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.


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.” “Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress”


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.” “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.


Epigenetic clocks so far in 2021

2021’s busiest researcher took time out this month to update progress on epigenetic clocks:

Hallmarks of aging aren’t all associated with epigenetic aging.

epigenetic aging vs. hallmarks of aging

Interventions that increase cellular lifespan aren’t all associated with epigenetic aging.

epigenetic aging vs. cellular lifespan

Many of his authored or coauthored 2021 papers developed human / mammalian species relative-age epigenetic clocks.

epigenetic clock mammalian maximum lifespan

Relative-age epigenetic clocks better predict human results from animal testing.

pan-mammalian epigenetic clock

Previously curated papers that were mentioned or relevant included:

Natural products vs. neurodegenerative diseases

I was recently asked about taking rapamycin for its effects on mTOR. I replied that diet could do the same thing. Here’s a 2021 review outlining such effects:

“As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt (Protein kinase B)/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials.

Growing evidence highlights the dysregulated PI3K/Akt/mTOR pathway and interconnected mediators in pathogenesis of NDDs. Side effects and drug-resistance of conventional neuroprotective agents urge the need for providing alternative therapies.


Polyphenols, alkaloids, carotenoids, and terpenoids have shown to be capable of a great modulation of PI3K/Akt/mTOR in NDDs. Natural products potentially target various important oxidative/inflammatory/apoptotic/autophagic molecules/mediators, such as Bax, Bcl-2, p53, caspase-3, caspase-9, NF-κB, TNF-α, GSH, SOD, MAPK, GSK-3β, Nrf2/HO-1, JAK/STAT, CREB/BDNF, ERK1/2, and LC3 towards neuroprotection.

This is the first systematic and comprehensive review with a simultaneous focus on the critical role of PI3K/Akt/mTOR in NDDs and associated targeting by natural products.” “Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration” (not freely available) Thanks to Dr. Sajad Fakhri for providing a copy.

Natural products mentioned in this review that I eat in everyday foods are listed below. The most effective ones are broccoli and red cabbage sprouts, and oats and oat sprouts:

  • Artichokes – luteolin;
  • Blackberries – anthocyanins;
  • Blueberries – anthocyanins, gallic acid, pterostilbene;
  • Broccoli and red cabbage sprouts – anthocyanins, kaempferol, luteolin, quercetin, sulforaphane;
  • Carrots – carotenoids;
  • Celery – apigenin, luteolin;
  • Green tea – epigallocatechin gallate;
  • Oats and oat sprouts – avenanthramides;
  • Strawberries – anthocyanins, fisetin;
  • Tomatoes – fisetin.

Four humpback whales



All about vasopressin

This 2021 review subject was vasopressin:

“Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes, thereby implicated in pathomechanisms of many disorders. The most striking is its central effect in stress-axis regulation, as well as regulating many aspects of our behavior.

Arginine-vasopressin (AVP) is a nonapeptide that is synthesized mainly in the supraoptic, paraventricular (PVN), and suprachiasmatic nucleus of the hypothalamus. AVP cell groups of hypothalamus and midbrain were found to be glutamatergic, whereas those in regions derived from cerebral nuclei were mainly GABAergic.

In the PVN, AVP can be found together with corticotropin-releasing hormone (CRH), the main hypothalamic regulator of the HPA axis. The AVPergic system participates in regulation of several physiological processes, from stress hormone release through memory formation, thermo- and pain regulation, to social behavior.

vasopressin stress axis

AVP determines behavioral responses to environmental stimuli, and participates in development of social interactions, aggression, reproduction, parental behavior, and belonging. Alterations in AVPergic tone may be implicated in pathology of stress-related disorders (anxiety and depression), Alzheimer’s, posttraumatic stress disorder, as well as schizophrenia.

An increasing body of evidence confirms epigenetic contribution to changes in AVP or AVP receptor mRNA level, not only during the early perinatal period, but also in adulthood:

  • DNA methylation is more targeted on a single gene; and it is better characterized in relation to AVP;
  • Some hint for bidirectional interaction with histone acetylation was also described; and
  • miRNAs are implicated in the hormonal, peripheral role of AVP, and less is known about their interaction regarding behavioral alteration.” “Epigenetic Modulation of Vasopressin Expression in Health and Disease”

Find your way, regardless of what the herd does.


PTSD susceptibility?

This 2021 rodent study investigated post-traumatic stress disorder (PTSD) susceptibility:

“PTSD is an incapacitating trauma-related disorder, with no reliable therapy. We show distinct DNA methylation profiles of PTSD susceptibility in the nucleus accumbens (NAc). Data analysis revealed overall hypomethylation of different genomic CpG sites in susceptible animals.

Is it possible to treat PTSD by targeting epigenetic processes? Such an approach might reverse genomic underpinning of PTSD and serve as a cure.

To test plausibility of such an approach, a reliable animal (rat) model with high construct validity is needed. Previously, we reported one such model, which uses predator-associated trauma, and cue reminders to evoke recurring trauma. This simulates clinical PTSD symptoms including re-experiencing, avoidance, and hyperarousal.

Individual PTSD-like (susceptible) behavior is analyzed, enabling identification of susceptible animals separately from those that are non-PTSD-like (resilient). This model captures salient features of this disorder in humans, in which only a fraction of trauma victims develop PTSD, while others are resilient.

experimental model

Sprague–Dawley rats were exposed to trauma and to three subsequent trauma-associated reminders. Freezing behavior was measured under conditions of:

  • Exploration;
  • Social interaction (with a companion); and
  • Hyperarousal.

Controls were exposed to identical conditions except for the traumatic event.

PTSD-like behavior of each animal was compared with baseline and with the population. Two unambiguous sub-populations were identified, resilient and susceptible.

After exposure to trauma and its reminders, susceptible animals showed an increase from baseline in freezing behavior, and over time in all three behavioral tests, as opposed to resilient and control groups.


Differentially methylated sites in susceptible and resilient animals compared to control group.

Although we focused in this study on DNA methylation changes that associate with susceptibility, we also report unique changes in DNA methylation that occur in resilient animals. Inhibition of critical genes that are downregulated in susceptible animals convert resilient animals to become susceptible.” “Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy” (registration required)

Rodents with the same genetics and environment displayed individual differences in their responses to traumatic events. Please provide evidence for that before venturing elsewhere.

Not sure why it took 3+ years for this study received in November 2017 to finally be published in July 2021. Sites other than are more transparent about their peer review and publication processes.

No causes for PTSD susceptibility were investigated. PTSD effects and symptoms aren’t causes, notwithstanding this study’s finding that:

“Our results support a causal role for the NAc as a critical brain region for expression of PTSD-like behaviors, and a role for programming genes by DNA methylation in the NAc in development of PTSD-like behaviors.”

Can’t say that I understand more about causes for PTSD susceptibility now than before I read this study. Researchers attaching significance to gene functional groups seemed like hypothesis-seeking efforts to overcome limited findings.

Will this study’s combination of a methyl donor with a Vitamin A metabolite address PTSD causes in humans? If it only temporarily alleviates symptoms, what lasting value will it have?

Several brain and body areas that store traumatic memories other than the nucleus accumbens were mentioned in The role of recall neurons in traumatic memories. A wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address each individual, their whole body, and their entire history.


Osprey breakfast

Take acetyl-L-carnitine for early-life trauma

This 2021 rodent study traumatized female mice during their last 20% of pregnancy, with effects that included:

  • Prenatally stressed pups raised by stressed mothers had normal cognitive function, but depressive-like behavior and social impairment;
  • Prenatally stressed pups raised by control mothers did not reverse behavioral deficits; and
  • Control pups raised by stressed mothers displayed prenatally stressed pups’ behavioral phenotypes.

Acetyl-L-carnitine (ALCAR) protected against and reversed depressive-like behavior induced by prenatal trauma:

alcar regime

ALCAR was supplemented in drinking water of s → S mice either from weaning to adulthood (3–8 weeks), or for one week in adulthood (7–8 weeks). ALCAR supplementation from weaning rendered s → S mice resistant to developing depressive-like behavior.

ALCAR supplementation for 1 week during adulthood rescued depressive-like behavior. One week after ALCAR cessation, however, the anti-depressant effect of ALCAR was diminished.

Intergenerational trauma induces social deficits and depressive-like behavior through divergent and convergent mechanisms of both in utero and early-life parenting environments:

  • We establish 2-HG [2-hydroxyglutaric acid, a hypoxia and mitochondrial dysfunction marker, and an epigenetic modifier] as an early predictive biomarker for trauma-induced behavioral deficits; and
  • Demonstrate that early pharmacological correction of mitochondria metabolism dysfunction by ALCAR can permanently reverse behavioral deficits.” “Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction”

Previously curated studies cited were:

This study had an effusive endorsement of acetyl-L-carnitine in its Discussion section, ending with:

“This has the potential to change lives of millions of people who suffer from major depression or have risk of developing this disabling disorder, particularly those in which depression arose from prenatal traumatic stress.”

I take a gram daily. Don’t know about prenatal trauma, but I’m certain what happened during my early childhood.

I asked both these researchers and those of Reference 70 for their estimates of a human equivalent to “0.3% ALCAR in drinking water.” Will update with their replies.


Let β-glucan train your brain

This 2021 rodent study investigated yeast cell wall β-glucan’s effects on the brain’s immune system:

“Innate immune memory can manifest in two different ways, [1] immune training and [2] immune tolerance, which means [1] an enhanced or [2] suppressed immune response towards a secondary challenge. Lipopolysaccharide (LPS) and β-glucan (BG) are two commonly used ligands to induce immune training and tolerance.

Microglia, the innate immune cells of the central nervous system, can adopt diverse phenotypes and functions in health and disease. In our previous study, we have shown that LPS preconditioning induces immune tolerance in microglia.

Compared to LPS, relatively little is known about effects of BG on microglia. In this study, we report for the first time that systemic administration of BG activates microglia in vivo, and that BG preconditioning induces immune training in microglia.


Our results show that BG activated microglia without inducing significant cytokine expression.

BG- and LPS-preconditioning both induced immune training in microglia two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning induced immune tolerance in microglia where BG-induced immune training was no longer detected.” “Systemic administration of β-glucan induces immune training in microglia”

One solution to “BG-induced immune training was no longer detected” after 7 days is to take β-glucan every day. I haven’t seen studies that found β-glucan induced immune tolerance, i.e. “suppressed immune response towards a secondary challenge.”

I take allergy medicine twice a day. Switched over to a different β-glucan vendor and dose per Year One of Changing to a youthful phenotype with broccoli sprouts.

I take 1 gram of Glucan 300 capsules without eating anything an hour before or an hour afterwards. I’ve only been doing it for a week, though, and haven’t been able to separate out β-glucan effects on seasonal allergies. I’ll try stopping allergy medicine when pollen stops coating my car.

Swarming a spring sea trout run. Ospreys outcompeted gulls for breakfast.

Eat broccoli sprouts for depression

This 2021 rodent study investigated sulforaphane effects on depression:

“Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by:

  • Activating BDNF;
  • Inhibiting expression of its transcriptional repressors (HDAC2 [histone deacetylase 2, a negative regulator of neuroplasticity], mSin3A, and MeCP2); and
  • Revising abnormal synaptic transmission.

In a mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the medial prefrontal cortex and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, protein levels of BDNF transcriptional repressors in CSDS-susceptible mice were higher than those of control and CSDS-resilient mice.

These data suggest that Nrf2 activation increases expression of Bdnf and decreases expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.

Nrf2-induced BDNF transcription in a model of depression.

  • Stress inhibits Nrf2 expression, which inhibits BDNF transcriptional and leads to abnormal synaptic transmission, causing depression-like behaviors in mice.
  • SFN induces BDNF transcription by activating Nrf2 and correcting abnormal synaptic transmission, resulting in antidepressant-like effects.

In conclusion:

  1. Nrf2 regulates transcription of Bdnf by binding to its exon I promoter.
  2. Inhibition of Nrf2-induced Bdnf transcription may play a role in the pathophysiology of depression.
  3. Activation of Nrf2-induced Bdnf transcription promoted antidepressant-like effects.
  4. Alterations in crosstalk between Nrf2 and BDNF may contribute to resilience versus susceptibility after stress.” “Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents”

Treat your gut microbiota as one of your organs

Two 2021 reviews covered gut microbiota. The first was gut microbial origins of metabolites produced from our diets, and mutual effects:

“Gut microbiota has emerged as a virtual endocrine organ, producing multiple compounds that maintain homeostasis and influence function of the human body. Host diets regulate composition of gut microbiota and microbiota-derived metabolites, which causes a crosstalk between host and microbiome.

There are bacteria with different functions in the intestinal tract, and they perform their own duties. Some of them provide specialized support for other functional bacteria or intestinal cells.

Short-chain fatty acids (SCFAs) are metabolites of dietary fibers metabolized by intestinal microorganisms. Acetate, propionate, and butyrate are the most abundant (≥95%) SCFAs. They are present in an approximate molar ratio of 3 : 1 : 1 in the colon.

95% of produced SCFAs are rapidly absorbed by colonocytes. SCFAs are not distributed evenly; they are decreased from proximal to distal colon.

Changing the distribution of intestinal flora and thus distribution of metabolites may have a great effect in treatment of diseases because there is a concentration threshold for acetate’s different impacts on the host. Butyrate has a particularly important role as the preferred energy source for the colonic epithelium, and a proposed role in providing protection against colon cancer and colitis.

There is a connection between acetate and butyrate distinctly, which suggests significance of this metabolite transformation for microbiota survival. The significance may even play an important role in disease development.

  • SCFAs can modulate progression of inflammatory diseases by inhibiting HDAC activity.
  • They decrease cytokines such as IL-6 and TNF-α.
  • Their inhibition of HDAC may work through modulating NF-κB activity via controlling DNA transcription.” “Gut Microbiota-Derived Metabolites in the Development of Diseases”

A second paper provided more details about SCFAs:

“SCFAs not only have an essential role in intestinal health, but also enter systemic circulation as signaling molecules affecting host metabolism. We summarize effects of SCFAs on glucose and energy homeostasis, and mechanisms through which SCFAs regulate function of metabolically active organs.

Butyrate is the primary energy source for colonocytes, and propionate is a gluconeogenic substrate. After being absorbed by colonocytes, SCFAs are used as substrates in mitochondrial β-oxidation and the citric acid cycle to generate energy. SCFAs that are not metabolized in colonocytes are transported to the liver.

  • Uptake of propionate and butyrate in the liver is significant, whereas acetate uptake in the liver is negligible.
  • Only 40%, 10%, and 5% of microbial acetate, propionate, and butyrate, respectively, reach systemic circulation.
  • In the brain, acetate is used as an important energy source for astrocytes.

Butyrate-mediated inhibition of HDAC increases Nrf2 expression, which has been shown to lead to an increase of its downstream targets to protect against oxidative stress and inflammation. Deacetylase inhibition induced by butyrate also enhances mitochondrial activity.

SCFAs affect the gut-brain axis by regulating secretion of metabolic hormones, induction of intestinal gluconeogenesis (IGN), stimulation of vagal afferent neurons, and regulation of the central nervous system. The hunger-curbing effect of the portal glucose signal induced by IGN involves activation of afferents from the spinal cord and specific neurons in the parabrachial nucleus, rather than afferents from vagal nerves.

Clinical studies have indicated a causal role for SCFAs in metabolic health. A novel targeting method for colonic delivery of SCFAs should be developed to achieve more consistent and reliable dosing.

The gut-host signal axis may be more resistant to such intervention by microbial SCFAs, so this method should be tested for ≥3 months. In addition, due to inter-individual variability in microbiota and metabolism, factors that may directly affect host substrate and energy metabolism, such as diet and physical activity, should be standardized or at least assessed.” “Modulation of Short-Chain Fatty Acids as Potential Therapy Method for Type 2 Diabetes Mellitus”

Mid-life gut microbiota crisis

This 2019 rodent study investigated diet, stress, and behavioral relationships:

“Gut microbiome has emerged as being essential for brain health in ageing. We show that prebiotic supplementation with FOS-Inulin [a complex short- and long-chain prebiotic, oligofructose-enriched inulin] is capable of:

  • Dampening age-associated systemic inflammation; and
  • A profound yet differential alteration of gut microbiota composition in both young adult and middle-aged mice.

Middle-aged mice exhibited an increased influx of inflammatory monocytes into the brain. However, neuroinflammation at this stage was not significant enough to manifest in major cognitive impairments.

A much longer exposure to prebiotics might be needed to achieve significant effects, suggesting that supplementation may have to start earlier to be effectively preventative before alterations in the brain occur. This is particularly evident for behaviour.

Targeting gut microbiota, as we have done with a prebiotic, can affect the brain and subsequent behaviour through a variety of potential pathways including SCFAs [short-chain fatty acids], amino acids and immune pathways. All of these are interconnected. Future studies are needed to better deconvolve [figure out] such pathways in eliciting beneficial effects of inulin.

Modulatory effects of prebiotic supplementation on monocyte infiltration into the brain and accompanied regulation of age-related microglia activation highlight a potential pathway by which prebiotics can modulate peripheral immune response and alter neuroinflammation in ageing. Our data suggest a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.” “Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome” (not freely available)

This study’s experiments subjected young and middle-aged mice to eight stress tests. I appreciated efforts to trace causes to behavioral effects, since behavior provided stronger evidence.

I’m in neither life stage investigated by this study. Still, per Reducing insoluble fiber, I’ll start taking inulin next week. See Increasing soluble fiber intake with inulin.

I came across this study through its citation in How will you feel?

Inauguration day

Clearing out the 2020 queue of interesting papers

I’ve partially read these 39 studies and reviews, but haven’t taken time to curate them.

Early Life

  1. Intergenerational Transmission of Cortical Sulcal Patterns from Mothers to their Children (not freely available)
  2. Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats
  3. Maternal Diabetes Induces Immune Dysfunction in Autistic Offspring Through Oxidative Stress in Hematopoietic Stem Cells
  4. Maternal prenatal depression and epigenetic age deceleration: testing potentially confounding effects of prenatal stress and SSRI use
  5. Maternal trauma and fear history predict BDNF methylation and gene expression in newborns
  6. Adverse childhood experiences, posttraumatic stress, and FKBP5 methylation patterns in postpartum women and their newborn infants (not freely available)
  7. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double‐blind, controlled feeding study
  8. Preterm birth is associated with epigenetic programming of transgenerational hypertension in mice
  9. Epigenetic mechanisms activated by childhood adversity (not freely available)

Epigenetic clocks

  1. GrimAge outperforms other epigenetic clocks in the prediction of age-related clinical phenotypes and all-cause mortality (not freely available)
  2. Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells
  3. An epigenetic clock for human skeletal muscle
  4. Immune epigenetic age in pregnancy and 1 year after birth: Associations with weight change (not freely available)
  5. Vasomotor Symptoms and Accelerated Epigenetic Aging in the Women’s Health Initiative (WHI) (not freely available)
  6. Estimating breast tissue-specific DNA methylation age using next-generation sequencing data


  1. The Intersection of Epigenetics and Metabolism in Trained Immunity (not freely available)
  2. Leptin regulates exon-specific transcription of the Bdnf gene via epigenetic modifications mediated by an AKT/p300 HAT cascade
  3. Transcriptional Regulation of Inflammasomes
  4. Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways
  5. Serotonin Modulates AhR Activation by Interfering with CYP1A1-Mediated Clearance of AhR Ligands
  6. Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats
  7. Double-edged sword: The evolutionary consequences of the epigenetic silencing of transposable elements
  8. Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation
  9. Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights
  10. Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
  11. Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice
  12. FKBP5-associated miRNA signature as a putative biomarker for PTSD in recently traumatized individuals
  13. Metabolic and epigenetic regulation of T-cell exhaustion (not freely available)


  1. Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches
  2. Epigenetic regulation of bone remodeling by natural compounds
  3. Microglial Corpse Clearance: Lessons From Macrophages
  4. Plasma proteomic biomarker signature of age predicts health and life span
  5. Ancestral stress programs sex-specific biological aging trajectories and non-communicable disease risk

Broccoli sprouts

  1. Dietary Indole-3-Carbinol Alleviated Spleen Enlargement, Enhanced IgG Response in C3H/HeN Mice Infected with Citrobacter rodentium
  2. Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress
  3. Effects of sulforaphane in the central nervous system
  4. Thiol antioxidant thioredoxin reductase: A prospective biochemical crossroads between anticancer and antiparasitic treatments of the modern era (not freely available)
  5. Quantification of dicarbonyl compounds in commonly consumed foods and drinks; presentation of a food composition database for dicarbonyls (not freely available)
  6. Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior (not freely available)

Treating psychopathological symptoms will somehow resolve causes?

This 2020 Swiss review subject was potential glutathione therapies for stress:

“We examine available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Several promising compounds could raise GSH levels in the brain by either increasing availability of its precursors or expression of GSH-regulating enzymes through activation of Nrf2.

GSH is the main cellular antioxidant found in all mammalian tissues. In the brain, GSH homeostasis has an additional level of complexity in that expression of GSH and GSH-related enzymes are not evenly distributed across all cell types, requiring coordination between neurons and astrocytes to neutralize oxidative insults.

Increased energy demand in situations of chronic stress leads to mitochondrial ROS overproduction, oxidative damage and exhaustion of GSH pools in the brain.

Several compounds can function as precursors of GSH by acting as cysteine (Cys) donors such as taurine or glutamate (Glu) donors such as glutamine (Gln). Other compounds stimulate synthesis and recycling of GSH through activation of the Nrf2 pathway including sulforaphane and melatonin. Compounds such as acetyl-L-carnitine can increase GSH levels.” “Therapeutic potential of glutathione-enhancers in stress-related psychopathologies” (not freely available)

Many animal studies of “stress-related psychopathologies” were cited without noting applicability to humans. These reviewers instead had curious none-of-this-means-anything disclaimers like:

“Comparisons between studies investigating brain disorders of such different nature such as psychiatric disorders or neurodegenerative diseases, or even between brain or non-brain related disorders should be made with caution.”

Regardless, this paper had informative sections for my 27th week of eating broccoli sprouts every day.

1. I forgot to mention in Broccoli sprout synergies that I’ve taken 500 mg of trimethyl glycine (aka betaine) twice a day for over 15 years. Section 3.1.2 highlighted amino acid glycine:

“Endogenous synthesis is insufficient to meet metabolic demands for most mammals (including humans) and additional glycine must be obtained from diet. While most research has focused on increasing cysteine levels in the brain in order to drive GSH synthesis, glycine supplementation alone or in combination with cysteine-enhancing compounds are gaining attention for their ability to enhance GSH.”

2. Taurine dropped off my supplement regimen last year after taking 500 mg twice a day for years. It’s back on now after reading Section 3.1.3:

“Most studies that reported enhanced GSH in the brain following taurine treatment were performed under a chronic regimen and used in age-related disease models.

Such positive effects of taurine on GSH levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

3. A study in Upgrade your brain’s switchboard with broccoli sprouts was cited for its potential:

“Thalamic GSH values significantly correlated with blood GSH levels, suggesting that peripheral GSH levels may be a marker of brain GSH content. Studies point to the capacity of sulforaphane to function both as a prophylactic against stress-induced behavioral changes and as a positive modulator in healthy animals.”

Sunrise minus 5 minutes

Unraveling oxytocin – is it nature’s medicine?

This 2020 review attempted to consolidate thousands of research papers on oxytocin:

“Chemical properties of oxytocin make this molecule difficult to work with and to measure. Effects of oxytocin are context-dependent, sexually dimorphic, and altered by experience. Its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Widely used medical interventions i.e.:

  • Exogenous oxytocin, such as Pitocin given to facilitate labor;
  • Opioid medications that block the oxytocin system; or
  • Cesarean sections that alter exposure to endogenous oxytocin

have lasting consequences for the offspring and/or mother.

Such exposures hold the potential to have epigenetic effects on the oxytocin systems, including changes in DNA methylation. These changes in turn would have lasting effects on the expression of receptors for oxytocin, leaving individuals differentially able to respond to oxytocin and also possibly to the effects of vasopressin.

Regions with especially high levels of OXTR [oxytocin receptor gene] are:

  • Various parts of the amygdala;
  • Bed nucleus of the stria terminalis;
  • Nucleus accumbens;
  • Brainstem source nuclei for the autonomic nervous system;
  • Systems that regulate the HPA axis; as well as
  • Brainstem tissues involved in pain and social attention.

Oxytocin protects neural cells against hypoxic-ischemic conditions by:

  • Preserving mitochondrial function;
  • Reducing oxidative stress; and
  • Decreasing a chromatin protein that is released during inflammation

which can activate microglia through the receptor for advanced glycation end products (RAGE). RAGE acts as an oxytocin-binding protein facilitating the transport of oxytocin across the blood-brain barrier and through other tissues.

Directionality of this transport is 5–10 times higher from the blood to the brain, in comparison with brain to blood transport. Individual differences in RAGE could help to predict cellular access to oxytocin and might also facilitate access to oxytocin under conditions of stress or illness.

Oxytocin and vasopressin and their receptors are genetically variable, epigenetically regulated, and sensitive to stressors and diet across the lifespan. As one example, salt releases vasopressin and also oxytocin.

Nicotine is a potent regulator of vasopressin. Smoking, including prenatal exposure of a fetus, holds the potential to adjust this system with effects that likely differ between males and females and that may be transgenerational.

Relative concentrations of endogenous oxytocin and vasopressin in plasma were associated with:

These studies support the usefulness of measurements of both oxytocin and vasopressin but leave many empirical questions unresolved.

The vast majority of oxytocin in biosamples evades detection using conventional approaches to measurement.” “Is Oxytocin Nature’s Medicine?”

I appreciated efforts to extract worthwhile oxytocin research from countless poorly performed studies, research that wasted resources, and research that actually detracted from science.

I was disappointed that at least one of the reviewers didn’t take this review as an opportunity to confess their previous wastes like three flimsy studies discussed in Using oxytocin receptor gene methylation to pursue an agenda.

Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.

Although these reviewers didn’t provide concrete answers to many questions, they highlighted promising research areas, such as:

  • Improved approaches to oxytocin measurements;
  • Prenatal epigenetic experience associations with oxytocin and OXTR; and
  • Possible transgenerational transmission of these prenatal epigenetic experiences.


If you can stand the woo of two Californians trying to outwoo each other, listen to these five podcasts with a sleep scientist.

“Ambien, sedation, hypnotives, are not sleep.

Sleep is a life support system. It’s the Swiss army knife of health.

Lack of sleep is like a broken water pipe in your home that leaks down into every nook and cranny of your physiology.

Sleep research is not being transmitted to clinical practice.”

I live on the US East Coast. Hyperbole in normal conversations outside of urban centers is an exception.

It’s different on the West Coast. For example:

  • Interviewer assertions regarding heart rate variability should be compared and contrasted with Dead physiological science zombified by psychological research evidence that:

    “A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.”

  • Interviewer favorable comments for MDMA (Ecstasy) “to deal with issues of underlying trauma, anxiety, and depression.”