Month: October 2025

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?

Ancient DNA fragments enable adult neurogenesis

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

A 2025 rodent study investigated mechanisms by which erythropoietin (EPO) enables adult neurogenesis and cognitive function:

“We mapped epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discovered significant lineage-specific remodelling of chromatin accessibility predominantly in newly formed pyramidal neurons, highlighting a robust EPO-driven neurogenic response. Notably, transposable elements (TEs), particularly ancient LINEs and SINEs, emerged as critical cis-regulatory elements (cCREs).

EPO is known to be upregulated in the brain under hypoxic or injury conditions, and it has been considered a natural neuroprotective agent. We demonstrated that EPO, a traditionally hematopoietic hormone, can profoundly reprogram the adult neural epigenome to drive neurogenesis.

EPO may activate a specific subclass of dormant regulatory elements to drive nearby genes. Such a mechanism would represent a previously unappreciated mode of gene regulation: the de novo recruitment of ancient genomic elements to drive a contemporary cellular response.

Our data support the model that EPO drives differentiation of progenitors rather than inducing widespread cell division. The net effect is an enrichment of pyramidal neurons at the cost of interneurons. Pyramidal neurons integrate in the hippocampal circuitry, leading to potential implications for mood, memory, cognitive enhancement, and recovery from brain injury.

We propose a conserved evolutionary mechanism at play: ancient TEs embedded in the genome have been repurposed as cCREs in neural cells, and during an EPO-induced neurogenic stimulus, the brain taps into this reservoir of regulatory elements to rapidly reshape gene expression. In evolutionary terms, this represents an efficient strategy.”

https://www.biorxiv.org/content/10.1101/2025.10.13.682070v1.full “Transposable Element-Mediated Epigenomic Remodeling Drives Erythropoietin-Induced Neurogenesis in the Adult Hippocampus”

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.”

Sulforaphane and migraines

gettingwell4 4-5 stars Advanced knowledge, Brainstem, Lower brain

A 2025 rodent study compared protective effects of sulforaphane and a migraine compound on nitroglycerin-induced migraines:

“Activation of trigeminal vascular pathways and the release of calcitonin gene‐related peptide (CGRP) are central to migraine pathogenesis. The amylin‐1 (AMY1) receptor is expressed in key structures implicated in migraine mechanisms.

This study evaluated protective effects of sulforaphane (SFN) against nitroglycerin induced migraine in female mice, comparing its efficacy to the standard migraine medication, topiramate. Migraine was induced using nitroglycerin (10 mg/kg, i.p., administered every other day), and treatments included sulforaphane (5 mg/kg/day, i.p.) or topiramate (30 mg/kg/day, i.p.) for a duration of 9 days.

Sulforaphane demonstrated significant improvements in behavioral symptoms such as photophobia, head grooming, and both mechanical and thermal allodynia. These behavioral changes were accompanied by reductions in serum levels of nitric oxide, CGRP, and pro‐inflammatory cytokines.

Histological analysis revealed that sulforaphane ameliorated nitroglycerin-induced damage in the trigeminal ganglia and trigeminal nucleus caudalis. Additionally, sulforaphane reduced AMY1 receptor expression in the medulla and inhibited its downstream signaling components, including phosphorylated ERK1/2, P38, and c‐Fos. Sulforaphane further enhanced the Nrf2/HO‐1 pathway while suppressing the NF‐κB/NLRP3/caspase‐1 signaling cascade.

These findings indicate that SFN has a potential as a novel therapeutic candidate for migraine management by targeting the downstream signaling pathways of the AMY1 receptor.”

https://onlinelibrary.wiley.com/doi/10.1002/ardp.70107 “The Role of the AMY1 Receptor Signaling Cascade in the Protective Effect of Sulforaphane Against Nitroglycerin-Induced Migraine in Mice” (not freely available)

This study’s Reference 34 was a 2016 study curated in Do broccoli sprouts treat migraines?.