Nrf2 regulation

gettingwell4 5+ stars Premium, Cortisol, Epigenetics, Glutamate, Neurochemicals, Stress

This 2025 review explored what’s known so far about Nrf2 post-translational regulators:

“Nrf2 is controlled at multiple levels, including epigenetic, transcriptional, translational, and post-translational. The focus of this review is on proteins that control Nrf2 at the post-translational level because in normal cells they are of preeminent importance.

We outline mechanisms by which multiple E3 ubiquitin ligases act to repress Nrf2 expression, how derepression of Nrf2 (and induction of its target genes) by oxidative stressors occurs, and why tissue injury and endoplasmic reticulum stress downregulate Nrf2. This update also explains how Nrf2 is embedded in thiol biochemistry, and outlines signaling pathways and endogenous signaling molecules that control its activity.

Nrf2 not only positively controls the basal and/or inducible expression of a substantial number of genes in all tissues but also downregulates many genes. Estimates of the number of antioxidant/electrophile-responsive element (ARE/EpRE)-driven genes that are positively regulated by Nrf2 vary from several hundred to >2000 depending on the experimental method, species, cell type, physiology, age, sex, diet, and the magnitude of the change that is deemed to be significant.

Induction of ARE/EpRE-driven genes allows adaptation to oxidative, electrophilic, and inflammatory stress. Nrf2 positively regulates clusters of genes encoding proteins classed broadly as antioxidant, drug-, heme-, and iron-metabolizing, pentose phosphate pathway, NADPH-generating, and autophagy-related, as well as fatty acid oxidation enzymes, lipases, transcription factors, and Keap1.

Genes that are negatively regulated by Nrf2 include those encoding the cytokines IL-1β and IL-6, myosin light-chain kinase (MYLK), and NADPH oxidase 4 (NOX4). Nrf2 also regulates some microRNAs, which represents another mechanism by which Nrf2 can downregulate the expression of genes such as those encoding collagens 1A2, 3A1, and 5A1, heat shock protein 47, fibronectin, and elastin. In addition, several lipogenesis-related genes such as fatty acid synthase 1 (FASN1) and acetyl-CoA carboxylase 1 (ACC1), stearoyl-CoA desaturase (SCD1), and fatty acid elongase 6 (ELOVL6) are downregulated upon Nrf2 activation, particularly under conditions of lipid overload. Given that lipogenesis is a highly NADPH-consuming process, it seems that Nrf2 activation redirects NADPH consumption from lipid synthesis towards redox reactions, although the mechanisms underlying the negative regulation of these genes are incompletely understood.

de novo synthesized Nrf2 upon Keap1 inactivation enables a rapid increase of levels of the transcription factor in response to metabolic changes and environmental challenges, allowing cells to adapt and restore homeostasis.”

https://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(24)00282-2 “Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis”

This review’s primary audience is other researchers, and it ended with 15 outstanding items that Nrf2 research hasn’t yet adequately addressed.

Timeout for memes

gettingwell4 Just me

Starting this blog’s eleventh year with meme relief.

Every day I challenge myself to read at least one paper with which I strongly disagree. But I don’t want to fill up my life and this blog by curating papers that detract from science or are a waste of resources.

Maybe tomorrow I’ll return with Max Planck’s observation that science advances one funeral at a time.



Don’t leave any battles for your children that you should have won

gettingwell4 Just me

This is a perspective of a U. S. military member who refused to obey unlawful orders earlier this decade:

“Dr. Sam Sigoloff is one of the three US military doctors who, under whistleblower protection, reported on the Defense Medical Data Base (DMED data) that showed evidence of widespread injuries sustained by US active service members following the mandated covid 19 injections.

It’s illegal to tell me to take a EUA drug. It’s not a lawful order. The only lawful order is if they actually had Comirnaty, which doesn’t exist. We have seen no evidence that it exists.

Look this says, safe and effective. That’s a false statement. We know it’s not safe nor effective. And effective isn’t even the word that we should be looking for. We should be using the word efficacious. Efficacious means it does what it’s supposed to do, meaning what we expect it to do, as you and I expect it to stop disease. It doesn’t do that.

There is no justification that you have to give. If you don’t want to do it, you don’t do it. If you keep wearing a mask, this will never end.”

https://transcriberb.dreamwidth.org/195901.html “After Hours with Dr. Sigoloff”

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

gettingwell4 5+ stars Premium, Epigenetics, Stress ,

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?

gettingwell4 Just me , , ,

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

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 , , , , ,

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

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Memory , , , ,

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

An elevator pitch for plasmalogen precursors

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Serotonin, Stress, Thalamus , , ,

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.”

PXL_20241117_185248742~2

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

Confirming a smell and taste anecdote

gettingwell4 Just me

My sense of smell returned this time last year per A smell and taste anecdote. Yesterday my primary olfactory nervous system had exceptionally strong function: Freshly ground coffee; roses; the last lemony magnolia flowers of the season; the period pad of a woman in her forties as we exchanged greetings from ten feet away on our opposing beach walks; decomposing reeds and other annual vegetation near a trail.

Most of the credit goes to taking ProdromeGlia and ProdromeNeuro every day. The company hasn’t mentioned that effect in their promotion material or Dr. Goodenowe’s videos AFAIK.

I still spend 3-5 hours a day reading abstracts and studies, and material that challenges my ideas and beliefs. I skip over obvious propaganda, but it’s so pervasive that occasionally I slip.

Here’s a 3-minute excerpt noting November 5:

PXL_20241101_193217604.MP~2