Minds of their own

It’s the weekend, so it’s time for: Running errands? Watching sports? Other conditioned behavior?

Or maybe broadening our cognitive ability with Dr. Michael Levin’s follow-ups to his 2021 Basal cognition paper and 2020 Electroceuticals presentation with a 2022 paper and presentation starting around the 13:30 mark:

Michael Levin - Cell Intelligence in Physiological and Morphological Spaces

“A homeostatic feedback is usually thought of as a single variable such as temperature or pH. The set point has been found to be a large-scale geometry, a descriptor of a complex data structure.”


His 2022 paper Technological Approach to Mind Everywhere: An Experimentally-Grounded Framework for Understanding Diverse Bodies and Minds:

“It is proposed that the traditional problem-solving behavior we see in standard animals in 3D space is just a variant of evolutionarily more ancient capacity to solve problems in metabolic, physiological, transcriptional, and morphogenetic spaces (as one possible sequential timeline along which evolution pivoted some of the same strategies to solve problems in new spaces).

Developmental bioelectricity works alongside other modalities such as gene-regulatory networks, biomechanics, and biochemical systems. Developmental bioelectricity provides a bridge between the early problem-solving of body anatomy and the more recent complexity of behavioral sophistication via brains.

This unification of two disciplines suggests a number of hypotheses about the evolutionary path that pivoted morphogenetic control mechanisms into cognitive capacities of behavior, and sheds light on how Selves arise and expand.

While being very careful with powerful advances, it must also be kept in mind that existing balance was not achieved by optimizing happiness or any other quality commensurate with modern values. It is the result of dynamical systems properties shaped by meanderings of the evolutionary process and the harsh process of selection for survival capacity.”


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Gut microbiota, SCFAs, and hypertension

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).

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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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Glucoraphanin is not sulforaphane

A poorly-conceived and intentionally-misrepresented human 2022 broccoli product study:

“We investigated whether a sulforaphane (SFN) [actually, sulforaphane precursor glucoraphanin] intake intervention improved cognitive performance and mood states in healthy older adults in a 12-week, double-blinded, randomized controlled trial.

The SFN group showed improvement in processing speed and a decrease in negative mood compared to the placebo group. However, there were no significant results in other biomarkers of oxidant stress, inflammation, or neural plasticity.

These results indicate that nutrition interventions using SFN can have positive effects on cognitive functioning and mood in healthy older adults.”

https://www.frontiersin.org/articles/10.3389/fnagi.2022.929628/full “Effects of sulforaphane intake on processing speed and negative moods in healthy older adults: Evidence from a randomized controlled trial”


Contrary to this study’s title, actual sulforaphane intake was not measured. The glucoraphanin product used in this study was the same item and daily dose as Eat broccoli sprouts for your workouts, which investigated effects with 19-to-23-year-old men. The treatment was taken all at once at an unspecified time of day rather than three times a day with young subjects.

These researchers knew from the 2012 study cited for dose that:

“Individual conversions of glucosinolates [like glucoraphanin] to isothiocyanates [like sulforaphane] varied enormously, from about 1% to more than 40% of dose. In contrast, administration of isothiocyanates (largely sulforaphane)-containing broccoli sprout extracts, resulted in uniformly high (70-90%) conversions to urinary dithiocarbamates.”

Young or old, a daily 30 mg glucoraphanin intake isn’t sufficient to fully activate human Nrf2 signaling pathways. A daily 17 mg sulforaphane intake could accomplish that.


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Don’t bother eating broccoli sprouts if you’re old?

I try to not curate research that wastes resources. Couldn’t help but present this 2022 rodent study:

“We aimed to evaluate if sulforaphane (SFN) long-term treatment was able to prevent age-associated cognitive decline in adult (15-month-old) and old (21-month-old) female and male rats.

Our results showed that SFN restored redox homeostasis in brain cortex and hippocampus of adult rats, preventing cognitive decline in both sexes. However, redox responses were not the same in males and females.

Old rats were not able to recover their redox state as adults did, but they had a mild improvement. These results suggest that SFN mainly prevents rather than reverts neural damage; though, there might also be a range of opportunities to use hormetins like SFN, to improve redox modulation in old animals.”

https://link.springer.com/article/10.1007/s10522-022-09984-9 “Long-term sulforaphane-treatment restores redox homeostasis and prevents cognitive decline in middleaged female and male rats, but cannot revert previous damage in old animals” (not freely available)


These researchers cited Sulforaphane in the Goldilocks zone for hormetic effects of sulforaphane, so I asked:

“Did you develop any preliminary dose/response data for stating ‘there might also be a range of opportunities to use hormetins like SFN to improve redox modulation in old animals’?”

They cited Broccoli sprouts activate the AMPK pathway for long-term effects of a small sulforaphane dose, so I asked:

“Also, the three studies cited for ‘0.5 mg/Kg, i.e. 2.82 μmol/Kg BW for 3 months’ were all mouse studies. Since this was a rat study, wouldn’t there be increased dose and duration equivalencies?”

I’ll update this blog post in the event either of my questions to these researchers are answered.

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Sulforaphane nose drops

This 2022 rodent study compared capabilities of intranasal nanoparticle sulforaphane and free sulforaphane to mitigate brain damage caused by a common cancer treatment:

“Non-invasive intranasal (IN) trafficking of therapeutic agents with nanocarriers can enhance efficacy of drug delivery, biodistribution, bioavailability, and absorption against enzymatic degradation and extracellular transportation. Direct IN trafficking of nanocarriers is expected to reduce drug wastage, administration frequency, and undesirable adverse effects.

The nasal route for brain-targeted delivery of sulforaphane (SF) loaded within iron oxide nanoparticles (Fe3O4-NPs) was based on improving physicochemical stability of SF, and to enhance its bioavailability by avoiding oral route drawbacks like extensive first-pass metabolism and intestinal drug degradation.

Cisplatin (CIS) significantly induced a significant increase in acetylcholinesterase activities and lipid peroxides, and a significant decrement in glutathione and nitric oxide contents. We aimed to explore the nanotherapeutic potential of intranasally delivered SF loaded within Fe3O4-NPs (N.SF) against CIS-induced neurotoxicity through different biochemical, behavioral, and histological investigations.

hippocampus damage

Treatment with N.SF was more capable of mitigating both CIS-induced striatal and cortical injuries. IN treatment with either SF or N.SF showed equal alleviative potential regarding CIS-induced hippocampal or cerebellar injury.

These encouraging results demonstrated the potential use of iron-oxide NPs as neurotherapeutic agents, and confirmed the possibility of developing a novel promising and non-invasive intranasal delivery system for treatment of CIS-induced neurotoxicity.”

https://link.springer.com/article/10.1007/s12640-022-00555-x “Neuroprotective Potential of Intranasally Delivered Sulforaphane-Loaded Iron Oxide Nanoparticles Against Cisplatin-Induced Neurotoxicity”


I found this study from it citing a paper in Do broccoli sprouts treat migraines?

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Non-patentable boron benefits

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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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”


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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


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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. A follow-on study could 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”


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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”


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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”


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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.

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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 #5: Blood

Two 2022 papers investigated taurine’s effects in blood, starting with a review of platelets:

“Taurine is the most abundant free amino acid in the human body, with a six times higher concentration in platelets than any other amino acid. It is highly beneficial for the organism, has many therapeutic actions, and is currently approved for heart failure treatment in Japan. Only the lack of large-scale phase 3 clinical trials restricts taurine use as a therapeutic agent in several other pathologies for treatment of which it has been shown to be effective (hypertension, atherosclerosis, stroke, neurodegenerative diseases, metabolic diseases, e.g., diabetes mellitus, and others).

Because taurine was seen as a non-patentable nutrient, the pharmaceutical industry has not shown much interest in its research. Considering that taurine and its analogues display permissible side effects, along with the need of finding new, alternative antithrombotic drugs with minimal side effects and long-term action, the potential clinical relevance of this fascinating nutrient and its derivatives requires further consideration.”

https://www.mdpi.com/2077-0383/11/3/666/htm “Taurine and Its Derivatives: Analysis of the Inhibitory Effect on Platelet Function and Their Antithrombotic Potential”

Figure 1 provided details of taurine and its derivatives’ effects on various processes involved in platelet activation and aggregation.


A second paper was a rodent study:

“To evaluate chronic effects of taurine on cholesterol levels, we analyzed mice fed a taurine-rich diet for 14–16 weeks. Long-term feeding of taurine lowered plasma cholesterol and bile acids without significantly changing other metabolic parameters, but hardly affected these levels in the liver.

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Taurine upregulates transcriptional activity of Cyp7a1 by suppressing FGF21 production in the liver. Bile acids are converted from blood cholesterol by CYP7A1, and more efficiently enter enterohepatic circulation via taurine conjugation.

This study shows that long-term feeding of taurine lowers both plasma cholesterol and bile acids, reinforcing that taurine effectively prevents hypercholesterolemia.”

https://www.mdpi.com/1422-0067/23/3/1793/htm “Long-Term Dietary Taurine Lowers Plasma Levels of Cholesterol and Bile Acids”

A human equivalent of this male C57BL/6J mouse 16-week taurine intervention is roughly 17 years. That strain’s male maximum lifespan is around 800 days, and human maximum lifespan is currently 122.5 years.


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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.

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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.

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