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.”

https://pharmrev.aspetjournals.org/content/pharmrev/72/4/829.full.pdf “Is Oxytocin Nature’s Medicine?”

I appreciate attempts to ferret out worthwhile research from countless poorly performed studies, research that wasted resources, and research that actually detracted from science.

Although these reviewers didn’t provide concrete answers to many questions, they did point the way toward 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.

Get serious about advanced glycation end products (AGEs)

Ever heard about AGEs? Here are three papers that describe how AGEs affect humans.

First is a 2020 Italian review Common Protective Strategies in Neurodegenerative Disease: Focusing on Risk Factors to Target the Cellular Redox System:

“Neurodegenerative disease is an umbrella term for different conditions which primarily affect the neurons in the human brain. Currently, neurodegenerative diseases are incurable, and the treatments available only control the symptoms or delay the progression of the disease.

Neurotoxicity can be induced by glycation reactions. Since glycation is a nonenzymatic process, proteins characterized by a slow turnover are those that more easily accumulate AGEs.

Methylglyoxal (MG) can occur as glycolysis by-product, but it is also present in foods (especially cooked and baked), beverages (mainly those fermented), and cigarette smoke, and it is considered the most potent precursor of AGE formation. More than 20 different AGEs have been identified in foods and in human tissues.

AGE accumulation, oxidative stress, and inflammation are related to AGE ability to bind specific receptors called RAGE. RAGE expression increases during aging, cancer, cardiovascular diseases, AD [Alzheimer’s], PD [Parkinson’s], and other neurodegenerative diseases.”

A 2015 study by some of the same authors Antiglycative activity of sulforaphane: a new avenue to counteract neurodegeneration? was cited for a treatment in addition to changing one’s diet to be AGE-less.

“When MG production is increased by high glucose or oxidative stress, glycated proteins accumulate in the brain and lead to glycative stress, playing a fundamental role in the establishment of different neurodegenerative disorders.

Our results indicated that SF [sulforaphane] counteracts ROS by two possible mechanisms of action: an increase of intracellular GSH [glutathione] levels and an enhancement of MG-detoxification through the up-regulation of the glyoxalase (GLO1) systems. GLO1 up-regulation is mediated by the transcription factor Nrf2. SF has been demonstrated to activate Nrf2.

Another mechanism by which SF exerts its neuroprotective activity against MG-induced glycative damage is the modulation of mitogen-activated protein kinase (MAPK) signaling pathways involved in apoptotic cell death. All MAPK signaling pathways are activated in AD.

Brain-derived neurotrophic factor (BDNF) is associated with neuronal survival through its interactions with the tyrosine receptor kinase B (TrkB) and p75 cellular receptors. BDNF expression levels are reduced in the brain of AD patients. SF pre-treatment, before MG addition, not only further increased BDNF levels, but also significantly induced TrkB protein levels reverting MG negative effect on this receptor.

SF totally reverts the reduction of glucose uptake caused by MG exposure. SF can be defined as a multitarget agent modulating different cellular functions leading to a pro-survival frame of particular importance in the prevention / counteraction of multifactorial neurodegenerative diseases.”

A 2020 review Non-enzymatic covalent modifications: a new link between metabolism and epigenetics investigated glycation:

“Non-enzymatic covalent modifications (NECMs) by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription. Unlike canonical post-translational modifications (PTMs), NECMs accumulate over time and are much more dependent on the cellular microenvironment.

A. Guanine residues in DNA and RNA can undergo methylglyoxal glycation, thereby inducing DNA and RNA damage. This DNA damage has few corresponding repair pathways.

B. Histones are primary glycation substrates because of their long half-lives and abundant lysine and arginine residues. Histone glycation was found to induce epigenetic dysregulation through three distinct mechanisms:

  1. Competition with essential enzymatic PTMs for sites (e.g., glycation adducts replace H3K4me3 and H3R8me2);
  2. Changing the charge states of histone tails and subsequently affecting the compaction state of the fiber; and
  3. Altering three-dimensional chromatin architecture by inducing both histone-histone and histone-DNA crosslinking.

Epigenetic impacts of histone glycation were shown to be dependent on sugar concentration and exposure time. Histone and DNA glycation may lead to long term epigenetic impacts on immune responses.

C. Glycation of multiple lysine residues of NRF2 inhibits its oncogenic function. Sugar molecules can influence epigenetic events through glycation of transcription factors and/or their associated regulatory proteins.”

The Transcription factor glycation section referenced a 2011 paper Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications:

“Nrf2 mRNA level is unaffected by treatment with sulforaphane, suggesting that cellular expression of Nrf2 protein is posttranscriptionally regulated. Posttranslational modifications of Keap1 and Nrf2 proteins seem to play an important role in the regulation of ARE‐dependent gene expression.”

Other curated AGEs papers include:

Part 3 of Do broccoli sprouts treat migraines?

This 2019 Swedish review subject was the role of inflammation in migraines:

“In this article, we argue that inflammation could have an important role in migraine chronification through a mechanism termed neurogenic neuroinflammation, a phenomenon whereby activation of trigeminal sensory pathways leads to an orchestrated inflammatory response involving immune cells, vascular cells and neurons.

No studies to date have directly linked hypothalamic neuroinflammation with migraine, and we therefore looked to other studies. Overactivity of the NF-κB–IKKβ signalling pathway has been shown to be a critical modulator of hypothalamic inflammation.

We do not believe that CNS inflammation is involved in the triggering of migraine attacks, as BBB alterations, glial cell activation and leukocyte infiltration have not been observed in individuals with this condition. Peripheral sensitization is an important factor in migraine chronification, as opposed to migraine triggering.”

https://www.nature.com/articles/s41582-019-0216-y “Does inflammation have a role in migraine?” (not freely available)

See Reevaluate findings in another paradigm for other views of hypothalamic inflammation.

I came across this review through its citation in the 2020 medical paper The fifth cranial nerve in headaches with the same lead author:

“Reduced serotonergic transmission seems to be involved in medication overuse headache development, possibly through a facilitation of the sensitization process via a maladaptive plasticity. In humans, common neurophysiological investigation of central sensitization shows an abnormal cortical response to repetitive sensory stimuli, with an increased response amplitude after low numbers of stimuli and a lacking habituation, suggesting an altered plasticity.

Neurons, under repetitive, persistent nociceptive, become sensitized and produce exaggerated and prolonged responses to lower threshold stimuli. Over time, a neuroplastic adaptation in medullary and cortical pain areas causes a shift in the pain modulatory system creating a new threshold and favouring a net pain facilitation rather than pain alleviation.

Targets are almost exclusively found in the nerves of trigeminal ganglion; the hub of the fifth cranial nerve. Although we believe that the headache-trigger most likely have the origin in the CNS, this review underscores the importance of trigeminal neurons in the perception of pain.”

This second paper listed various treatments of symptoms. Remarkable for no focus on treatments of causes.

Per Parts 1 and 2, I rarely get headaches anymore, much less migraines. 23 weeks of eating a clinically relevant amount of broccoli sprouts every day resolved causes for me. I didn’t appreciate how migraines and many other things changed until awakening during Week 9.

Broccoli sprout synergies

I was asked for examples of broccoli sprout synergies with supplements mentioned in Week 19 of Changing to a youthful phenotype with broccoli sprouts. I take them together an hour or two before meals to keep meal contents from lowering sulforaphane bioavailability. Sulforaphane peaks in plasma between 1 and 2 hours after ingestion.

sulforaphane peak plasma

I started splitting broccoli sprout doses after reading the first study of A pair of broccoli sprout studies. The second study was Untargeted metabolomic screen reveals changes in human plasma metabolite profiles following consumption of fresh broccoli sprouts.

Those subjects ate only “a single dose of fresh broccoli sprouts (providing 200 μmol SFN equivalents) at 8 AM on study day 1.” A 200 μmol amount of sulforaphane is a 35 mg weight.

For comparison, my daily consumption is a worst-case 52 mg sulforaphane from microwaving 131 g of 3-day-old broccoli sprouts per Estimating daily consumption of broccoli sprout compounds. Every day for 22 weeks now. 🙂

The second study’s measurements through 48 hours produced this informative graphic and text:

“Of the features we identified using metabolite databases and classified as endogenous, eleven were significantly altered.

  • Glutathione (GSH) – a major intracellular antioxidant that conjugates with SFN during metabolism – was significantly decreased in plasma at 6, 12 and 24 hours following sprout intake.
  • GSH precursors glutamine (3 and 24 hours) and cysteine (12 and 24 hours) also decreased.
  • We observed significant decreases in dehydroepiandrosterone (DHEA) at 3, 6 and 12 hours.
  • Decreases in fatty acids reported here suggest that even a single dose of broccoli sprouts may alter plasma lipids in healthy adult populations.

While this study focuses largely on potential effects of SFN, broccoli sprouts contain many other bioactive components (e.g., indoles) that could be responsible for our observations as well as additional health benefits.”

Supplements I take twice daily with broccoli sprouts:

  • 1 gram L-glutamine for replenishment and other purposes;
  • 25 mg DHEA to replenish and other effects;
  • 15 mg then 50 mg zinc, which has a role in GSH metabolism;
  • 500 mg glucosamine (anti-inflammatory, crosstalk with Nrf2 signaling pathway);
  • 500 mg acetyl-L-carnitine (induces Nrf2-dependent mitochondrial biogenesis); and
  • 1400 IU then 2000 IU Vitamin D. A major portion of its effects is Nrf2 activation, like sulforaphane. A virtuous circle develops when taken with broccoli sprouts in that the Vitamin D receptor is a Nrf2 target gene inducible by sulforaphane, which then upregulates Nrf2 expression levels.

One of the things eating Boring Chicken Vegetable Soup twice a day does is replenish cysteine. I eat that and steel-cut oats (another cysteine source) separately from broccoli sprouts.

I take 1 gram flax oil with breakfast and dinner instead of with broccoli sprouts. Haven’t found relevant research on whether broccoli sprout compounds decrease omega-3 polyunsaturated alpha linolenic acid C18:3 as they do these six endogenous fatty acids.

Both studies investigated effects of fresh broccoli sprouts. Timing of their measured decreases and increases are different for me because I microwave broccoli sprouts up to but not exceeding 60°C (140°F).

A section of Microwave broccoli seeds to create sulforaphane highlighted metabolic differences among fresh broccoli sprouts, microwaved broccoli sprouts, and broccoli sprout supplements.

“A metabolic profile resulting from my current practices is probably between the Sprout and BSE (broccoli sprout extract) divided-dose statistics:

  1. Sulforaphane intake is greater than eating raw broccoli sprouts because microwaving 3-day-old broccoli sprouts creates an increased amount of sulforaphane in them before eating.
  2. Sulforaphane uptake from microwaved broccoli sprouts is quicker than eating raw broccoli sprouts. It may not be as immediate as taking sulforaphane supplements, which are usually powders.
  3. Sulforaphane dose from microwaved broccoli sprouts is less dependent on an individual’s metabolism than eating raw broccoli sprouts.
  4. Sulforaphane release from microwaved broccoli sprouts continues on to the gut as does eating raw broccoli sprouts. Sulforaphane release from supplements typically ends in the stomach.”

One thing I didn’t mention in that blog post was that glucoraphanin also increased by microwaving per Microwave broccoli to increase sulforaphane levels. A coauthor clarified a chart’s 60°C (140°F) glucoraphanin amount increased by 27% (2.78 / 2.18 μmol).

Metabolism of broccoli sprout glucoraphanin and other glucosinolates that aren’t preferentially hydrolyzed by microwaving and thorough chewing is assisted in the gut twice a day by:

  • 6 billion IU acidophilus; and
  • 750 mg fructo-oligosaccharides.

Day 70 results from Changing to a youthful phenotype with broccoli sprouts

Here are my Day 70 measurements* to follow up Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts, which had these findings:

Keep in mind that I’m not in the population represented by the clinical trial sample:

  1. My chronological age is above their inclusion range;
  2. My BMI is below their inclusion range; and
  3. I take supplements and meet other exclusion criteria.

I also didn’t take Day 0 measurements.

June 2019 BMI: 24.8

June 2020 BMI: 22.4

2020 IL-6: 1.0 pg / ml. See Part 2 of Rejuvenation therapy and sulforaphane for comparisons.

2020 C-reactive protein: < 1 mg / l.

2019 and 2020 No biological age measurements. Why aren’t epigenetic clocks standard and affordable?

I’ve made four lifestyle “interventions” since last summer:

  1. In July 2019 I started to reduce my consumption of advanced glycation end products after reading Dr. Vlassara’s AGE-Less Diet: How a Chemical in the Foods We Eat Promotes Disease, Obesity, and Aging and the Steps We Can Take to Stop It.
  2. In September I started non-prescription daily treatments of Vitamin D, zinc, and DHEA per clinical trial Reversal of aging and immunosenescent trends.
  3. Also in September, I started non-prescription intermittent quercetin treatments of Preliminary findings from a senolytics clinical trial.
  4. I started eating broccoli sprouts every day eleven weeks ago.

1. Broccoli sprouts oppose effects of advanced glycation end products (AGEs) provided examples of Items 1 and 4 interactions.

2. Two examples of Item 2 treatment interactions with Item 4 are in Reversal of aging and immunosenescent trends with sulforaphane:

  • “The effects of the combined treatment with BSE [broccoli sprout extract] and zinc were always greater than those of single treatments.”
  • “Vitamin D administration decreased tumor incidence and size, and the co-administration with SFN [sulforaphane] magnified the effects. The addition of SFN decreased the activity of histone deacetylase and increased autophagy.”

3. How broccoli sprout compounds may complement three supplements I take was in a 2020 review Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer’s Disease: Targeting Mitochondria for Diagnosis and Prevention:

“The nutrients benefit mitochondria in four ways, by:

  • Ameliorating oxidative stress, for example, lipoic acid;
  • Activating phase II enzymes that improve antioxidant defenses, for example, sulforaphane;
  • Enhancing mitochondrial remodeling, for example, acetyl-l-carnitine; and
  • Protecting mitochondrial enzymes and/or stimulating mitochondrial enzyme activities, for example, enzyme cofactors, such as B vitamins and coenzyme Q10 .

In addition to using mitochondrial nutrients individually, the combined use of mitochondrial nutrients may provide a better strategy for mitochondrial protection.”

The review provided a boatload of mitochondrial multifactorial analyses for Alzheimer’s. But these analyses didn’t include effective mitochondrial treatments of ultimate aging causes. I didn’t see evidence of why, after fifteen years of treating mitochondrial effects with supplements, treating one more effect could account for my Week 9 vastly different experiences.

I nod to An environmental signaling paradigm of aging explanations. Its Section 10 reviewed IL-6, C-reactive protein, senescence, and NF-κB in terms of feedback loops, beginning with:

“It is clear that the increasing number of senescent cells depends on the post-adult developmental stage rather than chronological age. The coincidence that these processes result in particular forms of impairment in old age does not seem to be random as it is present in all mammals, and may be causative of many aspects of aging.”

A derived hypothesis: After sufficient strength and duration, broccoli sprout compounds changed my signaling environment, with appreciable effects beginning in Week 9.

I offered weak supporting evidence in Upgrade your brain’s switchboard with broccoli sprouts where a study’s insufficient one week duration of an insufficient daily 17.3 mg sulforaphane dosage still managed to change a blood antioxidant that may have changed four thalamus-brain-area metabolites. For duration and weight comparisons, I doubled my daily amount of broccoli seeds from one to two tablespoons just before Week 6 (Day 35), and from that point onward consumed a estimated 30 52 mg sulforaphane with microwaving 3-day-old broccoli sprouts every day.

Maybe a promised “In a submitted study, we will report that peripheral GSH levels may be correlated with cognitive functions” will provide stronger evidence? I’m not holding my breath for relevant studies because:

  • There wouldn’t be potential payoffs for companies to study any broccoli sprout compound connections with research areas such as aging, migraines, etc. Daily clinically-relevant broccoli sprout dosages can be grown for < $500 a year.
  • Sponsors would have to change paradigms, a very-low-probability event. They’d have to explain why enormous resources dedicated to current frameworks haven’t produced effective long-term treatments.

What long-term benefits could be expected if I continue eating broccoli sprouts every day?

The longest relevant clinical trial I’ve seen – referenced in Part 2 of Reversal of aging and immunosenescent trends with sulforaphane – was twelve weeks. Part 2 also provided epigenetic clock examples of changes measured after 9 months, which accelerated from there to the 12-month end-of-trial point.

Reviewing clinical trials of broccoli sprouts and their compounds pointed out:

“Biomarkers of effect need more time than biomarkers of exposure to be influenced by dietary treatment.”

A contrary argument: Perhaps people don’t require long durations to effectively change their signaling environments?

I apparently didn’t start eating an effective-for-me daily broccoli sprouts dosage until Day 35, when I changed from one to two tablespoons of broccoli seeds a day. If so, Weeks 6 through 8 may account for my substantial responses during Week 9.

  • Could eating broccoli sprouts every day for four weeks dramatically change a person’s signaling environment?
  • Do you have four weeks and $38 to find out? Two tablespoons of broccoli seeds = 38 21.4 g x 30 days = .642 kg or 1.42 lbs.

This is what twice-a-day one-tablespoon starting amounts of broccoli seeds look like through three days:

Maintaining the sprouting process hasn’t been a big effort compared with the benefits.

In the absence of determinative evidence, I’ll continue eating broccoli sprouts every day. Several areas of my annual physical have room for improvements. Extending my four lifestyle “interventions” a few more months may also provide hints toward inadequately researched connections.

* Results may not be extrapolatable to other people, to any specific condition, etc.

A review of sulforaphane and aging

This 2019 Mexican review stated:

“We describe some of the molecular and physical characteristics of SFN, its mechanisms of action, and the effects that SFN treatment induces in order to discuss its relevance as a ‘miraculous’ drug to prevent aging and neurodegeneration. SFN has been shown to modulate several cellular pathways in order to activate diverse protective responses, which might allow avoiding cancer and neurodegeneration as well as improving cellular lifespan and health span.

NF-κB is in charge of inflammatory response regulation. Under basal conditions, NF-κB is sequestrated into the cytosol by IκB, but when pro-inflammatory ligands bind to its receptors, the IKK protein family phosphorylates IκB to degrade it via proteasome, so NF-κB is able to translocate into the nucleus and transcript several inflammatory mediators. Sulforaphane is capable to inhibit IκB phosphorylation and NF-κB nuclear translocation.

SFN upregulated Nrf2 expression by reducing DNA demethylation levels of the Nrf2 promoter. In another model using the triple-transgenic mouse model of Alzheimer’s disease (3 × Tg-AD), the use of SFN regulates the expression of the Brain-derived neurotrophic factor (BDNF) via HDAC inhibition, thus increasing H3 and H4 acetylation on the BDNF promoter. Enhancing BDNF expression as an effect of SFN treatment increased the neuronal content of several synaptic molecules like MAP 2, synaptophysin, and PSD-95 in primary cortical neurons of 3 × Tg-AD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885086/ “Sulforaphane – role in aging and neurodegeneration”

I came across this review while searching PubMed for sulforaphane commonalities with presentation topics in Part 2 of Reversal of aging and immunosenescent trends with sulforaphane. The review outlined some aging aspects and presented relevant sulforaphane studies. Others such as eye and muscle decline weren’t addressed.

Since sulforaphane’s “a ‘miraculous’ drug” in the Abstract, I expected but didn’t see corresponding excitement in the review body. Just phrases like “it is known” and non-specific “more research is needed.”

Other papers published after this review were found by a PubMed “sulforaphane signal aging” search:

Clearing out the 2019 queue of interesting papers

I’m clearing out the below queue of 27 studies and reviews I’ve partially read this year but haven’t taken the time to curate. I have a pesky full-time job that demands my presence elsewhere during the day. :-\

Should I add any of these back in? Let’s be ready for the next decade!

Early life

https://link.springer.com/article/10.1007/s12035-018-1328-x “Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid” (not freely available)

https://www.sciencedirect.com/science/article/pii/S0166432818309392 “Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex” (not freely available)

https://www.nature.com/articles/s41380-018-0265-4 “Intergenerational transmission of depression: clinical observations and molecular mechanisms” (not freely available)


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454089/ “Epigenomics and Transcriptomics in the Prediction and Diagnosis of Childhood Asthma: Are We There Yet?”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628997/Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770436/ “Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study”

https://www.sciencedirect.com/science/article/pii/S0889159119306440 “Environmental influences on placental programming and offspring outcomes following maternal immune activation”

https://academic.oup.com/mutage/article-abstract/34/4/315/5581970 “5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns” (not freely available)

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP278270 “Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13751 “Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811979/ “Genome-wide DNA methylation data from adult brain following prenatal immune activation and dietary intervention”

https://link.springer.com/article/10.1007/s00702-019-02048-2miRNAs in depression vulnerability and resilience: novel targets for preventive strategies”

Later life

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543991/ “Effect of Flywheel Resistance Training on Balance Performance in Older Adults. A Randomized Controlled Trial”

https://www.mdpi.com/2411-5142/4/3/61/htm “Eccentric Overload Flywheel Training in Older Adults”

https://www.nature.com/articles/s41577-019-0151-6 “Epigenetic regulation of the innate immune response to infection” (not freely available)

https://link.springer.com/chapter/10.1007/978-981-13-6123-4_1 “Hair Cell Regeneration” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422915/Histone Modifications as an Intersection Between Diet and Longevity”

https://www.sciencedirect.com/science/article/abs/pii/S0306453019300733 “Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0047637419300338 “Frailty biomarkers in humans and rodents: Current approaches and future advances” (not freely available)

https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12901 “Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627480/ “In Search of Panacea—Review of Recent Studies Concerning Nature-Derived Anticancer Agents”

https://www.sciencedirect.com/science/article/abs/pii/S0028390819303363 “Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus” (not freely available)

https://www.futuremedicine.com/doi/10.2217/epi-2019-0102 “Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834159/ “The Beige Adipocyte as a Therapy for Metabolic Diseases”

https://www.sciencedirect.com/science/article/abs/pii/S8756328219304077 “Bone adaptation: safety factors and load predictability in shaping skeletal form” (not freely available)

https://www.nature.com/articles/s41380-019-0549-3 “Successful treatment of post-traumatic stress disorder reverses DNA methylation marks” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0166223619301821 “Editing the Epigenome to Tackle Brain Disorders” (not freely available)

Caloric restriction’s epigenetic effects

This 2019 US review subject was caloric restriction (CR) without malnutrition:

“Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Short- and long-term CRs produce significant changes in different tissues and across species, in some animal models even with sex-specific effects. Early CR onset may cause a different and even an opposite effect on physiological outcomes in animal models such as body weight.”


1. Charts usually don’t have two different values plotted on the same axis. The review didn’t present evidence to equate survival (left axis) with methylation drift (right axis) per the above graphic. Methylation drift should point in the opposite direction of survival, if anything.

2. No mention was made of the epigenetic clock method of measuring age acceleration, although it’s been available since 2013 and recent diet studies have used it. The sole citation of an age acceleration study was from 2001, which was unacceptable for a review published in 2019.

3. The review provided many cellular-level details about the subject. However, organism-level areas weren’t sufficiently evidenced:

A. Arguments for an effect usually include explanations for no effect as well as opposite effects. The reviewers didn’t provide direct evidence for why, if caloric restriction extended lifespan, caloric overabundance produced shorter lifespans.

B. Caloric restriction evidence was presented as if only it was responsible for organism-level effects. Other mechanisms may have been involved.

An example of such a mechanism was demonstrated in a 2007 rodent study Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet which compared two 40%-calorie-restricted diets.

The calories and composition of both diets were identical. However, advanced glycation end product (AGE) levels were doubled in standard chow because heating temperatures were “sufficiently high to inadvertently cause standard mouse chow to be rich in oxidant AGEs.”

The study found that a diet with lower chow heating temperatures increased lifespan and health span irrespective of caloric restriction!

  • The low-AGE calorie-restricted diet group lived an average of 15% longer (>20 human equivalent years) than the CR group.
  • 40% of the low-AGE calorie-restricted diet group were still alive when the last CR group member died.
  • The CR group also had significantly more: 1) oxidative stress damage; 2) glucose and insulin metabolism problems; and 3) kidney, spleen, and liver injuries.

https://academic.oup.com/advances/article-abstract/10/3/520/5420411 “Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction” (not freely available)

A drug that countered effects of a traumatizing mother

This 2019 US rodent study concerned transmitting poor maternal care to the next generation:

“The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. Infant experiences with a caregiver have lifelong behavioral consequences.

Maternal behavior is a complex behavior requiring the recruitment of multiple brain regions including the nucleus accumbens, bed nucleus of the stria terminalis, ventral tegmental area, prefrontal cortex, amygdala, and medial preoptic area. Dysregulation within this circuitry can lead to altered or impaired maternal responsiveness.

We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring.

  1. We replicate that dams with a history of maltreatment mistreat their own offspring.
  2. We show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring.
  3. We show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care.
  4. We show altered methylation and gene expression in maltreated dams normalized by zebularine.

These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.”

“Maternal behavior is an intergenerational behavior. It is important to establish the neurobiological underpinnings of aberrant maternal behavior and explore treatments that can improve maternal behavior to prevent the perpetuation of poor maternal care across generations.”

The study authors demonstrated intergenerational epigenetic effects, and missed an opportunity to also investigate transgenerational epigenetically inherited effects. They cited reference 60 for the first part of the above quotation, but the cited reviewer misused the transgenerational term by applying it to grand-offspring instead of the great-grand-offspring.

There were resources available to replicate the study authors’ previous findings, which didn’t show anything new. Why not use such resources to uncover evidence even more applicable to humans by extending experiments to great-grand-offspring that would have no potential germline exposure to the initial damaging cause?

Could a study design similar to A limited study of parental transmission of anxiety/stress-reactive traits have been integrated? That study’s thorough removal of parental behavior would be an outstanding methodology to confirm by falsifiability whether parental behavior is both an intergenerational and a transgenerational epigenetic inheritance mechanism.

Rodent great-grand-offspring can be studied in < 9 months. It takes > 50 years for human studies to reach the great-grand-offspring transgenerational generation.

  • Why not attempt to “prevent the perpetuation of poor maternal care across generations?”
  • Isn’t it a plausible hypothesis that humans “with a history of maltreatment mistreat their own offspring?”
  • Isn’t it worth the extra effort to extend animal research to investigate this unfortunate chain?

https://www.nature.com/articles/s41598-019-46539-4 “Pharmacological manipulation of DNA methylation normalizes maternal behavior, DNA methylation, and gene expression in dams with a history of maltreatment”

OCD and neural plasticity

This 2019 New York rodent study investigated multiple avenues to uncover mechanisms of obsessive-compulsive disorder:

“Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum) may be causally linked. Numerous genetic and environmental factors may reduce striatum sensitivity and lead to maladaptive overcompensation, potentially accounting for a significant proportion of cases of pathological OCD-like behaviors.

Our results indicate that both the development and reversal of OCD-like behaviors involve neuroplasticity resulting in circuitry changes in BLA-DLS and possibly elsewhere.”

The researchers explored two genetic models of OCD, showed why these insufficiently explained observed phenomena, then followed up with epigenetic investigations. They demonstrated how and the degree to which histone modifications and DNA methylation regulated both the development and reversal of OCD symptoms.

However, the researchers also carelessly cited thirteen papers outside the specific areas of the study to support one statement in the lead paragraph:

“Novel studies propose that modulations in gene expression influenced by environmental factors, are connected to mental health disorders.”

Only one of the thirteen citations was more recent than 2011, and none of them were high-quality studies.

https://www.nature.com/articles/s41598-019-45325-6.pdf “Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism”