Infants

Plasmalogens, Part 1

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The person who knows the most about this subject is Dayan Goodenowe, PhD. Some recent publications include:

https://www.frontiersin.org/articles/10.3389/fcell.2022.864842/full “Targeted Plasmalogen Supplementation: Effects on Blood Plasmalogens, Oxidative Stress Biomarkers, Cognition, and Mobility in Cognitively Impaired Persons”

https://www.frontiersin.org/articles/10.3389/fcell.2022.866156/full “Brain ethanolamine phospholipids, neuropathology and cognition: A comparative post-mortem analysis of structurally specific plasmalogen and phosphatidyl species”

plasmalogens and cognition

A sample of links freely available at https://drgoodenowe.com/.

1. Presentations to professional groups. Have your mouse ready to click the pause button.

https://drgoodenowe.com/dr-goodenowe-presents-at-the-iagg2023-in-yokohama-japan/ “A rare children’s disease that may be the key to reversing neurological decline in aging”

Includes videos of a treatment’s effects on a child.

https://neomarkgroup.wistia.com/medias/0qln0wy93t “The most influential biomarkers for aging and disease”

Despite the title, a considerable number of studies were presented on prenatal, infant, and early childhood development. He misspoke a few times, so read the slides.

“Phenotype is reality. Genotype is possibility. Communications links between different fields are very poorly connected in science.

Peroxisomes are islands. They don’t have DNA like your mitochondria do. Peroxisomal transport issues are important things to understand.

All aging-related cross-sectional analyses are on the rate of decline. You’re declining from a previous well state. Age-matched controls are the most ridiculous thing to do.”

2. I’ll highlight the longest of several interviews because there was plenty of room to expand on points. Maybe the best detailed explanations came as responses to that interviewer challenging with contrasting AD, traumatic brain injury, and cholesterol paradigms. Its transcript is more accurate than a usual YouTube interpretation, but there are still mistakes such as “fossil lipid” vs. phospholipid.

https://www.betterhealthguy.com/episode186 “Plasmalogens with Dr. Dayan Goodenowe, PhD”

“Science is how do you push things to its failure, until you can’t fail it again. We’ve lost that. It’s become more hypothesis proving.

Plasmalogens levels go up for a different reason than people think. The reason why it peaks in our 40s and 50s is because we’ve been myelinating. The white matter of our brain is still increasing. It’s not because we’re making more plasmalogens. It’s because the lake, the reservoir, gets full. What you’re measuring in blood is overflow from the lake. The lower plasmalogens start trickling down in your blood, the bigger drain that’s occurring on that system.

Low plasmalogens don’t just predict dementia in the elderly population. It predicts the rate of decline of that dementia. It predicts the rate of death.

The biggest drivers of plasmalogen manufacturing and the biggest reasons why they decrease with age, or in other circumstances is two things. One, the failure to maintain a fasting state of the human body. The second one is muscle atrophy.

Amyloid has absolutely nothing to do with Alzheimer’s, or dementia. It’s just a bystander on the road watching an accident happen.

Age-related cognitive decline is clearly where plasmalogens have the greatest impact. You’re always going to have mixed pathologies in the brain.

Nutritional availability of plasmalogens is virtually non-existent. As soon as they hit the hydrochloric acid of your stomach, they’re gone. They don’t make it past the stomach, or the upper intestine.”

I came across Dr. Goodenowe’s work last month from clicking a comment on this blog that linked back to her blog. Always be curious.

Continued in Part 2.

Three years after

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A delayed commemoration of Week 9 of Changing to a youthful phenotype with broccoli sprouts:

Yes, Awakening continues to be a common occurrence due to continuous broccoli compound intake. Understanding what I didn’t understand yesterday. Noticing what I couldn’t see yesterday. I’m sure there’s more to go.

Appreciate last week’s experiences with people associated with my fourth grandchild’s birth. So miraculous, so beautiful that everything happened when it needed to. She’s perfect.

The current idiocracy prohibits saying anymore.

Ripe wild persimmons. They really taste good if you wait until they’re completely ripened.

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Neuritogenesis

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Three 2023 papers on the initial stage of neuronal differentiation, starting with a rodent study of taurine’s effects:

“We aimed to assess the role of taurine (TAU) in axonal sprouting against cerebral ischemic injury, clarify the function of mitochondria in TAU-induced axonal sprouting, and further determine the underlying potential molecular mechanism.

experiment design

We determined that TAU improved motor function recovery and restored neurogenesis in ischemic stroke. This possibly occurred via improvements in mitochondrial function.

We investigated that the Sonic hedgehog (Shh) pathway exerted an important role in these effects. Our study findings highlighted the novel viewpoint that TAU promoted axonal sprouting by improving Shh-mediated mitochondrial function in cerebral ischemic stroke.”

https://www.scielo.br/j/acb/a/nxKvGXGk9g6gRkHxybMfbYJ/?lang=en “Taurine promotes axonal sprouting via Shh-mediated mitochondrial improvement in stroke”

A rodent study investigated effects of a soy isoflavone gut microbiota metabolite:

“Perinatally-infected adolescents living with HIV-1 (pALHIV) appear uniquely vulnerable to developing substance use disorders (SUD). Medium spiny neurons (MSNs) in the nucleus accumbens core (NAcc), an integrator of cortical and thalamic input, have been implicated as a key structural locus for the pathogenesis of SUD.

Treatment with estrogenic compounds (e.g., 17β-estradiol) induces prominent alterations to neuronal and dendritic spine structure in the NAcc supporting an innovative means to remodel neuronal circuitry. The carcinogenic nature of 17β-estradiol, however, limits its translational utility.

Plant-derived polycyclic phenols, or phytoestrogens, whose chemical structure resembles 17β-estradiol may afford an alternative strategy to target estrogen receptors. The phytoestrogen S-Equol (SE), permeates the blood-brain barrier, exhibits selective affinity for estrogen receptor β (ERβ), and serves as a neuroprotective and/or neurorestorative therapeutic for HIV-1-associated neurocognitive and affective alterations.

Beginning at approximately postnatal day (PD) 28, HIV-1 transgenic (Tg) animals were treated with a daily oral dose of 0.2 mg of SE. The SE dose of 0.2 mg was selected for two primary reasons, including:

  1. A dose-response experimental paradigm established 0.2 mg of SE as the most effective dose for mitigating neurocognitive deficits in sustained attention in the HIV-1 Tg rat; and
  2. The dose, which yielded a daily amount of 0.25–1.0 mg/kg/SE (i.e., approximately 2.5–10 mg in a 60 kg human), is translationally relevant (i.e., well below the daily isoflavone intake of most elderly Japanese.

Daily oral treatment continued through PD 90.

j_nipt-2023-0008_fig_002

HIV-1 Tg animals exhibited an initial increase in dendrite length (A) and the number of dendritic spines (B) early in development; parameters which subsequently decreased across time. In sharp contrast, dendrite length and the number of dendritic spines were stable across development in control animals.

Targeting these alterations with the selective ERβ agonist SE during the formative period induces long-term modifications to synaptodendritic structure, whereby MSNs in the NAcc in HIV-1 Tg animals treated with SE resemble control animals at PD 180.”

https://www.degruyter.com/document/doi/10.1515/nipt-2023-0008/html “Constitutive expression of HIV-1 viral proteins induces progressive synaptodendritic alterations in medium spiny neurons: implications for substance use disorders”

A rodent brain cell study investigated soy isoflavones’ effects on a different estrogen receptor:

“We evaluated effects of isoflavones using mouse primary cerebellar culture, astrocyte-enriched culture, Neuro-2A clonal cells, and co-culture with neurons and astrocytes. Soybean isoflavone-augmented estradiol mediated dendrite arborization in Purkinje cells.

These results indicate that ERα plays an essential role in isoflavone-induced neuritogenesis. However, G-protein-coupled ER (GPER1) signaling is also necessary for astrocyte proliferation and astrocyte–neuron communication, which may lead to isoflavone-induced neuritogenesis.

We highlight the novel possibility that isoflavones enhance dendritogenesis and neuritogenesis, indicating that they can be a useful supplementary compound during brain development or in the injured brain.”

https://www.mdpi.com/1422-0067/24/10/9011 “Isoflavones Mediate Dendritogenesis Mainly through Estrogen Receptor α”

Adverse Childhood Experiences, Part 2

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A request was made to present studies that investigated epigenetic impacts of corporal punishments or physical trauma to children or adolescents. Here’s a follow-on of the 2015 Grokking an Adverse Childhood Experiences (ACE) score, since physical abuse is one factor of an ACE score.

1. The largest problem is that a person filling out an ACE questionnaire or Childhood Trauma Questionnaire can’t provide first-hand answers of their own experiences during womb life, infancy, and early childhood. These critical development periods are more impacted by adversity than are later life windows.

Human brains aren’t developed enough before age 3 to provide retrospective answers using cerebral memories. A self-reported ACE score can’t possibly address what happened during the times when we were most vulnerable to disrupted neurodevelopment. And good luck with parents providing factual histories of whether they physically or emotionally neglected, physically or emotionally abused, or otherwise adversely treated their fetus, infant, and young child.

2. Another problem is researchers can pretty much choose whatever questions they want as input criteria. I’ve seen pliable ACE scores developed from 5- to 25-item questionnaires.

Do these questionnaires cover all relevant adverse childhood experiences? For example, are researchers permitted to use as inputs societal-created adversities a child may have lived through such as the Khmer Rouge or Cultural Revolution? Studies are just starting to investigate adverse childhood experiences created by worldwide abuses of authority since 2020.

3. Other problems were discussed in a 2023 paper https://www.sciencedirect.com/science/article/abs/pii/S0145213423003162 “Adverse childhood experiences and adult outcomes using a causal framework perspective: Challenges and opportunities” (not freely available), two of which were:

  • Adding up ACE factors to a cumulative score ignores the impact of synergistic sets. For example, although both cumulative ACE scores are 2, a child who was physically and sexually abused would probably be more adversely affected than a child whose parents divorced or separated, and also had a family member incarcerated.
  • At any given time point, and especially with older people, there’s a potential selection bias against those most affected by adverse childhood experiences, such as those who died.

Using flawed, squishy, cumulative ACE scores as inputs, here are two 2023 studies that found epigenetic associations:

“We tested the following pre-registered hypotheses: Mothers’ adverse childhood experiences are correlated with DNA methylation (DNAm) in peripheral blood during pregnancy (hypothesis 1) and in cord blood samples from newborn infants (hypothesis 2), and women’s depression and anxiety symptoms during pregnancy mediate the association between mothers’ ACE exposure and prenatal/neonatal DNA methylation (hypothesis 3).

  1. Hypothesis 1: In 896 mother−infant pairs with available methylation and ACE exposure data, there were no significant associations between mothers’ ACE score and DNAm from antenatal peripheral blood, after controlling for covariates.
  2. Hypothesis 2: In infant cord blood, there were 5 CpG sites significantly differentially methylated in relation to mothers’ ACEs (false discovery rate < .05), but only in male offspring. Effect sizes were medium. CpG sites were in genes related to mitochondrial function and neuronal development in the cerebellum.
  3. Hypothesis 3: There was no mediation by maternal anxiety/depression symptoms found between mothers’ ACEs score and DNAm in the significant CpG sites in male cord blood.”

https://www.jaacap.org/article/S0890-8567(23)00313-1/fulltext “Epigenetic Intergenerational Transmission: Mothers’ Adverse Childhood Experiences and DNA Methylation”

“In this study, the effect of cumulative ACEs experienced on human maternal DNAm was estimated while accounting for interaction with domains of ACEs in prenatal peripheral blood mononuclear cell samples. Intergenerational transmission of ACE-associated DNAm was explored used paired maternal and neonatal cord blood samples. Replication in buccal samples was also explored.

We used a four-level categorical indicator variable for ACEs exposure: none (0 ACEs), low (1–3 ACEs), moderate (4–6 ACEs), and high (> 6 ACEs). 🙄

125a4c3cacfe4b922e5b864c

https://www.researchsquare.com/article/rs-2977515/v1 “Effect of Parental Adverse Childhood Experiences on Intergenerational DNA Methylation Signatures”

Remembering life before birth

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This 2023 primate study investigated the body’s capability to remember prenatal experiences influencing later life:

“Maternal stressors and other environmental factors affect the developing embryo and fetus in ways that lead to increased susceptibility for chronic disease in later life. Developmental programming of chronic low-grade inflammation plays an important role in onset and progression of these diseases.

Establishing innate immune cell memory involves increased glycolysis, reduced oxidative phosphorylation, and expression of transcription factors which prime for pro-inflammatory activity. This memory relies on propagation of epigenetic modifications that develop in hematopoietic stem and progenitor cells (HSPCs), which can be passed on to progeny immune cells (i.e., macrophages).

These changes persist with altered epigenetic regulation for years after weaning – even when offspring are fed a conventional diet – predisposing offspring to inflammatory disease across their lifespans.

cell memory

Several factors may initiate metabolomic reprogramming in fetal HSPCs:

  • We found increased chromatin accessibility of gene regulatory regions and RNA signatures supporting activation of factors with a major role in regulating macrophage inflammatory activation, including FOS/JUN, NF-κB, C/EBPβ, and STAT6.
  • Our prior work demonstrated a persistently altered histone code in liver tissue from juvenile animals.
  • Maternal diet-supplied lipids, including oleic acid, in hematopoietic tissues may play an important role in priming inflammation and metabolism in fetal HSPCs and bone marrow-derived macrophages with postnatal persistence.

Striking changes in fetal bone marrow and liver HSPCs observed here suggest that the primary driver for developmental programming of inflammation takes place in utero. However, we cannot rule out that exposure to maternal diet during lactation postnatally triggers shifts in microbiome composition or function contributing to inflammation.

Components of maternal diet, rather than maternal obesity per se, are a modifiable risk factor with potential to alter developmental programming of offspring immune systems.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00404-7 “Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring”

And there are other ways we remember everything that happened then and along the way. Big clues are in our out-of-context responses to present day events.

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If you were given a lens to see clearly, would you accept it?

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Two papers, starting with a 2022 rodent study of maternal behaviors’ effects on offspring physiologies:

“Early life adversity (ELA) is a major risk factor for development of pathology. Predictability of parental care may be a distinguishing feature of different forms of ELA.

We tested the hypothesis that changes in maternal behavior in mice would be contingent on the type of ELA experienced, directly comparing predictability of care in limited bedding and nesting (LBN) and maternal separation (MS) paradigms. We then tested whether predictability of ELA environment altered expression of corticotropin-releasing hormone (Crh), a sexually-dimorphic neuropeptide that regulates threat-related learning.

MS was associated with increased expression of Crh-related genes in males, but not females. LBN primarily increased expression of these genes in females, but not males.”

https://www.sciencedirect.com/science/article/pii/S2352289522000595 “Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala”

I came across this first study by it citing a republished version of 2005 epigenetic research from McGill University:

“Early experience permanently alters behavior and physiology. A critical question concerns the mechanism of these environmental programming effects.

We propose that epigenomic changes serve as an intermediate process that imprints dynamic environmental experiences on the fixed genome, resulting in stable alterations in phenotype. These findings demonstrate that structural modifications of DNA can be established through environmental programming and that – in spite of inherent stability of this epigenomic marker – it is dynamic and potentially reversible.”

https://www.tandfonline.com/doi/full/10.31887/DCNS.2005.7.2/mmeaney “Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome”

This post commemorates the five-year anniversary of Dr. Arthur Janov’s death. Its title is taken from my reaction to his comment on Beyond Belief: Symptoms of hopelessness. Search his blog for mentions of the second paper’s coauthors, Drs. Meaney and Szyf.

Our lives are substantially a product of our parents’ actualized and unsatisfied needs. Our children and their children are reflections of us with our problems (unfelt needs) or elucidations (felt needs).

What if the price we pay for avoiding and pressuring down our feelings is: A wasted life?

What if the grand hypothesis worth proving is: For one’s life to have meaning, each individual has to regain their feelings?

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Gut microbiota, SCFAs, and hypertension

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Two 2022 rodent studies from the same research group on short-chain fatty acid effects, beginning with butyrate:

“Maternal nutrition, gut microbiome composition, and metabolites derived from gut microbiota are closely related to development of hypertension in offspring. A plethora of metabolites generated from diverse tryptophan metabolic pathways show both beneficial and harmful effects.

Butyrate, one of the short-chain fatty acids (SCFAs), has shown vasodilation effects. We examined whether sodium butyrate administration in pregnancy and lactation can prevent hypertension induced by a maternal tryptophan-free diet in adult progeny, and explored protective mechanisms.

Decreased tryptophan metabolites indole-3-acetamide and indoleacetic acid observed in offspring born to dams that received the trytophan-free (TF) diet coincided with hypertension. This suggested that gut microbiota-derived tryptophan metabolites might be an offsetting mechanism, but not a cause of TF-induced hypertension. Considering that TF intervention reduced abundance of Romboutsia and Akkermansia, and many species are able to metabolize tryptophan, further studies linking abundance of bacterial species and concentrations of tryptophan metabolites are still required to identify main tryptophan metabolite producers.

Sodium butyrate treatment during pregnancy and lactation offset effects of maternal tryptophan-deficiency-induced offspring hypertension, mainly related to shaping gut microbiome, mediating SCFA receptor GPR41 and GPE109A, and restoring the renin–angiotensin system. A better understanding of mechanisms behind tryptophan metabolism implicated in programming of hypertension is critical for developing gut microbiota-targeted therapies to halt hypertension.”

https://www.sciencedirect.com/science/article/abs/pii/S0955286322001619 “Sodium butyrate modulates blood pressure and gut microbiota in maternal tryptophan-free diet-induced hypertension rat offspring” (not freely available) Thanks to Dr. You-Lin Tain for providing a copy.

A second study was on propionate effects:

“Early-life disturbance of gut microbiota has an impact on adult disease in later life. Propionate, one of predominant SCFAs, has been shown to have antihypertensive property.

We examined whether perinatal propionate supplementation can prevent offspring hypertension induced by maternal chronic kidney disease (CKD). CKD is closely linked to adverse maternal and fetal outcomes, and is reported to affect at least 3%-4% women of childbearing age.

Male offspring were divided into four groups: control, CKD, control+propionate (CP), and CKD+propionate (CKDP).

nutrients-14-03435-g001

Perinatal propionate supplementation:

  • Prevented offspring hypertension;
  • Shaped gut microbiota with increases in species richness and evenness;
  • Increased plasma propionate level; and
  • Upregulated renal GPR41 expression.

Results reveal the feasibility of manipulating gut microbiota by altering their metabolites with early-life use of propionate to prevent offspring hypertension in later life.”

https://www.mdpi.com/2072-6643/14/16/3435/htm “Perinatal Propionate Supplementation Protects Adult Male Offspring from Maternal Chronic Kidney Disease-Induced Hypertension”

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Non-patentable boron benefits

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To follow up Is boron important to health? I’ll highlight a 2022 review of boron intake:

“Boron is essential for activity of several metabolic enzymes, hormones, and micronutrients. It is important for growth and maintenance of bone, reduction in inflammatory biomarkers, and increasing levels of antioxidant enzymes.

The average person’s daily diet contains 1.5 to 3 milligrams of boron. Boron intakes of 1–3 mg/day have been shown to improve bone and brain health in adults when compared to intakes of 0.25–0.50 mg/day.

One week of 10 mg/d boron supplementation resulted in a 20% reduction in inflammatory biomarkers TNF-α, as well as significant reductions (nearly 50%) in plasma concentrations of hs-CRP and IL-6. Calcium fructoborate, a naturally occurring, plant-based boron-carbohydrate complex, had beneficial effects on osteoarthritis (OA) symptoms. A double-blind study in middle-aged patients with primary OA found that all groups except the placebo group saw a reduction in inflammatory biomarkers after 15 days of food supplementation with calcium fructoborate.

Dietary boron intake significantly improves brain function and cognitive functioning in humans. Electroencephalograms showed that boron pharmacological intervention after boron deficiency improved functioning in older men and women, such as less drowsiness and mental alertness, better psychomotor skills (for example, motor speed and dexterity), and better cognitive processing (e.g., attention and short-term memory). Boron compounds can help with both impaired recognition and spatial memory problems.

We discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. Boron reagents will play a significant role to improve dysbiosis.”

https://www.mdpi.com/1420-3049/27/11/3402/htm “The Role of Microbiome in Brain Development and Neurodegenerative Diseases”

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Trained immunity epigenetics

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Two papers on trained immunity, starting with a 2022 review:

“Live attenuated vaccines such as the Bacillus Calmette–Guérin, measles-containing vaccines, and the oral polio vaccine have been shown to reduce overall mortality beyond their effects attributable to the targeted diseases.

After an encounter with a primary stimulus, epigenetic and metabolic reprogramming of bone marrow progenitor cells and functional changes of tissue immune cell populations result in augmented immune responses against a secondary challenge. This process has been termed trained immunity.

Main epigenetic events during induction of trained immunity are:

  1. Chromosomal reorganization on the level of topologically associated domains;
  2. Induction of long noncoding RNA activity;
  3. Histone modifications and chromatin accessibility; and
  4. DNA (de)methylation.

trained immunity mechanisms

An epigenetic enzyme belonging to the lysine methyltransferase family, Set7, possesses vital function in β-glucan training of monocytes. When inhibited, trained immunity phenotype is diminished, while Set7 deficient mice cannot establish innate immune memory.

β-glucan is recognized by Dectin-1, and has been known to lead to a shift from oxidative phosphorylation (OXPHOS) to glycolysis as an ATP source. However, a more recent study reported an increase in both glycolysis and oxygen consumption following training, which signals a higher rate of OXPHOS. This discrepancy is explained by the difference in concentration of β-glucan used in the experiments.

Stopping vaccination with measles and polio once the pathogens are eradicated, or replacing live attenuated polio with inactivated polio, should be done with caution, as it may have a substantial impact on childhood mortality. Trained immunity may also represent an important new approach to improve current vaccines, or to develop novel vaccines that combine induction of classical adaptive immune memory and innate immune memory.”

https://www.sciencedirect.com/science/article/pii/S0952791522000371 “Trained immunity: implications for vaccination”

Reference 34 was a 2020 study by two of the same coauthors that provided details on the above discrepancy:

“Findings presented by the current study suggest that the disparity in terms of the role of OXPHOS arises from the stimulatory dose of β-glucan [by intraperitoneal injection]. A β-glucan concentration of 1 μg/mL induces both glycolysis and OXPHOS, whereas a concentration of 10 μg/mL induces glycolysis but inhibits OXPHOS.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30458-7 “The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan”

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Beneficial dietary erucic acid?

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A 2022 review to follow up Caution on broccoli seed erucic acid content?:

“Erucic acid is found to cause cardiac lipidosis in young animals, yet direct evidence of cardiac injury does not exist for young humans. Concerns about erucic acid safety and cardiotoxicity have been published in the press which are based on scientific reports in the 1970s that erucic acid disrupted oxidative phosphorylation and lead to accumulation of lipids in rat cardiac tissue.

Spanish toxic oil syndrome was a major concern, leading to questions about erucic acid cardiotoxicity. Yet it was found that not rapeseed oil per se, rather its carcinogen anilin-dye refined derivative caused cardiotoxicity.

Later, it was understood that reduced ATP production with erucic acid treatment was due to unapt isolation of rat cardiac mitochondria and lipid accumulation that was unique to rats that inherently harbour a low β-oxidative peroxisomal activity and tissue-specific metabolism of erucic acid. Similar structural or metabolic perturbations and tissue injuries were not encountered in monkeys, humans, and pigs.

Potential mechanisms regarding antineoplastic effects of erucic acid in brain tumors:

erucic acid

In children (0 to 14 years), medulloblastomas accounted for less than 10% of brain neoplasias in China, African countries, and Ireland. The ratio was in the range 20%–29% in Brazil, Argentina, Thailand, Korea and Poland, the proportion was 30% in Ecuador, 31% in Taiwan and Jordan.

In adults, the ratio of brain neoplasias diagnosed as glioblastoma was:

  • Below 10% only in China;
  • In the range 10%–29% in India, Thailand, Malaysia, Nigeria, Algeria, Malta, Costa Rica, Ecuador, and the Russian Federation;
  • In the range 30%–49% in some South American countries, Singapore, Taiwan, Japan, Korea, Turkey, Denmark, Iceland, Italy, and Spain among others; and
  • In the range 50%–70% in North America, Puerto Rico, Martinique, Israel, Cyprus, Jordan, Kuwait, and in Oceania.

The low ratio of medulloblastomas in children and of glioblastomas in adult Chinese population cannot be easily attributed to a single genetic and nurture pattern. Very likely, many complex factors interact to explain this difference regarding the Chinese population.

Several hypotheses can be put forward to illuminate the cause of reduced ratios of high grade brain tumors in Chinese which would be of benefit for global reduction and prevention of brain tumors. Erucic acid is very highly consumed in the Chinese diet, and 8-fold higher erucic acid levels exist in Chinese women’s milk in comparison to many other countries.

We hypothesized that dietary erucic acid may be – at least among many factors – associated with reduced ratios of high grade brain tumors in Chinese. If epidemiological and animal studies would prove such an association, an effective, cheap, and relatively non-toxic dietary supplementary strategy may be employed to prevent brain tumors at erucic acid doses lower than those associated with any cardiotoxic effects.”

https://link.springer.com/article/10.1007/s11011-022-01022-4 “Could dietary erucic acid lower risk of brain tumors? An epidemiological look to Chinese population with implications for prevention and treatment” (not freely available) Thanks to Dr. Meric Altinoz for providing a copy.

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Exercise substitutes?

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Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)

A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

  • Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.
  • Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.
  • Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.
  • It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).
  • Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”

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Thyroid function

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Hypothalamus, Immune system, Limbic system , , , ,

This 2022 review subject was thyroid function changes:

“Circulating concentrations of thyrotropin (TSH) and thyroxine (T4) are tightly regulated. Each individual has setpoints for TSH and free T4 which are genetically determined, and subject to environmental and epigenetic influence.

What is normal for one individual may not be normal for another, even within conventional definitions of euthyroidism. Notably, circulating TSH exists in several different isoforms with varying degrees of glycosylation, sialylation, and sulfonation which affect tissue availability and bioactivity. This is not reflected in immunoreactive TSH concentrations determined by routine laboratory assays.

enm-2022-1463f2

TSH and free T4 relationship analyzed by age in 120,403 patients who were not taking thyroxine treatment. Median TSH for each free T4 integer value (in pmol/ L) was calculated, then plotted as 20-year age bands in adults. Dotted horizontal and vertical lines mark the TSH reference range (0.4 to 4.0 mU/L) and free T4 reference range (10 to 20 pmol/L), respectively.

Mild TSH elevation in older people does not predict adverse health outcomes. In fact, higher TSH is associated with greater life expectancy, including extreme longevity.

In older people, TSH increases with aging without an accompanying fall in free T4. Clinical guidelines now recommend against routine levothyroxine treatment in older people with mild subclinical hypothyroidism.”

https://e-enm.org/journal/view.php?doi=10.3803/EnM.2022.1463 “Thyroid Function across the Lifespan: Do Age-Related Changes Matter?”

PXL_20220427_190457415

State-dependent memory

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Anterior cingulate cortex, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress, Thalamus , , ,

This 2021 review by two coauthors of What can cause memories that are accessible only when returning to the original brain state? provided evidence for alternative interpretations of memory experiments:

“Memory consolidation hypotheses postulate a long series of various and time consuming elaborate processes that come to protect memory from disruption after various periods of time. For more than fifty years, consolidation hypotheses led to the idea that:

  1. Memories are fragile and can easily be disrupted; and
  2. Memories require several hours to be encoded (Cellular Consolidation), and extensive periods of time (days to weeks and even months and years), to be definitely stabilized (Systems Consolidation).

Although these views rely on well substantiated findings, their interpretation can be called into question.

An alternative position is that amnesia reflects retrieval difficulties due to contextual changes. This simple explanation is able to account for most, if not all, results obtained in consolidation studies.

memory state dependency

Systems Consolidation can be explained in terms of a form of state-dependency.

Recent memory remains detailed, context-specific (in animals), and vivid (in humans) and very susceptible to contextual changes. With the passage of time, memories become less precise, and retention performance less and less affected by contextual changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763421005510 “Revisiting systems consolidation and the concept of consolidation” (not freely available)

I came across this review while trying to understand why a 2022 rodent study felt wrong. That study followed the standard memory paradigm, and I appreciate its lead author providing a copy since it wasn’t otherwise available.

But those researchers boxed themselves in with consolidation explanations for findings. They used drugs to change subjects’ memories’ contexts between training and testing. They didn’t see that tested memories were dependent on subjects’ initial brain states.

This review cited a paper abstracted in Resiliency in stress responses, namely Neurobiological mechanisms of state-dependent learning.

Crab for lunch

PXL_20220419_190655701

Vascular memory

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Primal Therapy, Stress , ,

This 2022 rodent study investigated effects of inducing hypertension for two weeks:

“Hypertension is conventionally associated with a neurohormonal activation from the sympathetic nervous and the renin-angiotensin-aldosterone systems. Angiotensin II (AngII) is a potent regulator of blood pressure, and is also a key player in hypertension development.

An initial 2-week exposure to AngII induced profound changes in cardiac and vascular remodeling, including endothelial activation, vascular inflammation and oxidant stress, all of which were maintained up to 3 weeks after AngII withdrawal. This phenotype was sustained despite early normalization of blood pressure after AngII withdrawal.

Our RNAseq pathway analysis suggests involvement of epigenetic regulators involved in methylation, such as PRC2. PRC2 complex catalyzes trimethylation of histone H3 on lysine 27 (H3K27me3), a histone mark necessary for maintaining transcriptional repression during multicellular development.

H3K27me3 AngII

Cell type-specific patterns of H3K27me3 are crucial for preserving cell identity. Consistent with this analysis, we observed a significant increase in H3K27me3 epigenetic mark in aortic tissue, intriguingly, only in both memory conditions.

Transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting, supporting a memory effect despite stimulus withdrawal. Future characterization of underlying AngII-dependent signaling might unveil new targets for its therapeutic modulation and reversal of this adverse legacy effect.”

https://www.frontiersin.org/articles/10.3389/fcvm.2022.854361/full “Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of Vascular Memory”

These subjects’ ages were equivalent to a 20-year-old human:

  • How much earlier could our vascular system retain events we experienced such as epigenetic H3K27me3 increases? Teenaged, late childhood, early childhood, infancy, fetal parts of our lives?
  • How long would these vascular system memories and their continued signaling linger?
  • What experiences could change these long-lasting memories?

Icy fire

PXL_20220329_185742880

Gut microbiota knowledge through 2021

gettingwell4 2-3 stars Required further work, Amygdala, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress , , , , , , ,

I’ll curate this 2022 review of what’s known and unknown about our trillions of gut microbiota through its topic headings:

“Most microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases.

A. Understanding the Microbiome Composition and Factors That Shape Its Diversity
Effect of Diet Composition on the Microbiome Diversity

  • Macronutrients and Microbiome Diversity
  • Nutrient and Mineral Supplements and Microbiome Diversity

Stress

Drugs

Race and Host Genetics

Aging

Lifestyle

  • Exercise
  • Smoking
  • Urbanization

B. Understanding the Microbiome Function and Its Association With Onset and Progression of Many Diseases

Microbiome Association With Inflammatory and Metabolic Disorders

  • Chronic Inflammation in GIT and Beyond
  • Development of Malignant Tumors
  • Obesity
  • Coronary Artery Disease
  • Respiratory Diseases

Microbiome Role in Psychiatric, Behavioral, and Emotional Disorders

C. Understanding the Microbiome Function as Mediated by Secreted Molecules

D. Conclusion and Future Directions – A pioneering study aimed to computationally predict functions of microbes on earth estimates the presence of 35.5 million functions in bacteria of which only 0.02% are known. Our knowledge of its functions and how they mediate health and diseases is preliminary.”

https://www.frontiersin.org/articles/10.3389/fmicb.2022.825338 “Recent Advances in Understanding the Structure and Function of the Human Microbiome”

I took another test last month at the 14-month point of treating my gut microbiota better. Compared with the 7-month top level measurements, what stood out was an increase in relative abundance from 1% to 7% in the Verrucomicrophia phylum that pretty much exclusively comprises species Akkermansia muciniphilia in humans:

top 5 phylum 2-2022

This review termed Akkermansia muciniphilia relative increases as beneficial. Go with the Alzheimer’s Disease evidence didn’t.

Preventing human infections with dietary fibers inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But I already eat much more fiber than our human ancestors’ estimated 100 grams of fiber every day, so lack of fiber definitely didn’t cause this relative increase.

Resistant starch therapy observed:

“Relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders increase in relative abundance to a greater extent.”

I’ll wait for further evidence while taking responsibility for my own one precious life.

Didn’t agree with this review’s statements regarding microbial associations with fear. These reviewers framed such associations as if gut microbiota in the present had stronger influences on an individual’s fear responses than did any of the individual’s earlier experiences. No way.

I came across this review by it citing The microbiome: An emerging key player in aging and longevity, which was Reference 25 of Dr. Paul Clayton’s blog post What are You Thinking?

Also didn’t agree with some of the doctor’s post:

  • Heterochronic parabiosis of young and old animals is wildly different from fecal transfer. Can’t really compare them to any level of detail.
  • Using a rodent young-to-old fecal microbiota transplant study to imply the same effects would happen in humans? Humans don’t live in controlled environments, so why would a young human individual’s gut microbiota necessarily have healthier effects than an old individual’s?
  • Another example was the penultimate paragraph: “By adding a mix of prebiotic fibers to your diet and maintaining a more youthful and less inflammatory microbiome you will have less inflammation, less endotoxaemia and less inflammageing. You will therefore live healthier and longer.” I’m okay with the first sentence. Equivalating the first sentence to both healthspan and lifespan increases in the second sentence wasn’t supported by any of the 45 cited references.