Control group

Reversing hair greying, Part 2

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Neurochemicals, Stress, Testosterone , ,

Three papers that cited the 2021 Reversing hair greying study, starting with a 2024 rodent study:

“External treatment with luteolin, but not that with hesperetin or diosmetin, alleviated hair graying in model mice. Internal treatment with luteolin also mitigated hair graying.

Both treatments suppressed the increase in p16ink4a-positive cells in bulges [senescent keratinocyte stem cells (KSCs)]. Both treatments also suppressed decreases in expression levels of endothelins in KSCs and their receptor (Ednrb) in melanocyte stem cells (MSCs), and alleviated hair graying in mice.”

https://www.mdpi.com/2076-3921/13/12/1549 “Anti-Graying Effects of External and Internal Treatments with Luteolin on Hair in Model Mice”

This study treated subjects internally and externally with luteolin and hesperetin, which are ranked #7 (effective treatment) and #14 (not an effective treatment) per Nrf2 activator rankings. I wonder what these researchers would have found if they used the #1 ranked Nrf2 activator, sulforaphane.

A 2024 review managed to cover the Nrf2 activation subject without mentioning sulforaphane:

“Certain types of hair graying can be prevented or treated by enhancing MSC maintenance or melanocyte function, reducing oxidative stress, and managing secretion and action of stress hormones.

Tactical approaches to pursue this goal may include a selective activation of the p38 MAPK–MITF axis, enhancing cellular antioxidant capacity through activating NRF2, and modulating the norepinephrine–β2AR–PKA signaling pathway.”

https://www.mdpi.com/2076-3417/14/17/7450 “Intrinsic and Extrinsic Factors Associated with Hair Graying (Canities) and Therapeutic Potential of Plant Extracts and Phytochemicals”

This reviewer also avoided citing the 2021 Sulforaphane and hair loss, although hair loss was mentioned multiple times. I suspect that institutional politics was involved, as both papers are from South Korea.

Reference 32 of this review was a 2023 review that covered mainly unintentional hair greying reversal as a side effect noted when people had pharmaceutical treatments for various diseases:

“Hair graying is a common and visible sign of aging resulting from decreased or absence of melanogenesis. It has long been thought that reversal of gray hair on a large scale is rare. However, a recent study reported that individual gray hair darkening is a common phenomenon, suggesting the possibility of large-scale reversal of gray hair.

All these treatments rely on the presence of a sufficient population of active McSCs. Maintaining a healthy population of McSCs is also an urgent problem that needs to be addressed.”

https://www.ijbs.com/v19p4588.htm “Reversing Gray Hair: Inspiring the Development of New Therapies Through Research on Hair Pigmentation and Repigmentation Progress”

I published A hair color anecdote two months into eating broccoli sprouts every day when I first noticed dark hair growing in. Since it’s been over 4 years that I’ve continued eating broccoli sprouts daily, I think it’s alright to stop referring to my continuing reversal of hair greying as an anecdote.

But it was apparently too late to address hair loss, which started before I turned 30. So now you know what to do. 🙂

A sulforaphane review

gettingwell4 0-1 star Wasted resources, Beliefs, Brain development, Epigenetics, Immune system , , ,

Here’s a 2025 review where the lead author is a retired researcher whose words readers might interpret as Science. As a reminder, unlike study researchers, reviewers are free to:

  • Express their beliefs as facts;
  • Over/under emphasize study limitations; and
  • Disregard and misrepresent evidence as they see fit.

Reviewers also aren’t obligated to make post-publication corrections for their errors and distortions. For examples:

1. After the 7. Conclusions section, there’s an 8. Afterword: I3C and DIM section. The phrase “As detailed in our earliest work on broccoli sprouts..” indicated a belief carried over from last century of the low importance of those research subjects.

Then, contrary to uncited clinical trials such as Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts and Eat broccoli sprouts for DIM, “Broccoli sprouts had next to no indole glucosinolates.” And in the middle of downplaying I3C and DIM research, they stated: “There are 149 clinical studies on DIM and 11 on I3C listed on clinicaltrials.gov, suggesting a good safety profile. Potential efficacy and mode of action in humans are a subject of intense current investigation, though definitive answers will not come for some time.” 🧐

2. In the 3. Sulforaphane section, they asserted: “Glucosinolates such as glucoraphanin are ‘activated’ or converted to isothiocyanates such as sulforaphane by an enzyme called myrosinase, which is present in that same plant tissue (e.g., seed, sprout, broccoli head, or microgreen) and/or in bacteria that all humans possess in their gastrointestinal tracts.” and cited a 2016 book they coauthored that I can’t access.

The first 2021 paper of Broccoli sprout compounds and gut microbiota didn’t assert that “all humans” had certain gut microbiota that converted glucosinolates to isothiocyanates. That paper instead stated: “Human feeding trials have shown inter-individual variations in gut microbiome composition coincides with variations in ITC absorption and excretion, and some bacteria produce ITCs from glucosinolates.”

3. Nearly half of their cited references were in vitro cancer papers. I rarely curate those types of studies because of their undisclosed human-irrelevant factors. For example, from the second paper of Polyphenol Nrf2 activators:

Bioavailability studies reveal that maximum concentrations in plasma typically do not exceed 1 µM following consumption of 10–100 mg of a single phenolic compound, with the maximum concentration occurring typically less than 2 h after ingestion, then dropping quickly thereafter. In the case of the in vitro studies assessed herein, and with few exceptions, most of the studies employed concentrations >10 µM with some studies involving concentrations in the several hundred µM range, with the duration of exposure typically in the range of 24–72 h, far longer duration than the very short time interval of a few minutes to several hours in human in vivo situations.

applsci-15-00522-g001-550

https://www.mdpi.com/2076-3417/15/2/522 “The Impact of Sulforaphane on Sex-Specific Conditions and Hormone Balance: A Comprehensive Review”

Nrf2 activator rankings

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A 2024 cell study compared and contrasted findings of previous plant compound Nrf2 inducer studies with a newer assay type:

“Various plants have been reported to contain compounds that promote transcriptional activity of Nuclear factor erythroid 2-related factor 2 (Nrf2) to induce a set of xenobiotic detoxifying enzymes, such as NAD(P)H-quinone acceptor oxidoreductase 1 (NQO1), via the antioxidant response element (ARE). An ARE luciferase reporter assay was recently developed to specifically assess Nrf2 induction potency of compounds.

33 compounds were sorted in the order of their transcriptional activity of Nrf2. CD value is the concentration of a compound required to double the basal activities of individual enzymes or luciferase activity.

nrf2 induction

This study is the first to examine consistency of the transcriptional activity of Nrf2 evaluated using ARE reporter and NQO1 assays for multiple compounds. Future comparisons of CD values by each assay across cell types may be used to demonstrate consistency between the assays, as well as to reveal the factors that influence Nrf2 induction potency.”

https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-024-07038-6 “Nrf2 induction potency of plant-derived compounds determined using an antioxidant response element luciferase reporter and conventional NAD(P)H-quinone acceptor oxidoreductase 1 activity assay”

A 2019 ranking of sulforaphane with 18 other Nrf2 activators was curated in Part 2 of Rejuvenation therapy and sulforaphane, and pointed out bioavailability differences:
OMCL2019-2716870.006

It [sulforaphane] is not only a potent Nrf2 inducer but also highly bioavailable [around 80%], so that modest practical doses can produce significant clinical responses. Other Nrf2 activators [shown in the above image] not only lack potency, but also lack the bioavailability to be considered as significant intracellular Nrf2 activators.”

This study attempted to explain differences in the two assay findings with numerous “may” and “could” statements. Okay.

But if you want to activate your body’s endogenous detoxification and antioxidant systems with a natural plant compound, sulforaphane remains the number one choice.

PXL_20241223_185836159

Too dangerous to investigate?

gettingwell4 0-1 star Wasted resources, Hippocampus, Immune system, Limbic system, Memory , ,

This blog’s 1100th curation is a clinical trial of ergothioneine’s effects on cognitive decline:

“We recruited participants aged between 60–90 years of age, from three study cohorts diagnosed with mild cognitive impairment (MCI) and provided them with ergothioneine (ET)  (25 mg capsules administered orally three times a week) or placebo in a double-blinded and randomized manner. Blood samples were collected at baseline and quarterly (visits 1, 4, 7, 10, 14) for clinical safety assessment and biomarker analyses). Neuro-cognitive assessments were conducted biannually (visits 7 and 14).

Following ET intake, an increase in Z-scores was observed in the Rey Auditory Verbal Learning Test (RAVLT) (immediate and delayed recalls), which evaluates learning ability and memory.

ravlt

wbc

Participants in both ET and placebo groups recorded a lower total white blood cell count compared to baseline at visit 7, both of which recovered subsequently. The reasons for this anomaly are unclear but values were all still within the expected range for their age.”

https://journals.sagepub.com/doi/epub/10.1177/13872877241291253 “Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study”

I rated this study a waste of time and money for the researchers’ incurious lack of following where their data led. Significant WBC signals of both treatment and placebo subjects’ immune system responses were shrugged off with an “expected range” non-explanation.

What can’t white tea do?

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An effusive 2024 review of white tea’s beneficial effects:

“This comprehensive examination contributes nuanced perspectives, paving the way for continued research, innovation, and integration of white tea into diverse consumer preferences. Overall, white tea emerges as a multifaceted beverage with far-reaching implications for health, wellness, and the future landscape of the tea industry.”

white tea

https://www.sciopen.com/article/10.26599/FSHW.2024.9250424 “New insights into chemical compositions and health benefits of white tea and development of new products derived from white tea” (click pdf link)

I didn’t see a mention of white tea drinkers’ ability to levitate and fly the astral plane like the Red Bull commercials. Maybe it’s just obvious?

TFEB and autophagy

gettingwell4 2-3 stars Required further work, Stress ,

Two 2024 papers that cited Precondition your defenses with broccoli sprouts, starting with an in vitro study of influences on auditory cell function:

“Although various studies have focused on the effect of oxidative stress on the inner ear as an inducer of age-related hearing loss (ARHL), there are no effective preventive approaches for ARHL.

We focused on the function of TFEB and the impact of intracellular ROS as a potential target for ARHL treatment in a NaAsO2-induced auditory premature senescence model. Our results suggested that short exposure to NaAsO2 leads to DNA damage, lysosomal damage and mitochondrial damage in auditory cells, triggering temporary signals for TFEB transport into the nucleus and, as a result, causing insufficient autophagic flux and declines in lysosomal function and biogenesis and mitochondrial quality.

41420_2024_2139_Fig6_HTML

This is the first report to indicate that the inactivation of TFEB directly causes oxidative stress (NaAsO2)-induced premature auditory senescence and SASP induction via decreases in autophagic flux and lysosomal dysfunction, with a lowered pH at the transcriptional level and, as a consequence, ROS production with decreasing mitochondrial quality in auditory cells. The activator of TFEB might have a pivotal antiaging effect in the inner ear.”

https://www.nature.com/articles/s41420-024-02139-4 “Premature senescence is regulated by crosstalk among TFEB, the autophagy lysosomal pathway and ROS derived from damaged mitochondria in NaAsO2-exposed auditory cells”

These researchers used exposure concentrations and durations that had no relevance to humans. Human irrelevance made it difficult to assess the above graphic that shows both TFEB activation and inactivation as stress-related. “No effective preventive approaches for ARHL” was asserted as a given, although “TFEB activation via transport into the nucleus contributes to anti-senescence activity in auditory cells and represents a new therapeutic target for ARHL” was also stated.

Just like the two papers in Eat broccoli sprouts for your hearing, preconditioning’s importance wasn’t investigated. So this study didn’t have findings about how mild TFEB activation or inactivation might precondition auditory cells for other stress that might damage hearing.

Next is a review of muscle regeneration and autophagy:

“Satellite cells, also known as muscle stem cells when activated, are essential for muscle repair. These adult stem cells typically remain in a dormant state. In response to tissue injury, these cells are rapidly activated and divided to generate new stem cells, which proliferate to form myoblasts, which further differentiate into myocytes to repair damaged muscle tissue. However, muscle regeneration can be significantly impaired under various conditions due to dysfunctional satellite cell activity.

mTORC1 activity is suppressed during amino acid starvation, leading to autophagy activation. Under these conditions, TFEB, TFE3, and MITF translocate to the nucleus, where they enhance the transcription of genes involved in autophagy and lysosomal function. When nutrients are abundant, mTORC1 suppresses autophagy. This inhibition ensures that resources are directed toward growth and proliferation rather than cellular recycling.

Chronic injuries are typically associated with sustained metabolic or oxidative stress, leading to prolonged or impaired autophagy. While autophagy serves a compensatory and beneficial role in acute injuries, its role in chronic muscle diseases is more complex. On the one hand, autophagy alleviates oxidative stress and mitigates aging. On the other hand, dysregulated autophagy may contribute to muscle fibrosis and loss of muscle mass.

The function of autophagy varies across different stages of satellite cell activity. Autophagy:

  1. Maintains cellular homeostasis by clearing damaged organelles.
  2. Preserves the number of satellite cells by antagonizing apoptosis.
  3. Sustains the quiescence of satellite cells by reducing reactive oxygen species (ROS).
  4. Promotes the activation of satellite cells by supplying energy.
  5. Facilitates the differentiation of satellite cells by mitochondrial remodeling.”

ijms-25-11901-g003-550

https://www.mdpi.com/1422-0067/25/22/11901 “Autophagy in Muscle Regeneration: Mechanisms, Targets, and Therapeutic Perspective”

I’ve curated a few other of the 110 papers that cited the 2020 “Sulforaphane activates a lysosome-dependent transcriptional program to mitigate oxidative stress” over the years, to include:

Sulforaphane’s effects on autism and liver disease;

Bridging Nrf2 and autophagy; and

Eat broccoli sprouts to maintain your cells.

Polyphenol Nrf2 activators

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Two 2024 reviews by the same group that published Sulforaphane in the Goldilocks zone investigated dietary polyphenols’ effects as “hormetic nutrients”:

“Polyphenols display biphasic dose–response effects by activating at a low dose the Nrf2 pathway resulting in the upregulation of antioxidant vitagenes [see diagram]. We aimed to discuss hormetic nutrients, including polyphenols and/or probiotics, targeting the Nrf2 pathway and vitagenes for the development of promising neuroprotective and therapeutic strategies to suppress oxidative stress, inflammation and microbiota deregulation, and consequently improve cognitive performance and brain health.

antioxidants-13-00484-g001

Hormetic nutrition through polyphenols and/or probiotics targeting the antioxidant Nrf2 pathway and stress resilient vitagenes to inhibit oxidative stress and inflammatory pathways, as well as ferroptosis, could represent an effective therapy to manipulate alterations in the gut microbiome leading to brain dysfunction in order to prevent or slow the onset of major cognitive disorders. Notably, hormetic nutrients can stimulate the vagus nerve as a means of directly modulating microbiota-brain interactions for therapeutic purposes to mitigate or reverse the pathophysiological process, restoring gut and brain homeostasis, as reported by extensive preclinical and clinical studies.”

https://www.mdpi.com/2076-3921/13/4/484 “Hormetic Nutrition and Redox Regulation in Gut–Brain Axis Disorders”

I’m not onboard with this study’s probiotic assertions because most of the cited studies contained unacknowledged measurement errors. Measuring gut microbiota, Part 2 found:

“The fecal microbiome does not represent the overall composition of the gut microbiome. Despite significant roles of gut microbiome in various phenotypes and diseases of its host, causative microbes for such characteristics identified by one research fail to be reproduced in others.

Since fecal microbiome is a result of the gut microbiome rather than the representative microbiome of the GI tract of the host, there is a limitation in identifying causative intestinal microbes related to these phenotypes and diseases by studying fecal microbiome.”

These researchers also erroneously equated isothiocyanate sulforaphane’s Nrf2-activating mechanisms with polyphenols activating Nrf2.

This research group did better in clarifying polyphenols’ mechanisms in a review of hormetic dose-response effects of the polyphenol rosmarinic acid:

“This article evaluates whether rosmarinic acid may act as a hormetic agent, mediating its chemoprotective effects as has been shown for similar agents, such as caffeic acid, a derivative of rosmarinic acid.

Rosmarinic acid enhanced memory in institute of cancer research male mice in the Morris water maze (escape latency).

untitled

Of importance in the evaluation of rosmarinic acid are its bioavailability, metabolism, and tissue distribution (including the capacity to affect and/or cross the BBB and its distribution and half-life within the brain). In the case of polyphenols, including rosmarinic acid, they are typically delivered at low doses in the diet and, in most instances, they do not escape first-pass metabolism, with the prominent chemical forms being conjugates of glucuronides and sulfates, with or without methylation.

These conjugated metabolites are chemically distinct from the parent compound, showing considerable differences in size, polarity, and ionic form. Their biological actions are quite different from the parent compound.

Bioavailability studies reveal that maximum concentrations in plasma typically do not exceed 1 µM following consumption of 10–100 mg of a single phenolic compound, with the maximum concentration occurring typically less than 2 h after ingestion, then dropping quickly thereafter. In the case of the in vitro studies assessed herein, and with few exceptions, most of the studies employed concentrations >10 µM with some studies involving concentrations in the several hundred µM range, with the duration of exposure typically in the range of 24–72 h, far longer duration than the very short time interval of a few minutes to several hours in human in vivo situations.

We strongly recommend that all experiments using in vitro models to study biological responses to dietary polyphenols use only physiologically relevant flavonoids and their conjugates at appropriate concentrations, provide evidence to support their use, and justify any conclusions generated. When authors fail to do this, referees and editors must act to ensure that data obtained in vitro are relevant to what might occur in vivo.”

https://www.degruyter.com/document/doi/10.1515/med-2024-1065/html “The chemoprotective hormetic effects of rosmarinic acid”

Failed aging paradigms

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A 2024 paper with 81 coauthors presented different views of aging:

“This article highlights the lack of consensus among aging researchers on fundamental questions such as the definition, causes, and onset of aging as well as the nature of rejuvenation. Our survey revealed broad disagreement and no majority opinion on these issues.

We obtained 103 responses (∼20% of which were submitted anonymously). The respondents included 29.8% professors, 25% postdoctoral fellows, 22.1% graduate students, 13.5% industry professionals, and 9.6% representing other categories (a total of eight additional groups).

When does aging begin? At 20 years (22%), gastrulation (18%), conception (16.5%), gametogenesis (13%), 25 years (11%), birth (8%), 13 years (5%), and 9 years (4%). Nobody chose the only remaining option (30 years).

m_pgae499f3

It is clear from responses that aging remains an unsolved problem in biology. While most scientists think they understand the nature of aging, apparently their understanding differs. Where some may stress the importance of targeting underlying mechanisms, others focus on ameliorating the phenotypes.”

https://academic.oup.com/pnasnexus/article/3/12/pgae499/7913315?login=false “Disagreement on foundational principles of biological aging”

I’ll assert that these researchers were unable to incorporate information outside of their chosen paradigm. This would explain why only 18% understood the embryonic stage of gastrulation as aging’s start, although the 2022 paper Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in Xenopus laevis provided epigenetic clock evidence that:

“It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.”

I’ve cited Josh Mitteldorf’s work about aging a few times. His paradigm of aging is in his 2017 book Cracking the Aging Code: The New Science of Growing Old – And What It Means for Staying Young that:

“Aging has an evolutionary purpose: to stabilize populations and ecosystems.”

However, there isn’t evidence of such causal inheritance mechanisms that would begin an organism’s aging during embryogenesis, i.e., that an embryo’s development of aging elements at gastrulation is causally affected by population and ecosystem factors.

Dr. Goodenowe recently had a casual conversation Episode 8 – Perpetual Health, Exploring The Science Behind Immortality where he asserted items such as:

“What we’re all fighting is entropy. Entropy is the tendency of all things to reach a level of randomness. Aging is not a disease. It’s just apathy and entropy. The body just doesn’t care – people don’t pay attention.

This notion that we are programmed for death is wrong. We’re not programmed to die. We actually teach ourselves to die. The body learns how to die, so as your function decreases, it adjusts. It appears to be programmed because of the association with chronological age.”

I haven’t seen any of his papers that put these and his other assertions up for review. For example, I doubt the entropy-caused randomness assertion would survive peer review per Stochastic methylation clocks?:

“Entropic theories of aging have never been coherent, but they are nevertheless experiencing a resurgence in recent years, primarily because neo-Darwinist theories of aging are all failing. I find this ironic, because the neo-Darwinist theories arose precisely because scientists realized that the Second Law of Thermodynamics does not apply to living systems.”

The funny thing about failed aging paradigms is that quite a few of their treatments improve healthspan, but not lifespan. If they don’t “target aging underlying mechanisms” they “ameliorate aging phenotypes.” None so far have positively affected both human healthspan and lifespan.

PXL_20241129_174732711.MP~2

Sulforaphane in a tablet?

gettingwell4 0-1 star Wasted resources

A 2024 randomized placebo-controlled human study by the product manufacturer investigated enteric-coated sulforaphane:

“The safety, tolerability, and pharmacokinetics of an enteric-coated tablet formulation of SFX-01 were evaluated in a randomized, double-blind, placebo-controlled, dose-escalation study [300 mg once daily (46.2 mg sulforaphane (SFN)), 300 mg twice daily or 600 mg once daily (92.4 mg SFN)] over 7 days in healthy male participants. Treatment-emergent adverse events occurred in 94% of participants who received SFX-01 and were most commonly gastrointestinal events.

The observed peak blood concentration (Cmax) for the sum of SFN and metabolites (total thiol) across all treatment cohorts ranged from 0.43 to 2.12 µmol/L in 3–6 hours. Urinary excretion of SFN and individual metabolites ranged from < 1 to 41%, and the proportion excreted did not appear to be influenced by the dose.

12325_2024_3018_Fig2_HTML

Pharmacokinetic analyses demonstrated that the behavior of SFX-01 enteric-coated tablets was in line with expectations (i.e., rapid absorption following a lag phase attributed to the enteric coating on the tablet formulation), and individual Cmax and AUC values for combined SFN and metabolites were within the range required for pharmacological activity based on in vitro data. Future studies in relevant patient populations/disease indications will look to evaluate pharmacodynamics and target engagement.”

https://link.springer.com/article/10.1007/s12325-024-03018-1 “A Phase 1 Randomized, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Enteric-Coated Stabilized Sulforaphane (SFX-01) in Male Participants”

This study’s referenced a 2017 study for:

“The proportion excreted via the urine in this study (15–60%) broadly agreed with a 2017 report in which 10 patients were administered 200 µmol of SFN in a 1:1 alpha-cyclodextrin solution, and a mean excretion of 62.3% of the administered dose was measured.”

I’ve curated that 2017 study several times, such as in the second discussion topic of Microwave broccoli seeds to create sulforaphane.

I’m sure these researchers feel that they did a good job for their sponsor. But this current study didn’t address items that would advance science past the 2017 study done at a lower 35 mg dose. For example:

  1. Why did subject bioavailability vary from < 1 to 41% as measured by urinary excretion of sulforaphane and metabolites? The 62.3% average of the 2017 study was meaningless considering those subjects varied from 86.9% to 19.5% (> 400% higher).
  2. Why did subject peak blood concentration vary from 2.12 to 0.43 µmol/L (almost 500% higher)? These researchers knew that would happen as the 2017 study subjects varied from 2.032 to 0.359 μmol (over 500% higher).
  3. Why did almost all (94%) subjects have adverse reactions to the 46.2 to 92.4 mg sulforaphane doses? 60% of the 2017 study subjects also had adverse reactions to a lower 35 mg dose. In what normal situation would people want to take tablets that made them nauseous?

PXL_20241101_192705828

Do broccoli sprouts help treat colonic inflammation?

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

A 2024 human study investigated broccoli sprouts’ effects as an adjunct to ulcerative colitis treatment:

“A dietary approach with sulforaphane (SFN)-rich broccoli sprouts (BS) mitigates colonic inflammation in human ulcerative colitis (UC) patients treated with mesalazine. Subjects were instructed to take 20 g of raw BS or alfalfa sprouts (AS) daily for 8 weeks, with BS containing 4.4 mg/g glucoraphanin, a precursor of sulforaphane, and AS containing no glucoraphanin.

Our findings indicate that the positive effects of SFN-rich BS may be driven by activation of the Nrf2-dependent antioxidant system, which helps combat chronic oxidative stress.

broccoli sprouts and ulcerative colitis

Instead of using glucoraphanin tablets, we used raw BS in our study. Most of the glucoraphanin in BS is converted to biologically active SFN by myrosinase activity in raw BS during chewing BS in the oral cavity. The rest of the glucoraphanin is converted into biological active SFN by myrosinase activity in intestinal microbiota.

Oral intake of BS induces much higher concentrations of systemic SFN compared to taking the same amount of oral glucoraphanin tablets. Another clinical trial using pure SFN, such as via glucoraphanin tablets, instead of using BS, must be conducted.”

https://www.ffhdj.com/index.php/ffhd/article/view/1440/4044 “Dietary intake of sulforaphane-rich broccoli sprouts decreases fecal calprotectin levels in patients with ulcerative colitis”

This study’s daily 20 grams of broccoli sprouts and 88 mg (4.4 mg x 20) glucoraphanin is about what I take, with red cabbage sprouts (which also contain glucoraphanin) and mustard sprouts comprising the other two thirds of total 60-65 grams. Sulforaphane amounts weren’t calculated, as they depend on whether sprouts were eaten with other foods (I’ve eaten them alone since Week 19), how thoroughly sprouts were chewed (I chew each mouthful for at least a minute before swallowing), the presence of certain gut microbiota, sprout age, and other factors.

PXL_20241006_161510628

Brain restoration with plasmalogens, Part 2

gettingwell4 5+ stars Premium, Acetylcholine, Amygdala, Brain development, Brainstem, Cerebellum, Cerebrum, Dopamine, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Stress , , , ,

This September 2024 presentation adds data points and concepts to Part 1:

supplementation

  1. “Your brain is dynamically connected to and adaptively responsive to its environment.
  2. You are in control of this environment (nutrition, stimulation, adversity).
  3. Need to measure the environment (lab testing, physiology) and adaptive response to the environment (MRI) to optimize your environment (nutrition, lifestyle) to achieve optimal brain structure, function, health, and longevity.

neurovascular

From a global cortical volume and thickness perspective, 17 months of high dose plasmalogens reversed about 15 years of predicted brain deterioration. 31 months reversed almost 20 years. So you can get more out of life.”

https://drgoodenowe.com/immortal-neurology-building-maintaining-an-immortal-brain/

Dr. Goodenowe also added case studies of two patients:

1. A 50-year-old woman with MS who had been legally blind in one eye for 32 years who regained sight in that eye after eight months of supplementation.

“This is the adaptability of the human brain. Her eye is not actually impaired. What’s impaired is the ability, the adaptability of the brain to the signal of light, to actually start interpreting what that light signal is.”

2. A 61-year-old man with dementia from firefighting work for the U.S. Navy in a toxic environment with head injuries after nine months of supplementation.

“The brain can heal itself is the point of the story. His executive function skills in everyday life are getting better.”

Activate Nrf2 to reduce biological age

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A 2024 primate study investigated effects of an off-patent drug on age-related changes:

“We evaluated geroprotective effects of metformin on adult male cynomolgus monkeys. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin’s influence on delaying age-related phenotypes at the organismal level.

monkey nrf2

Results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability.

Geroprotective effects on primate neurons were partially mediated by activation of Nrf2, a transcription factor with anti-oxidative capabilities.”

https://www.cell.com/cell/abstract/S0092-8674(24)00914-0 “Metformin decelerates aging clock in male monkeys” (not freely available). Thanks to Dr. Pradeep Reddy for providing a copy.

From this study’s Nrf2 activation findings:

“Metformin treatment resulted in increased nuclear phosphorylated Nrf2, accompanied by up-regulation of Nrf2 target genes like HO-1, NQO-1, SOD3, GPX2, and GPX1, which were generally suppressed and typically down-regulated during human neuron senescence.

Genes pivotal for neuronal function, such as dendrite morphogenesis/extension and synapse assembly (e.g., GSK3B, GRID2, and NRG3), were down-regulated during aging in excitatory neurons (ExN), inhibitory neurons (InN), oligodendrocytes (OL), oligodendrocyte progenitor cells (OPC), microglia, and astrocyte but were restored by metformin treatment. By contrast, pathways that were up-regulated during aging, including activation of the immune response, complement activation, and regulation of the TGF-b receptor signaling pathway, were reset to lower levels by metformin treatment.

metformin neuronal gene pathways

We verified that markers associated with brain aging and progression of neurodegenerative diseases were restored by metformin treatment to levels similar to those observed in young monkeys. Additionally, we observed that reduced myelin sheath thickness, a characteristic of aged monkeys, was rebuilt to a younger state following metformin treatment.

These findings align with the levels of nuclear-localized phosphorylated Nrf2, suggesting that Nrf2 pathway activation is a key mechanism in metformin’s role in delaying human neuronal aging and, by extension, brain aging. Consistent with our in vitro findings, Nrf2 pathway activation was also detected across multiple tissues in metformin-treated monkeys, including frontal lobe neurons.

At last count, I’ve curated 250+ papers this decade on cruciferous vegetables, and many of these explored relationships with Nrf2 activation. Basically, eating a clinically-relevant daily dose of 3-day-old cruciferous sprouts and taking off-patent metformin both induce Nrf2 activation effects.

Don’t expect to see many researchers highlighting this equivalency. They’d rather wait another decade to nitpick other studies with not-enough-subjects / not-exactly replicated / other nitpicks before expressing opinions urging caution from their nursing home beds.

But even then, they won’t get their facts straight. For example, a contemporaneous opinion article https://www.nature.com/articles/d41586-024-02938-w “The brain aged more slowly in monkeys given a cheap diabetes drug” attempted to summarize this study, and flubbed two points:

1. The study said: “We conducted a proof-of-concept study involving male cynomolgus monkeys (Macaca fascicularis) aged between 13 and 16 years, roughly equivalent to approximately 40–50 years in humans. Monkeys adhered to this regimen for a period of 1,200 days, approximately 3.3 years, which corresponds to about 10 years in humans.”

The opinion claimed: “Animals took the drug for 40 months, which is equivalent to about 13 years for humans.”

2. The opinion quoted a New York City researcher involved in a separate metformin study and employed at a medical school for:

“Research into metformin and other anti-ageing candidates could one day mean that doctors will be able to focus more on keeping people healthy for as long as possible rather than on treating diseases.”

This statement is a big break from the realities of medical personnel daily actions at least so far this decade, which is when I started to pay close attention:

  • Doctors have very little diet and exercise training in medical school. There’s no way they can give health advice. There’s no way that a “keeping people healthy” paradigm will emerge from the current medical system.
  • Fixing a disease doesn’t restore a patient’s health. Dr. (PhD) Goodenowe cites several examples in his talks, such as a study that compared colorectal cancer therapy with post-operation patient health.
  • If you listen to yesterday’s two-hour-long podcast, the currently injured person in the first hour gave plenty of contrary evidence of doctors’ focuses: behaviors of trying to blame and gaslight the patient, thinly-disguised punitive actions, CYA etc., all of which they will be sued for one day. The doctor in the second hour provided an example of the quoted researcher in her explanation of how doctors higher in the hierarchy either can’t see or can’t admit realities of doctor/patient interactions, and what therapies have actually benefited or harmed a patient.

Eat broccoli sprouts to help repair nerve damage

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

A 2024 rodent study investigated sulphoraphane’s capability to enhance injured peripheral nerve regeneration:

“We provide in vivo evidence for the regenerative potency of sulforaphane (SFN) for peripheral nerve injury. This effect appears to be predominantly based on the ability of SFN to activate the Nrf2 transcription factor and its versatile downstream effector, HO-1, in cells of the peripheral nerve, in particular Schwann cells.

With regard to translational implications, we chose a dosage of SFN in our mouse model that corresponds to a human equivalent dose of approximately 50–100 mg per day. This dosage of SFN is well achievable with commercially available dietary supplements.

nrf2 and ho-1 expression

Regenerative benefits of Nrf2/HO-1 activation in the peripheral nerve were previously established in a study using dimethyl fumarate (DMF). Due to the immunosuppressive effects of DMF and its potential side effects such as gastrointestinal effects and flushes, this drug can only be used to a limited extent to promote nerve regeneration.

Given the ubiquitous expression and versatile actions of HO-1, our findings suggest that SFN may also be beneficial for neuropathies in general. As a downstream effector of IL-10, the protective and regenerative potency of HO-1 may also apply to inflammatory neuropathies in particular.

SFN sustains the Nrf2/HO-1 pathway, promoting nerve regeneration and facilitating Schwann cell functions, which may include survival, proliferation, and autophagy for myelin debris clearance. These findings suggest that SFN could serve as a valuable therapeutic approach for addressing peripheral nerve injuries, neuropathies, and inflammatory neuropathies, potentially offering renewed prospects for patients contending with these debilitating conditions.”

https://www.mdpi.com/2076-3921/13/9/1038 “Enhancement of Heme-Oxygenase 1 in the Injured Peripheral Nerve Following Sulforaphane Administration Fosters Regeneration via Proliferation and Maintenance of Repair Schwann Cells”

A human-equivalent to this study’s daily 10 mg sulforaphane dose is (10 mg x .081) x 70 kg = 57 mg, albeit the mouse dose was injected intraperitoneally. These researchers apparently hedged their human equivalent of “approximately 50–100 mg per day” to account for administration method differences in bioavailability between oral and intraperitoneal.

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A heterochromatin loss theory of aging? Or just an unhealthy system?

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Telomeres , ,

A 2024 rodent study investigated epigenetic effects of loosening compacted chromatin:

“We show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit:

  • Reduced lifespan;
  • Lower body weight;
  • Increased frailty index;
  • Multi-organ degeneration;
  • Transcriptional changes with significant upregulation of transposable elements; and
  • Accelerated epigenetic age.

TKOc survival

Through simultaneous depletion of Setdb1 and Suv39h1/2 methyltransferases, crucial to formation of constitutive heterochromatin, our model analyzes consequential transcription changes including a potential source of genomic instability by activation of endogenous mobile genetic elements, specifically transposable elements.

These findings reveal the importance of epigenetic regulation in aging, and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline.”

https://www.biorxiv.org/content/10.1101/2024.07.24.604929v1.full “Loss of H3K9 trimethylation leads to premature aging”

Many of these findings could be restated without viewing them as age-related, i.e.: failure to maintain an adult’s methyltransferase system results in a loss of health. For example, an unhealthy methyltransferase system indicated by parameters like homocysteine levels (not mentioned) can be reversed to healthy function regardless of age. Healthy vs. unhealthy system function wasn’t the paradigm these researchers operated under, though.

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Eat broccoli sprouts to reduce knee pain?

gettingwell4 2-3 stars Required further work, Epigenetics ,

A 2024 preprint published results of feasibility trial NCT03878368:

“High glucosinolate broccoli soup is a novel approach to managing osteoarthritis (OA) that is widely accessible and can be used on a large scale. This study shows that it is an acceptable way of delivering dietary bioactives and has potential for therapeutic benefit.

Limitations of the study:

1. COVID-19 curtailed data collection and restricted sample size below that originally planned, however we remained able to derive meaningful interpretation and meet our original study aims.

2. The study had a short time scale (12 weeks). A longer study would be useful to understand how a long-term intervention might be accepted, important for chronic conditions such as OA.

3. The full sample size fell short of the number anticipated, therefore we were unable to use the data to provide a reliable estimate of sample size for a full trial.

4. Participants were excluded if they did not like broccoli to maximise compliance and retention, and so a food intervention should account for this in future developments. While most patients tolerated the soups well, two patients withdrew because they did not like the soup.”

https://www.medrxiv.org/content/10.1101/2024.06.20.24309233v1.full-text “The BRoccoli In Osteoarthritis (BRIO study) – A randomised controlled feasibility trial to examine the potential protective effect of broccoli bioactives, (specifically sulforaphane), on osteoarthritis”

The glucoraphanin dose used was the highest of three tested in 2017 via NCT02300324:

“This study seeks to quantify the exposure of human tissues to glucoraphanin and sulforaphane following consumption of broccoli with contrasting Myb28 genotypes. Myrosinases are intentionally denatured during soup manufacture. Threefold and fivefold higher levels of sulforaphane occur in the circulation following consumption of Myb28V/B and Myb28V/V broccoli soups, respectively.

6b

Myb28V/V and Myb28B/V broccoli soups contained 452 ± 10.6 μmoles glucoraphanin per 300 mL portion and 280 ± 8.8 μmoles glucoraphanin per 300 mL portion respectively, approximately five- and threefold greater glucoraphanin levels compared to Myb28B/B broccoli soup that contained 84 ± 2.8 μmoles glucoraphanin per 300 mL.

The percentage of sulforaphane excreted in 24 h relative to the amount of glucoraphanin consumed varies among volunteers from 2 to 15%, but does not depend on the broccoli genotype.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.201700911 “Bioavailability of Glucoraphanin and Sulforaphane from High-Glucoraphanin Broccoli”

Unlike these two papers, I don’t depend primarily on my gut microbiota for results. Microwaving 3-day-old broccoli sprouts to 60°C to create 80% bioavailable sulforaphane then immediately eating it is way more efficient. If depending on an individual’s gut microbiota to convert glucoraphanin into sulforaphane, the best that can be expected is 15% bioavailability.

Don’t think an osteoarthritis clinical trial that depends on a person’s gut microbiota could have steady, predictable results when there could be more than 700% variability (2% to 15%) among subjects’ sulforaphane conversions. If a treatment subject doesn’t have relief from knee pain, there would have to be additional methods to detect that subject’s effective sulforaphane dose based on their gut microbiota conversion ability. Would these researchers suggest that subject change their gut microbiota? What study has reliable results for that?

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