebo-controlled trial with 55 subjects at risk for type 2 diabetes. Evidence for a trophic chain including Bifidobacterium and Anaerostipes spp. was recapitulated by in vitro incubations that resulted in high levels of butyrate and propionate production from the treatment product.

butyrate and propionate microbial network

We observed a simultaneous increase in faecal and circulating SCFA levels, and a marked improvement in dynamic markers of glucose control. In subjects with a low relative abundance of Blautia spp. – a genus that previously has been associated with T2D – static glycaemic markers also decreased pronouncedly.

Our results demonstrate a strong modulatory potential on gut health and microbial metabolism by native inulin and cell wall fibres pectin, cellulose and hemicellulose in the intrinsic form of dried chicory roots.”

https://www.cambridge.org/core/journals/gut-microbiome/article/dried-chicory-root-improves-bowel-function-benefits-intestinal-microbial-trophic-chains-and-increases-faecal-and-circulating-short-chain-fatty-acids-in-subjects-at-risk-for-type-2-diabetes/6209AEAFBDDB181197F22AE24388186B# “Dried chicory root improves bowel function, benefits intestinal microbial trophic chains and increases faecal and circulating short chain fatty acids in subjects at risk for type 2 diabetes”

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Another use of a routine blood test

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A 2022 human study investigated three measurements of the CBC with Differential/Platelet test:

“This study explored the relationship between the systemic immune-inflammation index (SII) and stroke prognosis. SII was defined as neutrophils × platelets/lymphocytes. Neutrophils and lymphocytes are involved in the inflammatory and immune response, whereas platelets have a primary role in the thrombo-inflammation of stroke.

Patients were divided into four groups according to SII values: quartile (Q)1 <366; Q2 366–533; Q3 534–799; and Q4 ≥800. As the SII quartile increased, patients with acute ischemic stroke were more likely to have poor functional outcomes during follow-up.

Although age, smoking status, and alcohol consumption are risk factors, and female estrogen is a protective factor for stroke, we did not identify subgroups specifically being affected by these factors. Even if we adjusted our model for factors identified by previous studies as immune-inflammation markers that might affect prognosis, such as the high-sensitivity C-reactive protein level, our results still suggested that SII is closely related to short- and long-term prognosis of patients with acute ischemic stroke.

As a new type of immune-inflammation index, the SII integrates neutrophils, platelets, and lymphocytes, and can reflect the balance of the systemic immune response and inflammatory response.”

https://www.aging-us.com/article/204228/text “Correlation of the systemic immune-inflammation index with short- and long-term prognosis after acute ischemic stroke”

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Non-patentable boron benefits

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To follow up Is boron important to health? I’ll highlight a 2022 review of boron intake:

“Boron is essential for activity of several metabolic enzymes, hormones, and micronutrients. It is important for growth and maintenance of bone, reduction in inflammatory biomarkers, and increasing levels of antioxidant enzymes.

The average person’s daily diet contains 1.5 to 3 milligrams of boron. Boron intakes of 1–3 mg/day have been shown to improve bone and brain health in adults when compared to intakes of 0.25–0.50 mg/day.

One week of 10 mg/d boron supplementation resulted in a 20% reduction in inflammatory biomarkers TNF-α, as well as significant reductions (nearly 50%) in plasma concentrations of hs-CRP and IL-6. Calcium fructoborate, a naturally occurring, plant-based boron-carbohydrate complex, had beneficial effects on osteoarthritis (OA) symptoms. A double-blind study in middle-aged patients with primary OA found that all groups except the placebo group saw a reduction in inflammatory biomarkers after 15 days of food supplementation with calcium fructoborate.

Dietary boron intake significantly improves brain function and cognitive functioning in humans. Electroencephalograms showed that boron pharmacological intervention after boron deficiency improved functioning in older men and women, such as less drowsiness and mental alertness, better psychomotor skills (for example, motor speed and dexterity), and better cognitive processing (e.g., attention and short-term memory). Boron compounds can help with both impaired recognition and spatial memory problems.

We discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. Boron reagents will play a significant role to improve dysbiosis.”

https://www.mdpi.com/1420-3049/27/11/3402/htm “The Role of Microbiome in Brain Development and Neurodegenerative Diseases”

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Findings, or fun with numbers?

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This 2022 rodent study investigated bone mass phenotypes and sulforaphane:

“Mouse strains can have divergent basal bone mass, yet this phenotype is seldom reflected in the design of studies seeking to identify new modulators of bone resorption by osteoclasts. Sulforaphane exerts inhibitory effects on in vitro osteoclastogenesis in cells from C57BL/6 mice. We explore whether a divergent basal bone mass in different mouse strains is linked both to in vitro osteoclastogenic potential and to SFX-01 sensitivity.

osteoclasts in three mouse strains

Powerful antioxidants are an alternative to achieve beneficial bone effects and avoidance of osteoporotic bone loss. Sulforaphane (SFN) is a natural antioxidant found at high levels (as glucoraphanin) in cruciferous vegetables. SFN activates the NRF2 pathway and has anti-inflammatory effects, protecting against oxidative stress in many cell types.

These findings suggest that BM cells derived from animals with a high in vivo bone mass are less sensitive to M-CSF and RANKL in vitro leading to lower osteoclastogenesis. They also support the hypothesis that similar sensitivity extends to inhibitory effects of SFX-01 on osteoclast formation/function.

It is important to stress that osteoclasts generated in these strains may simply undergo multinucleation in a manner related to their underpinning genetics, and that by coincidence alone this is matched to their bone mass.”

https://onlinelibrary.wiley.com/doi/10.1002/cbf.3734 “High bone mass in mice can be linked to lower osteoclast formation, resorptive capacity, and restricted in vitro sensitivity to inhibition by stable sulforaphane”

I curated this study primarily for its honesty. I’ll link this post to future posts of studies where researchers lack similar honesty.

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Broccoli sprouts and your brain

gettingwell4 0-1 star Wasted resources, Brain development, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress , , , , ,

A 2022 review of Nrf2 signaling hilariously avoided mentioning sulforaphane, although of ~4,000 sulforaphane published articles, two were cited. I’ll curate it anyway to highlight referenced brain effects.

“A good stability of NRF2 activity is crucial to maintain redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, ageing, and ageing-related neurodegenerative diseases.

A functional NRF2 system is important to regulate both neuroinflammation, i.e., activation of microglia and astrocytes, and oxidative stress in the brain. NRF2 and NF-κB transcription factors regulate cellular responses to inflammation and oxidative stress in order to maintain brain homeostasis. Both pathways have been described to inhibit each other.

Nrf2 brain aging

Future challenges will be to establish novel therapies to:

  • Increase NRF2 activation in specific cell types and/or brain regions; and
  • Modulate NRF2 pathway in senescent cells.

Modulation of NRF2 signalling pathway by using specific food products [like unmentioned broccoli sprouts] and phytochemicals [like unmentioned sulforaphane], dietary supplements [like unmentioned Vitamin D3], drugs, and epigenetic modifiers, alone or in combination, will help to limit inflammatory diseases, ageing process, and subsequently ageing-related diseases.”

https://www.mdpi.com/2076-3921/11/8/1426/htm “Normal and Pathological NRF2 Signalling in the Central Nervous System”

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Week 120 of Changing to a youthful phenotype with sprouts

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Epigenetics, Immune system ,

It was time for an annual physical last Wednesday. My focus was to see whether reducing sulforaphane intake per Week 87 had the desired effect on thyroid measurements.

That and other adjustments did! Readings of TSH 2.91 (0.45 – 4.50 uIU/mL), free T4 1.22 (0.82 − 1.77 ng/dL), and free T3 2.4 (2.0 – 4.4 pg/mL) were all in-range. 🙂

thyroid

I won’t repeat the Week 63 workbook calculations done after last year’s annual physical. To me, that’s another form of magical thinking.

Every explanation of those reference ranges, and optimal ranges built from all-cause mortality statistics, requires a suffix “of people who didn’t positively change their healthspan and lifespan.” What value is there in optimizing (pick a measurement) against those outcomes? Why compare my efforts, or results, or any other aspect of my life, to people who didn’t actionably care about their one precious life?

I’m not deflecting with poor measurements:

  • 3 of the 5 values in last year’s optimal ranges got better, and the other 2 stayed the same; and
  • 2 of the 4 values that weren’t in last year’s optimal ranges came into those ranges, and the other 2 got better but stayed outside an optimal range.

We each have a lot at stake. Bad things like diseases of old age happen on their own. If we want good things to happen, we have to make them happen.

Consider this from The impact of transgenerational epigenetic inheritance and early life experiences:

“Every disease is connected to the immune system.”

Are people making good choices every day for their immune systems?

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Is boron important to health?

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress, Testosterone , ,

Three papers on boron, starting with a 2022 review:

“Boron-containing compounds (BCC) have effects in the metabolism of living organisms. Information regarding effects and interaction of these compounds was compiled, and potential applications for treating human metabolic disorders was suggested.

Dietary boron supplementation affects metabolism of calcium, magnesium, triglycerides, glucose, amino acids, reactive oxygen, nitrogen species, and hormones such as 17β-estradiol, calcitonin, and 25-hydroxy-cholecalciferol. When food is boron-deprived, there are adverse effects like depressed growth, reduced serum steroid hormone concentrations, changes in plasma and organ calcium and magnesium concentrations, plasma alkaline phosphatase, and bone calcification on animal biological functions.

boron effects

Exploration of basic BCC as metabolism regulators is expanding. Although mechanisms of action are uncertain, limitation of damage induced by reactive species, inflammatory modulation, or activities on some enzymes and membrane transporters are often related to reported effects.

An increasing number of new BCC are emerging as potential tools for prevention, diagnosis, and therapy of metabolism maladies such as diabetes, metabolic syndrome, osteoporosis, cardiovascular, and liver diseases. For those innovative BCC, mechanisms of action are often clear.”

https://link.springer.com/article/10.1007/s12011-022-03346-9 “Boron‑Containing Compounds for Prevention, Diagnosis, and Treatment of Human Metabolic Disorders” (not freely available) Thanks to Dr. Marvin A Soriano-Ursúa for providing a link to a freely available document.

A second paper was a 2021 human study:

“In our elderly population-based sample, a boron-rich diet appeared to be characterized by high intakes of plant foods presumed to be healthy, low intakes of plant foods presumed to be less healthy, and low intakes of all kinds of animal foods.

Higher plasma boron concentrations were related to lower BMI and circulating concentrations of CRP. Plasma boron concentrations were associated with age, phosphate, and plasma lipid metabolism, and showed seasonal variations.

Human intervention studies are warranted to derive causal relationships of circulating and dietary boron with human health and metabolism. Robust databases on boron content of foods are needed to facilitate investigation of dietary boron intake in human studies.

Clarification of the non-/essentiality of trace element boron for human health will form the basis to derive recommendations for a dietary boron intake being sufficient to exert boron’s proposed beneficial physiological roles.”

https://link.springer.com/article/10.1007/s00394-021-02730-w “Plasma boron concentrations in the general population: a cross-sectional analysis of cardio-metabolic and dietary correlates”

As noted in this study, public agencies don’t consider dietary boron content important enough to include in public databases. My daily boron dietary intake estimated from published private databases is:

  • Walnuts, 1.63 mg x (28.3 g / 100 g) = .5 mg
  • Red kidney beans, 1.4 mg x (12 g / 100 g) = .2 mg
  • Chickpeas, 0.71 mg x (40 g / 100 g) = .3 mg
  • Celery, 0.5 mg x (72 g / 100 g) = .4 mg
  • Carrots, 0.3 mg x ( 76 g / 100 g) = .3 mg
  • Coffee .07 mg x 3 cups = .2 mg

2 mg boron daily dietary total

A third paper was a 2022 rodent study:

“Sodium pentaborate pentahydrate (NaB) 1 and 2 mg elemental B/kg supplementation induces the anagen phase in rats via Wnt-1, β-catenin, VEGF, PDGF, and TGF-β1 signaling pathways, which are important molecular mechanisms involved in hair growth.

NaB 4 mg B/kg suppresses these pathways and adversely affects hair growth.”

https://www.sciencedirect.com/science/article/abs/pii/S0946672X22000876 “Sodium pentaborate pentahydrate promotes hair growth through the Wnt/β-catenin pathway and growth factors” (not freely available)

A human equivalent of this study’s rat 1 mg elemental boron intake is (1 mg x .162) x 70 kg = 11 mg.

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