Maintaining your myelin, Part 1

April 25, 2024April 27, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Corpus callosum, Critical period, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

Three papers on myelin and oligodendrocytes, starting with a 2023 review:

“Myelin is the spiral ensheathment of axons by a lipid and cholesterol-rich glial cell membrane that reduces capacitance and increases resistance of the axonal membrane. Axonal myelination speeds up nerve conduction velocity as a function of axon diameter.

While myelination proceeds rapidly after birth in the peripheral nervous system, central myelination is a spatially and temporally more regulated process. Ongoing myelination of the human brain has been documented at up to 40 years of age. This late myelination in the adult cortex is followed by exhaustion of oligodendrocyte precursor cells (OPC) with senescence and a gradual loss of myelin integrity in the aging brain.

The brain is well known for its high energy demands, specifically in gray matter areas. In white matter tracts, energy consumption is lower. Myelination poses a unique challenge for axonal energy generation where myelin sheaths cover more than 95% of the axonal surface areas.

Oligodendrocytes help support axonal integrity. Oligodendrocytes survive well in the absence of mitochondrial oxidative phosphorylation, and without signs of myelin loss, cell death, neurodegeneration or secondary inflammation.

Glycolysis products of oligodendroglial origin are readily metabolized in axonal mitochondria. Oligodendroglial metabolic support is critical for larger and faster-spiking myelinated axons that also have a higher density of mitochondria. An essential requirement for the direct transfer of energy-rich metabolites from oligodendrocytes to the myelinated axonal compartment is ‘myelinic channels’ within the myelin sheath.

Interactions of oligodendrocytes and myelin with the underlying axon are complex and exceed the transfer of energy-rich metabolites. Continuous turnover of myelin membranes by lipid degradation and fatty acid beta-oxidation in mitochondria and peroxisomes leads to recycling of acetate residues by fatty acid synthesis and membrane biogenesis.

In human multiple sclerosis (MS) and its animal model myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis (MOG-EAE), acute inflammatory demyelination is followed by axonal degeneration in lesion sites that is mechanistically not fully understood. It is widely thought that demyelination and the lack of an axon-protective myelin sheath in the presence of numerous inflammatory mediators are the main causes of axon loss.

But unprotected axons improve rather than worsen the overall clinical phenotype of EAE mice which exhibited the same degree of autoimmunity. Thus, ‘bad myelin is worse than no myelin’ because MS-relevant myelin injuries perturb the integrity of myelinic channels and metabolic support.

Dysfunctional or injured oligodendrocytes that do not allow for compensation by any other cell types turn the affected myelin ensheathment into a burden of the underlying axonal energy metabolism, which causes irreversible axon loss. Any loss of myelin integrity, as seen acutely in demyelinating disorders or more gradually in the aging brain, becomes a risk factor for irreversible neurodegeneration.”

https://www.sciencedirect.com/science/article/pii/S0959438823001071 “Expanding the function of oligodendrocytes to brain energy metabolism”

A 2024 review focused on myelin and oligodendrocyte plasticity:

“This review summarizes our current understanding of how myelin is generated, how its function is dynamically regulated, and how oligodendrocytes support the long-term integrity of myelinated axons.

Apart from its unique ultrastructure, there are several other exceptional features of myelin. One is certainly its molecular composition. Another is its extraordinary stability. This was compellingly illustrated when 5000-year-old myelin with almost intact ultrastructure was dissected from a Tyrolean Ice Man.

Myelin is a stable system in contrast to most membranes. However, myelin is compartmentalized into structurally and biochemically distinct domains. Noncompacted regions are much more dynamic and metabolically active than tightly compacted regions that lack direct access to the membrane trafficking machinery of oligodendrocytes.

The underlying molecular basis for stability of myelin is likely its lipid composition with high levels of saturated, long chain fatty acids, together with an enrichment of glycosphingolipids (∼20% molar percentage of total lipids) and cholesterol (∼40% of molar percentage of total lipids). In addition, myelin comprises a high proportion of plasmalogens (ether lipids) with saturated long-chain fatty acids. In fact, ∼20% of the fatty acids in myelin have hydrocarbon chains longer than 18 carbon atoms (∼1% in the gray matter) and only ∼6% of the fatty acids are polyunsaturated (∼20% in gray matter).

With maturation of oligodendrocytes, the plasma membrane undergoes major transformations of its structure. Whereas OPCs are covered by a dense layer of large and negatively charged self-repulsive oligosaccharides, compacted myelin of fully matured oligodendrocytes lacks most of these glycoprotein and complex glycolipids.

Schematic depiction of an oligodendrocyte that takes up blood-derived glucose and delivers glycolysis products (pyruvate/lactate) via monocarboxylate transporters (MCT1 and MCT2) to myelinated axons. Oligodendrocytes and myelin membranes are also coupled by gap junctions to astrocytes, and thus indirectly to the blood–brain barrier.

Adaptive myelination refers to dynamic events in oligodendroglia driven by extrinsic factors such as experience or neuronal activity, which subsequently induces changes in circuit structure and function. Understanding how these adaptive changes in neuron-oligodendroglia interactions impact brain function remains a pressing question for the field.

Transient social isolation during adulthood results in chromatin and myelin changes, but does not induce consequent behavioral alterations. When mice undergo a social isolation paradigm during early life development, they similarly exhibit deficits in prefrontal cortex function and myelination, but these deficiencies do not recover with social reintroduction. This implicates a critical period for social deprivation effects on myelin dynamics. Experience-dependent changes in myelin dynamics may depend on not only the age, brain region, and cell type studied, but also the specific myelin structural change assessed.

Local synaptic neurotransmitter release along an axon not only affects the number of OPCs and oligodendrocytes associated with that axon and local synthesis of myelin proteins, but also drives preferential selection of active axons for myelination over the ensheathment of electrically silenced neighboring axons. Neuronal activity–induced plasticity may preferentially impact brain regions that remain incompletely myelinated compared to more fully myelinated tracts.

Whereas the myelin sheath has been regarded for a long time as an inert insulating structure, it has now become clear that myelin is metabolically active with cytoplasmic-rich pathways, myelinic channels, for movement of macromolecules into the periaxonal space. The myelin sheath and its subjacent axon need to be regarded as one functional unit, which are not only morphological but also metabolically coupled.”

https://cshperspectives.cshlp.org/content/early/2024/04/15/cshperspect.a041359 “Oligodendrocytes: Myelination, Plasticity, and Axonal Support” (not freely available) Thanks to Dr. Klaus-Armin Nave for providing a copy.

A 2024 rodent study investigated oligodendrocyte precursor cell transcriptional and epigenetic changes:

“We used single-cell RNA sequencing (scRNA-seq), single-cell ATAC sequencing (scATAC-seq), and single-cell spatial transcriptomics to characterize murine cortical OPCs throughout postnatal life. One group (active, or actOPCs) is metabolically active and enriched in white matter. The second (homeostatic, or hOPCs) is less active, enriched in gray matter, and predicted to derive from actOPCs. Relative to developing OPCs, both actOPCs and hOPCs are less active metabolically and have less open chromatin.

In adulthood, these two groups are transcriptionally but not epigenetically distinct, indicating that they may represent different states of the same OPC population. If that is the case, then one model is that the parenchymal environment maintains adult OPCs within an hOPC state, whereas those OPCs recruited into white matter or exposed to demyelinated axons may transition toward an actOPC state in preparation for making new oligodendrocytes. We do not yet know the functional ramifications of these differences, but this finding has clear implications for the development of therapeutic strategies for adult remyelination.

Another finding is that developing but not adult actOPC chromatin is preferentially open for binding motifs associated with neural stem cells, transit-amplifying precursors, and neurogenesis. Although this may simply reflect their origin as the immediate progeny of neonatal neural precursor cells, it may also explain why developing but not adult OPCs have the capacity to make neurons in culture.

If we could, at least in part, reverse the global chromatin shutdown that occurs between development and adulthood, then perhaps adult OPCs may reacquire the ability to make neurons or become better able to generate new oligodendrocytes for remyelination.”

https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(24)00077-8 “Single-cell approaches define two groups of mammalian oligodendrocyte precursor cells and their evolution over developmental time”

Continued in Part 2.

Three years after

October 3, 2023 gettingwell4 2-3 stars Required further work, Beliefs Critical period, Infants

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.

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”

Eat broccoli sprouts for depression, Part 3

March 13, 2023March 16, 2023 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Stress Brain neurons, Control group, Critical period, Genetic factors, Neural plasticity, Prefrontal cortex

Here are two papers published after Part 2 that cited the Part 1 rodent study, starting with a 2023 rodent study performed by several Part 1 coauthors:

“We used a low-dose LPS-induced endotoxaemia model to mimic clinical characteristics of sepsis. We found that adolescent LPS treatment was sufficient to increase levels of inflammatory factor TNF-α in both the medial prefrontal cortex (mPFC) and hippocampus at post-natal day P22.

P21 LPS-treated mice were injected with sulforaphane (SFN) or saline intraperitoneally at P49 and then subjected to subthreshold social defeat stress (SSDS). We found that SFN preventative treatment significantly:

Decreased the social avoidance, anhedonia, and behavioural despair detected by the social interaction test, sucrose preference test, tail suspension test, and forced swim test, respectively.

Decreased anxiety-like behaviours without affecting locomotor activities.

Increased Nrf2 and brain-derived neurotrophic factor (BDNF) levels in the mPFC of P21 LPS-treated mice after SSDS compared with saline control mice.

The above results suggest that activation of the Nrf2-BDNF signalling pathway prevents the effect of adolescent LPS-induced endotoxaemia on stress vulnerability during adulthood.

These results suggest that early adolescence is a critical period during which inflammation can promote stress vulnerability during adulthood. This might be due to increased inflammatory response in the mPFC, and mediated by decreased levels of Nrf2 and BDNF. These findings may shed light on the potential use of SFN as an alternative preventative intervention for inflammation-induced stress vulnerability.”

https://link.springer.com/article/10.1007/s00213-022-06285-4 “Lipopolysaccharide-induced endotoxaemia during adolescence promotes stress vulnerability in adult mice via deregulation of nuclear factor erythroid 2-related factor 2 in the medial prefrontal cortex” (not freely available)

This study demonstrated that adolescent diseases and stresses don’t necessarily develop into adult social problems. A timely intervention may even prevent future adult problems.

The one-time 10 mg/kg sulforaphane dose was the same as Part 1’s dose, a human equivalent of which is (10 mg x .081) x 70 kg = 57 mg.

Per Human relevance of rodent sulforaphane studies, that’s above a tolerable oral dose of ≈ 50 mg in one serving.
I didn’t have a problem with eating half that twice a day via microwaved broccoli sprouts from Week 6 through Week 56.

I’d like to know more about how subjects’ memories of adverse events were retained, and subsequently affected their biology and behavior. Pretty sure limbic structures like the hypothalamus as well as lower brain structures played a part.

A 2022 review summarized what was known up to that time regarding Nrf2 and depression:

“Sulforaphane, an organosulfur compound isolated from Brassicaceae plants, is a potent natural NRF2 activator. Sulforaphane:

Exerts antidepressant- and anxiolytic-like activities and inhibits HPA axis and inflammatory response.

Has both therapeutic and prophylactic effects on inflammation-related depression.

Confers stress resilience.

Protects neurons via autophagy and promotes mitochondrial biogenesis by activating Nrf2.”

https://www.sciencedirect.com/science/article/pii/S2213231722002944 “Nrf2: An all-rounder in depression”

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.”

Non-CpG methylation

July 16, 2022January 3, 2023 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Stress Antidepressants, Brain neurons, Control group, Critical period, DNA methylation, Genetic factors, Neurodegenerative disease, Prefrontal cortex

Three 2022 papers on methylation epigenetic modifiers, starting with a human study focused on mitochondrial DNA non-CpG methylation involving nucleobases other than guanine (arginine, cytosine, or thymine):

“We collected brain tissue in the nucleus accumbens and prefrontal cortex from deceased individuals without (n = 39) and with (n = 14) drug use, and used whole-genome bisulfite sequencing to cover cytosine sites in the mitochondrial genome. Epigenetic clocks in illicit drug users, especially in ketamine users, were accelerated in both brain regions by comparison with nonusers.

Unlike the predominance of CpG over non-CpG methylation in the nuclear genome, the average CpG and non-CpG methylation levels in the mitochondrial genome were almost equal. The utility of non-CpG methylation was further illustrated by the three indices constructed in this study with non-CpG sites having better distinction between brain areas, age groups, and the presence or absence of drug use than indices consisting of CpG sites only. Results of previous studies on the mitochondrial genome that were solely based on CpG sites should be interpreted cautiously.

The epigenetic clock made up of age-related cytosine sites in mtDNA of the control group was consistently replicated in these two brain regions. One possibility for the correlation is the cycle theory that involves mitochondrial activity, mitochondrial DNA methylation, and alpha-ketoglutarate.

As mitochondrial activity fades with aging, mitochondria gradually lose the ability to eliminate methylation on cytosines through alpha-ketoglutarate. Further investigation of the underlying mechanisms is warranted.

To our knowledge, this is the first report that ketamine might change the mitochondrial epigenetic clock in human brain tissues. We believe this is the first report to elucidate comprehensively the importance of mitochondrial DNA methylation in human brain.”

https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-022-01300-z “Mitochondrial DNA methylation profiling of the human prefrontal cortex and nucleus accumbens: correlations with aging and drug use”

A second rodent study focused on RNA methylation:

“We investigated the role of RNA N⁶-methyladenosine (m6A) in improved resilience against chronic restraint stress. A combination of molecular, behavioral, and in vivo recording data demonstrates exercise-mediated restoration of m6A in the mouse medial prefrontal cortex, whose activity is potentiated to exert anxiolytic effects. To provide molecular explanations, it is worth noting that epigenetic regulation, such as histone modification, microRNA, and DNA methylation all participate in mental and cognitive rehabilitation following exercise.

To generalize these rodent data to humans, we recruited a small group of patients with major depressive disorder with prominent anxiety disorders. Compared to age- and sex-matched healthy individuals, patients displayed decreased circulating methyl donor S-adenosyl methionine (SAM) levels. Serum SAM levels were found to be inversely correlated with the Hamilton Anxiety Scale, suggesting the potential value of SAM as a biomarker for depression or anxiety disorders.

Hepatic biosynthesis of methyl donors is necessary for exercise to improve brain RNA m6A to counteract environmental stress. The dependence on hepatic-brain axis suggests the ineffectiveness of exercise training on people with hepatic dysfunctions.

This novel liver-brain axis provides an explanation for brain network changes upon exercise training, and provides new insights into diagnosis and treatment of anxiety disorders. Exercise-induced anxiolysis might be potentiated by further replenishment of RNA methylation donors, providing a strategy of exercise plus diet supplement in preventing anxiety disorders.”

https://onlinelibrary.wiley.com/doi/10.1002/advs.202105731 “Physical Exercise Prevented Stress-Induced Anxiety via Improving Brain RNA Methylation”

A third paper was a review of mitochondrial-to-nuclear epigenetic regulation. I’ll highlight one mitochondrial metabolite, alpha-ketoglutarate (α-KG):

“Apart from established roles in bioenergetics and biosynthesis, mitochondria are signaling organelles that communicate their fitness to the nucleus, triggering transcriptional programs to adapt homeostasis stress that is essential for organismal health and aging. Emerging studies revealed that mitochondrial-to-nuclear communication via altered levels of mitochondrial metabolites or stress signals causes various epigenetic changes, facilitating efforts to maintain homeostasis and affect aging.

Metabolites generated by the tricarboxylic acid (TCA) cycle, the electron transport chain (ETC), or one-carbon cycle within mitochondria can act as substrates or cofactors to control epigenetic modification, especially histone acetylation and methylation and DNA methylation. α-KG produced in the TCA cycle serves as an essential cofactor for the chromatin-modifying Jumonji C (JmjC) domain-containing lysine demethylases (JMJDs) and ten-eleven translocation (TETs) DNA demethylases. Changes in α-KG levels are capable of driving nuclear gene expression by affecting DNA and histone methylation profiles.

α-KG deficiency in progenitor stem cells increases with age. For example, the level of α-KG is reduced in follicle fluids of aged humans, and supplementation with α-KG preserves ovarian function in mice.

α-KG extends lifespan in Drosophila by activating AMPK signaling and inhibiting the mTOR pathway. Supplementing α-KG in the form of a calcium salt promoted a longer and healthier life associated with decreased levels of inflammatory cytokines in old mice.

A human study showed a nearly 8-year reversal in DNA methylation clock biological ages of 42 individuals taking an α-KG based formulation for 4–10 months. α-KG supplementation leads to both demethylation and hypermethylation of some CpG sites in the genome, suggesting that α-KG may have a broader effect on methylation-based aging, such as metabolic functions.

Outstanding questions:

How is production of mitochondrial metabolites regulated both spatially and temporally to elicit epigenetic changes in response to mitochondrial dysfunction?

What are specific epigenetic factors involved in mitochondrial-to-nuclear communications, and how do they cooperate with transcription factors in response to various external and internal stimuli?

Do various mitochondrial metabolites act alone or in concert on the epigenome to regulate the aging process?

Are some organs or tissues more at risk than others in maintaining mitochondrial-to-nuclear communication during aging?

Can intervention of mitochondrial-to-nuclear communications mimic beneficial epigenetic changes to delay aging or alleviate age-onset diseases?”

https://www.sciencedirect.com/science/article/pii/S0968000422000676 “Mitochondrial-to-nuclear communication in aging: an epigenetic perspective”

Immune system aging

December 19, 2021December 19, 2021 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres Brain neurons, Control group, Critical period, DNA methylation, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease

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

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

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

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

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

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

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

The impact of transgenerational epigenetic inheritance and early life experiences

December 14, 2021December 14, 2021 gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Immune system, Memory, Neurochemicals, Primal Therapy, Stress Brain neurons, Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Infants, Neural plasticity, Unconscious memories

A 2021 interview with McGill University’s Moshe Szyf:

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

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

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

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

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

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

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

One way is the immune-inflammatory connection to other diseases. I think this is where the secret of epigenetic aging lies, as well as epigenetics of other diseases.

Every disease is connected to the immune system. The brain translates the behavioral environment to the immune system, and then the immune system sends chemical signals across the body to respond to these challenges.

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

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

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

Reworking evolutionary theory

November 7, 2021November 7, 2021 gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Memory, Primal Therapy, Stress Brain neurons, Conscious awareness, Control group, Critical period, DNA methylation, Dr. Arthur Janov, Embryo development, Genetic factors, Infants, Levels of consciousness, Neural plasticity, Unconscious feelings, Unconscious memories

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

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

Identical twins have essentially the same genetics, but generally develop discordant disease as they age.

Only a low frequency (generally 1% or less) of individuals that have a specific disease have a correlated genetic mutation.

Dramatic increases in disease frequency in the population cannot be explained with genetics alone.

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

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

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

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

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

Gut microbiota and critical development periods

September 25, 2021 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Immune system, Neurochemicals, Stress Control group, Critical period, Embryo development, Genetic factors, Infants

This 2021 rodent study focused on global histone acetylation as a model to understand roles of microbially produced short-chain fatty acids in liver function:

“Despite the utility of germ-free mice in probing complex interactions between gut microbiota and host physiology, germ-free mice are developmentally, physiologically, and metabolically unique when compared with their conventionally housed counterparts. We sought to determine whether antibiotic-mediated microbiota depletion would affect global hepatic histone acetylation states through SCFA-dependent mechanisms, as previously observed in germ-free mice.

The inability of antibiotic-mediated microbiota depletion to recapitulate findings observed in germ-free mice suggests that the transition from a germ-free to a colonized mouse leads to resilient alterations in hepatic histone acetylation states that cannot be altered by further modulating the microbial environment. This finding is distinct from other germ-free phenotypes that are considered to be partially reversible, with clear alterations in their function observed after antibiotic treatment.

Comparing antibiotic-treated and untreated mice that both received CCl₄ at 24 and 48 hours after injury, there were almost no histone acetylation differences. This demonstrates that hepatic injury leads to a global shift in histone acetylation that is primarily independent of gut microbiota.

Major chromatin reorganization driven by histone acetylation leads to markers of differentiation, and addition of targeted differentiation signals induces events to stabilize these histone acetylation patterns – a key feature of embryonic development and terminal cellular differentiation. Differences in histone acetylation patterns seen between germ-free and conventionally raised mice may be a developmental-like effect of hepatocytes not yet exposed to microbial by-products.

Results suggest that microbial and dietary modifications to the gut microbiome in conventionally raised mice are not a means to modulate global hepatic histone acetylation. Microbiota-dependent landscaping of the hepatic epigenome appears static in nature, while the hepatic transcriptome is responsive to alterations in the gut microbiota, yet independent of global histone acetylation.

Findings underscore significant differences between these model systems that should be taken into account when considering their relevance to human biology.”

https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32043 “Global Microbiota-Dependent Histone Acetylation Patterns Are Irreversible and Independent of Short Chain Fatty Acids” (not freely available) Thanks to Dr. Elliot S. Friedman for providing a copy.

1. By describing “a key feature of embryonic development,” this study provided a gut microbiota-liver analogy of critical periods. If developmental events don’t happen when they are required, it’s probable that their window is missed, and won’t reopen later for a second chance at normalizing.

2. Many studies used a germ-free animal model, such as:

This study provided evidence for a limitation of this model, especially when extrapolating germ-free animal results to humans without similarly testing humans.

Happy Mothers Day

May 8, 2021May 10, 2021 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Primal Therapy, Stress Control group, Critical period, DNA methylation, Genetic factors, Infants

This 2021 rodent study investigated effects on offspring of maternal high-fat diet (HFD) during gestation and lactation, and offspring HFD during young adulthood:

“We found that gestation was the most sensitive period to induce obesity in late life, and there was no difference between sexes in chance of obesity. Furthermore, we found that lactation and administration of a HFD post‐weaning increased incidence of lipid metabolism disorders and obesity in offspring.

There are different windows of opportunity for programming epigenetically labile genes. Some studies support the alteration of epigenetic status during development as an important cause induced adult obesity.

Gestation is considered as the most sensitive period because high DNA synthesis and DNA methylation patterns are established for normal tissue development during the embryonic period. These two programming events are the times when the epigenetic state changes most widely in the life cycle.”

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.16551 “Gestational high-fat diet impaired demethylation of Pparα and induced obesity of offspring”

Hey mothers! Do what you please. But don’t turn around and deny consequences of your behavior and choices on your descendants’ physiology and behavior, and possibly those of further descendants.

Gestation, birth, infancy, and early childhood are critical periods for humans. There’s no going back to correct errors and problems.

Gut microbiota topics

April 2, 2021April 3, 2021 gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory, Stress Antidepressants, Brain neurons, Control group, Critical period, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease

Here are thirty 2019 and 2020 papers related to Switch on your Nrf2 signaling pathway topics. Started gathering research on this particular theme three months ago.

There are more researchers alive today than in the sum of all history, and they’re publishing. I can’t keep up with the torrent of interesting papers.

2020 A prebiotic fructo-oligosaccharide promotes tight junction assembly in intestinal epithelial cells via an AMPK-dependent pathway

2019 Polyphenols and Intestinal Permeability: Rationale and Future Perspectives

2020 Prebiotic effect of dietary polyphenols: A systematic review

2019 Protease‐activated receptor signaling in intestinal permeability regulation

2020 Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

2019 Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

2020 The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals

2019 Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis

2019 Prebiotics, Probiotics, and Bacterial Infections

2020 Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

2020 Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor

2019 Involvement of Astrocytes in the Process of Metabolic Syndrome

2020 Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice (not freely available)

2019 Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1−/Δ7 mice

2020 Plasticity of Paneth cells and their ability to regulate intestinal stem cells

2020 Coagulopathy associated with COVID-19 – Perspectives & Preventive strategies using a biological response modifier Glucan

2020 Synergy between Cell Surface Glycosidases and Glycan-Binding Proteins Dictates the Utilization of Specific Beta(1,3)-Glucans by Human Gut Bacteroides

2020 Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

2020 Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

2019 Prebiotic supplementation in frail older people affects specific gut microbiota taxa but not global diversity

2020 Effectiveness of probiotics, prebiotics, and prebiotic‐like components in common functional foods

2020 Postbiotics-A Step Beyond Pre- and Probiotics

2019 Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential

2020 Postbiotics: Metabolites and mechanisms involved in microbiota-host interactions

2020 Postbiotics against Pathogens Commonly Involved in Pediatric Infectious Diseases

2019 Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis

2019 Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice

2020 Live and heat-killed cells of Lactobacillus plantarum Zhang-LL ease symptoms of chronic ulcerative colitis induced by dextran sulfate sodium in rats

2019 Health Benefits of Heat-Killed (Tyndallized) Probiotics: An Overview

2020 New Horizons in Microbiota and Metabolic Health Research (not freely available)

Our first 1000 days

March 14, 2021March 24, 2021 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Epigenetics, Hypothalamus, Limbic system, Lower brain, Neurochemicals, Primal Therapy, Stress Brain neurons, Critical period, DNA methylation, Dr. Arthur Janov, Embryo development, Genetic factors, Infants, Neural plasticity

This 2021 review subject was a measurable aspect of our early lives:

“The first 1000 days from conception are a sensitive period for human development programming. During this period, environmental exposures may result in long-lasting epigenetic imprints that contribute to future developmental trajectories.

The present review reports on effects of adverse and protective environmental conditions occurring on glucocorticoid receptor gene (NR3C1) regulation in humans. Thirty-four studies were included.

The hypothalamic-pituitary-adrenal (HPA) axis is key in regulating mobilization of energy. It is involved in stress reactivity and regulation, and it supports development of behavioral, cognitive, and socio-emotional domains.

The NR3C1 gene encodes for specific glucocorticoid receptors (GRs) in the mammalian brain, and it is epigenetically regulated by environmental exposures.

When mixed stressful conditions were not differentiated for their effects on NR3C1 methylation, no significant results were obtained, which speaks in favor of specificity of epigenetic vestiges of different adverse conditions. Specific maternal behaviors and caregiving actions – such as breastfeeding, sensitive and contingent interactive behavior, and gentle touch – consistently correlated with decreased NR3C1 methylation.

If the neuroendocrine system of a developing fetus and infant is particularly sensitive to environmental stimulations, this model may provide the epigenetic basis to inform promotion of family-centered prevention, treatment, and supportive interventions for at-risk conditions. A more ambiguous picture emerged for later effects of NR3C1 methylation on developmental outcomes during infancy and childhood, suggesting that future research should favor epigenome-wide approaches to long-term epigenetic programming in humans.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763421001081 “Glucocorticoid receptor gene (NR3C1) methylation during the first thousand days: Environmental exposures and developmental outcomes” (not freely available). Thanks to Dr. Livio Provenci for providing a copy.

I respectfully disagree with recommendations for an EWAS approach during infancy and childhood. What happened to each of us wasn’t necessarily applicable to a group. Group statistics may make interesting research topics, but they won’t change anything for each individual.

Regarding treatment, our individual experiences and needs during our first 1000 days should be repeatedly sensed and felt in order to be therapeutic. Those memories are embedded in our needs because cognitive aspects of our brains weren’t developed then.

To become curative, we first sense and feel early needs and experiences. Later, we understand their contributions and continuations in our emotions, behavior, and thinking.

And then we can start to change who we were made into.

Don’t brew oat sprouts – eat them!

February 6, 2021March 4, 2021 gettingwell4 4-5 stars Advanced knowledge, Dopamine, Neurochemicals Critical period, Embryo development, Genetic factors

This 2020 study chemically analyzed four grains and their brew-processing products:

“Side-stream products of malting, particularly rootlet, are currently treated as animal feed. Instead of ending up in final products (e.g., malt and beer), a substantial portion of phytochemicals end up in side streams.

Rootlets are being increasingly investigated to overcome their bitter taste and to unleash their potential. Adding the fact that side-stream products produced in high quantity are also rich in protein, their nutritional value may be too high to justify usage as feed rather than food.

Grains were steeped for 26 to 30 h with a wet–dry–wet steeping program. Oats were wet steeped for 4 h at 13 °C before and after 18 h of dry steeping at 15 °C.

All grains were germinated for 6 days at 15 °C, after which they were dried with a gentle kilning program to a final temperature of 83 °C and moisture of 4%. Rootlets were separated from malt after drying.

Statistically significant changes occurred in abundance of all 285 annotated phytochemicals during malting, when comparing whole grain with malted grain or rootlet. In oats, cumulative levels of avenanthramides increased by 2.6-fold in the malted grain compared to intact whole grain. Up to 25-fold increase has been reported previously after a slightly longer germination.

Phenolamides cumulative levels in oats increased in both malted grain (11-fold) and rootlet (50-fold). Cumulative flavonoid levels were nearly 3-fold higher in malted grain and rootlet compared to whole grain.

Avenanthramides and phenolamides had much lower extractability into the water extract and wort.

To our knowledge, this is the first time avenanthramides are reported from any other species than oats, suggesting that the synthesis pathway for avenanthramides evolved before oats diverged from the other cereals. Furthermore, benzoxazinoids are herein reported for the first time in oats.

Several previously uncharacterized saponins were found in oats in addition to the previously known avenacins and avenacosides. However, because of limited reference data currently available, their identity could not be determined beyond compound class and molecular formula in this study.

Plants can synthetize up to hundreds of thousands of secondary metabolites, and current spectral databases only contain a fraction of them to allow identification. Compounds found in this study do not represent the complete range of phytochemicals existing in cereals.”

https://www.nature.com/articles/s41538-020-00081-0 “Side-stream products of malting: a neglected source of phytochemicals”

Twice a day for six weeks I’ve eaten oat sprouts 3-to-6-days old from two species and three varieties. I’ve never noticed any “bitter taste” of rootlets mentioned.

Maybe “a final temperature of 83 °C and moisture of 4%” had something to do with it? Oat sprouts I ate never got above 25°C, and I doubt their moisture content was < 80%.

Maybe “Oats were wet steeped for 4 h at 13 °C before and after 18 h of dry steeping at 15 °C” gave oat sprouts a bitter taste? I process oat sprout batches the same way I do broccoli sprout batches. A new batch soaks to start germination every 12 hours, then is rinsed three times every 24 hours on a 6 hours – 6 hours – 12 hours cycle. Temperature in my kitchen is 21°C (70°F) because it’s winter outside.

The above graphic is a heat map of 29 studied C-type avenanthramides. Don’t know why 26 known A-type avenanthramides described in Eat oats today! weren’t analyzed. The second study of Sprouting oats stated: