Coffee compound effects

February 17, 2025February 18, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Neurochemicals, Serotonin, Stress, Telomeres Control group, Genetic factors, Neurodegenerative disease

Three papers continue Polyphenol Nrf2 activators themes starting with a 2025 review of chlorogenic acid:

“Chlorogenic acid may comprise between 70 and 350 mg per cup of coffee. Chlorogenic acid can reduce reactive oxygen species (ROS) levels via the upregulation of antioxidant enzymes, decreasing oxidative stress/damage due to the action of adaptive hormetic mechanisms. There is also a substantial literature of hormetic dose responses for metabolites of chlorogenic acid, such as caffeic acid and ferulic acid.

Chlorogenic acid-induced hormetic biphasic dose responses in a spectrum of experimental designs:

Responses to direct exposures in a range of cell types;

Preconditioning experiments in which a prior dose of chlorogenic acid protected against a subsequent stressor agent;

Studies that included direct exposure, showing hormesis dose responses and then selecting the optimal hormetic dosage as a preconditioning treatment to protect against a subsequent exposure to a toxic agent; and

A mixed group of experiments in which preconditioning was conducted, including several neuronal cellular models, all showing protection against the subsequent exposure to the toxic agent.

However, in the context of translating experimental data to clinical relevance, the concentrations employed in the majority of the in vitro studies with chlorogenic acid far exceeded transitory peak levels, even in heavy coffee drinkers (i.e., approximately 3 μM). In addition to the use of unrealistically high chlorogenic acid concentrations, exposures were prolonged, ranging from 1 to 3 days. These studies are of limited relevance to humans, a similar concern raised by other researchers involved with polyphenol research.

The present paper has framed the hypothesis that key coffee constituents, such as chlorogenic acid, show hormetic effects in a range of cell types and endpoints. Chlorogenic acid may affect some of the health benefits of coffee drinking via its role in GI tract health and beneficial brain-gut interaction.”

https://www.sciencedirect.com/science/article/abs/pii/S0009279724004897 “Do the hormetic effects of chlorogenic acid mediate some of the beneficial effects of coffee?” (not freely available) Thanks to Dr. Evgenios Agathokleous for providing copies of this and the following paper.

A 2024 review by the same research group was on hormetic effects of caffeic acid:

“Caffeic acid is a polyphenol present in numerous fruits and vegetables, especially in coffee. Diets contain about 5–10 to 50 milligrams per day of caffeic acid while coffee ingestion provides about another 250–600 milligrams per day. For the moderate to heavy coffee drinker this would result in an ingestion of about 600–1000 milligrams of caffeic acid from food and coffee consumption.

The present paper evaluates whether caffeic acid may act as an hormetic agent, mediating its chemoprotective effects as has been shown for related agents, such as rosmarinic acid, ferulic acid, and chlorogenic acid. Caffeic acid protective effects were mediated via the upregulation of a series of antioxidant enzymes related to activation of Nrf2.

Caffeic acid enhanced the lifespan of C. elegans along with similar observations for rosmarinic acid that can be hydrolyzed to caffeic acid. Several hundred plant-based agents can enhance lifespan in experimental models such as C. elegans, and there is a competition to find the most effective agents with potential commercial applications.

Hormetic effects typically show a 30 to 60% stimulation above control. This is far below the 2 to 3-fold greater than control detection limit for statistical significance based on human variability/bioplasticity and are often reported as false negatives.

A weight-of-evidence approach was proposed based on multiple in vivo and in vitro test results to derive a study design strategy to increase detection of hormetic effects within the clinical trial framework. Such research should explore hormetic based interactions linking protective catabolic-based adaptive responses with activation and regulation of anabolic mediated hormetic growth effects.”

https://www.tandfonline.com/doi/full/10.1080/19390211.2024.2410776 “Caffeic Acid: Numerous Chemoprotective Effects are Mediated via Hormesis” (not freely available)

A 2024 review provided an overall picture of coffee compounds’ cardiometabolic effects:

“This review provides a comprehensive synthesis of longitudinal observational and interventional studies on the cardiometabolic effects of coffee consumption.

Findings indicate that while coffee may cause short-term increases in blood pressure, it does not contribute to long-term hypertension risk.

There is limited evidence indicating that coffee intake might reduce the risk of metabolic syndrome and non-alcoholic fatty liver disease.

Coffee consumption is consistently linked with reduced risks of type 2 diabetes (T2D) and chronic kidney disease (CKD), showing dose-response relationships.

The relationship between coffee and cardiovascular disease is complex, showing potential stroke prevention benefits but ambiguous effects on coronary heart disease.

Moderate coffee consumption, typically ranging from 1 to 5 cups per day, is linked to a reduced risk of heart failure, while its impact on atrial fibrillation remains inconclusive. Coffee consumption is associated with a lower risk of all-cause mortality, following a U-shaped pattern, with the largest risk reduction observed at moderate consumption levels.

Except for T2D and CKD, Mendelian randomization studies do not robustly support a causal link between coffee consumption and adverse cardiometabolic outcomes.

Potential beneficial effects of coffee on cardiometabolic health are consistent across age, sex, geographical regions, and coffee subtypes and are multi-dimensional, involving antioxidative, anti-inflammatory, lipid-modulating, insulin-sensitizing, and thermogenic effects. Based on its beneficial effects on cardiometabolic health and fundamental biological processes involved in aging, moderate coffee consumption has the potential to contribute to extending healthspan and increasing longevity.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC11493900 “Coffee consumption and cardiometabolic health: a comprehensive review of the evidence”

A sulforaphane review

January 10, 2025 gettingwell4 0-1 star Wasted resources, Beliefs, Brain development, Epigenetics, Immune system Brain neurons, Control group, Genetic factors, Neurodegenerative disease

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.

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

Too dangerous to investigate?

December 29, 2024December 29, 2024 gettingwell4 0-1 star Wasted resources, Hippocampus, Immune system, Limbic system, Memory Brain neurons, Control group, Neurodegenerative disease

This blog’s 1100^th 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.

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.

Polyphenol Nrf2 activators

December 19, 2024May 3, 2025 gettingwell4 2-3 stars Required further work, Acetylcholine, Amygdala, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress, Vasopressin Brain neurons, Control group, Genetic factors, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

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.

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).

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”

An elevator pitch for plasmalogen precursors

November 24, 2024November 24, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Serotonin, Stress, Thalamus Brain neurons, Genetic factors, Infants, Neurodegenerative disease

An excerpt from the latest video at Dr. Goodenowe’s Health Matters podcast, Episode 7 “The Truth about Parkinson’s”, starting at 50:30:

“What’s exciting about this community medicine focus that we’ve switched to which basically says: How do we develop technologies in a way that they can be incorporated into a community model versus a pharmaceutical drug model? People can actually do I would say self-experiment just the way you self-experiment with your own diet because these are fundamentally dietary nutrition molecules.

Could you give me an elevator pitch because there are probably people listening who are thinking what is this plasmalogen precursor and for sure how is it having this dramatic effect?

Plasmalogens are the most important nutrient that nobody knows about. Normally you don’t know about it because the body is usually pretty good at making them. What makes plasmalogens unique is that your body makes them kind of like cannon fodder, the first group of people that go into war. Your body throws them out for destruction. They absorb oxidative stress and get destroyed in the process.

They’re stored in your cell membranes. 50% of the membranes of your heart are these plasmalogen molecules. When your heart gets inflamed, what your heart does is it dumps these plasmalogens out of its membranes to douse the flame of inflammation. After inflammation is under control, your body naturally builds these things back up again.

But if you have an inability to make enough plasmalogens, these inflammation events knock you down and keep you down. So plasmalogen precursors are critical for maintaining high levels of plasmalogens across your body, not just in your brain (30% of the lipids in your brain) but in your heart, your lungs, your kidneys.”

Do broccoli sprouts help treat colonic inflammation?

October 15, 2024January 8, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group

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.

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.

Activate Nrf2 to reduce biological age

September 22, 2024November 13, 2024 gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Control group, DNA methylation, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

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.

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.

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.

The largest cause of coincidences

September 21, 2024March 31, 2025 gettingwell4 4-5 stars Advanced knowledge, Immune system

Good luck finding reporting of this September 2024 medical malpractice (first hour) outside of uncensored social media. Followed in the second hour by how common this type of hospital care is.

1:04:30 Interviewee, who risked her career for stating the truth about what she saw: “Sometimes I don’t even have words.” Interviewer: “For how stupid it is.”

See Part 2 for a longer interview with Dr. Suzanne Humphries.

Eat broccoli sprouts to help repair nerve damage

August 31, 2024 gettingwell4 4-5 stars Advanced knowledge, Immune system, Stress Control group

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.

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.

Astaxanthin and aging

June 26, 2024January 19, 2026 gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Stress Control group, Genetic factors

A 2023 rodent study investigated two NRF2-activating compounds for their effects in increasing median and maximum lifespan:

“In genetically heterogeneous (UM-HET3) mice, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12%. Astaxanthin (Asta) is a naturally occurring xanthophyll carotenoid that is an efficient Nrf2 activator, with potent antioxidant activity, broad health applications, and excellent safety.

Asta is distributed systemically and incorporated into cellular membranes, where it spans and stabilizes the lipid bilayer and reduces lipid peroxidation. Asta localizes in mitochondria and protects against mitochondrial dysfunction.

It has anti-inflammatory properties, showing equivalent efficacy to prednisolone in an animal model. Geroprotective mechanisms of Asta regulate FOXO3, Nrf2, Sirt1, and Klotho, and the influence of Asta on autophagy via modulation of AMPK (a direct upstream regulator of mTOR), PI3K/Akt, and MAPK (JNK and p38) signaling pathways.

The present Interventions Testing Program (ITP) study is the first evaluation of Asta in a mammalian lifespan model, so the target dose of 4000 ppm in the diet is based on chronic mammalian studies other than lifespan. Despite the fact that the average diet contained 1840 ppm Asta (only 46% of the target), median lifespans of male UM-HET3 mice were significantly improved.

Asta and dimethyl fumarate (DMF) are both Nrf2 inducers; while both had low concentrations sometimes in the diet, we used about 30 times more Asta, which may explain why it increased the lifespan in males while DMF had no effect. Amounts of DMF in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects.”

https://link.springer.com/article/10.1007/s11357-023-01011-0 “Astaxanthin and meclizine extend lifespan in UM‑HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4‑phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used”

This study repeated an astaxanthin supplier’s claims without investigating its low bioavailability issues mentioned in Astaxanthin bioavailability. No explanations were forthcoming for unintentional low doses of astaxanthin and DMF in the treatment chows.

A human equivalent for the intended astaxanthin dose was 22 mg (4000 ppb x .081 x 70 kg), whereas the actual dose human equivalent was 10 mg (1840 ppb x .081 x 70 kg). Dose/response studies weren’t performed, so no conclusions could be drawn as to whether the target dose or other astaxanthin doses may be optimal for increasing lifespan.

A previous ITP study of another commercial NRF2 activator (PB125) found no lifespan benefits. Maybe one day, ITP or others will come around to testing sulforaphane that has 80% bioavailability (regardless of sex) and dose/response studies, which should end the uncertainty about NRF2’s anti-aging effects.

How to choose your medical professional

June 22, 2024July 24, 2024 gettingwell4 4-5 stars Advanced knowledge, Beliefs, Epigenetics, Immune system, Stress Embryo development, Genetic factors, Infants, Neurodegenerative disease

Two+ decades ago (before smart phones) I wrote a series of short books entitled How To Choose Your Lawyer, ..Accountant, ..Financial Advisor. My customers were mainly public libraries.

This is a short post on choosing doctors, although I’ve fired all my doctors and don’t have one. Everything that’s happened this decade has made me wonder why I trusted doctors in the first place.

1. It takes certain behavioral quirks for doctors to assert they know better than you do about what is good for you. These behaviors usually have nothing to do with these doctors’ patients, but patients somehow believe doctors.

These behaviors are almost always doctors’ act-outs of early-life traumas of unfulfilled needs. Pain keeps people from feeling their actual histories, though, so we don’t deal with our real histories therapeutically until we absolutely have to.

If your doctor listens to you at all, it’s only because they are constantly vigilant for some way to fulfill their own unsatisfied needs. But that neither resolves anything for them, as an early need can’t be satisfied years later, nor has anything to do with what you need from a medical professional.

2. If you’ve read extensively about an area and have questions, a doctor may know less than you. That won’t keep them from gaslighting you due to 1. above, but it does keep you from getting what you need from them. Discussing facts you know with a medical professional who is intentionally ignorant about a medical subject gets you nowhere.

3. If your doctor has not publicly disclaimed their advocacy of this decade’s misguided genetic therapy, they are compromised and can’t be trusted. It doesn’t matter what else they said, because they weren’t honest about what they knew or should have known, as revealed by their actions or inactions.

For example, two studies published in June 2024 established that:

Neurologic issues (68% increase in depression, and a 44% increase in anxiety / dissociative / stress-related / somatoform disorders) followed COVID gene therapy: https://www.nature.com/articles/s41380-024-02627-0 “Psychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea” (2,027,353 people)
COVID gene therapy increased the risk of mild cognitive impairment 138% and the risk of Alzheimer’s by 23%: https://academic.oup.com/qjmed/advance-article-abstract/doi/10.1093/qjmed/hcae103/7684274 “A potential association between COVID-19 vaccination and development of Alzheimer’s disease” (558,017 people). These graphics showed rapidly increasing MCI and AD incidences. The study’s analysis showed incidence increases could not have happened by chance.

A doctor’s only honest response to this malfeasance is to publicly apologize, and tell their trusting patients they will make it up to them by providing free healthcare to help mitigate results of their unprofessional conduct. If they tell you something else, it’s a distraction from consequences that are beyond words.

Eat broccoli sprouts to support muscle growth

June 19, 2024June 19, 2024 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system Control group, Genetic factors

A 2024 rodent study investigated sulforaphane’s effects on skeletal muscle:

“Sulforaphane (SFN) shows a promising application in skeletal muscle protection and recovery from muscle atrophy and damage. However, limited work has focused on the role of SFN in maintaining the balance of protein and lipid metabolism in skeletal muscle.

The current work investigates effects of SFN at an everyday consumption level on protein and lipid metabolism in skeletal muscle. Investigating SFN at lower levels over an extended period more closely resembles human consumption habits. Four-week-old mice received SFN at a dosage of 1 mg per kilogram of body weight per day (1 mg/kg/d BW) using i.p. injection (SFN1 group) and 3 mg/kg/d BW (SFN3 group) for eight weeks, equivalent to concentrations of 0.14 μM and 0.42 μM.

Histological analysis was performed for the Longissimus dorsi [the largest back muscle]. LD muscle fiber diameter and cross-section area was significantly increased in the SFN3 group, not in the SFN1 group.

The levels of triglycerides and total cholesterol in the LD muscle were found to be decreased in both SFN groups.

This study reported, for the first time, that SFN administration increased peroxisome activity and enhanced the peroxisomal protein shuttle, which supports enhanced peroxisomal fatty acid β-oxidation. SFN redirects the flux of fatty acid to be utilized through β-oxidation in peroxisomes and mitochondria to support muscle growth. Furthermore, SFN treatment influenced lipid and protein metabolism related pathways including AMPK signalling, fatty acid metabolism signalling, cholesterol metabolism signalling, PPAR signalling, peroxisome signalling, TGFβ signalling, and mTOR signalling.”

https://portlandpress.com/bioscirep/article/doi/10.1042/BSR20240084/234562/Sulforaphane-enhanced-muscle-growth-by-promoting “Sulforaphane enhanced muscle growth by promoting lipid oxidation through modulating key signaling pathways”

A human equivalent to this study’s 3 mg daily dose is (3 mg x .081) x 70 kg = 17 mg, albeit doses were intraperitoneally injected. An oral 17 mg is a common sulforaphane floor dose in human studies, and is approximately what I get from eating 60 grams of a microwaved broccoli / red cabbage / mustard 3-day-old sprouts mix daily.

Maintaining your myelin, Part 2

April 27, 2024April 27, 2024 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Corpus callosum, Neural plasticity, Neurodegenerative disease

Continuing Part 1 with three 2024 preprint studies, starting with an investigation of neuroinflammation in high school athletes:

“Axons are long fibers conducting nerve impulses from nerve cells to synaptic ends. Like electric wires, axons are insulated by the myelin sheath produced by oligodendrocytes (ODC) in the brain or Schwann cells in the periphery. The myelin sheath is vulnerable to mechanical stresses after head injuries, as well as targets for autoimmune attack in multiple sclerosis and degeneration in various white matter diseases.

It is challenging to definitively validate axonal neuroinflammation, because axonal neuroinflammation is only diagnosed at post-mortem autopsy, or wait for more than a decade to potentially witness progression to chronic traumatic encephalopathy, or white matter dementia. Advanced imaging analysis of computed tomography and magnetic resonance imaging are not sensitive enough to identify such microscopic abnormalities.

We developed a sandwich immunoassay detecting dual signals of myelin oligodendrocyte glycoprotein (MOG) and interleukin 1B (IL1B) in human plasma, [IL1B on MOG]. MOG is a transmembrane protein specifically expressed in ODC and Schwann cells membranes, and doesn’t freely exist in plasma. We found that serum from capillary blood is acceptable, and we tested control and athlete samples using only 5 mL samples. When we tested 63 control plasma samples, values were widely distributed over 2 logs, so we focused on longitudinal studies.

Damaged neurons are not easily detectable using conventional physical examinations, because the brain’s inherent adaptability allows it to compensate for localized damage by finding alternate routes. While this adaptability is advantageous, it also means that these concealed lesions can go unnoticed, potentially leading to future complications.

Elevation of [IL1B on MOG] was seen in some athletes who did not show concussion or traumatic brain injury (TBI). While the occurrence of concussion is relatively limited, potential prevalence of subconcussion or subconcussive condition is expected to be substantially higher.

If [IL1B on MOG] levels remain unchanged during this early post-concussion period (2-4 weeks), it may suggest that neuroinflammation has not been induced, potentially providing reassurance for the athletes to return to play. Conversely, if [IL1B on MOG] levels increase within this timeframe, it may indicate the need for intervention or closer monitoring. Thus, there is compelling potential for incorporating this test into concussion guidelines.”

https://www.researchsquare.com/article/rs-3997676/v1 “An approach for the analysis of axonal neuroinflammation by measuring dual biomarkers of oligodendrocytes and inflammatory cytokine in human plasma”

A rodent study investigated the immune system’s influence on oligodendrocyte lineage cells after TBI:

“White matter injury is thought to be a major contributor to long-term cognitive dysfunctions after TBI. This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after injury, triggered directly by the trauma or in response to degenerating axons.

Our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation, and required the presence of T cells. This suggests that T cells are an important mechanistic link by which the gut microbiota modulate oligodendrocyte response and white matter recovery after TBI.

Our findings suggest that oligodendrocytes are not passive in the neuroinflammatory and degenerative environment caused by brain trauma, but instead could exert an active role in modulation of immune response.”

https://www.researchsquare.com/article/rs-4289147/v1 “Gut Microbiota Shape Oligodendrocyte Response after Traumatic Brain Injury”

A rodent study investigated whether oligodendrocyte precursor cells had myelination-independent roles in brain aging:

“OPCs, the source cells of myelin-forming cells in the central nervous system, have been linked to brain aging by their compromised differentiation and regeneration capability. Our results demonstrate that macroautophagy influx declines in aged OPCs, which results in the accumulation of senescent OPCs in aged brains. Senescent OPCs impair neuronal plasticity and exacerbate neurodegeneration, eventually leading to cognitive decline.

Inactivation of autophagy in OPCs exhibits a limited effect on myelin thickness but a loss of myelin in middle-aged mice. The loss of myelin observed is an adaptational change to suppressed neuronal plasticity. However, neither the number of OLs nor oligodendrogenesis is altered by inactivation of autophagy in adult OPCs.

The present study indicates that the intervention of senescent OPCs is an additional promising therapeutic strategy for aging and aging-related cognitive deficits. Autophagy regulates senescence by impairing protein turnover, mitochondrial homeostasis, oxidative stress, and maintaining senescence-associated secretory phenotype. Further investigation remains on whether autophagy in OPCs shares the exact mechanism to promote senescence as that in other types of cells.

Considering autophagy declines with aging, our study brings a novel mechanism in brain aging. Declined autophagy causes senescence of OPCs, which impairs neuronal plasticity and exacerbates neurodegeneration via CCL3/5-CCR5 signaling.”

https://www.researchsquare.com/article/rs-3926942/v1 “Impaired Macroautophagy in Oligodendrocyte Precursor Cells Exacerbates Aging-related Cognitive Deficits via a Senescence Associated Signaling”

Maintaining your myelin, Part 1

April 25, 2024April 27, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Corpus callosum, Critical period, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

Three papers on myelin and oligodendrocytes, starting with a 2023 review:

“Myelin is the spiral ensheathment of axons by a lipid and cholesterol-rich glial cell membrane that reduces capacitance and increases resistance of the axonal membrane. Axonal myelination speeds up nerve conduction velocity as a function of axon diameter.

While myelination proceeds rapidly after birth in the peripheral nervous system, central myelination is a spatially and temporally more regulated process. Ongoing myelination of the human brain has been documented at up to 40 years of age. This late myelination in the adult cortex is followed by exhaustion of oligodendrocyte precursor cells (OPC) with senescence and a gradual loss of myelin integrity in the aging brain.

The brain is well known for its high energy demands, specifically in gray matter areas. In white matter tracts, energy consumption is lower. Myelination poses a unique challenge for axonal energy generation where myelin sheaths cover more than 95% of the axonal surface areas.

Oligodendrocytes help support axonal integrity. Oligodendrocytes survive well in the absence of mitochondrial oxidative phosphorylation, and without signs of myelin loss, cell death, neurodegeneration or secondary inflammation.

Glycolysis products of oligodendroglial origin are readily metabolized in axonal mitochondria. Oligodendroglial metabolic support is critical for larger and faster-spiking myelinated axons that also have a higher density of mitochondria. An essential requirement for the direct transfer of energy-rich metabolites from oligodendrocytes to the myelinated axonal compartment is ‘myelinic channels’ within the myelin sheath.

Interactions of oligodendrocytes and myelin with the underlying axon are complex and exceed the transfer of energy-rich metabolites. Continuous turnover of myelin membranes by lipid degradation and fatty acid beta-oxidation in mitochondria and peroxisomes leads to recycling of acetate residues by fatty acid synthesis and membrane biogenesis.

In human multiple sclerosis (MS) and its animal model myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis (MOG-EAE), acute inflammatory demyelination is followed by axonal degeneration in lesion sites that is mechanistically not fully understood. It is widely thought that demyelination and the lack of an axon-protective myelin sheath in the presence of numerous inflammatory mediators are the main causes of axon loss.

But unprotected axons improve rather than worsen the overall clinical phenotype of EAE mice which exhibited the same degree of autoimmunity. Thus, ‘bad myelin is worse than no myelin’ because MS-relevant myelin injuries perturb the integrity of myelinic channels and metabolic support.

Dysfunctional or injured oligodendrocytes that do not allow for compensation by any other cell types turn the affected myelin ensheathment into a burden of the underlying axonal energy metabolism, which causes irreversible axon loss. Any loss of myelin integrity, as seen acutely in demyelinating disorders or more gradually in the aging brain, becomes a risk factor for irreversible neurodegeneration.”

https://www.sciencedirect.com/science/article/pii/S0959438823001071 “Expanding the function of oligodendrocytes to brain energy metabolism”

A 2024 review focused on myelin and oligodendrocyte plasticity:

“This review summarizes our current understanding of how myelin is generated, how its function is dynamically regulated, and how oligodendrocytes support the long-term integrity of myelinated axons.

Apart from its unique ultrastructure, there are several other exceptional features of myelin. One is certainly its molecular composition. Another is its extraordinary stability. This was compellingly illustrated when 5000-year-old myelin with almost intact ultrastructure was dissected from a Tyrolean Ice Man.

Myelin is a stable system in contrast to most membranes. However, myelin is compartmentalized into structurally and biochemically distinct domains. Noncompacted regions are much more dynamic and metabolically active than tightly compacted regions that lack direct access to the membrane trafficking machinery of oligodendrocytes.

The underlying molecular basis for stability of myelin is likely its lipid composition with high levels of saturated, long chain fatty acids, together with an enrichment of glycosphingolipids (∼20% molar percentage of total lipids) and cholesterol (∼40% of molar percentage of total lipids). In addition, myelin comprises a high proportion of plasmalogens (ether lipids) with saturated long-chain fatty acids. In fact, ∼20% of the fatty acids in myelin have hydrocarbon chains longer than 18 carbon atoms (∼1% in the gray matter) and only ∼6% of the fatty acids are polyunsaturated (∼20% in gray matter).

With maturation of oligodendrocytes, the plasma membrane undergoes major transformations of its structure. Whereas OPCs are covered by a dense layer of large and negatively charged self-repulsive oligosaccharides, compacted myelin of fully matured oligodendrocytes lacks most of these glycoprotein and complex glycolipids.

Schematic depiction of an oligodendrocyte that takes up blood-derived glucose and delivers glycolysis products (pyruvate/lactate) via monocarboxylate transporters (MCT1 and MCT2) to myelinated axons. Oligodendrocytes and myelin membranes are also coupled by gap junctions to astrocytes, and thus indirectly to the blood–brain barrier.

Adaptive myelination refers to dynamic events in oligodendroglia driven by extrinsic factors such as experience or neuronal activity, which subsequently induces changes in circuit structure and function. Understanding how these adaptive changes in neuron-oligodendroglia interactions impact brain function remains a pressing question for the field.

Transient social isolation during adulthood results in chromatin and myelin changes, but does not induce consequent behavioral alterations. When mice undergo a social isolation paradigm during early life development, they similarly exhibit deficits in prefrontal cortex function and myelination, but these deficiencies do not recover with social reintroduction. This implicates a critical period for social deprivation effects on myelin dynamics. Experience-dependent changes in myelin dynamics may depend on not only the age, brain region, and cell type studied, but also the specific myelin structural change assessed.

Local synaptic neurotransmitter release along an axon not only affects the number of OPCs and oligodendrocytes associated with that axon and local synthesis of myelin proteins, but also drives preferential selection of active axons for myelination over the ensheathment of electrically silenced neighboring axons. Neuronal activity–induced plasticity may preferentially impact brain regions that remain incompletely myelinated compared to more fully myelinated tracts.

Whereas the myelin sheath has been regarded for a long time as an inert insulating structure, it has now become clear that myelin is metabolically active with cytoplasmic-rich pathways, myelinic channels, for movement of macromolecules into the periaxonal space. The myelin sheath and its subjacent axon need to be regarded as one functional unit, which are not only morphological but also metabolically coupled.”

https://cshperspectives.cshlp.org/content/early/2024/04/15/cshperspect.a041359 “Oligodendrocytes: Myelination, Plasticity, and Axonal Support” (not freely available) Thanks to Dr. Klaus-Armin Nave for providing a copy.

A 2024 rodent study investigated oligodendrocyte precursor cell transcriptional and epigenetic changes:

“We used single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and single-cell spatial transcriptomics to characterize murine cortical OPCs throughout postnatal life. One group (active, or actOPCs) is metabolically active and enriched in white matter. The second (homeostatic, or hOPCs) is less active, enriched in gray matter, and predicted to derive from actOPCs. Relative to developing OPCs, both actOPCs and hOPCs are less active metabolically and have less open chromatin.

In adulthood, these two groups are transcriptionally but not epigenetically distinct, indicating that they may represent different states of the same OPC population. If that is the case, then one model is that the parenchymal environment maintains adult OPCs within an hOPC state, whereas those OPCs recruited into white matter or exposed to demyelinated axons may transition toward an actOPC state in preparation for making new oligodendrocytes. We do not yet know the functional ramifications of these differences, but this finding has clear implications for the development of therapeutic strategies for adult remyelination.

Another finding is that developing but not adult actOPC chromatin is preferentially open for binding motifs associated with neural stem cells, transit-amplifying precursors, and neurogenesis. Although this may simply reflect their origin as the immediate progeny of neonatal neural precursor cells, it may also explain why developing but not adult OPCs have the capacity to make neurons in culture.

If we could, at least in part, reverse the global chromatin shutdown that occurs between development and adulthood, then perhaps adult OPCs may reacquire the ability to make neurons or become better able to generate new oligodendrocytes for remyelination.”

https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(24)00077-8 “Single-cell approaches define two groups of mammalian oligodendrocyte precursor cells and their evolution over developmental time”

Continued in Part 2.

Changing a cancerous phenotype

April 9, 2024April 11, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Epigenetics, Glutamate, Immune system, Neurochemicals, Stress Control group, Genetic factors, Neurodegenerative disease

A 2024 Dr. Goodenowe presentation to a professional audience. He ended the presentation by using his 86-year-old father as a case study of treatment to create an inhospitable environment for cancer.

1. Get the body ready

2. Starve the cancer and boost the immune system

3. Characteristics

4. 2019 sample biochemistry

5. 2023 biochemistry (compare HDL (33 vs. 80), see off-the-chart hsCRP, Hcy 16)

6. Treatment details #1

7. Treatment details #2

https://drgoodenowe.com/tfim-2024-recording-now-available/ “Breaking Cancer: The Biochemistry of Cancer Risk Assessment, Prevention, and Treatment—Real Knowledge That You Can Use In Your Practice”