Stress

Plasmalogens Week #1 – Overview

gettingwell4 2-3 stars Required further work, Immune system, Stress , , , , ,

It’s been a while since I curated plasmalogen papers. Let’s start out a week’s worth of 2025 papers with a review of plasmalogens as biomarkers:

“Reduced levels of plasmalogens in circulation or in cell membranes are associated with rare peroxisomal disorders, systemic disease, neurological impairment, cancer, and diseases of the heart, kidney, and liver. Roles for plasmalogens have been identified in lipid rafts, myelin, chlorolipids, bromolipids, hemostasis, cholesterol metabolism, and redox responses.

Plasmalogens account for approximately 5-20% of the phospholipids in mammalian cell membranes. Circulating choline and ethanolamine are incorporated into lipid membranes through the synthesis of plasmalogens. These lipids are formed through a separate multistep process involving precursors in the cytoplasm, peroxisome, and endoplasmic reticulum.

Cytochrome c (cyt-c) typically serves as an electron carrier in the mitochondrial membrane, but under oxidative stress, cyt-c undergoes a conformational alteration conferring peroxidase activity that cleaves the vinyl-ether linkage in plasmalogens. Plasmalogens may act as precursors to platelet-activating factor (PAF), and PAF can be enzymatically converted to plasmalogens. PAF is a potent pro-inflammatory mediator in cancer, cardiovascular, neurological, chronic and infectious disease, suggesting that increased PAF levels may inversely correspond to lower ethanolamine plasmalogen levels identified in human diseases.

Plasmalogens are abundant in myelin, and crucial to the function of central nervous system oligodendrocytes and peripheral nervous system Schwann cells in supporting neuronal action potential.

Catabolism of plasmalogens occurs in response to oxidative stress and activation of TLRs, which promote pro-inflammatory responses during disease progression. Release of fatty acids (e.g., arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid) during plasmalogen catabolism can either exacerbate or resolve pro-inflammatory and thrombotic responses depending on the type of fatty acid released and mediator produced.

Continued research of the types of plasmalogens and plasmalogen precursors and their natural or synthetic sources, the frequency and amount of plasmalogens administered, the route of administration, and the timing of treatment is needed.”

https://www.jlr.org/article/S0022-2275(25)00188-9/fulltext “Plasmalogens as biomarkers and therapeutic targets”

A second review highlighted various strategies for regulating plasmalogen levels:

“Plasmalogens serve as significant structural components of cellular membranes, particularly enriched in tissues with high membrane trafficking. Plasmalogens are recognized as major reservoirs for polyunsaturated fatty acids (PUFAs), notably docosahexaenoic acid (DHA) and arachidonic acid (AA). Incorporation of these PUFAs influences membrane physical properties, including fluidity and the propensity to form non-lamellar structures.

Effective delivery of plasmalogens or their precursors faces significant hurdles, including chemical instability (especially oxidation of the vinyl-ether bond), low oral bioavailability, and challenges in crossing biological barriers like the blood–brain barrier (BBB). Exploration of plasmalogen-based nanoparticles is currently quite limited.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fba.2025-00010 “Plasmalogen as a Bioactive Lipid Drug: From Preclinical Research Challenges to Opportunities in Nanomedicine”

Yeah, no. Everything the public was told about lipid nanoparticles this decade was propaganda in service of an agenda. The real stories are gathered in papers I haven’t curated, such as Lipid Nanoparticles as Active Biointerfaces: From Membrane Interaction to Systemic Dysregulation.

Combining exercise with sulforaphane

gettingwell4 5+ stars Premium, Epigenetics, Glutamate, Immune system, Neurochemicals, Stress ,

A 2025 clinical trial with old people compared NRF2 effects of acute exercise with pre- and post-exercise sulforaphane treatment:

“This study tested the hypothesis that combining acute exercise (in vivo stimulus) with ex vivo sulforaphane (SFN) treatment would induce greater NRF2 activation and signaling in older adults compared to either treatment alone. This approach was used to bypass the potential issue of inter-individual variability in metabolism and bioavailability of SFN supplementation through oral consumption and thereby provide more rigorous biological control to establish mechanistic feasibility.

Twenty-five older adults (12 men, 13 women; mean age: 67 ± 5 years) performed 30-min cycling exercise. Blood was drawn before and immediately after exercise to isolate peripheral blood mononuclear cells (PBMCs) and incubate with and without SFN (5 μM) treatment.

Acute exercise induced modest transcriptional changes across the four tested transcripts compared to the robust upregulation elicited by SFN. This disparity was notable given the comparable NRF2/ARE binding activity observed between EX and SFN.

Near-significant trends were observed for EX in heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione reductase (GR) (after Bonferroni correction), while glutamate-cysteine ligase catalytic subunit (GCLC) was not induced by EX. In contrast, SFN alone robustly induced expression of NQO1, HO-1, GR, and GCLC.

We had chosen 5 μM as the dose based on pilot data from our laboratory and existing literature from in vitro experiments. However, typically, SFN is not combined with another stimulus.

To test this speculation, we ran a post hoc dose–response experiment where we stimulated PBMCs (n = 5) at six different SFN concentrations ranging from 0 to 20 μM (incubated for 5 h) and analyzed responses across the four genes used in the present study. The dose responses displayed hormetic curves for NQO1, GR, and GCLC, with 5 μM eliciting the peak response, suggesting that the lack of difference between SFN and the combined treatment was due to a ceiling effect of the SFN dose. Interestingly, HO-1 displayed a linear/curvilinear response with the maximal observed response at 20 μM.

In future ex vivo studies, a sulforaphane concentration of 1–2 μM in combination with acute exercise is predicted to enhance the expression of these antioxidant genes in the PBMCs of older adults to a greater extent than either treatment alone. Furthermore, lower SFN plasma concentrations are more likely to be achievable with oral supplementation.

To our knowledge, this is the first trial to measure responses to acute exercise combined with sulforaphane stimulation on NRF2 signaling in older men and women. We did not observe any statistically significant differences in any of our outcome variables between men and women.

Our results demonstrate that combining acute exercise with a sulforaphane stimulus elicits a greater response in nuclear NRF2 activity in older adults. While the response in gene expression did not completely mirror the response in NRF2 activation, it is important to note that NRF2 induces hundreds of cytoprotective genes. The four transcripts we measured are among those most commonly used to represent NRF2 signaling but do not capture the full picture. Full transcriptomics in future studies would address this question.”

https://link.springer.com/article/10.1007/s11357-025-01939-5 “Sulforaphane improves exercise-induced NRF2 signaling in older adults: an in vivo-ex vivo approach” (not freely available) Thanks to Dr. Tinna Traustadóttir for providing a copy.

I asked two questions, and will follow up with replies:

  1. Did a second experiment test effects of these subjects eating broccoli sprouts prior to acute exercise? The clinical trial’s NCT04848792 Study Overview section indicated that was the researchers’ intent.
  2. What studies have the data that produced this study’s graphical abstract’s younger vs. older NRF2 response graph?

Activating Nrf2 pathways with sunlight

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Stress , ,

A 2025 review subject was non-electrophilic Nrf2 activators:

“NRF2 can be induced via:

  1. Non-specific electrophile/ROS generation,
  2. Disruption of the NRF2–KEAP1 protein–protein interaction,
  3. Autophagy-mediated KEAP1 degradation,
  4. Direct modulation of NRF2 protein stability, and
  5. Post-transcriptional/post-translational modifications.

Except for a single intervention, therapeutic hypothermia, every non-pharmacological strategy with defined mechanisms employs more than one of these routes, most frequently pairing post-translational modification with either protein-stability regulation or limited electrophile production. This combinatorial activation elevates both NRF2 abundance and transcriptional competence while minimizing the liabilities of purely electrophilic agents and circumventing the efficacy limitations.

Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency.”

https://www.mdpi.com/2076-3921/14/9/1047 “Non-Electrophilic Activation of NRF2 in Neurological Disorders: Therapeutic Promise of Non-Pharmacological Strategies”

These researchers exaggerated problems of electrophilic Nrf2 activators such as “mitochondrial impairment, and systemic toxicity” so they could have something to write about. Just like every intervention, the dose determines the response. I can’t imagine not eating broccoli sprouts in favor of brain zapping with electroconvulsive therapy or transcranial magnetic stimulation just to avoid sulforaphane’s temporary mild oxidative stress that activates Nrf2 for 15-20 minutes.

But there are limitations to how an unwell person can benefit from Nrf2 activation. For example, I haven’t curated many cancer papers because healthy body functioning can’t be assumed.

I walk the beach at sunrise, weather permitting, because it makes me feel good, and I’m always happy afterwards that I made the effort to get outside. That doing so combines two of the above non-electrophilic Nrf2 activators, physical exercise and photobiomodulation, hasn’t been a consideration.

These reviewers didn’t include human studies of sunlight’s effects. Nevermind that hospitals used to have sundecks for patients, and John Ott published relevant human and animal studies over fifty years ago.

Many studies have an undisclosed limitation in that they were performed without controlling for light. For example, knowing that mitochondria are light-activated, I don’t trust those studies’ in vivo, ex vivo, or in vitro results.

None of the 100 most recent 2025 photobiomodulation papers examined natural sunlight. Maybe it wouldn’t sell red light, green light, and blue light lasers and other products to show that people could produce the same effects themselves with sunlight at different times of the day? Would researchers damage their reputations to study a freely-available intervention, one where they don’t “do something”?

Sulforaphane and malaria

gettingwell4 4-5 stars Advanced knowledge, Glutamate, Neurochemicals, Stress

A 2025 rodent study investigated sulforaphane’s capability as an adjunct with standard treatment to inhibit resistant malaria strains:

“In this study, we performed proteomic analysis on a range of sensitive and artemisinin-resistant parasites, revealing specific dysregulation of PfK13 protein abundance. Reduced PfK13 levels were linked to impaired hemoglobin digestion, decreased free heme levels, and consequently, decreased artemisinin activation. Artemisinin resistant parasites also exhibited elevated thiol levels, indicating a more reduced cellular state.

Modulation of PfK13 levels or localisation modifies glutathione (GSH) levels, and elevated GSH decreases artemisinin potency. Elevated levels of reduced GSH and its precursor γ-glutamyl cysteine (gGlu-Cys) were observed in resistant parasites, while oxidised glutathione (GSSG) was lower.

In mammalian cells, SFN conjugates GSH, either passively or through the activity of glutathione-S-transferases, and the SFN-GSH conjugate causes oxidative stress. In response to this stress, Nrf2 translocates to the nucleus and interacts with the antioxidant response element (ARE) of target genes, resulting in expression of antioxidant genes, which induces an antioxidant response. However, P. falciparum has no identified Nrf2 orthologue and so likely lacks a KEAP1-Nrf2 mediated antioxidant response, which suggests that the SFN-GSH conjugate should only cause oxidative stress in parasites.

SFN has antioxidant properties for the host through activation of Nrf2. Therefore our molecule of choice would not only kill the parasite, but will boost the host antioxidant capacity. This differs from most other available pro-oxidants, which do not have this host antioxidant capacity.

5mg/kg SFN was found to be sufficient to significantly prolong the survival of artesunate-treated mice infected with parasites.

PfK13 mutations drive artemisinin resistance in Plasmodium parasites by enhancing antioxidant defences, which can be targeted by redox modulators such as sulforaphane. By leveraging SFN’s ability to induce oxidative stress and deplete thiol levels in parasites, this approach can enhance the efficacy of artemisinin and potentially restore its effectiveness against resistant strains.”

https://www.biorxiv.org/content/10.1101/2025.10.05.680568v1.full “PfK13-associated artemisinin resistance slows drug activation and enhances antioxidant defence, which can be overcome with sulforaphane”

Sulforaphane and skin aging

gettingwell4 0-1 star Wasted resources, Epigenetics, Immune system, Stress

A 2025 rodent study investigated sulforaphane effects on natural skin aging:

“Aging is a multifactorial process that progressively impairs skin integrity by diminishing dermal fibroblast function, which is macroscopically manifested by wrinkling, laxity, and pigmentary abnormalities. The potential mechanism by which sulforaphane (SFN) delays intrinsic skin aging was explored through skin proteomic sequencing and immune cell infiltration analysis. Associations between SFN administration and phenotypic changes in skin aging, immune cell populations, and key signaling pathway targets were further examined.

WBC count results indicated that mice from the Aged group were significantly immunosuppressed. T cells occupied the main lymphocyte lineages.

The present study illuminated the skin protective mechanism of SFN by network pharmacology and proteomics analyses in a natural aging mouse model. SFN therapy showed significant alterations in skin structure, redox balance, and composition of immune cell populations after an intervention duration of 2 months.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.70281 “Integrative Network Pharmacology and Proteomics Decipher the Immunomodulatory Mechanism of Sulforaphane Against Intrinsic Skin Aging” (not freely available)

I rated this study Wasted resources for using sulforaphane doses not relevant to humans. I usually don’t curate such studies. Its lowest sulforaphane 50 mg/day dose is a ((50 mg * .081) * 70 kg) = 284 mg human equivalent.

I decided to curate it for its informative young controls vs. aged controls results in the above graphic. WBC counts are available on almost every standard human blood test.

This study’s young and aged groups per Grok: “A 2-month-old mouse aging for two more months (reaching 4 months) is approximately equivalent to a human aging from about 12–15 years to 17–21 years old. An 18-month-old mouse (human equivalent: ~45–50 years) aging for two months would be roughly equivalent to a human aging from ~45–50 years to ~51–58 years.”

Glucosinolate and isothiocyanate human interventions

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Stress ,

A 2025 review covered human evidence from glucosinolate and isothiocyanate research through April 2025:

“Glucosinolates (GSLs) and their breakdown products, isothiocyanates (ITCs), are biogenesis compounds with anti-inflammatory, antioxidant, and anticancer properties, mediated through key pathways such as Nrf2, NF‐κB, and epigenetic regulation. However, their limited and variable bioavailability remains a key challenge. This review summarises the current clinical evidence on GSLs and ITCs, with a focus on their health effects and metabolic fate in humans.”

https://www.mdpi.com/2304-8158/14/16/2876 “Bioavailability, Human Metabolism, and Dietary Interventions of Glucosinolates and Isothiocyanates: Critical Insights and Future Perspectives”

In the above graphic, notice how the inactive myrosinase column has no small intestine participation, but the active myrosinase column does. This point wasn’t adequately emphasized, that for complete effects, an individual has to do whatever they can to thoroughly chew or otherwise activate myrosinase to hydrolyze glucosinolates before swallowing.

Researchers don’t rely on individuals taking responsibility for their own health, of course. Just swallow these pills, we’ll do it for you, as if humans are lab rats. This lack of emphasis is understandable, if not optimal.

This review provided longish coverage of studies, which is preferable to the usual treatment of citing a reference without much explanation. Compare, for example, my longish curation of the 2023 Eat broccoli sprouts for your high intensity interval training with its reference 68 summary below:

“Another study investigated the effects of consuming GSL-rich broccoli sprout (GRS) supplements on oxidative stress and physiological adaptations to intense exercise training. In a randomised, double-blind, crossover design, nine healthy participants consumed either a GRS supplement (75 g of sprouts) or a placebo twice daily over a 7-day high-intensity interval training period. The findings revealed that GRS supplementation significantly reduced markers of oxidative stress, including carbonylated proteins in skeletal muscle and plasma myeloperoxidase levels, compared to the placebo condition. Furthermore, GRS intake led to reduced lactate accumulation during submaximal exercise and enhanced exercise performance, as indicated by a longer time to exhaustion during maximal exercise tests. At the molecular level, supplementation with GRS was associated with elevated Nrf2 protein levels in muscle tissue, suggesting activation of endogenous antioxidant defence mechanisms. In addition, GRS intake mitigated nocturnal hypoglycaemic episodes and lowered average blood glucose levels, indicating improved glucose regulation during intense training. Collectively, these results suggest that GRS supplementation may enhance physiological adaptations to high-intensity exercise by reducing oxidative stress and supporting metabolic homeostasis.”

Oats sprouts treat gut inflammation

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

A 2025 rodent study investigated differing effects of regular oats and oat sprouts to treat induced colitis:

“This study aims to test our hypothesis that germinated oats exert stronger anti-inflammatory effects than raw oats due to their higher levels of bioactive phytochemicals. First, the nitric oxide (NO) production assay was used to screen [22] commercially available oat seed products and identify the product with the highest anti-inflammatory activity after germination [for five days]. The selected oat seed product was then produced in larger quantities and further evaluated in an in vivo study using the dextran sulfate sodium (DSS)-induced colitis mouse model to compare the anti-inflammatory effects of phytochemical extracts from germinated and raw oats.

The guideline states that for a healthy U.S.-style dietary pattern at a 2000 calorie level, a daily intake of 6 ounces of grains is recommended, with at least 3 ounces (84 g) coming from whole grains (WGs). For a 60 kg human, consuming 3 ounces of WGs per day translates to a 17.2 g/kg daily dose in mice. Given that the daily food intake of a 20 g mouse is approximately 2.5 g, the 17.2 g/kg daily dose corresponds to 14% of the total diet as WGs. Therefore, the 7 and 21% WG equivalent doses used in this study are relevant to human consumption.

Germination led to an overall increase in the content of all avenanthramides (AVAs) and avenacins (AVCs) as well as some avenacosides (AVEs):

  • For AVAs, the compounds 2c, 2p, 2f, 2cd, 2pd, and 2fd significantly increased by 10.0-, 6.3-, 9.6-, 20.7-, 10.6-, and 4.6-fold, respectively, which is consistent with previous reports.
  • This study is the first to report an increase in AVCs after germination, with AVC-A2, B2, A1, and B1 contents significantly increasing by 2.5-, 2.2-, 3.6-, and 4.2-fold, respectively.
  • Although germination resulted in a decrease in certain AVEs, it significantly increased the levels of AVE-C, Iso-AVE-A, AVE-E, and AVE-F by 1.8-, 3.3-, 3.3-, and 5.0-fold, respectively. Notably, AVE-E has been previously reported to have the strongest anti-inflammatory activity among all of the major AVEs.

In summary, germination enhances the anti-inflammatory properties of oats in both cells and DSS-induced colitis in mice by increasing levels of bioactive phytochemicals. Correlation analysis showed a significant inverse relationship between pro-inflammatory cytokines and phytochemical content in feces, especially AVAs and their microbial metabolites.

The observation of a stronger anti-inflammatory effect in the low-dose germinated oat group compared with the high-dose group is intriguing and warrants further investigation. One possible explanation is the phenomenon of hormesis, where low doses of bioactive compounds can exert beneficial effects, while higher doses may lead to diminished efficacy or even adverse effects. Further studies involving a broad range of doses would be valuable to define the effective intake range and provide insight into the underlying mechanisms.

It is possible that AVAs, AVEs, and AVCs act synergistically to enhance the overall anti-inflammatory efficacy, potentially by targeting different inflammatory pathways or modulating each other’s bioavailability and activity. Further investigation into the synergistic interactions among these compounds is warranted.”

https://pubs.acs.org/doi/10.1021/acs.jafc.5c02993 “Phytochemical-Rich Germinated Oats as a Novel Functional Food To Attenuate Gut Inflammation”

I’ve eaten 3-day-old Avena sativa oat sprouts (started from 20 grams of groats) every day for 4.5 years now, and haven’t had gut problems. Here’s what they looked like this morning:

Get a little stress into your life, Part 2

gettingwell4 5+ stars Premium, Cortisol, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , , , ,

A 2025 reply to a letter to the editor cited 56 references to elaborate on Part 1 and related topics:

“A positive effect does not necessarily mean benefit, and positive effects on individual organisms may mean adverse effects on other coexisting organisms. However, a vast literature shows that hormetic stimulation can result in benefits depending on the context, for instance, clear growth, yield, and survival improvement.

There is some energetic cost to support hormetic stimulation, with a likely positive energy budget, which might also have negative consequences if there is insufficient energy substrate, especially under concurrent severe environmental challenges. Moreover, hormetic preconditioning could be particularly costly when there is a mismatch between the predicted environment and the actual environment the same individuals or their offspring might face in the future.

Hormesis should not be unilaterally linked to positive and beneficial effects without considering dose levels. For any research to answer the question of whether a stimulation represents hormesis and whether it is beneficial, robust dose–response evaluations are needed, which should be designed a priori for this purpose, meeting the requirements of the proper number, increment, and range of doses.

Both additivity and synergism are possible in the hormetic stimulatory zone, depending also on the duration of exposure and the relative ratio of different components. This might happen, for example, when a chemical primes stress pathways (e.g., heat shock proteins and antioxidants), thus enabling another chemical to trigger hormesis (defense cross-activation) and/or because combined low subtoxicity may modulate receptors (e.g., aryl hydrocarbon receptor and nuclear factor erythroid 2-related factor 2) differently than individual exposures (receptor binding synergy).

Moreover, even when stimulation occurs in the presence of individual components, stimulation may no longer be present when combined, and therefore, effects of mixtures cannot be accurately predicted based on the effects of individual components. There may be hormesis trade-offs; hormesis should be judged based on fitness-critical end points.

While often modeled mathematically, hormesis is fundamentally a dynamic biological process and should not be seen as a purely mathematical function, certainly not a linear one. Much remains to be learned about the role of hormesis in global environmental change, and an open mind is needed to not miss the forest for the trees.”

https://pubs.acs.org/doi/10.1021/acs.est.5c05892 “Correspondence on ‘Hormesis as a Hidden Hand in Global Environmental Change?’ A Reply”

Reference 38 was a 2024 paper cited for:

“Hormetic-based interventions, particularly priming (or preconditioning), do not weaken organisms but strengthen them, enhancing their performance and health under different environmental challenges, which are often more massive than the priming exposure.

The catabolic aspect of hormesis is primarily protective whereas the anabolic aspect promotes growth, and their integration could optimize performance and health. The concept of preconditioning has also gained widespread attention in biomedical sciences.”

https://www.sciencedirect.com/science/article/abs/pii/S1568163724004069 “The catabolic – anabolic cycling hormesis model of health and resilience” (not freely available)

Reference 40 was a 2021 review that characterized hormesis as a hallmark of health:

“Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology.

Biological causes or hallmarks of health include features of:

  • Spatial compartmentalization (integrity of barriers and containment of local perturbations),
  • Maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and
  • An array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration).

Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system.

A future ‘medicine of health’ might detect perilous trajectories to intercept them by targeted interventions well before the traditional ‘medicine of disease’ comes into action.”

https://www.sciencedirect.com/science/article/pii/S0092867420316068 “Hallmarks of Health”

Sulforaphane as a senotherapy, Part 2

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Hippocampus, Limbic system, Memory, Stress , ,

A 2025 rodent study by the same group as Part 1 investigated similar subjects from a different experimental angle of senotherapy effects on brain and behavior rather than cardioprotective effects of dasatinib / quercetin (a senolytic combination) and sulforaphane (senomorphic):

“This is the first study to analyze the effect of senotherapy in the brain of a model of chronic obesity in middle-aged female rats. D + Q reduced the pro-inflammatory cytokines evaluated in the obesity model. It did not improve memory and learning nor the expression of molecules associated with the maintenance of synapses.

In contrast, sulforaphane (SFN), which without eliminating senescent cells, decreased pro-inflammatory factors, increased IL-10, as well as brain-derived neurotrophic factor BDNF, synaptophysin (SYP), and postsynaptic density protein 95 (PSD-95), which, in turn, were associated with an improvement in behavioral tests in obese rats. This suggests that modulating the senescence-associated secretory phenotype (SASP), rather than eliminating senescent cells, might have better effects.”

https://www.sciencedirect.com/science/article/pii/S0014488625001955 “Senotherapy as a multitarget intervention in chronic obesity: Modulation of senescence, neuroinflammation, dysbiosis, and synaptic integrity in middle-aged female Wistar rats”

Activate Nrf2 with far-infrared light

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress ,

A 2025 rodent study investigated effects of far-infrared light on Alzheimer’s disease models. I’ll focus on its Nrf2 findings:

“Far-infrared radiation (FIR) is commonly utilized as a complementary treatment of a range of disease, for example, insomnia and rheumatoid arthritis. In this research, we explored how FIR light impacts cognitive functions of TgCRND8 AD mice and elucidated its underlying molecular mechanism.

Infrared radiation is a form of electromagnetic energy that has wavelengths between 750 nm and 1000 μm, which are longer than visible light. International Commission on Illumination categorizes infrared light as three sub-divisions according to the wavelength: (1) near-infrared radiation (0.7–1.4 μm), (2) middle infrared radiation (1.4–3.0 μm), and (3) far-infrared radiation (3.0–1000 μm).

Nrf-2/ HO-1 signaling, a key endogenous antioxidant system, helps mitigate oxidative stress and enhances expression of various endogenous genes. Activation of HO-1 during inflammatory conditions may serve as an adaptive response to reduce cytotoxicity through various mechanisms.

In this study, we applied EFFIT LITE® as the FIR spectrum transmitter which stably radiates an FIR spectrum with a wavelength of 4–20 μm, and the device was put within 1 cm directly above the head of the 3-month-old TgCRND8 mice for 30 min exposure once every day. FIR light notably enhanced cognitive function and spatial memory of TgCRND8 mice after 28-days consecutive treatment.

Underlying molecular mechanisms involve suppression of Aβ deposition, hyperphosphorylation of tau, and neuroinflammation through modulating Jak-2/Stat3 and Nrf-2/HO-1 pathways. Our current experimental findings amply indicate that FIR light is a potential non-pharmacological therapy for AD.”

https://link.springer.com/article/10.1007/s12017-025-08860-2“Far-Infrared Radiation Ameliorates the Cognitive Dysfunction in an Alzheimer’s Disease Transgenic Mouse via Modulating Jak-2/Stat3 and Nrf-2/HO-1 Pathways”

This study measured Nrf2 and its quickly-induced downstream enzyme HO-1 effects of daily far-infrared light exposure for 30 minutes. We’d have to see measurements of Nrf2’s more-slowly induced and longer-lasting downstream xenobiotic detoxifying enzyme NQO1 to compare far-infrared light Nrf2 activation effects with those of natural plant compounds.

Broccoli sprouts and your dog

gettingwell4 2-3 stars Required further work, Stress

This 2025 opinion paper compared nine broccoli sprouts supplements for dogs:

“Broccoli sprouts are key elements of 9 dietary supplements for dogs. Feeding directions of 6 products correspond with consumption of dry food containing 0.5 to 29 g dried broccoli sprouts/kg. Seven supplements claim to supply sulforaphane and to possess anti-inflammatory and/or anti-cancer effects.

Directions for use of a sulforaphane-producing supplement read as follows: ‘One chewable tablet daily for dogs of all sizes, six months and older. Tablets should be given on an empty stomach at least two hours after a meal or one hour before a meal.’

There was no information found on feeding studies in dogs, addressing the impact of broccoli sprouts on health. In mice, dietary, whole-broccoli sprouts counteracted development of mammary and prostate cancer. Weights of dried broccoli sprouts in these mouse studies were 150 and 260 g/kg dry food, much higher levels than equivalents of feeding instructions for dog supplements. Species contrast and high dose blunt extrapolation of results to dogs.

The Veterinary Clinical Trials Registry of the American Veterinary Medical Association has announced that recruiting has finished for a study entitled “Sulforaphane supplementation in canine lymphoma and evaluation of epigenetic proteomic profiles”. https://veterinaryclinicaltrials.org/study/VCT17004227

https://www.researchgate.net/publication/393656647_Beynen_AC_2025_Broccoli_sprouts_in_dog_nutrition “Beynen AC, 2025. Broccoli sprouts in dog nutrition” (registration required)

The author’s use of ResearchGate is mainly to publish opinion pieces on pet animal nutrition. This doesn’t require high fees of regular journals, but also bypasses peer review.

I appreciate comparisons to rodent studies, which often intentionally overdose, and so have no relevance to humans and other mammals. His 2025 pet nutrition papers include broccoli, glyphosphate, zinc, copper, and PFAS subjects.

Betaine as an exercise mimetic

gettingwell4 5+ stars Premium, Cortisol, Epigenetics, Immune system, Memory, Neurochemicals, Stress , ,

A 2025 human study investigated effects of long-term exercise:

“Exercise has well-established health benefits, yet its molecular underpinnings remain incompletely understood. We conducted an integrated multi-omics analysis to compare effects of acute vs. long-term exercise in healthy males.

Acute exercise induced transient responses, whereas repeated exercise triggered adaptive changes, notably reducing cellular senescence and inflammation and enhancing betaine metabolism. Exercise-driven betaine enrichment, partly mediated by renal biosynthesis, exerts geroprotective effects and rescues age-related health decline in mice.

Betaine binds to and inhibits TANK-binding kinase 1 (TBK1), retarding the kinetics of aging.

Betaine effectively alleviated senescence phenotypes by reduced senescence-associated β-galactosidase (SA-β-Gal)-positive cells, decreased p21 expression, lowered DNA damage indicator γ-H2A.X, and elevated heterochromatin mark H3K9me3. Betaine treatment also enhanced cellular antioxidant capacity, as evidenced by increased NRF2 phosphorylation and reduced ROS accumulation.

These findings systematically elucidate the molecular benefits of exercise, and position betaine as an exercise mimetic for healthy aging.”

https://doi.org/10.1016/j.cell.2025.06.001 “Systematic profiling reveals betaine as an exercise mimetic for geroprotection” (not freely available) Thanks to Dr. Weimin Ci for providing a copy.

Taurine and mitochondrial health

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

A 2025 review subject was taurine’s beneficial effects on mitochondria:

“Taurine has multiple and complex functions in protecting mitochondria against oxidative-nitrosative stress. We introduce a novel potential role for taurine in protecting from deuterium (heavy hydrogen) toxicity. This can be of crucial impact to either normal or cancer cells that have highly different mitochondrial redox status.

Deuterium is an isotope of hydrogen with a neutron as well as a proton, making it about twice as heavy as hydrogen. We first explain the important role that the gut microbiome and gut sulfomucin barrier play in deuterium management. We describe synergistic effects of taurine in the gut to protect against deleterious accumulation of deuterium in mitochondria, which disrupts ATP synthesis by ATPase pumps.

Taurine’s derivatives, N-chlorotaurine (NCT) and N-bromotaurine (NBrT), produced through spontaneous reaction of taurine with hypochlorite and hypobromite, have fascinating regulatory roles to protect from oxidative stress and beyond. We describe how taurine could potentially alleviate deuterium stress, primarily through metabolic collaboration among various gut microflora to produce deuterium depleted nutrients and deuterium depleted water (DDW), and in this way protect against leaky gut barrier, inflammatory bowel disease, and colon cancer.

Taurine cannot be metabolized by human cells, but gut microbes are able to break it down to release sulfite, which then gets oxidized to sulfate anions that become available to support synthesis of sulfomucins. Taurine protects against many diseases linked to mitochondrial defects, such as aging, metabolic syndrome, cancer, cardiovascular diseases and neurological disorders.

We present a novel view that gut microbes play an essential role in providing deuterium depleted (deupleted) nutrients, especially, butyrate, to the host colonocytes forming the gut barrier. We propose that sulfomucins synthesized by goblet cells not only protect the barrier from pathogens, but also trap and sequester deuterium, thus reducing mitochondrial deuterium levels, resulting in improved mitochondrial health.

Due to taurine, redox buffer glutathione (GSH) further stabilizes the membrane potential. GSH not only reduces radical oxygen species (ROS) during oxidative stress, but it also assists in production of deupleted water in mitochondria.

Spontaneous oxidation of two GSH molecules to produce GSSG in the presence of hydrogen peroxide yields two molecules of DDW. Just as for glutathione, bilirubin can produce DDW indefinitely through chronic recycling between bilirubin and biliverdin, capturing a deupleted proton in NADPH to produce a DDW molecule in each cycle.

A novelty that arises from this investigation is introduction of the role that deuterium plays in mitochondrial disease, and ways in which taurine may facilitate maintenance of low deuterium in mitochondrial ATPase pumps. Excess deuterium causes a stutter in the pumps, which leads to inefficiencies in ATP production and an increase in ROS.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC11717795/ “Taurine prevents mitochondrial dysfunction and protects mitochondria from reactive oxygen species and deuterium toxicity”

Stay away from NAC

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Hypothalamus, Immune system, Limbic system, Neurochemicals, Stress

A 2025 rodent study added several reasons to avoid non-emergency use of N-acetylcysteine:

“We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on impairment of negative feedback of the HPA axis induced by N-acetylcysteine (NAC).

Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after starting NAC supplementation.

NAC reduced expression of Nrf2 in the pituitary of mice. NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in GRα expression and an increase of GRβ expression in the pituitary gland.

We observed that dietary supplementation with NAC ( Figure 4A ) significantly increased plasma corticosterone levels in mice 24h ( Figure 4B ) as well as 15 days ( Figure 4C ) after the last administration of the antioxidant with the same magnitude of response (3.5-fold and 3.4-fold, respectively).

Chronic activation of the HPA axis can have damaging effects on immune, cardiovascular, metabolic, and neural functions, increasing the risk of immune system dysfunction, mood disorders, and metabolic and cardiovascular diseases. To prevent these deleterious effects of chronic hypercortisolism, HPA axis function is controlled by a glucocorticoid-dependent negative feedback system that is essential for ending the stress response.

These findings showed that NAC reduced Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC11827418/ “Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands”

A human equivalent to this study’s NAC dose is (150 mg x .081) x 70 kg = 851 mg. Human supplements are sold in 600 mg and 1000 mg doses.

Grok 3 replied to a question: Human equivalent time to 15 days in male Swiss-Webster mice aged between 4 and 6 weeks? by stating: “15 days in male Swiss-Webster mice aged 4 to 6 weeks corresponds to approximately 4.1 human years, advancing their equivalent human age from about 10–12 years to roughly 14–16 years.” Four+ years seems like a long time for NAC to steadily and continuously affect humans’ HPA axes per the above graphic. What do you think?

Previously mentioned reasons to avoid daily use of NAC were in the lower part of A good activity for bad weather days.

Eat broccoli sprouts for your HIIT, Part 2

gettingwell4 2-3 stars Required further work, Epigenetics, Stress

A 2025 human study followed up Eat broccoli sprouts for your high intensity interval training using red kale sprouts:

“Glucosinolate-rich broccoli sprouts combined with intense exercise training for 7 days have been shown to reduce blood lactate concentrations during exercise, attenuate hypoglycemic events, improve physical performance, and reduce markers of oxidative stress. This study aimed to investigate the acute, dose-dependent effects of glucosinolate-rich red kale sprouts (GRS) on blood lactate and blood glucose following the ingestion of three different doses.

Fifteen healthy participants [11 females, 4 males] consumed 37.5 g or 75 g of GRS or an isocaloric placebo blended into a beverage on three separate occasions. The participants cycled on an ergometer at three submaximal work rates before and three hours after ingestion.

Intake of glucosinolate-rich sprouts acutely decreased blood lactate levels during submaximal cycling and increased blood glucose levels at rest. The largest reduction in blood lactate was observed at the 37.5 g dose compared to placebo.

To identify the dose of GRS that results in the lowest blood lactate concentration during submaximal exercise, we applied a quadratic modeling approach. The optimal dose for minimizing lactate accumulation was calculated as 44 g of GRS.

In our previous study, we found a tendency towards a lower respiratory exchange ratio after one week of supplementation. Moreover, studies have demonstrated that mitochondrial oxidation of long-chain and short-chain fatty acids is depressed in the absence of Nrf2, and accelerated when Nrf2 is constitutively active.

We observed a reduction in myeloperoxidase levels approximately three hours after GRS intake, suggesting a decrease in oxidative stress. This finding indicates that the adaptive compensatory system may act rapidly, likely within just a few hours of GRS consumption.

A limitation is that we did not assess whether the lower lactate levels translated into improved performance. Theoretically, if the reduction in lactate results from the activation of pyruvate dehydrogenase, it could enhance performance by channeling more pyruvate into mitochondria for efficient oxidation, reducing reliance on glycolysis, and thereby sparing muscle glycogen. Alternatively, if the lower lactate levels are due to increased activity of the hepatic Cori cycle, lactate could be more rapidly converted to glucose, possibly supporting glycogen resynthesis or maintaining blood glucose levels during exercise. Both mechanisms could potentially contribute to improved performance.

Acute intake of small doses of GRS followed by submaximal ergometer cycling results in changes in lactate and glucose metabolism that could be beneficial for exercise performance.”

https://www.biorxiv.org/content/10.1101/2025.04.15.648889v1.full “A glucosinolate-rich beverage lowers blood lactate concentrations during submaximal exercise”

These researchers chose red kale sprouts of undisclosed age over the predecessor study’s broccoli raab five-day old sprouts, and two other undisclosed cruciferous vegetable sprouts.

This study is in its preprint phase. Items that could be clarified before publishing in final form include:

  • In the Abstract section, reference findings to red kale sprouts rather than broccoli sprouts;
  • Characterize the lactate U-shaped dose-response curve as hormesis; and
  • Reference other hormesis findings for context.