Hypothalamus

Get a little stress into your life, Part 2

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A 2025 reply to a letter to the editor cited 56 references to elaborate on Part 1 and related topics:

“A positive effect does not necessarily mean benefit, and positive effects on individual organisms may mean adverse effects on other coexisting organisms. However, a vast literature shows that hormetic stimulation can result in benefits depending on the context, for instance, clear growth, yield, and survival improvement.

There is some energetic cost to support hormetic stimulation, with a likely positive energy budget, which might also have negative consequences if there is insufficient energy substrate, especially under concurrent severe environmental challenges. Moreover, hormetic preconditioning could be particularly costly when there is a mismatch between the predicted environment and the actual environment the same individuals or their offspring might face in the future.

Hormesis should not be unilaterally linked to positive and beneficial effects without considering dose levels. For any research to answer the question of whether a stimulation represents hormesis and whether it is beneficial, robust dose–response evaluations are needed, which should be designed a priori for this purpose, meeting the requirements of the proper number, increment, and range of doses.

Both additivity and synergism are possible in the hormetic stimulatory zone, depending also on the duration of exposure and the relative ratio of different components. This might happen, for example, when a chemical primes stress pathways (e.g., heat shock proteins and antioxidants), thus enabling another chemical to trigger hormesis (defense cross-activation) and/or because combined low subtoxicity may modulate receptors (e.g., aryl hydrocarbon receptor and nuclear factor erythroid 2-related factor 2) differently than individual exposures (receptor binding synergy).

Moreover, even when stimulation occurs in the presence of individual components, stimulation may no longer be present when combined, and therefore, effects of mixtures cannot be accurately predicted based on the effects of individual components. There may be hormesis trade-offs; hormesis should be judged based on fitness-critical end points.

While often modeled mathematically, hormesis is fundamentally a dynamic biological process and should not be seen as a purely mathematical function, certainly not a linear one. Much remains to be learned about the role of hormesis in global environmental change, and an open mind is needed to not miss the forest for the trees.”

https://pubs.acs.org/doi/10.1021/acs.est.5c05892 “Correspondence on ‘Hormesis as a Hidden Hand in Global Environmental Change?’ A Reply”

Reference 38 was a 2024 paper cited for:

“Hormetic-based interventions, particularly priming (or preconditioning), do not weaken organisms but strengthen them, enhancing their performance and health under different environmental challenges, which are often more massive than the priming exposure.

The catabolic aspect of hormesis is primarily protective whereas the anabolic aspect promotes growth, and their integration could optimize performance and health. The concept of preconditioning has also gained widespread attention in biomedical sciences.”

https://www.sciencedirect.com/science/article/abs/pii/S1568163724004069 “The catabolic – anabolic cycling hormesis model of health and resilience” (not freely available)

Reference 40 was a 2021 review that characterized hormesis as a hallmark of health:

“Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology.

Biological causes or hallmarks of health include features of:

  • Spatial compartmentalization (integrity of barriers and containment of local perturbations),
  • Maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and
  • An array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration).

Disruption of any of these interlocked features is broadly pathogenic, causing an acute or progressive derailment of the system.

A future ‘medicine of health’ might detect perilous trajectories to intercept them by targeted interventions well before the traditional ‘medicine of disease’ comes into action.”

https://www.sciencedirect.com/science/article/pii/S0092867420316068 “Hallmarks of Health”

Stay away from NAC

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A 2025 rodent study added several reasons to avoid non-emergency use of N-acetylcysteine:

“We previously showed that antioxidants induced an impairment of negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in rats, in parallel to a down-regulation of glucocorticoid receptor (GR) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the pituitary gland. This study evaluated the role of the Nrf2-heme-oxygenase-1 (HO-1) pathway on impairment of negative feedback of the HPA axis induced by N-acetylcysteine (NAC).

Male Swiss-Webster mice were orally supplemented with NAC for 5 consecutive days. The Nrf2-HO-1 pathway activator cobalt protoporphyrin IX (CoPPIX) was injected intraperitoneally on days 2 and 5 after starting NAC supplementation.

NAC reduced expression of Nrf2 in the pituitary of mice. NAC induced adrenal enlargement and hypercorticoidism, along with a decrease in GRα expression and an increase of GRβ expression in the pituitary gland.

We observed that dietary supplementation with NAC ( Figure 4A ) significantly increased plasma corticosterone levels in mice 24h ( Figure 4B ) as well as 15 days ( Figure 4C ) after the last administration of the antioxidant with the same magnitude of response (3.5-fold and 3.4-fold, respectively).

Chronic activation of the HPA axis can have damaging effects on immune, cardiovascular, metabolic, and neural functions, increasing the risk of immune system dysfunction, mood disorders, and metabolic and cardiovascular diseases. To prevent these deleterious effects of chronic hypercortisolism, HPA axis function is controlled by a glucocorticoid-dependent negative feedback system that is essential for ending the stress response.

These findings showed that NAC reduced Nrf2-HO-1 pathway activation in the pituitary gland, in a mechanism probably related to a local downregulation of GRα and an up-regulation of GRβ, leading to a failure of negative feedback of the HPA axis and consequently to the hyperactivity of this neuroendocrine axis.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC11827418/ “Activation of the Nrf2/HO-1 pathway restores N-acetylcysteine-induced impairment of the hypothalamus-pituitary-adrenal axis negative feedback by up-regulating GRα expression and down-regulating GRβ expression into pituitary glands”

A human equivalent to this study’s NAC dose is (150 mg x .081) x 70 kg = 851 mg. Human supplements are sold in 600 mg and 1000 mg doses.

Grok 3 replied to a question: Human equivalent time to 15 days in male Swiss-Webster mice aged between 4 and 6 weeks? by stating: “15 days in male Swiss-Webster mice aged 4 to 6 weeks corresponds to approximately 4.1 human years, advancing their equivalent human age from about 10–12 years to roughly 14–16 years.” Four+ years seems like a long time for NAC to steadily and continuously affect humans’ HPA axes per the above graphic. What do you think?

Previously mentioned reasons to avoid daily use of NAC were in the lower part of A good activity for bad weather days.

Practice what you preach, or shut up

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A 2025 review subject was sulforaphane and brain health. This paper was the latest in a sequence where the retired lead author self-aggrandized his career by citing previous research.

He apparently doesn’t personally do what these research findings suggest people do. The lead author is a few weeks older than I am, and has completely white hair per an interview (Week 34 comments). I’ve had dark hair growing in (last week a barber said my dark hair was 90%) since Week 8 of eating broccoli sprouts every day, which is a side effect of ameliorating system-wide inflammation and oxidative stress.

If the lead author followed up with what his research investigated, he’d have dark hair, too. Unpigmented white hair and colored hair are both results of epigenetics.

Contrast this lack of personal follow-through of research findings with Dr. Goodenowe’s protocol where he compared extremely detailed personal brain measurements at 17 months and again at 31 months. He believes enough in his research findings to personally act on them, and demonstrate to others how personal agency can enhance a person’s life.

It’s every human’s choice whether or not we take responsibility for our own one precious life. I’ve read and curated on this blog many of this paper’s references. Five years ago for example:

So do more with their information than just read.

https://www.mdpi.com/2072-6643/17/8/1353 “Sulforaphane and Brain Health: From Pathways of Action to Effects on Specific Disorders”

Polyphenol Nrf2 activators

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Two 2024 reviews by the same group that published Sulforaphane in the Goldilocks zone investigated dietary polyphenols’ effects as “hormetic nutrients”:

“Polyphenols display biphasic dose–response effects by activating at a low dose the Nrf2 pathway resulting in the upregulation of antioxidant vitagenes [see diagram]. We aimed to discuss hormetic nutrients, including polyphenols and/or probiotics, targeting the Nrf2 pathway and vitagenes for the development of promising neuroprotective and therapeutic strategies to suppress oxidative stress, inflammation and microbiota deregulation, and consequently improve cognitive performance and brain health.

antioxidants-13-00484-g001

Hormetic nutrition through polyphenols and/or probiotics targeting the antioxidant Nrf2 pathway and stress resilient vitagenes to inhibit oxidative stress and inflammatory pathways, as well as ferroptosis, could represent an effective therapy to manipulate alterations in the gut microbiome leading to brain dysfunction in order to prevent or slow the onset of major cognitive disorders. Notably, hormetic nutrients can stimulate the vagus nerve as a means of directly modulating microbiota-brain interactions for therapeutic purposes to mitigate or reverse the pathophysiological process, restoring gut and brain homeostasis, as reported by extensive preclinical and clinical studies.”

https://www.mdpi.com/2076-3921/13/4/484 “Hormetic Nutrition and Redox Regulation in Gut–Brain Axis Disorders”

I’m not onboard with this study’s probiotic assertions because most of the cited studies contained unacknowledged measurement errors. Measuring gut microbiota, Part 2 found:

“The fecal microbiome does not represent the overall composition of the gut microbiome. Despite significant roles of gut microbiome in various phenotypes and diseases of its host, causative microbes for such characteristics identified by one research fail to be reproduced in others.

Since fecal microbiome is a result of the gut microbiome rather than the representative microbiome of the GI tract of the host, there is a limitation in identifying causative intestinal microbes related to these phenotypes and diseases by studying fecal microbiome.”

These researchers also erroneously equated isothiocyanate sulforaphane’s Nrf2-activating mechanisms with polyphenols activating Nrf2.

This research group did better in clarifying polyphenols’ mechanisms in a review of hormetic dose-response effects of the polyphenol rosmarinic acid:

“This article evaluates whether rosmarinic acid may act as a hormetic agent, mediating its chemoprotective effects as has been shown for similar agents, such as caffeic acid, a derivative of rosmarinic acid.

Rosmarinic acid enhanced memory in institute of cancer research male mice in the Morris water maze (escape latency).

untitled

Of importance in the evaluation of rosmarinic acid are its bioavailability, metabolism, and tissue distribution (including the capacity to affect and/or cross the BBB and its distribution and half-life within the brain). In the case of polyphenols, including rosmarinic acid, they are typically delivered at low doses in the diet and, in most instances, they do not escape first-pass metabolism, with the prominent chemical forms being conjugates of glucuronides and sulfates, with or without methylation.

These conjugated metabolites are chemically distinct from the parent compound, showing considerable differences in size, polarity, and ionic form. Their biological actions are quite different from the parent compound.

Bioavailability studies reveal that maximum concentrations in plasma typically do not exceed 1 µM following consumption of 10–100 mg of a single phenolic compound, with the maximum concentration occurring typically less than 2 h after ingestion, then dropping quickly thereafter. In the case of the in vitro studies assessed herein, and with few exceptions, most of the studies employed concentrations >10 µM with some studies involving concentrations in the several hundred µM range, with the duration of exposure typically in the range of 24–72 h, far longer duration than the very short time interval of a few minutes to several hours in human in vivo situations.

We strongly recommend that all experiments using in vitro models to study biological responses to dietary polyphenols use only physiologically relevant flavonoids and their conjugates at appropriate concentrations, provide evidence to support their use, and justify any conclusions generated. When authors fail to do this, referees and editors must act to ensure that data obtained in vitro are relevant to what might occur in vivo.”

https://www.degruyter.com/document/doi/10.1515/med-2024-1065/html “The chemoprotective hormetic effects of rosmarinic acid”

Brain restoration with plasmalogens, Part 2

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This September 2024 presentation adds data points and concepts to Part 1:

supplementation

  1. “Your brain is dynamically connected to and adaptively responsive to its environment.
  2. You are in control of this environment (nutrition, stimulation, adversity).
  3. Need to measure the environment (lab testing, physiology) and adaptive response to the environment (MRI) to optimize your environment (nutrition, lifestyle) to achieve optimal brain structure, function, health, and longevity.

neurovascular

From a global cortical volume and thickness perspective, 17 months of high dose plasmalogens reversed about 15 years of predicted brain deterioration. 31 months reversed almost 20 years. So you can get more out of life.”

https://drgoodenowe.com/immortal-neurology-building-maintaining-an-immortal-brain/

Dr. Goodenowe also added case studies of two patients:

1. A 50-year-old woman with MS who had been legally blind in one eye for 32 years who regained sight in that eye after eight months of supplementation.

“This is the adaptability of the human brain. Her eye is not actually impaired. What’s impaired is the ability, the adaptability of the brain to the signal of light, to actually start interpreting what that light signal is.”

2. A 61-year-old man with dementia from firefighting work for the U.S. Navy in a toxic environment with head injuries after nine months of supplementation.

“The brain can heal itself is the point of the story. His executive function skills in everyday life are getting better.”

Maintaining your myelin, Part 1

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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.

1-s2.0-S0959438823001071-gr2_lrg

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.

oligodendrocyte

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.

opcs

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.

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Taurine’s effects on healthspan and lifespan, Part 2

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Four 2023 papers that cited Part 1, starting with a review of hypothetical parameters for taurine clinical trials that aren’t going to happen because:

  • Drug companies can’t make money from a research area that’s cheap, not patentable, and readily accessible.
  • Government sponsors are likewise not incentivized to act in the public’s interest per their recent behavior.

“We propose the rationale that an adequately powered randomized-controlled-trial (RCT) is needed to confirm whether taurine can meaningfully improve metabolic and microbiome health, and biological age.

taurine hypothetical trial

Using long-term survival as a primary outcome is desirable but difficult; any demonstrable difference in this outcome will require a substantial sample size with prolonged follow-up (e.g., 5 years or longer) if the effect size is relatively small (or modest at best). Biological age based on DNA methylation biomarkers according to the Levine PhenoAge or newer biological age models is increasingly being recognized as an important dynamic health parameter, and hence it can also be used as a surrogate outcome in assessing benefits of taurine supplementation.

The recent taurine trial on nonhuman primates used an equivalent dose that was between 3 and 6 g per day for an 80-kg person, and this could represent a reasonable dose range for any human RCTs. We believe that a 6-month or longer interventional period matching what was successfully done on nonhuman primates will be an acceptable time frame in assessing potential efficacy of taurine on human metabolic health in a RCT.”

https://www.sciopen.com/article/10.26599/1671-5411.2023.11.004 “Flattening the biological age curve by improving metabolic health: to taurine or not to taurine, that’s the question”

A six-month duration and a 6 grams per day dose were in the above table’s desirable features column, but epigenetic clock measurements weren’t included as an outcome. I’d guess that its omission reflected disagreements among coauthors, because the desirability of using epigenetic clocks as surrogate measures of human healthspan and lifespan was mentioned several times.

Another review:

“As described in the first half of this review, recent advances in omics analysis technology have led to research to detect the causative gene of dilated cardiomyopathy. It has been found that rare mutations in the taurine transporter gene contribute to the development of dilated cardiomyopathy in humans. It is unlikely that a taurine-deficient diet is a factor in dilated cardiomyopathy, but taurine intake may have positive cardiovascular effects.

The second half summarizes the relationship between taurine and healthspan and lifespan. It is difficult to summarize the effect of age in whole body taurine content, which may vary in species, strain, sex, and age of animal models. Future human studies will clarify the relationship between dietary taurine intake and healthy life expectancy.”

https://www.sciencedirect.com/science/article/pii/S1347861323000749 “Taurine deficiency associated with dilated cardiomyopathy and aging”

A human study investigated brain chemicals that fluctuate with our circadian rhythm:

“We conducted a MRS study at 7 T, where occipital NAD content, lactate, and other metabolites were assessed in two different morning and afternoon diurnal states in healthy participants. Salivary cortisol levels were determined to confirm that the experiment was done in two circadian different physiological conditions.

Although no significant differences in NAD+, NADH, and NAD+/NADH were detected between the morning and afternoon sessions, there was a significant variance difference in NAD+/NADH, with a higher variance of NAD+/NADH redox ratio in the morning.

None of the over 30 measured brain metabolites were significantly affected by the circadian rhythm (CR) except for taurine, which decreased in the afternoon. Further CR studies should consider the prospective measurement of taurine levels in different regions of the human brain, and explore how taurine supplements could impact brain CR metabolism in health and diseases.”

https://www.frontiersin.org/articles/10.3389/fphys.2023.1285776/full “Effect of circadian rhythm on NAD and other metabolites in human brain”

I omitted findings regarding this study’s pathetic Balloon Analogue Risk Task (BART) test. Older studies that drew spurious findings from this video game include:

A rodent study modeled human childhood cataracts:

“Our analysis identified targets that are required for early normal differentiation steps and altered in cataractous lenses, particularly metabolic pathways involving glutathione and amino acids. Glutathione and taurine were spatially altered, and both taurine and the ratio of reduced glutathione to oxidized glutathione, two indicators of redox status, were differentially compromised in lens biology.

1-s2.0-S2213231723002707-ga1_lrg

Dietary amino acid supplementation has been shown to prevent cataract development, and dietary intake of taurine was protective in a glutathione depletion-derived opacity model. This opens up the possibility that dietary supplementation of taurine could be used as a strategy to prevent human congenital cataracts.

Our findings shed light on molecular mechanisms associated with congenital cataracts, and point out that unbalanced redox status due to reduced levels of taurine and glutathione, metabolites already linked to age-related cataracts, could be a major underlying mechanism behind lens opacities that appear early in life.”

https://www.sciencedirect.com/science/article/pii/S2213231723002707 “Unbalanced redox status network as an early pathological event in congenital cataracts”

PXL_20240103_191340418

Brain restoration with plasmalogens

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In this 2023 presentation for a professional audience, Dr. Dayan Goodenowe showed an example of what could be done (in the form of what he personally did at ages 53-54) to restore and augment brain structure and function over a 17-month period by taking plasmalogens and supporting supplements:

https://drgoodenowe.com/recording-of-dr-goodenowes-presentation-from-the-peptide-world-congress-2023-is-now-available/

Follow the video along with its interactive transcript. Restorative / augmentative supplements included:

1. Nutritional Supplementation Strategy

Forms of MRI used to document brain structure and function changes were:

2. Advanced MRI Technologies

Brain volume decreases are the rule for humans beginning at age 40. Dr. Goodenowe documented brain volume increases, which aren’t supposed to happen, but did per the below slide of overall results:

3. Reversing Brain Shrinkage

“From a global cortical volume and thickness perspective, 17 months of high-dose plasmalogens reversed ~15 years of predicted brain deterioration.”

Specific increased adaptations in brain measurements over 17 months included:

  1. Cortical thickness .07/2.51 = +3%.
  2. White matter microstructure fractional anisotropy +8%.
  3. Nucleus accumbens volume +30%.
  4. Dopaminergic striatal terminal fields’ volume +18%.
  5. Cholinergic cortical terminal fields’ volume +10%.
  6. Occipital cortex volume +10%.
  7. Optic chiasm volume +225%.
  8. Nucleus basalis connectivity.
  9. Neurovascular coupling signal controlled by noradrenaline integrity.
  10. Amygdala volume +4% and its connectivity to the insula, indicating ongoing anxiety and emotional stress response.
  11. Parahippocampus volume +7%.
  12. Hippocampus fractional anisotropy +5%.

No changes:

  1. Amygdala connectivity to the ventral lateral prefrontal cortex, the same part of the brain that relates to placebo effect.
  2. Hippocampus connectivity.

Decreased adaptations in brain measurements included:

  1. White matter microstructure radial diffusivity -10%.
  2. Amygdala connectivity to the anterior cingulate cortex to suppress / ignore / deny anxiety response.
  3. Amygdala connectivity to the dorsal lateral prefrontal cortex.
  4. Entorhinal cortex volume -14%.
  5. Hippocampus volume -6%.
  6. Hippocampus mean diffusivity (white matter improved, with more and tighter myelin) -4%.

The other half of this video was a lively and wide-ranging Q&A session.

The referenced 2023 study of 653 adults followed over ten years showed what brain deterioration could be expected with no interventions. Consider these annual volume decrease rates to be a sample of a control group:

etable 3

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2806488 “Characterization of Brain Volume Changes in Aging Individuals With Normal Cognition Using Serial Magnetic Resonance Imaging”

Also see a different population’s brain shrinkage data in Prevent your brain from shrinking.

The daily plasmalogen precursor doses Dr. Goodenowe took were equivalent to 100 mg softgel/kg, double the maximum dose of 50 mg softgel/kg provided during the 2022 clinical trial of cognitively impaired old people referenced in Plasmalogens Parts 1, 2, and 3.

He mentions taking 5 ml in the morning and 5 ml at night because he used the Prodrome oil products. 1 ml of a Prodrome oil plasmalogen precursor product equals 900 mg of their softgel product.

“My brain is trying to minimize long-term effects of pain/stress by suppressing my memory of it. But this can only go on for so long before it becomes an entrenched state.

I have solved the sustenance side of the equation. I need to work harder to solve the environmental side.”

While I agree that we each have a responsibility to ourselves to create an environment that’s conducive to our health, the above phenomenon isn’t necessarily resolvable by changing an individual’s current environment. My understanding is that long-term effects of pain, stress, and related human experiences are usually symptoms of causes that started much earlier in our lives.

Adjusting one’s present environment may have immediate results, but probably won’t have much therapeutic impact on long-term issues. Early life memories and experiences are where we have to gradually go in order to stop being driven by what happened back then.

See Dr. Arthur Janov’s Primal Therapy for its principles and explanations. I started Primal Therapy at a similar age, 53, and continued for three years.

Continued with Part 2.

Plasmalogens, Part 3

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The 2022 plasmalogen clinical trial mentioned in Parts 1 and 2 bypassed peroxisome metabolism of cognitively impaired people per discussion of the below diagram:

fcell-10-864842-g003

Increasing the body’s fasting state with time-restricted eating, and preventing muscle atrophy with resistance exercise, were offered as the two most important ways to improve peroxisomal function.

I didn’t find any relevant 2023 human studies (where I could access the full study) on different non-drug treatments that I was willing to do. A 2023 review outlined aspects of peroxisomes, to include a few older human studies:

“Peroxisomes are small, single-membrane-bound organelles, which are dynamic and ubiquitous. Peroxisomes directly interact with other organelles, such as endoplasmic reticulum, mitochondria, or lysosomes. Peroxisomes exert different functions in various cells through both catabolic and anabolic pathways.

The main functions of peroxisomes can be categorized as reactive oxygen species (ROS) metabolism, lipid metabolism, and ether-phospholipid biosynthesis. Peroxisomes also play important roles in inflammatory signaling and the innate immune response.”

1-s2.0-S2667325823001425-gr3_lrg

https://www.sciencedirect.com/science/article/pii/S2667325823001425 “Peroxisome and pexophagy in neurological diseases”

1. Since I haven’t recently tried the two main ways to improve peroxisomal function, I’ll give them a go over the next three months:

  • Expect to get my feeding timeframe to within eight hours. Don’t know about making it short like 6 hours, because my first meal of the day is 35 calories of microwaved cruciferous sprouts, then I wait an hour before eating anything else.
  • Resistance exercise progress should be measurable, as I recorded exercises during the first ten weeks of eating broccoli sprouts every day 3.5+ years ago.

2. Don’t know that I’ll recognize any cognitive improvements to the extent I did during Week 9.

  • I don’t have a young brain anymore, and I’m sure some decline could be measured in memory tests. But I’m not going to become a lab rat.
  • There’s an occasional annoyance that’s been going on for some time, especially when I’m distracted. It happens when I think of something to do, and it somehow becomes a short-term memory that I did it, instead of going into a Things To Do queue. It’s largely self-correcting. For example, regardless of what I paid, I’ll drive back to the grocery store self-checkout to retrieve a third bag that didn’t make it home. A pink-haired employee said young people leave their paid-for groceries behind all the time. It’s usually more of a reality disconnect for me than forgetfulness, because I have a memory that I performed the action. Definitely room for improvement.

3. Don’t know that I’d see biochemical changes such as some described in Part 1. Maybe I’ll move up an annual physical to compare it with the last one in May?

  • I already have very little oxidative stress, very little inflammation, low triglycerides, high HDL, and no major improvements are indicated on CBC / CMP / lipid panels.
  • Take supplements to ensure other things like acetylcholine neurotransmitter availability, one-carbon / methylation metabolism, vitamin / mineral adequacy.

4. I started the two Prodrome plasmalogen precursor supplements (ProdromeGlia and ProdromeNeuro) a week ago, and take their standard doses. My thought is that resultant plasmalogens won’t degrade very much if their primary use isn’t to immediately address oxidative stress and inflammation. That could give these extra plasmalogens a chance to make larger homeostatic contributions in myelin and membrane areas.

I don’t expect any particular effects to manifest. But I’m interested to see if these two areas would be affected:

  • My left ulnar nerve has been giving me problems for over five years, and several resistance exercises aggravate it. I’ve had two nerve continuity tests during that time to confirm. Numbness and pain are intermittent, though.
  • I still take acetaminophen several times a day for other pain.

None of the above treatments are specifically indicated. But if time-restricted feeding and/or extra plasmalogens have an effect on left ulnar or other pain, maybe I’ll be able to make better progress on resistance exercise.

Update #1 11/13/2023

Update #2 11/22/2023

Update #3 12/13/2023 comments

Update #4 1/30/2024

Update #5 3/31/2024

Fructose and survival

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This 2023 paper provided mechanistic evidence, evolutionary theory, and testable scenarios for fructose metabolism differences from other nutrients:

“The fructose survival hypothesis proposes that obesity and metabolic disorders may have developed from over-stimulation of an evolutionary-based biologic response (survival switch) that aims to protect animals in advance of crisis. The response is characterized by hunger, thirst, foraging, weight gain, fat accumulation, insulin resistance, systemic inflammation, and increased blood pressure.

Unlike other nutrients, fructose reduces the active energy (adenosine triphosphate) in the cell, while blocking its regeneration from fat stores. This is mediated by intracellular uric acid, mitochondrial oxidative stress, inhibition of AMP kinase, and stimulation of vasopressin.

rstb20220230f04

Fructose metabolism is associated with oxidative stress, mitochondrial dysfunction, loss of cytoprotective transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), and a reduction in sirtuins that characterize the ageing process. Fructose also induces generation of advanced glycation end products much more effectively than glucose.

The fructose pathway is almost inevitably strongest in early disease states, for over time there is often fibrosis, inflammation, or mitochondrial loss that results in persistence of the disease process. The best time for intervention may turn out to be in early disease before conditions become less reversible.”

https://royalsocietypublishing.org/doi/10.1098/rstb.2022.0230 “The fructose survival hypothesis for obesity”

Time to exit fructose survival mode.

PXL_20230904_140453607

Reversing biological age in rats

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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:

second follow-on results

“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

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

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

experiment design

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

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

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

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

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

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

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

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

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

Daily oral treatment continued through PD 90.

j_nipt-2023-0008_fig_002

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

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

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

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

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

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

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

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

Brain endothelial cells

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Six 2023 papers on the subject, starting with a rodent study:

“One of the primary discoveries of our study is that the endothelial cell (EC) transcriptome is dynamically regulated by both aging and heterochronic parabiosis. We found that ECs, when compared with other brain cell types, exhibited one of the highest fractions of aging-related genes that were rescued after heterochronic parabiosis in the old brain, and similarly, the highest fraction of aging-related genes that were disrupted after heterochronic parabiosis in the young brain. This finding supports our previous research that vasculature is strongly affected by aging and disease, and is capable of regrowth after heterochronic parabiosis or systemic GDF11 treatment.

parabiosis

We observed that a subset of ECs was classified as mitogenic. It is reasonable to speculate that the growth of these cells, which is probably prevented or suspended by the inflammatory environment of the aged brain, may be among the cell populations that respond to these interventions.

Although proteostasis in brain ECs has not been thoroughly investigated, they are apparently long-lived cells and, like neurons, might therefore accumulate protein aggregates with age, potentially compromising their function. ECs become senescent with age, but parabiosis may reverse that phenotype as well.

These findings underline the strong susceptibility and malleability of ECs, which are directly exposed to secreted factors in both brain parenchyma and blood, to adapt to changes in their microenvironment. ECs, despite comprising <5% of the total number of brain cells, are a promising and accessible target for treatment of aging and its associated diseases.”

https://www.nature.com/articles/s43587-023-00373-6 “Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types”

A review elaborated on endothelial cell senescence:

“ECs form highly dynamic and differentiated monolayers arranged in a vascular network. Within brain tissue, the ECs of arteries, capillaries, and veins present different molecular characteristics. The main functions of ECs as a major cellular component of the blood-brain barrier (BBB) are to express cell membrane transport proteins, produce inflammatory mediators, deliver nutrients to brain tissue, and prevent drugs and toxins from entering the central nervous system.

ECs are the first echelons of cells affected at the onset of senescence due to their special structural position in the vascular network. Senescent ECs produce reactive oxygen species (ROS), which directly inhibit smooth muscle potassium channels and cause vasoconstriction.

The vascular endothelium is in a constant process of damage and repair, and once damage occurs, ECs replenish themselves to remove damaged cells. EC senescence makes the endothelium less capable of self-repair. With the decline in endothelial function, excess accumulated senescent cells express senescence-associated secretory phenotypes (SASPs), which result in senescence of adjacent cells, and eventually degeneration of vascular function.”

https://www.aginganddisease.org/EN/10.14336/AD.2023.0226-1 “Endothelial Senescence in Neurological Diseases”

A human study investigated above-mentioned differences in brain endothelial cells:

“We performed single nucleus RNAseq on tissue from 32 Alzheimer’s Disease (AD) and non-AD donors each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex, and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors.

Visual cortex areas, which are affected late in AD progression and experience less neurodegeneration, expressed more genes related to vasculogenesis and angiogenesis. Highly vulnerable areas such as the entorhinal cortex expressed more oxidative stress-related genes in normal aged brain, suggesting endothelial dysfunction in this region even in the absence of severe AD pathology.

The present work shows that senescence-related gene signatures are increased across several brain regions, and confirms these changes in endothelial cells in the absence of other vascular cell types. While endothelial cells are not typically associated with protein aggregation, upregulated protein folding pathways suggest that proteostatic stress is a key pathway in this cell type.”

https://www.biorxiv.org/content/10.1101/2023.02.16.528825v1.full “Endothelial Cells are Heterogeneous in Different Brain Regions and are Dramatically Altered in Alzheimer’s Disease”

A human cell study abstract on above-mentioned blood-brain barrier endothelial cells:

“The BBB is a semi-permeable and protective barrier of the brain, primarily composed of endothelial cells interconnected by tight junction proteins, that regulates movement of ions and molecules between blood and neural matter. In pathological conditions such as traumatic brain injury (TBI), disruption of the BBB contributes to leakage of solutes and fluids into brain parenchyma, resulting in onset of cerebral edema and elevation of intracranial pressure.

The objective of this study was to determine upstream regulators of NLRP3 signaling and BBB hyperpermeability, particularly to determine if extracellular adenosine triphosphate (ATP) via P2X7R, a purinergic receptor, promotes NLRP3 inflammasome activation. Extracellular ATP is a major contributor of secondary injuries following TBI.

Our results suggest that extracellular ATP promotes NLRP3 inflammasome activation. Subsequent caspase-1 and MMP-9-mediated tight junction disorganization are major pathways that lead to BBB dysfunction and hyperpermeability following conditions such as TBI.”

https://journals.physiology.org/doi/abs/10.1152/physiol.2023.38.S1.5732827 “Regulation of Blood-Brain Barrier Endothelial Cell Hyperpermeability by NLRP3 Inflammasome Inhibition”

A human study further investigated effects of traumatic brain injury on brain endothelial cells:

“We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. Here, we enriched plasma EVs from TBI patients (TEVs), detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs, and found the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models.

HMGB1 is secreted by activated cells or passively released by necrotic or injured cells. After post-translational modifications, it interacts with receptors such as toll-like receptors (TLRs; e.g., TLRs 2, 4, and 9) and the receptor for advanced glycation end products (RAGE) to trigger multiple signaling pathways and mediate inflammatory and immune responses. Extracellular HMGB1 promotes endothelial dysfunction, leukocyte activation and recruitment, as well as thrombosis.

These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction. They contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for development of potential therapeutic targets and diagnostic biomarkers for TBI.”

https://www.sciencedirect.com/science/article/pii/S1043661823001470 “Circulating extracellular vesicles from patients with traumatic brain injury induce cerebrovascular endothelial dysfunction”

To wrap up, eat mushrooms to protect your brain endothelial cells!

“Natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage.

Protective effects of ET were diminished when endothelial cells were coincubated with verapamil hydrochloride (VHCL), a nonspecific inhibitor of the ET transporter OCTN1 (SLC22A4). This outcome demonstrates that ET-mediated protection against 7KC-induced mitochondrial damage occurred intracellularly and not through direct interaction with 7KC.

OCTN1 mRNA expression itself was significantly increased in endothelial cells after 7KC treatment, consistent with the notion that stress and injury may increase ET uptake. Our results indicate that ET can protect against 7KC-induced mitochondrial injury in brain endothelial cells.”

https://www.mdpi.com/1422-0067/24/6/5498 “Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells”

Transgenerational transmission of stress

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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.

ijms-24-03734-g001

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”

PXL_20230611_100728709

Don’t eat yourself into disease, Part 2

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This blog’s 1000th curation is a 2023 rodent study associating gut microbiota, behavior, memory, and food reward:

“Energy intake and energy expenditure is regulated by the hypothalamus, and is referred to as homeostatic regulation of food intake. The reward system is the non-homeostatic regulation of food intake – pleasure-related consumption of foods enriched in fat and sugar. The pleasure is encoded by dopamine release from dopaminergic neurons projecting from the ventral tegmental area to the striatum, the nucleus accumbens, and the prefrontal cortex.

Food reward can be divided into three components – liking, wanting, and learning:

  • Liking refers to food hedonic value;
  • Wanting to the motivational process to seek out and consume certain foods; and
  • Learning to reinforcing conditioning behavior associated with food intake stimulus.

We confirmed that obese mice have a dysregulation of the learning and the wanting components of  food reward. Our previous data showed that the liking component was transferable through fecal material transplantation.

We demonstrated that gut microbes play a role in the regulation of food reward, and could be responsible for compulsive behavior and excessive motivation to obtain sucrose pellets. Moreover, obese gut microbes affected dopaminergic and opioid markers involved in reward system.

We identified 33HPP (produced exclusively by gut bacteria) as particularly increased in mice recipients of gut microbes from obese mice. We were able to demonstrate its effects as key mediator of the gut-brain axis controlling the reward response to palatable food.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-023-01526-w “Obese-associated gut microbes and derived phenolic metabolite as mediators of excessive motivation for food reward”

PXL_20230415_195202937