Plasmalogens, Part 1

October 31, 2023November 3, 2023 gettingwell4 5+ stars Premium, Acetylcholine, Brain development, Brain hemispheres, Cerebellum, Cerebrum, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Brain neurons, Control group, Corpus callosum, DNA methylation, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease, Reciprocity

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”

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.

Reversing biological age in rats

August 12, 2023August 12, 2023 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Lower brain, Memory, Stress, Telomeres Brain neurons, Control group, DNA methylation, Genetic factors, Happiness, Neural plasticity, Neurodegenerative disease, Prefrontal cortex, Reputations

This 2023 rodent study wrapped together findings of the original study curated in A rejuvenation therapy and sulforaphane, and the second follow-on study mentioned in Signaling pathways and aging. I’ll start by highlighting specifics of the later study:

“Pronounced rejuvenation effects in male rats prompted us to conduct further confirmatory experiments. A particularly important consideration is the effectiveness of E5 with regards to sex, as sex-dependent rejuvenation by some interventions have previously been reported.

To assess E5’s applicability to both male and female Sprague Dawley rats, we studied 12 males (6 treated with E5, 6 with saline) and 12 females (6 treated with E5, 6 with saline). These rats were treated every 45 days with an injection of E5 or saline. Rats were monitored for 165 days, and blood was drawn at six time points: 0, 15, 30, 60, 150 and 165 days from the first injection.

We observed highly significant improvements in TNF alpha and IL-6 levels for both males and females in the blood of E5-injected rats over that of saline controls. We also observed a substantial improvement in grip strength.

Our study shows age reversal effects in both male and female rats, but E5 is more effective in males.”

Another experimental group was started with old rats of both sexes. Using the human / rat relative clock developed in the original study, a human equivalent age to these rats at 26 months old was ((112.7 weeks / 197.6 weeks maximum rat lifespan) x 122.5 years maximum human lifespan) = 69.8 years:

“To validate our epigenetic clock results, we conducted a second set of E5 experiments with Sprague Dawley rats of both sexes. When these rats turned 26 months old, half (9 rats) received the E5 treatment while the other half (8 rats) received only the control treatment (saline injection). We analyzed methylation data from two blood draws: blood draw before treatment (baseline) and a follow up sample (15 days after the E5/saline treatment).”

Treatment measurements were affected by one female control group outlier. Panels F through J were recalculated after removing the outlier to show significant effects in both sexes:

“A) Final version of the rat clock for blood. Baseline measurement (x-axis) versus follow up measurement (15 days after treatment, y-axis). Points (rats) are colored by treatment: red=treated by E5, black=treated with saline only. Rotated grey numbers underneath each bar reports the group sizes. Each bar plot reports the mean value and one standard error.

B,D,E) Difference between follow up measurement and baseline measurement (y-axis) versus treatment status in B) all rats, D) female rats only, E) male rats only. C) is analogous to B) but uses the pan tissue clock for rats.

Panels in the second row (F,G,H,I,J) are analogous to those in the first row but the analysis omitted one control rat (corresponding to the black dot in the lower right of panel A).”

https://www.biorxiv.org/content/10.1101/2023.08.06.552148v1 “Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction”

A description of how E5 plasma fraction was made starts on page 16 of the *.pdf file. The next E5 study will be done with dogs per July 2023 updates in blog post comments:

“On E5 our entire team is working hard towards the launch of an old Beagle dogs trial this month. We want to make them really young, healthy, happy, and jumping around like 1 and 2 year olds.

Primary endpoint is safety and toxicology to test various dose strengths and frequencies. Secondary endpoints are more than 20.

As you know, we like to test exhaustively to get a sharper perspective of what’s happening. In rat studies we tested 30 biomarkers, including functional. We are especially keen to check kidney markers.

There are two clocks for dogs we are interested in to get third party confirmation of age reversal. Horvath dog clock is ready and GlycanAge dog clock is under construction.

We are requesting all organizations that support pets and aging to financially support their project of building an accurate dog clock. Not only will it help veterinary aging research like ours, but also all the dog owners that may want to know how much improvement their dog received from treatment. Dr. Matt Kaeberlain is an advisor on their project.”

Neuritogenesis

July 30, 2023July 30, 2023 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Brain development, Brainstem, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Embryo development, Genetic factors, Infants, Neural plasticity, Prefrontal cortex

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.

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:

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

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.

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

July 17, 2023July 18, 2023 gettingwell4 2-3 stars Required further work, Brain development, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Limbic system, Lower brain, Memory, Stress Brain neurons, Critical period, DNA methylation, Embryo development, Empathy, Genetic factors, Infants

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).

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.

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.

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). 🙄

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

Transgenerational transmission of stress

June 17, 2023June 23, 2023 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress Critical period, Embryo development, Genetic factors, Inherited disease

This 2023 rodent study found that effects of stress during mid-late gestation were epigenetically transmitted to the first, second, and third female generations:

“We investigated effects of gestational chronic variable stress (CVS) in rats using restraint and social isolation stress in the parental F₀ generation. Only the F₀ pregnant dams were subjected to stress.

When a pregnant female experiences adversity, impacts of that stress affect exposed somatic tissues (F₀ generation), the fetuses (F₁ generation), and the fetuses’ germline (F₂ generation). A true transgenerational inheritance arises when germline epimutations are transmitted to unexposed F₃ offspring.

A subset of F₁ rats was housed in an enriched environment (EE) to mitigate adverse effects of CVS. F₂ offspring reared in EE had increased birth weights, but their uterine gene expression patterns remained comparable to those of stressed animals.

We provide evidence that psychological and psychosocial CVS alters inflammatory status and endocrine markers in uteri of adult dams through transgenerational programming of the female germline. EE therapy in prenatally stressed F₁ offspring had no beneficial effects on uterine expression of inflammatory and endocrine markers for them or their future offspring.”

https://www.mdpi.com/1422-0067/24/4/3734 “Environmental Enrichment Promotes Transgenerational Programming of Uterine Inflammatory and Stress Markers Comparable to Gestational Chronic Variable Stress”

Amphibian epigenetic clocks

June 7, 2023June 17, 2023 gettingwell4 2-3 stars Required further work, Brain development, Epigenetics DNA methylation, Embryo development, Genetic factors

This 2023 study of two frog species expanded one of the cited studies in Epigenetic clocks so far in 2022 to include post-embryonic epigenetic clock measurements:

“We generated DNA methylation data from African clawed frogs (Xenopus laevis) and Western clawed frogs (Xenopus tropicalis) and built multiple epigenetic clocks. Dual species clocks were developed that apply to both humans and frogs (human-clawed frog clocks), supporting that epigenetic aging processes are evolutionary conserved outside mammals.

The two species underlying our Xenopus clocks have markedly different maximum lifespans (30.3 for X. laevis and 16 for X. tropicalis), and average ages of sexual maturity (1 year for laevis and 0.375 for tropicalis). When building our Xenopus clocks, we addressed this fact in two ways:

In our pan-clock, we used a log-linear transformation of age that effectively normalizes ages with respect to age at sexual maturity.

In our relative pan-clock, we instead estimate relative age (chronological age divided by maximum lifespan), which normalizes ages with respect to maximum lifespan.

We also created dual-species clocks, referred to as human-clawed frog clocks, for estimates of chronological age and relative age. Relative age is the ratio of chronological age to maximum lifespan, and takes on values between 0 and 1. Maximum lifespan observed for humans was 122.5 years.

The relative age clock allows for alignment and biologically meaningful comparison between species with different lifespans.

Previous studies in humans showed that a hallmark of age-related CpGs is their association with target sites of Polycomb repressive complex 2 (PRC2), which gain methylation with age. This feature is fully recapitulated in Xenopus, and physiological significance of this association is an important open question.

PRC2 plays a prominent role during embryonic development and consequently, many aging-clock-associated genes relate to developmental processes. Given its evolutionary conservation from frogs to humans, methylation status of PRC2 targets supports some critical causal relationship to systemic aging.

Since the association with PRC2 with aging stems from analyses of adult postmitotic cells, and of different tissue origin rather than from embryonic cells, it is tempting to speculate that adult methylation status will get important input during embryonic development, the very phase when PRC2 target gene expression is prominent.

Genes associated with both positive and negative age-related CpGs relate to neural processes, although in somewhat opposite direction. While DNAm increase is linked to neural developmental genes, DNAm decrease links to synaptic transmission, roughly corresponding to processes of immature vs. mature neuronal cells, respectively. This leads to the counter-intuitive suggestion that studying Xenopus neural development may yield new insights into biological aging.”

https://link.springer.com/article/10.1007/s11357-023-00840-3 “DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging”

I’ve seen dual-species epigenetic clocks – introduced in A rejuvenation therapy and sulforaphane – referenced elsewhere, most recently in Selective Breeding for High Intrinsic Exercise Capacity Slows Pan-Tissue Epigenetic Aging in Rats. These clocks still aren’t in wide use by researchers, though. Don’t know what it will take to persuade researchers to use dual-species relative age clocks in their model organism studies so that they can justifiably invoke human applicability.

Nrf2 Week #2: Neurons

May 23, 2023 gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress Brain neurons, Embryo development, Genetic factors, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

To follow the Nrf2 Week #1 suggestion that Nrf2 target neurological disorders, this 2023 cell study investigated Nrf2 expression in neurons:

“Oxidative metabolism is inextricably linked to production of reactive oxygen species (ROS), which have the potential to damage all classes of macromolecules. Yet ROS are not invariably detrimental. Several properties make ROS useful signaling molecules, including their potential for rapid modification of proteins and close ties to cellular metabolism.

We used multiple single cell genomic datasets to explore Nrf2 expression and regulation in hundreds of neuronal and non-neuronal cell types in mouse and human. With few exceptions, Nrf2 is expressed at far lower levels in neurons than in non-neuronal support cells in both species.

This pattern is maintained in multiple disease states, and the chromatin accessibility landscape at the Nrf2 locus parallels these expression differences. These results imply that Nrf2 activity is limited in almost all neurons of the mouse and human central nervous system (CNS).

We separated cell types into neuron or non-neuronal ‘support’ cell categories. The general ‘support’ term is not meant to minimize the functional relevance of non-neuronal cells in the CNS, but is an umbrella term meant to cover everything from glial cell types (astrocytes, microglia, oligodendrocytes) to endothelial cells.

It is not clear why an important, near ubiquitous cytoprotective transcription factor like Nrf2 remains off in mature neurons, especially considering oxidative stress is a driver of many diseases. The simplest explanation is that Nrf2 activity also disrupts normal function of mature neurons.

ROS play a key role in controlling synaptic plasticity in mature neurons. These activity-dependent changes in synaptic transmission, which are important for learning and memory, are disrupted by antioxidants.

A subset of important Nrf2-targeted antioxidant genes (e.g., Slc3a2, Slc7a11, Nqo1, Prdx1) are also low in neurons. So it is likely that these and/or other Nrf2 targets must remain low or non-ROS-responsive in mature neurons. Future work exploring why this expression pattern persists in mature neurons will inform our models on roles of antioxidant genes in normal neuronal physiology and in neurological disorders.“

https://www.biorxiv.org/content/10.1101/2023.05.09.540014v1.full “Limited Expression of Nrf2 in Neurons Across the Central Nervous System”

Minds of their own

September 16, 2022September 17, 2022 gettingwell4 5+ stars Premium, Brain development, Brain hemispheres, Epigenetics, Memory, Neurochemicals, Serotonin, Stress Brain neurons, Critical period, Embryo development, Genetic factors, Happiness, Neural plasticity, Neurodegenerative disease

It’s the weekend, so it’s time for: Running errands? Watching sports? Other conditioned behavior?

Or maybe broadening our cognitive ability with Dr. Michael Levin’s follow-ups to his 2021 Basal cognition paper and 2020 Electroceuticals presentation with a 2022 paper and presentation starting around the 13:30 mark:

“A homeostatic feedback is usually thought of as a single variable such as temperature or pH. The set point has been found to be a large-scale geometry, a descriptor of a complex data structure.”

His 2022 paper Technological Approach to Mind Everywhere: An Experimentally-Grounded Framework for Understanding Diverse Bodies and Minds:

“It is proposed that the traditional problem-solving behavior we see in standard animals in 3D space is just a variant of evolutionarily more ancient capacity to solve problems in metabolic, physiological, transcriptional, and morphogenetic spaces (as one possible sequential timeline along which evolution pivoted some of the same strategies to solve problems in new spaces).

Developmental bioelectricity works alongside other modalities such as gene-regulatory networks, biomechanics, and biochemical systems. Developmental bioelectricity provides a bridge between the early problem-solving of body anatomy and the more recent complexity of behavioral sophistication via brains.

This unification of two disciplines suggests a number of hypotheses about the evolutionary path that pivoted morphogenetic control mechanisms into cognitive capacities of behavior, and sheds light on how Selves arise and expand.

While being very careful with powerful advances, it must also be kept in mind that existing balance was not achieved by optimizing happiness or any other quality commensurate with modern values. It is the result of dynamical systems properties shaped by meanderings of the evolutionary process and the harsh process of selection for survival capacity.”

Broccoli sprouts and your brain

August 9, 2022August 9, 2022 gettingwell4 0-1 star Wasted resources, Brain development, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress Brain neurons, DNA methylation, Embryo development, Genetic factors, Neural plasticity, Neurodegenerative disease

A 2022 review of Nrf2 signaling hilariously avoided mentioning sulforaphane, although of ~4,000 sulforaphane published articles, two were cited. I’ll curate it anyway to highlight referenced brain effects.

“A good stability of NRF2 activity is crucial to maintain redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, ageing, and ageing-related neurodegenerative diseases.

A functional NRF2 system is important to regulate both neuroinflammation, i.e., activation of microglia and astrocytes, and oxidative stress in the brain. NRF2 and NF-κB transcription factors regulate cellular responses to inflammation and oxidative stress in order to maintain brain homeostasis. Both pathways have been described to inhibit each other.

Future challenges will be to establish novel therapies to:

Increase NRF2 activation in specific cell types and/or brain regions; and

Modulate NRF2 pathway in senescent cells.

Modulation of NRF2 signalling pathway by using specific food products [like unmentioned broccoli sprouts] and phytochemicals [like unmentioned sulforaphane], dietary supplements [like unmentioned Vitamin D3], drugs, and epigenetic modifiers, alone or in combination, will help to limit inflammatory diseases, ageing process, and subsequently ageing-related diseases.”

https://www.mdpi.com/2076-3921/11/8/1426/htm “Normal and Pathological NRF2 Signalling in the Central Nervous System”

Eat broccoli sprouts for your offspring

August 2, 2022September 2, 2023 gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Stress Control group, Embryo development, Genetic factors

This 2022 rodent study investigated effects of glucoraphanin supplementation during pregnancy and lactation:

“We investigated whether dietary intake of sulforaphane glucosinolate (SGS [properly termed glucoraphanin]) during pregnancy and lactation influenced composition of gut microbiota in offspring:

Dietary intake of SGS during pregnancy and lactation caused significant changes in diversity of gut microbiota in 3-week-old offspring (SGS-3W) and 10-week-old offspring (SGS-10W).

Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in SGS-10W after injection of lipopolysaccharide were significantly lower than those of CON-10W group.

There were sex differences of gut microbiota composition in both SGS-3W and SGS-10W offspring.

This study has some limitations:

We did not investigate mechanisms of how dietary intake of SGS during pregnancy and lactation modulated gut microbial communities in offspring.

We found several signaling pathways in beneficial effects of SGS food pellet, and further study of the role of maternal intake of SGS food in these pathways is needed.

We did not investigate mechanisms of relationships between maternal intake of SGS and long-term anti-inflammatory action in adult offspring, and further detailed study including epigenetic modification is needed.

These data suggest that dietary intake of SGS during pregnancy and lactation might produce long-lasting beneficial effects in adult offspring through persistent modulation of gut microbiota. It is likely that modulation of gut microbiota by maternal nutrition may confer resilience versus vulnerability to stress-related psychiatric disorders in offspring.”

https://www.sciencedirect.com/science/article/pii/S0955286322001681 “Long-lasting beneficial effects of maternal intake of sulforaphane glucosinolate on gut microbiota in adult offspring”

This study published results of a mother’s glucoraphanin intake where offspring never ate glucoraphanin, with beneficial effects at both 3 weeks (~prepubescent human) and 10 weeks (~young human adult). Maybe future studies will continue this paradigm on to a second or third generation to see whether there are also transgenerational epigenetic effects.

This study’s methods extracted glucoraphanin from 1-day-old broccoli sprouts into a powder containing 135 mg (0.31 mmol) glucoraphanin per gram. Each 1 kg of treatment chow included pellets containing (2.3 mmol / 0.31 mmol) x 135 mg = 1 gram of broccoli sprout powder, 0.1% of food intake.

Per Drying broccoli sprouts, dried 3-day-old broccoli sprouts contain 10% moisture, and fresh 3-day-old broccoli sprouts contain 82.6% moisture. A gram of 1-day-old broccoli sprout powder may be an approximate equivalent of (.826 / .1) = 8 grams fresh 3-day-old broccoli sprouts for a mouse / kg of daily food intake. A human equivalent dose is (.826 / .1) x .081 x 70 kg = 47 grams of fresh 3-day-old broccoli sprouts / kg of daily food intake.

That’s about how much 3-day-old, microwaved, glucoraphanin-containing broccoli and red cabbage sprouts I eat every day, starting from 7.2 grams of seeds. I sprout another 3.5 grams of yellow mustard seeds into the mixture for taste.

Beneficial dietary erucic acid?

July 19, 2022May 21, 2023 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebellum, Epigenetics, Lower brain Control group, Corpus callosum, Embryo development, Genetic factors, Infants

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:

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.

Taurine week #7: Brain

June 18, 2022January 19, 2025 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Embryo development, Genetic factors, Neurodegenerative disease, Prefrontal cortex

Finishing a week’s worth of 2022 taurine research with two reviews of taurine’s brain effects:

“We provide a overview of brain taurine homeostasis, and review mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. Alterations to taurine homeostasis can impact a number of biological processes such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders.

Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given cytoprotective actions of taurine, such accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration.

Taurine release is mainly mediated by volume-regulated anion channels (VRAC) that are activated by hypo-osmotic conditions and electrical activity. They can be stimulated via glutamate metabotropic (mGluR) and ionotropic receptors (mainly NMDA and AMPA), adenosine A₁ receptors (A₁R), and metabotropic ATP receptors (P2Y).

Taurine mediates its neuromodulatory effects by binding to GABA_A, GABA_B, and glycine receptors. While taurine binding to GABA_A and GABA_B is weaker than to GABA, taurine is a rather potent ligand of the glycine receptor. Reuptake of taurine occurs via taurine transporter TauT.

Cytoprotective actions of taurine contribute to brain health improvements in subjects with obesity and diabetes through various mechanisms that improve neuronal function, such as:

Modulating inhibitory neurotransmission, which promotes an excitatory–inhibitory balance;

Stimulating antioxidant systems; and

Stabilizing mitochondria energy production and Ca²⁺ homeostasis.”

https://www.mdpi.com/2072-6643/14/6/1292/htm “Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes”

A second review focused on taurine’s secondary bile acids produced by gut microbiota:

“Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. Hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases.

Biliary acids may influence each of the following three mechanisms through which interactions within the brain-gut-microbiota axis take place: neurological, immunological, and neuroendocrine. These microbial metabolites can act as direct neurotransmitters or neuromodulators, serving as key modulators of the brain-gut interactions.

The gut microbial community, through their capacity to produce bile acid metabolites distinct from the liver, can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favour. Hydrophilic bile acids, currently regarded as important hormones, exert modulatory effects on gut microbiota composition to produce secondary bile acids which seem to bind a number of receptors with a higher affinity than primary biliary acids, expressed on many different cells.

TUDCA regulates expression of genes involved in cell cycle regulation and apoptotic pathways, promoting neuronal survival. TUDCA:

Improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition;

Reduces reactive oxygen species production, leading to protection against mitochondrial dysfunction;

Ameliorates endoplasmic reticulum stress; and

Inhibits expression of pro-inflammatory cytokines, exerting an anti-neuroinflammatory effect.

Although Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia have different disease progressions, they share similar pathways which can be targeted by TUDCA. This makes this bile acid a potentially strong therapeutic option to be tested in human diseases. Clinical evidence collected so far has reported comprehensive data on ALS only.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166453/ “Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases”

The misnomer of nonessential amino acids

June 4, 2022June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Control group, Embryo development, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

Three papers, starting with a 2022 review:

“Ideal diets must provide all physiologically and nutritionally essential amino acids (AAs).

Proposed optimal ratios and amounts of true digestible AAs in diets during different phases of growth and production. Because dynamic requirements of animals for dietary AAs are influenced by a plethora of factors, data below as well as the literature serve only as references to guide feeding practices and nutritional research.

Nutritionists should move beyond the ‘ideal protein’ concept to consider optimum ratios and amounts of all proteinogenic AAs in diets for mammals, birds, and aquatic animals, and, in the case of carnivores, also taurine. This will help formulate effectively low-protein diets for livestock (including swine and high-producing dairy cattle), poultry, fish, and crustaceans, as well as zoo and companion animals.”

https://journals.sagepub.com/doi/10.1177/15353702221082658 “The ‘ideal protein’ concept is not ideal in animal nutrition”

A second 2022 review focused on serine:

“The main dietary source of L-serine is protein, in which L-serine content ranges between 2 and 5%. At the daily intake of ~1 g protein per kg of body weight, the amount of serine obtained from food ranges between 1.4 and 3.5 g (13.2–33.0 mmol) per day in an adult.

Mechanisms of potential benefits of supplementing L-serine include increased synthesis of sphingolipids, decreased synthesis of 1-deoxysphingolipids, decrease in homocysteine levels, and increased synthesis of cysteine and its metabolites, including glutathione. L-serine supplementation has been suggested as a rational therapeutic approach in several disorders, particularly primary disorders of L-serine synthesis, neurodegenerative disorders, and diabetic neuropathy.

Unfortunately, the number of clinical studies evaluating dietary supplementation of L-serine as a possible therapy is small. Studies examining therapeutic effects of L-serine in CNS injury and chronic renal diseases, in which it is supposed that L-serine weakens glutamate neurotoxicity and lowers homocysteine levels, respectively, are missing.”

https://www.mdpi.com/2072-6643/14/9/1987/htm “Serine Metabolism in Health and Disease and as a Conditionally Essential Amino Acid”

A 2021 review subject was D-serine, L-serine’s D-isoform:

“The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-serine is necessary for activation of NMDAR and in maintenance of long-term potentiation, and is involved in brain development, neuronal connectivity, synaptic plasticity, and regulation of learning and memory.

The source of D-amino acids in mammals was historically attributed to diet or intestinal bacteria until racemization of L-serine by serine racemase was identified as the endogenous source of D-serine. The enzyme responsible for catabolism (breakdown) of D-serine is D-amino acid oxidase; this enzyme is most abundant in cerebellum and brainstem, areas with low levels of D-serine.

Activation of the NMDAR co-agonist-binding site by D-serine and glycine is mandatory for induction of synaptic plasticity. D-serine acts primarily at synaptic NMDARs whereas glycine acts primarily at extrasynaptic NMDARs.

In normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2021.754032/full “An Overview of the Involvement of D-Serine in Cognitive Impairment in Normal Aging and Dementia”

Brain changes

May 11, 2022May 11, 2022 gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Brain development, Brain hemispheres, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory DNA methylation, Genetic factors, Neurodegenerative disease, Prefrontal cortex

This 2022 human study investigated healthy young adult brain changes using MRI and epigenetic clock technologies:

“We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. It is largely unknown how accelerated epigenetic age affects multiple cortical features among young adults from 19 to 49 years. Prior findings imply not only that these dynamic changes reveal different aspects of cortical aging, but also that chronological age itself is not a reliable factor to understand the process of cortical aging.

Seventy-nine young healthy individuals participated in this study. Findings of our study should be interpreted within the context of relatively small sample size, without older adults, and with epigenetic age assessed from saliva.

Additional and unique regional changes due to advanced and accelerated epigenetic age, compared to chronological age-related changes, suggest that epigenetic age could be a viable biomarker of cortical aging. Longitudinal and cross-sectional studies with a larger sample and wider age range are necessary to characterize ongoing effects of epigenetic cortical aging, not only for healthy but also for pathological aging.”

https://doi.org/10.1093/cercor/bhac043 “The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults” (not freely available) Thanks to Dr. Yong Jeon Cheong for providing a copy.

Thyroid function

May 5, 2022 gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Hypothalamus, Immune system, Limbic system Control group, DNA methylation, Embryo development, Genetic factors, Infants

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.

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?”