Sulforaphane vs. too much oxygen

This 2021 rodent study investigated perinatal effects of hyperoxia and sulforaphane:

“We demonstrated that early-life oxidant-induced acute lung injury had significant consequences later in life on NRF2-dependent respiratory syncytial virus (RSV) susceptibility in mice. We also determined that increased antioxidant conditions in utero potentially contribute to a decreased risk of postnatal airway disease as we found that prenatal antioxidant sulforaphane (SFN) protected developing lungs from bronchopulmonary dysplasia (BPD)-like oxidative pathogenesis in mice.

Unexpectedly, our results indicated that prenatal SFN-mediated postnatal protection against BPD-like phenotypes are not NRF2-dependent. Prenatal SFN markedly improved hyperoxia-caused severe BPD-like lung injury parameters in Nrf2−/− pups while we observed relatively marginal protection by in utero SFN in hyperoxia-resistant Nrf2+/+ pups.

SFN is a strong NRF2 and ARE gene inducer for cytoprotection by NRF2 stabilization. However, SFN also acts through other mechanisms, including NF-κB inhibition, MAPK activation, and histone deacetylase inhibition for anti-inflammation, chemoprevention, apoptosis, and autophagy.

Our study provided new insights into infant oxidant lung injury severity influence on persistence of pulmonary morbidity and therapeutic intervention for NRF2 agonists. Our results also provided justification for further studies on feto–placental barrier crossing of SFN metabolites and SFN-triggered molecular and epigenetic aspects of maternal cues for barrier and fetal lung signaling.”

https://www.mdpi.com/2076-3921/10/12/1874/htm “Murine Neonatal Oxidant Lung Injury: NRF2-Dependent Predisposition to Adulthood Respiratory Viral Infection and Protection by Maternal Antioxidant”


This study’s oral human-equivalent dose for treatment dams was 9 mg sulforaphane (1.67 mg x .081 x 70 kg) every other day during the last half of pregnancy. A small dose per How much sulforaphane is suitable for healthy people?

“The daily SFN dose found to achieve beneficial outcomes in most of the available clinical trials is around 20-40 mg.”

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Gut microbiota vs. disease risks

This 2021 review subject was risk relationships between diseases from the perspective of gut microbiota:

“There is a significant inverse relationship between the onset of Alzheimer’s disease/Parkinson’s disease (AD/PD) and cancer, but the mechanism is still unclear. Considering that intestinal flora can connect them, we briefly introduced the relationship among AD/PD, cancer, and intestinal flora, studied metabolites or components of the intestinal flora, and the role of intestinal barriers and intestinal hormones in AD/PD and cancer.

According to existing evidence:

  • Bifidobacterium and Lactobacillus positively affect AD/PD and cancer;
  • Ruminococcaceae, Prevotellaceae, and Prevotella significantly improve on AD/PD but harm cancer; and
  • Blautia has universal anticancer ability, but it may aggravate AD pathology.

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This may partially explain the antagonistic relationship between neurodegenerative diseases and cancer. When some individuals suffer from one disease, their intestinal flora change to obtain a stronger resistance to the other disease than healthy individuals, which is consistent with statistical data.”

https://www.sciencedirect.com/science/article/pii/S0753332221011276 “Composition of intestinal flora affects the risk relationship between Alzheimer’s disease/Parkinson’s disease and cancer”


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Inevitable individual differences

This 2021 review subject was individual differences:

“We will focus on recent findings that try to shed light on the emergence of individuality, with a particular interest in Drosophila melanogaster.

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Another possible source of potential behavioral variability might come from the interaction of individuals with environmental microbes, from Wolbachia infections to changes in the gut microbiome. In this particular case, no genetic variation or neural circuit alteration would be responsible for the change in behavior.

Finally, from an evolutionary point of view, individuality might play an essential role in providing an adaptive advantage. For example, we have described that animals might use diversified bet-hedging as a mechanism to produce high levels of variation within a population to ensure that at least some individuals will be well-adapted when facing unpredictable environments.”

https://www.frontiersin.org/articles/10.3389/fphys.2021.719038/full “Behavior Individuality: A Focus on Drosophila melanogaster


Other papers on this subject include:

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Immune system aging

This 2021 review by three coauthors of Take responsibility for your one precious life – Trained innate immunity cast a wide net:

“Non-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. However, these mechanisms of memory generation and maintenance are compromised as organisms age.

This review discusses how immune function regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life. We aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory.

aging immune system

A comprehensive strategy is essential for human beings striving to lead long lives with healthy guts, functional brains, and free of severe infections.”

https://link.springer.com/article/10.1007/s12016-021-08905-x “Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics”


Attempts to cover a wide range of topics well are usually uneven. For example, older information in the DNA Methylation In Adaptive Immunity section was followed by a more recent Histone Modifications in Adaptive Immunity section.

This group specializes in tuberculosis vaccine trained immunity studies, and much of what they presented also applied to β-glucan trained immunity. A dozen previously curated papers were cited.

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Glutathione primes β-glucan-trained immunity

Two 2021 papers on glutathione interactions with β-glucan, with the first studying human cells from healthy donors:

“(1→3)-β-D-Glucan stimulation induces epigenetic and transcriptomic changes in monocytes associated with increased glutathione (GSH) synthesis and metabolism. Intracellular glutathione levels were crucial in regulating several monocyte antifungal functions including resilience to oxidative stress, immunometabolism, nitric oxide production, phagocytosis, and cytokine production.

Our findings demonstrate an important role for GSH in immunity, and outline a better understanding of the acute response of monocytes to infections.”

https://www.frontiersin.org/articles/10.3389/fimmu.2021.694152/full “Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan”


A second study investigated the subject with a dozen rodent experiments:

“We demonstrated that antioxidation by GSH supported an environment essential for β-glucan-induced metabolic and epigenetic changes in monocytes. We found that GSH induced glycolysis and glutaminolysis in β-glucan-trained immunity in a mTOR-dependent manner.

These results uncovered the GSH/mTOR/c-Myc signaling axis as the central effector of metabolic reprogramming in trained immunity. We revealed that the delicate GSH/ROS redox balance determines discrete, long lasting metabolic modifications that are causal to β-glucan-trained immunity.

Our results suggest that H3K27me3 demethylation is a necessary event. We identified H3K27me3 demethylation as a novel histone modification mark that was impaired by GSH deficiency in β-glucan-trained bone marrow derived macrophages.

We identified EZH2 as a potential tool to boost trained immunity under GSH deficiency conditions, or to enhance trained immunity in clinical settings where excessive inflammatory responses could be beneficial.

ezh2 survival

Overall, these insights contribute to unraveling metabolic and epigenetic changes during trained immunity.”

https://www.sciencedirect.com/science/article/pii/S2213231721003669 “Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity”


The second paper of Remembering encounters provides future benefits also explored this subject.

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Offspring brain effects from maternal adversity

This 2021 rodent study investigated conception through weaning effects on offspring from stressing their mothers:

“We investigated consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. We analyzed patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females, and found sex-dependent and sex-concordant influences of these insults.

The pair-fed (PF) group in the PAE model is a standard control for effects of alcohol in reducing food intake. However, compared to the PAE group that, albeit eating less, eats ad libitum, pair-feeding is a treatment in itself, with PF dams receiving a restricted ration, which results in both hunger and a disrupted feeding schedule. These stress-related effects could potentially parallel or model food scarcity or food insecurity in human populations.

We observed more DMRs (Differentially Methylated Regions) that showed decreased DNAm rather than increased DNAm in PF animals, suggesting that food-related stress may interfere with one-carbon metabolism and the pathways that deposit methylation on DNA. We also identified a sex-concordant DMR that showed decreased DNAm in PF animals in the glucocorticoid receptor Nr3c1, which plays a key role in stress responsivity and may reflect a reprogramming of the stress response.

This result is in line with previous studies that have shown that pair-feeding is a considerable stressor on dams, with lasting consequences on development, behavior, and physiology of their offspring. Altered DNAm of this key HPA axis gene may reflect broader alterations to stress response systems, which may in turn, influence programming of numerous physiological systems linked to the stress response, including immune function, metabolic processes, and circadian rhythms.

In PAE and PF animals compared to controls, we identified 26 biological pathways that were enriched in females, including those involved in cellular stress and metabolism, and 10 biological pathways enriched in males, which were mainly involved in metabolic processes. These findings suggest that PAE and restricted feeding, both of which act in many respects as prenatal stressors, may influence some common biological pathways, which may explain some of the occasional overlap between their resulting phenotypes.

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This study highlights the complex network of neurobiological pathways that respond to prenatal adversity/stressors and that modulate differential effects of early life insults on functional and health outcomes. Study of these exposures provides a unique opportunity to investigate sex-specific effects of prenatal adversity on epigenetic patterns, as possible biological mechanisms underlying sex-specific responses to prenatal insults are understudied and remain largely unknown.”

https://www.mdpi.com/2073-4425/12/11/1773/htm “Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress”


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The impact of transgenerational epigenetic inheritance and early life experiences

A 2021 interview with McGill University’s Moshe Szyf:

There is a rejection of transgenerational inheritance as it goes against progressive thinking because it ties us to previous generations. The theory faces rejection because it sounds deterministic.

But if you understand what epigenetics is, it’s not deterministic. There is stability, and there’s also room for dynamic change.

The only way things change in the body for the long term is via epigenetics. We don’t know everything yet, new discoveries are yet to happen, and then we will just say, ‘Wow, it’s so obvious!’

The immune system is tightly connected to the brain and is directly affected by early adversity. Even though we will not be able to learn what’s going on in the brain, as far as epigenetics in living people, we will gain a lot of information from how the immune system responds to early adversity, and how this is correlated with behavioral phenotype and with mental health.

This brings into question the whole field of neuroimmunology, of which there is a lot of data. But it seems that a lot of psychiatrists are totally oblivious to these data, which is astounding, because the glucocorticoid hormone – the major player in this mechanism due to its involvement in early life stress as well as control of behavior – also controls immune function.

Nobody can live long enough to oversee a human transgenerational study. In humans, correlations are usually in peripheral tissue, where changes are small. The jury’s not out yet, but if evolution used it for so many different organisms, some of which are very close to us in the evolutionary ladder, it’s impossible that humans don’t use it.

How are current findings in animal models relevant to humans? How do we develop human paradigms that will allow us to achieve a higher level of evidence than what we have now?

  • One way is the immune-inflammatory connection to other diseases. I think this is where the secret of epigenetic aging lies, as well as epigenetics of other diseases.
  • Every disease is connected to the immune system. The brain translates the behavioral environment to the immune system, and then the immune system sends chemical signals across the body to respond to these challenges.

We need to understand that epigenetic programs are a network. Move beyond candidate genes, understand the concept of a network, and really understand the challenge: Reset the epigenetic network.

Epigenetics is going to be rapidly translated to better predictors, better therapeutics, and more interesting therapeutics. Not necessarily the traditional drug modeled against a crystal structure of an enzyme, but a more networked approach. Ideas about early life stress are critical and have impacted the field of childcare by highlighting the importance of early childhood relationships.”

https://www.futuremedicine.com/doi/10.2217/epi-2021-0483 “The epigenetics of early life adversity and trauma inheritance: an interview with Moshe Szyf”


Trained immunity genes

This 2021 human cell study investigated trained immunity responses:

“We integrated genetic, epigenetic, and functional validation data to shed light on regulation of trained immunity responses. This data integration revealed a novel role of SIGLECs and KDM4 genes on trained immunity responses.

  • Siglec-5 is an inhibitory receptor that dampens the immune response, and was found to display reduced levels of activation mark H3K4me3 upon β-glucan training.
  • Siglec-14 has a ligand-binding domain almost identical to Siglec-5 but in contrast to Siglec-5, leads to activation of the inflammatory response. Differential expression of Siglec-14 has been shown to play a role in incidence of premature delivery in Group B Streptococcus-positive mothers, COPD exacerbation, and susceptibility to tuberculosis.
  • Within the family of histone demethylases, members of the KDM4 family showed the strongest association with trained immunity responses via modulation of methylation at H3K9.

We observed a high degree of inter-individual variability in both β-glucan and BCG-induced trained immunity responses in both cohorts. Age showed no correlation with induction of trained immunity, whereas male individuals showed higher trained immunity responses as assessed by measuring TNF-α production and IL-6.

By studying processes underlying heterogeneity of trained immunity responses, we prioritized and identified important candidate genes and pathways implicated in trained immunity that could be novel targets for diagnostic and therapeutic purposes. KDM4 demethylases and Siglecs are also considered attractive therapeutic targets in oncology and other immune cell-mediated diseases.”

https://onlinelibrary.wiley.com/doi/full/10.1002/eji.202149577 “An integrative genomics approach identifies KDM4 as a modulator of trained immunity”


Most of what this study found can be extrapolated to yeast cell wall β-glucan’s effects.

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Uses of the neutrophils-to-lymphocytes ratio

This 2021 review subject was recent history and uses of the neutrophils-to-lymphocytes ratio parameter to indicate systemic inflammation and stress:

“NLR is widely used across almost all medical disciplines as a reliable and easily available marker of immune response to various infectious and non-infectious stimuli. NLR reflects dynamic relationships between innate (neutrophils) and adaptive (lymphocytes) cellular immune response during illness and various pathological states.

A normal range of NLR is between 1–2, and values higher than 3.0 and below 0.7 in adults are pathological. NLR between 2.3–3.0 may serve as an early warning of cancer, atherosclerosis, infection, inflammation, psychiatric disorders, and stress.

nlr

Neutrophils play a pivotal role in innate immune response including phagocytosis, and release of a variety of cytokines and molecule mediators. Lymphocytopenia is a hallmark of stress while inflammation is due to demargination, redistribution, and accelerated apoptosis.

Opposite changes in neutrophil and lymphocyte counts are a multifactorial dynamic process depending on regulation of various immunologic, neuroendocrine, humoral, and biologic processes such as margination / demargination, mobilization / redistribution, accelerated / delayed apoptosis, influence of stress hormones, and sympathetic / parasympathetic nervous system imbalance. NLR is the best expression of a tight functional relation between two fundamental immunocompetent leukocyte populations.”

https://doi.org/10.4149/bll_2021_078 “Neutrophil-to-lymphocyte ratio, past, present and future perspectives”


The fourth study of Uses of the lymphocytes-to-monocytes ratio also commented on NLR.

Sunday morning stroll

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Eat broccoli sprouts to prevent radiation damage

This 2021 rodent study investigated effects of sulforaphane on skin damage from irradiation:

“Radiotherapy is currently the main treatment for various cancers. We observed the protective effect of sulforaphane (SFN) on radiation-induced skin injury (RISI), including oxidative stress and inflammatory response indexes, and Nrf2 expression with its downstream antioxidant genes:

  • SFN prevented DNA damage caused by radiation.
  • SFN prevented and treated radiation-induced skin inflammation.
  • SFN prevented radiation-induced oxidative stress in skin.
  • Activation of Nrf2 and expressions of its downstream genes in skin induced by SFN.

Nrf2 downstream antioxidant genes induced by SFN

Mice were randomly assigned to one of four groups (n = 8), including control group (CON), SFN group, irradiation (IR) group, and IR plus SFN (IR/SFN) group (* p < 0.05 vs. CON; & p < 0.05 vs. IR).

Our most innovative discovery was that SFN provided skin protection from IR. At present, there are a few drugs to treat RISI in clinical patients, but the effect is not very ideal, or some may cause certain side effects.

SFN extracted from natural broccoli has no toxicity and is easily accepted for usage in clinic. According to our findings, SFN will provide a new strategy for clinical treatment and prevention of RISI in the future.”

https://www.mdpi.com/2076-3921/10/11/1850/htm “Sulforaphane-Mediated Nrf2 Activation Prevents Radiation-Induced Skin Injury through Inhibiting the Oxidative-Stress-Activated DNA Damage and NLRP3 Inflammasome”


This study’s findings probably also apply to less-severe skin damage caused by sun exposure.

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Human agency vs. brain dysfunction

This 2021 human study used epigenetic clock technology to assess chronic inflammation as a driver of cognitive decline through its effects on brain structure:

“An epigenetic measure of C-reactive protein (DNAm CRP) was assembled for each participant. We found that higher inflammatory burden, indexed by DNAm CRP scores, associated with poor cognitive and neuroimaging brain health outcomes.

inflammation vs cognitive ability

DNAm CRP exhibited significantly larger associations with brain structural MRI metrics (including global grey and white matter atrophy, poorer white matter microstructure, and increased white matter hyperintensity burden) than serum CRP. Given that the 7 CpGs which make up DNAm CRP score reside in inflammation and vascular-related genes, these DNAm CRP-brain MRI associations may be capturing the impact of upstream inflammatory activity above and beyond that of serum CRP levels.

Our results indicate that some cognitive domains (processing speed) may be more mediated by brain structural consequences of chronic inflammation than others (verbal memory, visuospatial ability).

Our results add to the evidence base that DNAm-based predictors of inflammation may act as a quantifiable archive of longitudinal effects of these exposures – and other unaccounted for health and genetic profiles – that serum CRP levels fail to capture. By utilising an epigenetic inflammation measure, which integrates information from multiple immune-related CpG sites, we may provide a more reliable measure of chronic inflammation and thus a more comprehensive overview of consequences of chronic inflammation on brain structure and function.”

https://n.neurology.org/content/early/2021/11/17/WNL.0000000000012997.long “DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging”


These researchers essentially negated many of their findings by acknowledging:

“Although we endeavoured to remove participants with cognition-related pathology, these were screened via self-reported diagnoses, and we may be missing undiagnosed or subclinical incident neurodegenerative pathology.”

It wasn’t sufficient to claim in the Abstract section “Participants (N = 521) were cognitively normal, around 73 years of age” then include in the Discussion section a one-sentence limitation of relying on self-reports. Everyone defends themself against current and past realities and experiences.

Hard to imagine that objective measures such as the three comprising cognitive ability weren’t better screens. But then too many 73-year-old subjects may not have been “cognitively normal” and this study wouldn’t be adequately powered?

Can humans counteract inflammation? Non-communicable diseases? Smoking? Immune system degradation? Yes. No personal-agency actions were mentioned.

Also note this study’s social norming. The above-pictured 30-year-old female was busy at work, and subsequently hoisted a cat instead of a child in later years.

Take responsibility for your own one precious life.

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Saving bees by regulating epigenetics

This 2021 study investigated an epigenetic treatment for bees forgetting about their hives:

“Over the last few decades, numbers of both wild and managed bee pollinators have been declining. Although reasons for this decline are under debate, it is highly likely that a combination of multiple stressors is to blame, in particular, deformed wing virus (DWV).

Histone deacetylase inhibitors (HDACi) are a class of compounds which prevent deacetylation of histones and therefore increase gene expression. The present study found that HDACi sodium butyrate (NaB) significantly increased survival and reversed the learning / memory impairment of DWV-infected bees. We demonstrated the mechanism of how epigenetic regulation can resume honeybees’ memory function.

bee survival rates

  • When bees were infected with DWV, 50% of bees died by the end of day 2 and only 10% survived to the end of day 5.
  • When NaB was added to the diet prior to DWV infection, survival rate of DWV-infected bees (N/D group) remained >90% after 5 days.
  • Under laboratory rearing conditions, around 30% of control bees died over a period of 5 days.
  • When NaB was included in uninfected bees’ diet, less than 15% of bees died.

These results indicate that feeding bees with NaB could significantly increase survival with or without DWV infection.”

https://www.cell.com/iscience/fulltext/S2589-0042(21)01024-5 “Real-time monitoring of deformed wing virus-infected bee foraging behavior following histone deacetylase inhibitor treatment”


Interesting that these researchers didn’t attempt to eliminate either the virus cause of bee behavior or parasitical mites that carried the virus. They mainly depended on bees’ endogenous systems providing beneficial responses when stimulated.

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Reworking evolutionary theory

Dr. Michael Skinner coauthored a 2021 review arguing for inclusion of epigenetic transgenerational inheritance into evolutionary theory:

“Over the past 50 years, molecular technology has been used to investigate evolutionary biology. Many examples of finding no correlated genetic mutations or a low frequency of DNA sequence mutations suggest that additional mechanisms are also involved.

  • Identical twins have essentially the same genetics, but generally develop discordant disease as they age.
  • Only a low frequency (generally 1% or less) of individuals that have a specific disease have a correlated genetic mutation.
  • Dramatic increases in disease frequency in the population cannot be explained with genetics alone.

DNA methylation, histone modifications, changes to chromatin structure, expression of non-coding RNA, and RNA methylation can directly regulate gene expression independent of DNA sequence. These different epigenetic factors do not only act independently, but integrate with each other to provide a level of epigenetic complexity to accommodate the needs of cellular development and differentiation.

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Environmental epigenetics is the primary molecular mechanism in any organism that is used to promote physiological and phenotypic alterations. Actions of environmental factors early in development can permanently program the cellular molecular function, which then impacts later life disease or phenotypes.

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Integration of epigenetics and genetics contribute to a Unified Theory of Evolution that explains environmental impacts, phenotypic variation, genetic variation, and adaptation that natural selection acts on. The current review expands this proposed concept and provides a significant amount of supporting literature and experimental models to support the role of environmentally induced epigenetic transgenerational inheritance in evolution.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557805/ “Role of environmentally induced epigenetic transgenerational inheritance in evolutionary biology: Unified Evolution Theory”


Organisms cited in this review’s references are similar to humans in ancestral influences and developmental influences during the first 1000 days of our lives. Humans are different in that even after all these influences, we can choose to influence our own change and individually evolve. We can also change our internal environments per Switch on your Nrf2 signaling pathway and An environmental signaling paradigm of aging.

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Remembering encounters provides future benefits

Two 2021 papers on trained immunity, with the first a review:

“Effective memory immune responses rely on interaction between innate and adaptive immune cells. While activation of innate immunity provides the first line of defense against infections, it also primes the adaptive immune response.

Adaptive immunity can enhance antimicrobial machinery of innate cells, making them more effective at clearing pathogenic microorganisms. An additional layer of complexity adds to this network of interactions, with innate cells adopting a memory phenotype, which used to apply to only adaptive immunity. Furthermore, non-immune cells can develop some features of this memory-like phenotype.

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Cell subsets in which trained immunity has been described. Different stimuli including Bacillus Calmette Guerin (BCG), β-glucan, cytokines, cytomegalovirus (CMV), and bacterial components can induce a trained immunity phenotype. A common hallmark of trained immunity in these cases is H3K4me3 in promoters of genes encoding for different cytokines.

  • Mechanisms Underlying Establishment of Trained Immunity
  • Trained Immunity in Neutrophils
  • Trained Immunity in Monocytes and Macrophages: General Features
  • Metabolic Pathways Involved in Training of Monocytes and Macrophages
  • Hormonal Control of Trained Immunity Responses in Monocytes and Macrophages
  • Trained Immunity on Alveolar Macrophages and Involvement of Resident Cells
  • Trained Immunity in NK Cells
  • Trained Immunity in Innate Lymphoid Cells
  • Trained Immunity on Hematopoietic Stem Cells
  • Trained Immunity in Bronchial Epithelial Cells
  • Trained Immunity in Skin Stem Cells
  • Trained Immunity in the Gastrointestinal Tract
  • Immunity Training Against Protozoan-Mediated Pathologies
  • Trained Immunity in Non-Infectious Pathologies

Many gaps of knowledge remain in this field. For example, how long changes associated to trained immunity last, and if, in addition to epigenetic modulation, there are other post-translational modifications on proteins relevant for induction of trained immunity.”

https://www.frontiersin.org/articles/10.3389/fimmu.2021.745332/full “Molecular and Cellular Mechanisms Modulating Trained Immunity by Various Cell Types in Response to Pathogen Encounter”


This second paper was a human study cited for its glutathione findings as follows:

  • “Plasma concentration of IL-1β from BCG-vaccinated individuals are positively associated with serum glutathione concentrations.
  • Trained immunity up-regulates expression of genes involved in glutathione metabolism, suggesting an increase in glutathione synthesis and a higher glutathione recycling rate.
  • Single nucleotide polymorphisms in these genes are associated with changes in pro-inflammatory cytokine production after in vitro training by β-glucan and BCG.

Enzymes whose activities are dependent on glutathione could be used as novel targets to modulate trained immunity.”

IL-1β production

“We found a positive association between plasma glutathione concentration and ex vivo IL-1β production 90 days after BCG vaccination upon in vitro exposure to heterologous stimulus Staphylococcus aureus. Up-regulation of IL-1β production by BCG vaccination was also positively associated with circulating concentrations of other metabolites involved in glutathione metabolism, such as methionine, cysteine, glutamate, and glycine.

GSH metabolism was associated with trained immunity traits in 278 healthy individuals. Trained immunity mechanisms that are shaped by GSH metabolism remain to be further explored.”

https://www.mdpi.com/2073-4409/10/5/971/htm “Glutathione Metabolism Contributes to the Induction of Trained Immunity”


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Intergenerational epigenetic inheritance of trained immunity

I’ll curate this 2021 rodent study Transmission of trained immunity and heterologous resistance to infections across generations (not freely available) through two instances of its news coverage:

“Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. Progeny of trained mice exhibited cellular, developmental, transcriptional, and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment.

Progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous [elicits a reaction in a nonspecific antibody] Escherichia coli and Listeria monocytogenes infections. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections.”


Its most frequent coverages were repetitions of a press release from an institution that funded this research:

“How does this transmission of immunization to subsequent generations work? In contrast to the classical theory of evolution, which assumes slow adaptation through changes in genetic code, this involves very rapid changes via epigenetic regulation of gene activities, irrespective of genetic code.”

https://medicalxpress.com/news/2021-10-epigenetics-immunization-offspring.html “Epigenetics: Immunization is passed on to offspring”

Not much objectivity in a sponsor’s press release. May as well ask a coworker if they had a good vacation.


And the second:

“When either parent was subjected to real or simulated infection, offspring showed a stronger immune response to potential pathogens, including E. coli bacteria, than controls whose parents hadn’t been subjected to an immune system challenge. They had lower numbers of the bacteria in their lungs and liver, as well as higher concentrations of immune cells and pro-inflammatory cytokines. The effect persisted further: offspring of these second-generation mice also showed a lower bacterial burden after infection.

One weakness of the study is that results do not clearly show how enhanced immunity is being transferred from parent to offspring. The study found that fungal infection induced changes in sperm DNA methylation. But female mice who recovered from infection also produced offspring with fortified immune systems.”

https://www.the-scientist.com/news-opinion/mice-that-survive-infection-pass-on-stronger-immunity-69324 “Mice that Survive Infection Pass on Stronger Immunity”

This reporter gathered good comments from unassociated researchers, but whiffed overall by misinterpreting intergenerational epigenetic inheritance as transgenerational epigenetic inheritance. Per definitions in A review of epigenetic transgenerational inheritance of reproductive disease and Transgenerational effects of early environmental insults on aging and disease, for the term “transgenerational transmission” to apply, researchers need to provide evidence in at least the next 2 male or non-gestating female generations and/or 3 gestating female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

I’ll ask about their plans regarding continuing to a F3 generation for further epigenetic inheritance evidence. The interviewed coauthor didn’t indicate that was their current direction, though.

While we wait, train your body’s antioxidant response elements and immune system every day. Exercise your endogenous responses with weak pro-inflammatory isothiocyanates in broccoli sprouts, and your gut with weak antigens in yeast cell wall β-glucan. Daily drills will keep your body’s systems tuned up and ready for both these specific challenges as well as others per this study’s referenced heterologous findings.

Seconds to sunrise

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