Broccoli sprouts and your brain

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”


PXL_20220808_095334058

Week 120 of Changing to a youthful phenotype with sprouts

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 one 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?

PXL_20220731_093534095.NIGHT

Is boron important to health?

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.


PXL_20220731_094359216.NIGHT

Trained immunity epigenetics

Two papers on trained immunity, starting with a 2022 review:

“Live attenuated vaccines such as the Bacillus Calmette–Guérin, measles-containing vaccines, and the oral polio vaccine have been shown to reduce overall mortality beyond their effects attributable to the targeted diseases.

After an encounter with a primary stimulus, epigenetic and metabolic reprogramming of bone marrow progenitor cells and functional changes of tissue immune cell populations result in augmented immune responses against a secondary challenge. This process has been termed trained immunity.

Main epigenetic events during induction of trained immunity are:

  1. Chromosomal reorganization on the level of topologically associated domains;
  2. Induction of long noncoding RNA activity;
  3. Histone modifications and chromatin accessibility; and
  4. DNA (de)methylation.

trained immunity mechanisms

An epigenetic enzyme belonging to the lysine methyltransferase family, Set7, possesses vital function in β-glucan training of monocytes. When inhibited, trained immunity phenotype is diminished, while Set7 deficient mice cannot establish innate immune memory.

β-glucan is recognized by Dectin-1, and has been known to lead to a shift from oxidative phosphorylation (OXPHOS) to glycolysis as an ATP source. However, a more recent study reported an increase in both glycolysis and oxygen consumption following training, which signals a higher rate of OXPHOS. This discrepancy is explained by the difference in concentration of β-glucan used in the experiments.

Stopping vaccination with measles and polio once the pathogens are eradicated, or replacing live attenuated polio with inactivated polio, should be done with caution, as it may have a substantial impact on childhood mortality. Trained immunity may also represent an important new approach to improve current vaccines, or to develop novel vaccines that combine induction of classical adaptive immune memory and innate immune memory.”

https://www.sciencedirect.com/science/article/pii/S0952791522000371 “Trained immunity: implications for vaccination”


Reference 34 was a 2020 study by two of the same coauthors that provided details on the above discrepancy:

“Findings presented by the current study suggest that the disparity in terms of the role of OXPHOS arises from the stimulatory dose of β-glucan [by intraperitoneal injection]. A β-glucan concentration of 1 μg/mL induces both glycolysis and OXPHOS, whereas a concentration of 10 μg/mL induces glycolysis but inhibits OXPHOS.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30458-7 “The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan”


PXL_20220728_094358955.NIGHT

The goddess of rainbows

Two 2022 papers, starting with a review of irisin:

“This article is an overview of irisin generation, secretion, and tissue distribution. Its targeting of tissues or organs for prevention and treatment of chronic diseases is systematically summarized, with discussion of underlying molecular mechanisms.

Irisin is an exercise-induced myokine expressed as a bioactive peptide in multiple tissues and organs. Exercise and cold exposure are major inducers for its secretion.

Mechanistic studies confirm that irisin is closely correlated with lipid metabolism, insulin resistance, inflammation, ROS, endocrine, neurotrophic factors, cell regeneration and repairing, and central nervous system regulation. Irisin decreases with age, and is closely associated with a wide range of aging-related diseases.

A number of studies in elderly humans and animal models have shown that exercise can promote the body’s circulation and increase irisin levels in some tissues and organs. Resistance, aerobic, or combined exercise seem to play a positive role. However, exercise could not change serum irisin in some reported studies.

irisin human studies

There are large individual differences in exercise training in the elderly population. Since the half-life of irisin in the body is less than 1 h, it is necessary to pay attention to the time of blood sampling after a single exercise intervention. Some factors that impede detection of irisin levels in vivo include the half-life of irisin protein, sampling time, different tissues, and different health statuses before and after intervention.

It is worth noting that high-intensity exercise shows higher irisin levels even with the same energy expenditure during exercise. Precision studies of irisin in elderly subjects following exercise intervention need to be further clarified.”

https://www.sciencedirect.com/science/article/pii/S1568163722001222 “Irisin, An Exercise-induced Bioactive Peptide Beneficial for Health Promotion During Aging Process” (not freely available) Thanks to Dr. Ning Chen for providing a copy.


A second paper was a human study too recent to be cited by the first paper. I’ll highlight its irisin findings:

“We investigated the complex relationship among DNAm based biomarkers of aging, including DNAmFitAge, a variety of physiological functioning variables, blood serum measures including cholesterol, irisin level, and redox balance, and the microbiome on 303 healthy individuals aged between 33 and 88 years with a diverse level of physical fitness. Regular exercise was associated with younger biological age, better memory, and more protective blood serum levels.

Our research intends to show that regular physical exercise is related to microbiota and methylation differences which are both beneficial to aging and measurable. Our research provides the first investigation between microbiome derived metabolic pathways and DNAm based aging biomarkers.

Irisin levels decrease with age (0.23 average decrease for every 1 year older). We found age-related decreases in irisin levels were attenuated by exercise training. The link between irisin to GrimAge Acceleration and FitAge Acceleration is a novel observation.

HDL is positively associated with irisin. HDL and irisin have complex roles in physiology, and the positive relationship we observe between physical exercise and HDL and irisin align with protective effects seen between HDL and irisin with glucose homeostasis.

This work further supports the biological importance of irisin to the aging process. It is possible our research motivates interventions to boost irisin, like through physical exercise, as possible anti-aging therapies.”

https://www.medrxiv.org/content/10.1101/2022.07.22.22277842v1 “DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation


PXL_20220725_095201761

Variable aging measurements

Two papers on aging measurements, starting with a 2022 human study:

“We collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration / neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging.

blsa participant ages

We demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity, and shorter survival.”

https://www.nature.com/articles/s43587-022-00243-7 “Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging”


I disagree with this study’s methodology.

1. Although it acknowledged individual variability, nothing was done to positively adjust to those facts. What could have been done per A review of biological variability was:

“Obtain a measurement of variability that is independent of the mean to ensure to not confound changes in variability with shifts in mean.”

2. A usual research practice is to take at least three measurements, and use their average as representative. That wasn’t done here, maybe because of time and expense considerations?

3. An important measurement for physical function was the time to finish a 400 meter walk. I walk more than ten times that almost every day. I use the first 400 meters as a warmup period while getting to the beach to walk eastward and enjoy the predawn light and water animal activity. I concentrate on gait speed during the last third while walking westward on a straightaway bike path.

This study would measure my gait speed as a sometimes old person during the first 400 meters, rather than a gait speed that usually approaches a young person’s during the last 400 meters. Even if I tried to walk my fastest right out of the gate, I wouldn’t be surprised to find a decade or two difference by this study’s measurements between a morning walk’s first and last 400 meter gait speeds.

4. An important cognitive function measurement was the Digital Symbol Substitution Test, apparently taken during subjects’ fasted state? Sometimes after exercising, I’m okay cognitively when starting work in a fasted state at 6:30 a.m., and other times I’m tired.

Two days ago during the last hour of work 1:30-2:30 p.m., I did outstanding work, four hours after eating whole oats for breakfast, and after drinking two coffees and three teas. I took time to put together pieces of puzzles into proper contexts for management’s attention. My bosses weren’t too pleased with the story it told, but it is what it is.

5. Are measurements of how you start what matters? Or is it how you finish, as is common in competitive sports?

This study would measure my cognitive function as a sometimes old person, rather than performance that approaches a young person’s later in the workday. For both physical and cognitive function, my abilities to ramp up and come close to young people’s capabilities are features that I work on, not random, inconvenient measurement variability.

6. Blood measurements were downgraded as having “limited coverage of the four phenotypic domains.” These were taken to fit into specific paradigms and epigenetic clocks. They predictably failed to show causality, as acknowledged with:

“Our analysis showed strong associations between global longitudinal phenotypic score and changes in physical and cognitive function. We did not have sufficient observations to fully separate these two dimensions over time, which would have strengthened the assumption of causality.”

Nowhere in this study was it hinted that all measurements were downstream effects of unmeasured causes. Hopefully, a follow-on study will reanalyze these subjects’ blood samples, MRI, and other measurements for originating upstream factors of signaling pathways and cascades per Signaling pathways and aging and An environmental signaling paradigm of aging.


Reference 35 of this first study was a 2021 human and rodent study that was tossed in as a limitation with:

“We might not have all of the relevant phenotypic measures (for example, more detailed immune profiles) for all participants.”

Its findings included:

“From the blood immunome of 1,001 individuals aged 8–96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians.

Canonical markers of acute infection such as IL-6 and tumor necrosis factor-α were not major contributors to iAge, indicating that, except for IL-1β, infection-driven inflammatory markers of the acute inflammatory response do not contribute to age-related chronic inflammation.

We conducted a follow-up study in an independent cohort of 97 extremely healthy adults (aged 25–90 years) matched for cardiovascular risk factors (including conserved levels of high-sensitivity C-reactive protein), selected from a total of 151 recruited participants using strict selection criteria. In this healthy cohort, inflammation markers were measured using a 48-plex cytokine panel. Only 6 circulating immune proteins were significantly correlated with age, with CXCL9 again the largest contributor to age-related inflammation.

CXCL9 is a T-cell chemoattractant induced by IFN-γ and is mostly produced by neutrophils, macrophages and endothelial cells (ECs). We find that CXCL9 is mainly produced by aged endothelium and predicts subclinical levels of cardiovascular aging in nominally healthy individuals.

We did not find any significant correlation between known disease risk factors reported in the study (BMI, smoking, dyslipidemia) and levels of CXCL9 gene or protein expression. We hypothesize that one root cause of CXCL9 overproduction is cellular aging per se, which can trigger metabolic dysfunction.

As ECs but not cardiomyocytes expressed the CXCL9 receptor, CXCR3, we hypothesize that this chemokine acts both in a paracrine fashion (when it is produced by macrophages to attract T cells to the site of injury) and in an autocrine fashion (when it is produced by the endothelium) creating a positive feedback loop. In this model, increasing doses of CXCL9 and expression of its receptor in these cells leads to cumulative deterioration of endothelial function in aging.

IFN-γ did not increase in expression in our cellular aging RNA-seq experiment, suggesting that there are triggers of CXCL9 (other than IFN-γ) that play a role in cellular senescence in the endothelium that are currently unknown. However, in our 1KIP study, IFN-γ was in fact the second-most important negative contributor to iAge, which could be explained by the cell-priming effect of cytokines, where the effect of a first cytokine alters the response to a different one.

iAge derived from immunological cytokines gives us an insight into the salient cytokines that are related to aging and disease. A notable difference compared to other clocks is that iAge is clearly actionable as shown by our experiments in CXCL9 where we can reverse aging phenotypes. More practical approaches range from altering a person’s exposomes (lifestyle) and/or the use of interventions to target CXCL9 and other biomarkers described here.

Our immune metric for human health can identify within healthy older adults with no clinical or laboratory evidence of cardiovascular disease, those at risk for early cardiovascular aging. We demonstrate that CXCL9 is a master regulator of vascular function and cellular senescence, which indicates that therapies targeting CXCL9 could be used to prevent age-related deterioration of the vascular system and other physiological systems as well.”

https://www.nature.com/articles/s43587-021-00082-y “An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging”


PXL_20220721_093128925.NIGHT

Blanching broccoli sprouts

Three 2022 papers of interest cited Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. Let’s start with a fairly straightforward analysis of blanching broccoli sprouts to produce sulforaphane:

“We investigated the effect of blanching conditions to determine the optimal treatment that maximizes sulforaphane (SFN) content in broccoli sprouts. Broccoli seeds grown under controlled conditions were harvested after 11 days from germination and subjected to different blanching conditions based on a central composite design with temperature and time as experimental factors.

Optimum conditions were blanching at 61 °C for 4.8 min, resulting in 54.3 ± 0.20 µmol SFN/g dry weight, representing a 3.3-fold increase with respect to untreated sprouts. This is the highest SFN content reported for sprouts subjected to any treatment so far.

sfn heat response curve

Broccoli sprouts (20 g) were put in plastic bags, which were vacuum-sealed, and then subjected to time (3.4–11 min)–temperature (32–88 °C) combinations.

  • Blanching at 60 °C for less than 8 min resulted in the highest SFN content.
  • Above this temperature, SFN content decreases.
  • The exceptionally high values obtained in this work may be related to treatment, but also to broccoli cultivar and culture conditions.

Different broccoli tissues and developmental stages express different myrosinase isoforms, and catalytic properties of the enzyme may vary among different tissues. Myrosinase found in broccoli florets has an optimal temperature of around 40 °C, and considering myrosinases from other sources, this temperature may vary between 30 and 70 °C.”

https://www.mdpi.com/2304-8158/11/13/1906/htm “Maximization of Sulforaphane Content in Broccoli Sprouts by Blanching”

This first study used heat-only techniques similar to the uncited Enhancing sulforaphane content. It similarly found a 60°C (140°F) myrosinase cliff as have many other uncited studies.


A second paper was a rodent study:

“We investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks.

Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, a NRF2 repressor. Sulforaphane treatment did not affect renal NRF2 expression or activity and mitochondrial function in young rats.”

https://www.mdpi.com/2076-3921/11/1/156/htm “Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription Factor NRF2”

A human equivalent to this second study’s daily dose was intolerable at (.162 x 15 mg) x 70 kg = 170 mg. I curated this study anyway just to show an example of negligible treatment effects in young animals even when a dose is too high for humans.


A third paper was a review that focused on sulforaphane and its analogs’ chemistry:

“Analysis of the Web of Science database shows that, since 1992, about 3,890 articles have been published on SFN, and over 5,600 on isothiocyanates. Its natural analogs include iberin, alyssin, iberverin, erucin, berteroin, cheirolin, and erysolin.

SFN is a biologically active, natural isothiocyanate found in cruciferous vegetables, and is non-toxic. It has been selected for phase I and II clinical trials, where it is administered in the form of an extract or broccoli sprouts. There are no differences in biological activity between SFN and its natural analogs, such as erucin or alyssin.

No synthetic analogs of SFN described in this review qualified for clinical trials. This is likely due to the toxicity of these compounds in higher doses.”

https://www.mdpi.com/1420-3049/27/5/1750/htm “Sulforaphane and Its Bifunctional Analogs: Synthesis and Biological Activity”


PXL_20220712_100018566

Supplement evidence and counter-evidence

Three 2022 papers, starting with a rabbit study of dietary supplements:

“Adding native type II collagen (NC) to the combination of chondroitin sulfate (CS), glucosamine hydrochloride (GlHCl), and hyaluronic acid (HA) showed improvements on osteoarthritis progression. Disease progression was monitored at different time points using magnetic resonance imaging biomarkers, measurement of hyaluronic acid in synovial fluid, and macroscopic and microscopic evaluations of cartilage, synovial membrane and subchondral bone.

CTR (control group–no treatment), CGH (60.38 mg/kg CS + 75.47 mg/kg GlHCl + 3.35 mg/kg HA) and CGH-NC (60.38 mg/kg CS + 75.47 mg/kg GlHCl + 3.35 mg/kg HA + 0.67 mg/kg NC). Clearer colors result in an increase of the frequency of each stage of the disease. Significant differences can be appreciated in the CGH-NC group, compared to the other groups over time.

animals-12-01401-g003

Oral administration of CS with GlHCl and HA, with or without NC, is safe, and provides significant improvements in OA progression. Adding NC leads to better outcomes seen on macroscopic and microscopic evaluation and MRI biomarkers.”

https://www.mdpi.com/2076-2615/12/11/1401/htm “Improved Joint Health Following Oral Administration of Glycosaminoglycans with Native Type II Collagen in a Rabbit Model of Osteoarthritis”


A rodent study of bone growth and similar dietary supplements taken separately found pretty much the opposite:

“Female C57BL/6 mice bred in house were used. Starting at 11 weeks of age, animals were given dietary supplements of either hydrolyzed type I collagen at 1 g/kg, glucosamine sulfate potassium chloride at 300 mg/kg, chondroitin sulfate sodium salt at 250 mg/kg, or fish oil at 1 g/kg. These values were calculated using a body surface area (BSA) calculation from human dosage values of 81.1 mg/kg for collagen, 24.3 mg/kg for glucosamine, 20.3 mg/kg for chondroitin sulfate and 81.1 mg/kg for fish oil.

femur

Our findings indicate that dietary supplements had little impact on bone morphology or mechanics in young female mice and cannot be used to improve bone’s fracture resistance. Bone quality, inferred from material-level mechanical properties and fracture toughness, did not improve with treatment. The only alteration in bone quality was a decrease in elastic modulus with glucosamine or fish oil, which is considered negative and would not be advantageous in preventing fracture.

These data suggest that adding more basic components of the bone matrix into the diet of growing mice does not improve quality of bone tissue. Dietary supplements may be more beneficial in individuals without a balanced diet or in those with an increased risk of fracture, such as those experiencing estrogen loss.”

https://www.nature.com/articles/s41598-022-14068-2 “Dietary supplements do not improve bone morphology or mechanical properties in young female C57BL/6 mice”


This second study cited a 2015 article Translating dosages from animal models to human clinical trials—revisiting body surface area scaling in this context:

“Dosage in this study was determined by using the BSA formula. This technique does have its drawbacks as it does not take into differences in murine metabolism as discussed more in depth elsewhere, but the lack of pharmacokinetic data for dietary supplements in mice prevented a more complex conversion.”

That article has been cited many times, including in a 2022 review:

“Dose-based methodologies for predicting human clinical doses from preclinical data were assessed for oncology drugs. BSA-based approaches were predictive for small molecule oncology drugs, in particular for kinase inhibitors and cytotoxic agents, but prediction was poor for drugs with immune and endocrine components to their mechanisms.

BSA conversion of doses was clearly inappropriate for large molecules. Direct mg/kg-based prediction was more relevant to large molecules with molecular weight > 100 kDa and in particular antibody-drug conjugates.

This approach is theoretically applicable to other therapeutic areas, and if validated in other therapeutic areas, may provide an easy estimate of clinical doses early in the drug discovery and development process to facilitate compound selection and risk management. Later in the drug development process, dose-based methods should be superseded by exposure- and mechanism-based methodologies whenever possible.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087189/ “Predicting Approximate Clinically Effective Doses in Oncology Using Preclinical Efficacy and Body Surface Area Conversion: A Retrospective Analysis”


I’ve used body surface area calculations for human equivalent doses, for example, the small molecule sulforaphane at 177.3 g / mol or 177 Da.

Three of the first study’s human equivalent doses can be calculated by the body surface area factor 0.324 for rabbits since molecular weight of chondroitin sulfate is 463.37 g / mol, glucosamine hydrochloride is 215.63 g / mol, and hyaluronic acid is 403.31 g / mol. Human equivalent doses are:

  • Chondroitin sulfate (.324 x 60.38 mg) x 70 kg = 1,369 mg;
  • Glucosamine hydrochloride (.324 x 75.47 mg) x 70 kg = 1,712 mg; and
  • Hyaluronic acid (.324 x 3.35 mg) x 70 kg = 76 mg.

These three weights are all close to supplement weights advertised to be effective.

Undenatured type II collagen in the first study is 300 kDa, and hydrolyzed type I collagen in the second study varies from 0.3 to 8 kDa. Per the third paper’s recommendation of using mg/kg calculations for large molecules, human equivalent doses would be (0.67 mg x 70 kg) = 47 mg for type II and (81.1 mg x 70 kg) = 5,677 mg for type I, respectively. These two weights are also close to supplement weights advertised to be effective.

PXL_20220706_095337586

Eat broccoli sprouts for your gut

Two 2022 papers, starting with a review of sulforaphane’s effects on intestinal inflammation:

“This review summarizes characteristics of intestinal inflammation, the anti-inflammatory mechanism of sulforaphane (SFN) and its various protective effects on intestinal inflammation, and possible future applications of SFN for promoting intestinal health.

SFN is an effective agonist of Nrf2, and it is also able to inhibit expression of inflammation-related genes by activating Nrf2. This kind of anti-inflammatory mechanism has already been confirmed in treatment of intestinal mucositis using SFN.

sulforaphane and gut inflammation

The main absorption site of SFN after oral administration is the small intestine, and its achievable dose for the hind intestine may be lower than the expected dose. Although absorbed SFN can reach the large intestine through intestinal blood and other transportation routes, its therapeutic effect on target tissues may not be as efficient as it would be when the expected dose is directly absorbed by hindgut cells.

Considering that there are several predisposing factors that lead to intestinal inflammation, more research on the effect of SFN on intestinal inflammation with different causes and characteristics should be carried out. Appropriate carriers should be selected according to the onset site and related physiological environment, and a scientific and effective intestinal targeted delivery system for SFN needs to be developed.”

https://pubs.rsc.org/en/content/articlelanding/2022/FO/D1FO03398K “The functional role of sulforaphane in intestinal inflammation: a review” (not freely available). Thanks to Professor Lei Zheng for providing a copy.


Reference 89 – Sulforaphane Normalizes Intestinal Flora and Enhances Gut Barrier in Mice with BBN-Induced Bladder Cancer (not freely available) – in the above graphic was cited for:

“The effect of SFN intervention on intestinal injury in mice with bladder cancer was investigated. It was found that SFN significantly reduced tissue damage in the colon and cecum of mice and normalized the imbalance in intestinal flora caused by BBN, which manifested as an increase in Bacteroides fragilis and Clostridium cluster 1, thus promoting SCFA production.

SFN administration upregulated expression of tight junction proteins including ZO-1, occludin, claudin-1 and glucagon-like peptide 2 (GLP2) to repair damage of mucosal epithelium of the colon and caecum, while reducing release of IL-6 and the secreted immunoglobulin A (SIgA). This study showed for the first time SFN’s alleviating effect on intestinal inflammation may be produced by regulating intestinal flora structure, suggesting that the protective effect of SFN on intestinal health could be multidirectional.”

That study’s 2022 follow-on rodent study also used oral sulforaphane doses:

“This study was undertaken to assess the potential efficacy of SFN in ameliorating dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to elucidate underlying mechanisms.

Male C57BL/6 mice were treated with various doses of SFN (2.5, 5, 10, and 20 mg/kg body weight). In DSS colitis mice, the hallmarks of disease observed as shortened colon lengths, increased disease activity index scores and pathological damage, higher proinflammatory cytokines and decreased expression of tight junction proteins, were alleviated by SFN treatment.

  • 5, 10, and 20 mg/kg/day of SFN treatment significantly ameliorated inflammatory damage in mice colon tissue when compared to the colitis group.
  • 5, 10, and 20 mg/kg/day of SFN remarkably mitigated morphological alterations and protected colonic tissue integrity.
  • Nrf2 expression was increased significantly by 5, 10, and 20 mg/kg/day of SFN treatment.
  • SFN partially restored perturbed gut microbiota composition, and increased production of volatile fatty acids (especially caproic acid) induced by DSS administration.
  • The contents of butyric acid, iso-butyric acid, valeric acid, and iso-valeric acid were all decreased in DSS-induced colitis mice and in 2.5 mg/kg/day of the SFN treatment group, whereas this decreased tendency was reversed by 10 and 20 mg/kg/day of SFN.

A proposed mechanism by which SFN protects against colitis:

fnut-09-893344-g009

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Signal Transducer and Activator of Transcription 3 (STAT3), and Phase II enzyme UDP-glucuronosyltransferase (UGT) were involved in the protective effect of SFN against DSS-induced colitis.

Nrf2 activation followed by STAT3 signaling pathway play a pivotal role in the protective effect of SFN on colitis. SFN can be considered a potential candidate in the treatment of IBD.”

https://www.frontiersin.org/articles/10.3389/fnut.2022.893344/full “The Protective Effect of Sulforaphane on Dextran Sulfate Sodium-Induced Colitis Depends on Gut Microbial and Nrf2-Related Mechanism”


A human equivalent dose of the second paper’s oral dose of 20 mg sulforaphane / kg body weight is (.081 x 20 mg) x 70 kg = 113 mg. Per Estimating daily consumption of broccoli sprout compounds, I ate about half that every day by microwaving 3-day-old broccoli sprouts through Week 56, when I cut back to about 35 mg a day. I dialed that back in Week 87 to about 17 mg a day (100 μmol), which is used in a plethora of studies.

I’ve never had ulcerative colitis or inflammatory bowel disease. If I would be diagnosed with either, it would take about five minutes to get back to this study’s equivalent of 10 mg / kg body weight with broccoli seeds and sprouts.

Doubling that to 20 mg may involve taking supplements, though. Haven’t checked for commercial availability lately, but I’ve read a dozen or so studies on encapsulating sulforaphane so that it could reach the colon.

PXL_20220628_190302158

The soluble receptor for AGEs

Two 2022 human studies on sRAGE, starting with one of hypoxia-related diseases:

“The receptor for advanced glycation end products is found on endothelial and inflammatory cell surfaces. It binds to circulating advanced glycation end products, activating a proinflammatory protein cascade that contributes to systemic oxidative stress and inflammation.

sRAGE is the soluble isoform of RAGE and acts as a protective decoy by buffering inflammatory ligands, decreasing inflammatory injury. Therefore, low levels of sRAGE are a biomarker of deficient inflammatory control.

We show that plasma concentrations of the anti-inflammatory molecule sRAGE are reduced in patients with chronic obstructive pulmonary disease (COPD) and in patients with obstructive sleep apnoea (OSA). Overlap of COPD and OSA does not lead to an additive effect.

Effective treatment by continuous positive airway pressure (CPAP) of subjects with obstructive apnoeas (with or without associated COPD) increases the level of sRAGE, while in healthy subjects and COPD without OSA, these levels do not change over time. This is the first study to investigate the effect of CPAP on plasma levels of sRAGE.”

https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02092-9 “Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea”


A second study introduced sRAGE isoforms:

“We explored associations of circulating levels of soluble RAGE, its endogenous secretory (esRAGE) and cleaved (cRAGE) isoforms, AGEs, and their respective ratios with 15-year all-cause mortality in type 2 diabetes. The potential prognostic value of sRAGE as a marker of disease and occurrence of adverse events seems to be suitable for individuals with chronic disease or multimorbidity, and not for the general population.

Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects. At an average follow-up of 15 years, 130 deaths [in T2D subjects] were observed.

A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Kaplan-Meier survival function for patients with type 2 diabetes grouped according to quartiles of the nomogram-based mortality risk score:

diabetes survival

An increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes. The AGEs/cRAGE ratio led to a significant, albeit modest, improvement in the already established RECODe model of predicting 10-year all-cause mortality in type 2 diabetes based on age, sex, ethnicity, smoking, systolic blood pressure, history of major adverse cardiovascular events (MACE), HbA1c, total cholesterol, HDL-C, serum creatinine, and urinary albumin-to-creatinine ratio.

While none of the parameters was significantly associated with development of any complication in patients without complications at the time of enrollment, sRAGE was associated with the development of MACE over a 15-year follow-up in patients with type 2 diabetes who had no history of MACE at recruitment.”

https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01535-3 “Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study”


PXL_20220703_093033903

Gut microbiota therapy

This June 2022 review cited twenty 2022 papers for relationships between Parkinson’s disease and gut microbiota:

“Clinical diagnosis of PD is based on typical motor symptoms, and novel diagnostic biomarkers have been developed such as imaging markers, and α-synuclein fluid and tissue markers. Multimorbidity of non-motor disorders heighten the risk of adverse outcomes for patients with PD, which usually appear 20 years before onset of motor symptoms.

The gut microbiota is intimately connected to occurrence, development, and progression of PD, especially in early stages. A better understanding of the microbiota–gut–brain axis in PD can provide an opportunity to monitor an individual’s health by manipulating gut microbiota composition.

Several approaches like administration of probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, FMT, and dietary modifications have been tried to mitigate dysbiosis-induced ill effects and alleviate PD progression.

fimmu-13-937555-g001

Epidemiological studies have reported that diet affects (positively or negatively) onset of neurodegenerative disorders. Evidence suggests that diet composition’s effects on brain health is not due to diet-induced inflammatory response, but because of its effects on the gut microbiome.

Dysbiotic gut microbiota (including altered microbial metabolites) may play crucial roles in PD via various mechanisms, such as:

  • Increased intestinal permeability;
  • Aggravated intestinal inflammation and neuroinflammation;
  • Abnormal aggregation of α-synuclein fibrils;
  • Imbalanced oxidative stress; and
  • Decreased neurotransmitters production.

Future studies are essential to further elucidate cause-effect relationships between gut microbiota and PD, improved PD therapeutic and diagnostic options, disease progression tracking, and patient stratification capabilities to deliver personalized treatment and optimize clinical trial designs.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.937555/full “Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease”


PXL_20220619_184650557

Taurine week #7: Brain

Finishing a week’s worth of 2022 taurine research with two reviews of taurine’s brain effects:

“We provide a overview of brain taurine homeostasis, and review mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. Alterations to taurine homeostasis can impact a number of biological processes such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders.

Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given cytoprotective actions of taurine, such accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration.

nutrients-14-01292-g003

Taurine release is mainly mediated by volume-regulated anion channels (VRAC) that are activated by hypo-osmotic conditions and electrical activity. They can be stimulated via glutamate metabotropic (mGluR) and ionotropic receptors (mainly NMDA and AMPA), adenosine A1 receptors (A1R), and metabotropic ATP receptors (P2Y).

Taurine mediates its neuromodulatory effects by binding to GABAA, GABAB, and glycine receptors. While taurine binding to GABAA and GABAB is weaker than to GABA, taurine is a rather potent ligand of the glycine receptor. Reuptake of taurine occurs via taurine transporter TauT.

Cytoprotective actions of taurine contribute to brain health improvements in subjects with obesity and diabetes through various mechanisms that improve neuronal function, such as:

  • Modulating inhibitory neurotransmission, which promotes an excitatory–inhibitory balance;
  • Stimulating antioxidant systems; and
  • Stabilizing mitochondria energy production and Ca2+ homeostasis.”

https://www.mdpi.com/2072-6643/14/6/1292/htm “Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes”


A second review focused on taurine’s secondary bile acids produced by gut microbiota:

“Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. Hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases.

Biliary acids may influence each of the following three mechanisms through which interactions within the brain-gut-microbiota axis take place: neurological, immunological, and neuroendocrine. These microbial metabolites can act as direct neurotransmitters or neuromodulators, serving as key modulators of the brain-gut interactions.

The gut microbial community, through their capacity to produce bile acid metabolites distinct from the liver, can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favour. Hydrophilic bile acids, currently regarded as important hormones, exert modulatory effects on gut microbiota composition to produce secondary bile acids which seem to bind a number of receptors with a higher affinity than primary biliary acids, expressed on many different cells.

40035_2022_307_Fig1_HTML

TUDCA regulates expression of genes involved in cell cycle regulation and apoptotic pathways, promoting neuronal survival. TUDCA:

  • Improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition;
  • Reduces reactive oxygen species production, leading to protection against mitochondrial dysfunction;
  • Ameliorates endoplasmic reticulum stress; and
  • Inhibits expression of pro-inflammatory cytokines, exerting an anti-neuroinflammatory effect.

Although Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia have different disease progressions, they share similar pathways which can be targeted by TUDCA. This makes this bile acid a potentially strong therapeutic option to be tested in human diseases. Clinical evidence collected so far has reported comprehensive data on ALS only.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166453/ “Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases”

Taurine week #6: Stress

Two 2022 rodent studies of taurine’s associations with long-term stress, starting with a chronic restraint stress model:

“We show that chronic restraint stress can lead to hyperalgesia accompanied by changes in gut microbiota that have significant gender differences. Corresponding changes of bacteria can further induce hyperalgesia and affect different serum metabolism in mice of the corresponding sex.

Different serum metabolites between pseudo-germ-free mice receiving fecal microbiota transplantation from the chronic restraint stress group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice.

Effects of gut microbiota transplantation on serum metabolomics of female host: Taurine and hypotaurine metabolism, tryptophan metabolism, serotonergic synapse, arachidonic acid metabolism, and choline metabolism in cancer were the five identified pathways in which these different metabolites were enriched.

1-s2.0-S1043661822000743-gr11_lrg

Taurine and hypotaurine play essential roles in anti-inflammation, anti-hypertension, anti-hyperglycemia, and analgesia. Taurine can be used as a diagnostic index for fibromyalgia syndrome and neuropathic pain.

These findings improve our understanding of sexual dimorphism in gut microbiota in stress-induced hyperalgesia and the effect of gut microbiota on blood metabolic traits. Follow-up research will investigate causal relationships between them.”

https://www.sciencedirect.com/science/article/pii/S1043661822000743 “Gut microbiota and its role in stress-induced hyperalgesia: Gender-specific responses linked to different changes in serum metabolites”

Human equivalents:

  • A 7-8 month-old mouse would be a 38-42 year-old human.
  • A 14-day stress period is about two years for humans.

A second study used a chronic social defeat stress model:

“The level of taurine in extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice.

Male C57BL/6 J mice (∼ 23 g) and male CD-1 mice aged 7–8 months (∼ 45 g) were used. CD-1 mice were screened for aggressive behavior during social interactions for three consecutive days before the start of the social defeat sessions. Experimental C57BL/6 J mice were subjected to physical interactions with a novel CD-1 mouse for 10 min once per day over 10 consecutive days.

We found significant reductions in taurine and betaine levels in mPFC interstitial fluid of CSDS mice compared with control mice.

csds taurine betaine

We additionally investigated levels of interstitial taurine in chronic restraint stress (CRS) mice, another depressive animal model. After 14 days of CRS treatment, mice showed typical depression-like behaviors, including decreased sucrose preference and increased immobility time. mPFC levels of interstitial taurine were also significantly decreased in CRS mice.

Taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and proportions of different types of spines. Expression of N-methyl D-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation.

These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits.”

https://link.springer.com/article/10.1007/s10571-022-01218-3 “Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss”

Human equivalents:

  • A 7-8 month-old mouse would be a 38-42 year-old human.
  • A 500 mg/kg taurine dose injected intraperitoneally is (.081 x 500 mg) x 70KG = 2.835 g.
  • A 10-day stress period is about a year and a half for humans.

Don’t think aggressive humans would have to be twice as large to stress those around them. There may be choices other than enduring a year and a half of that.

Taurine week #3: Organs

Three 2022 papers investigated taurine’s effects on organs, starting with a rodent study of sepsis:

“Sepsis usually causes multiple organ dysfunctions and high mortality. Pathogenesis of sepsis is thought to be driven by hyperactive inflammation following pathogen invasion. If the immune system fails to eradicate pathogens, immune homeostasis is disturbed, leading to an overwhelming inflammation accompanied by immunosuppression.

Metabolomic analysis showed large amounts of taurine in neutrophils and monocytes and a dramatic decrease in taurine levels after lipopolysaccharides (LPS) exposure:

taurine decrease

Cecal ligation and puncture (CLP) model mice and CLP plus taurine mice were injected intraperitoneally with saline (200 μl) or taurine (200 mg/kg, in 200 μl) respectively at 6, 24, and 48 h after the operation. Taurine protected septic mice from death, improving tissue injuries in the lung, liver, and kidney by reducing neutrophil infiltration and TNF-α production.

taurine survival

Our data indicate that a supplement with taurine might be a promising therapeutic strategy for sepsis to reduce hyperactive inflammation and improve multiple organ dysfunctions.”

https://www.sciencedirect.com/science/article/abs/pii/S0008874922000272 “Mechanism of taurine reducing inflammation and organ injury in sepsis mice” (not freely available) Thanks to Dr. Liuluan Zhu for providing a copy.

Taurine demonstrated the only decrease in 17 amino acids measured in monocytes above. It was the same story for those amino acids and neutrophils.

A human equivalent to each of three mouse taurine doses administered over two days was (.081 x 200 mg) x 70 kg = 1.134 g. A second dose given at the 12-hour point may have improved treated subjects’ survival, as half of them died before the study’s 24-hour point of a second dose.


A second rodent study was on liver injury:

“We investigated the beneficial effects of taurine on fatty liver injury in vivo induced by tunicamycin, a chemical endoplasmic reticulum (ER) stressor.

The unfolded protein response (UPR) is a protein homeostasis-maintaining system that monitors ER conditions by sensing inadequacy in ER protein folding capacity. The ER is both a protein homeostasis-maintaining system and the primary site of lipid metabolism. The UPR plays vital roles in maintaining metabolic and lipid homeostasis.

Glutathione (GSH), a final byproduct of sulfur-containing amino acid metabolism, is not only a powerful antioxidant, but also a principal redox buffer in the ER. Depletion of reduced glutathione can cause additional oxidative stress.

Cysteine, the metabolic precursor of GSH, is also an essential substrate for taurine synthesis. Utilization of cysteine to generate GSH and taurine is competitive.

In this study, availability of cysteine is favored for GSH synthesis due to sufficient taurine supply. Taurine supplementation restored GSH levels, which were attenuated by tunicamycin treatment, by increasing expression of GCLC, an enzyme mediating GSH synthesis.

life-12-00354-g005

The protective effect of taurine on tunicamycin-induced hepatic injury results from its concurrent mitigation of both ER and oxidative stress.”

https://www.mdpi.com/2075-1729/12/3/354/htm “Taurine Ameliorates Tunicamycin-Induced Liver Injury by Disrupting the Vicious Cycle between Oxidative Stress and Endoplasmic Reticulum Stress”

This study provided further evidence for an idea in Treating psychopathological symptoms will somehow resolve causes? that:

“Such positive effects of taurine on glutathione levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”


A third rodent study investigated lung pneumonia:

“We evaluated anti-inflammatory effects of taurine derivative N-chlorotaurine (also known as taurine chloramine; TauCl) against LPS-induced pneumonia in obese mice maintained on a high fat diet.

Taurine is present in immune system cells such as macrophages and neutrophils. When an organism is infected by pathogens, immune cells produce hypochlorous acid to kill pathogens. Taurine reacts with excessive hypochlorous acid to produce TauCl, which reduces high levels of hypochlorous acid and its toxicity to surrounding host cells.

Intraperitoneal TauCl suppressed excessive immune response in lungs. TauCl treatment attenuates acute pneumonia-related pulmonary and systemic inflammation, including muscle wasting.”

https://www.mdpi.com/2218-1989/12/4/349/htmN-Chlorotaurine Reduces the Lung and Systemic Inflammation in LPS-Induced Pneumonia in High Fat Diet-Induced Obese Mice”


PXL_20220529_183605897

Taurine week #2: Bile acids

Two papers investigated taurine’s integration into bile acids, starting with a review:

“Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver, and stored in the gallbladder. BAs are released from the gallbladder into the small intestine via food intake to facilitate digestion and absorption of lipids and lipophilic vitamins by forming micelles in the small intestine.

After deconjugation by the gut microbiome, primary BAs are converted into secondary BAs. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine.

microorganisms-10-00068-g001

Some BAs reabsorbed from the intestine spill into systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues. Some BAs are not reabsorbed and bind to receptors in the terminal ileum.

BAs can affect cell-surface and intracellular membranes, including those of mitochondria and the endoplasmic reticulum. BAs are also hormones or signaling molecules, and can regulate BA, glucose, and lipid metabolism in various tissues, including the liver, pancreas, and both brown and white adipose tissue. BAs also affect the immune system.

BAs can affect the nervous system. More than 20 BAs have been detected in the brain of humans and rodents. The brain communicates with the gut and gut microbiome through BAs.”

https://www.mdpi.com/2076-2607/10/1/68/htm “Physiological Role of Bile Acids Modified by the Gut Microbiome”


Reference 56 was a human study:

“Centenarians (individuals aged 100 years and older) have a decreased susceptibility to ageing-associated illnesses, chronic inflammation, and infectious diseases. Centenarians have a distinct gut microbiome enriched in microorganisms that are capable of generating unique secondary bile acids.

We identified centenarian-specific gut microbiota signatures and defined bacterial species as well as genes and/or pathways that promote generation of isoLCA, 3-oxoLCA, 3-oxoalloLCA, and isoalloLCA. To our knowledge, isoalloLCA is one of the most potent antimicrobial agents that is selective against Gram-positive microorganisms, including multidrug-resistant pathogens, suggesting that it may contribute to maintenance of intestinal homeostasis by enhancing colonization-resistance mechanisms.”

https://www.nature.com/articles/s41586-021-03832-5 “Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians” (not freely available)


A few more papers will be coming on taurine and bile acids. I haven’t seen one investigate both taurine and glycine treatments to aid bile acid in achieving therapeutic results.

PXL_20220612_193749935