Hippocampus

Maintaining your myelin, Part 2

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , , ,

Continuing Part 1 with three 2024 preprint studies, starting with an investigation of neuroinflammation in high school athletes:

“Axons are long fibers conducting nerve impulses from nerve cells to synaptic ends. Like electric wires, axons are insulated by the myelin sheath produced by oligodendrocytes (ODC) in the brain or Schwann cells in the periphery. The myelin sheath is vulnerable to mechanical stresses after head injuries, as well as targets for autoimmune attack in multiple sclerosis and degeneration in various white matter diseases.

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It is challenging to definitively validate axonal neuroinflammation, because axonal neuroinflammation is only diagnosed at post-mortem autopsy, or wait for more than a decade to potentially witness progression to chronic traumatic encephalopathy, or white matter dementia. Advanced imaging analysis of computed tomography and magnetic resonance imaging are not sensitive enough to identify such microscopic abnormalities.

We developed a sandwich immunoassay detecting dual signals of myelin oligodendrocyte glycoprotein (MOG) and interleukin 1B (IL1B) in human plasma, [IL1B on MOG]. MOG is a transmembrane protein specifically expressed in ODC and Schwann cells membranes, and doesn’t freely exist in plasma. We found that serum from capillary blood is acceptable, and we tested control and athlete samples using only 5 mL samples. When we tested 63 control plasma samples, values were widely distributed over 2 logs, so we focused on longitudinal studies.

Damaged neurons are not easily detectable using conventional physical examinations, because the brain’s inherent adaptability allows it to compensate for localized damage by finding alternate routes. While this adaptability is advantageous, it also means that these concealed lesions can go unnoticed, potentially leading to future complications.

Elevation of [IL1B on MOG] was seen in some athletes who did not show concussion or traumatic brain injury (TBI). While the occurrence of concussion is relatively limited, potential prevalence of subconcussion or subconcussive condition is expected to be substantially higher.

If [IL1B on MOG] levels remain unchanged during this early post-concussion period (2-4 weeks), it may suggest that neuroinflammation has not been induced, potentially providing reassurance for the athletes to return to play. Conversely, if [IL1B on MOG] levels increase within this timeframe, it may indicate the need for intervention or closer monitoring. Thus, there is compelling potential for incorporating this test into concussion guidelines.”

https://www.researchsquare.com/article/rs-3997676/v1 “An approach for the analysis of axonal neuroinflammation by measuring dual biomarkers of oligodendrocytes and inflammatory cytokine in human plasma”

A rodent study investigated the immune system’s influence on oligodendrocyte lineage cells after TBI:

“White matter injury is thought to be a major contributor to long-term cognitive dysfunctions after TBI. This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after injury, triggered directly by the trauma or in response to degenerating axons.

Our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation, and required the presence of T cells. This suggests that T cells are an important mechanistic link by which the gut microbiota modulate oligodendrocyte response and white matter recovery after TBI.

Our findings suggest that oligodendrocytes are not passive in the neuroinflammatory and degenerative environment caused by brain trauma, but instead could exert an active role in modulation of immune response.”

https://www.researchsquare.com/article/rs-4289147/v1 “Gut Microbiota Shape Oligodendrocyte Response after Traumatic Brain Injury”

A rodent study investigated whether oligodendrocyte precursor cells had myelination-independent roles in brain aging:

“OPCs, the source cells of myelin-forming cells in the central nervous system, have been linked to brain aging by their compromised differentiation and regeneration capability. Our results demonstrate that macroautophagy influx declines in aged OPCs, which results in the accumulation of senescent OPCs in aged brains. Senescent OPCs impair neuronal plasticity and exacerbate neurodegeneration, eventually leading to cognitive decline.

Inactivation of autophagy in OPCs exhibits a limited effect on myelin thickness but a loss of myelin in middle-aged mice. The loss of myelin observed is an adaptational change to suppressed neuronal plasticity. However, neither the number of OLs nor oligodendrogenesis is altered by inactivation of autophagy in adult OPCs.

The present study indicates that the intervention of senescent OPCs is an additional promising therapeutic strategy for aging and aging-related cognitive deficits. Autophagy regulates senescence by impairing protein turnover, mitochondrial homeostasis, oxidative stress, and maintaining senescence-associated secretory phenotype. Further investigation remains on whether autophagy in OPCs shares the exact mechanism to promote senescence as that in other types of cells.

Considering autophagy declines with aging, our study brings a novel mechanism in brain aging. Declined autophagy causes senescence of OPCs, which impairs neuronal plasticity and exacerbates neurodegeneration via CCL3/5-CCR5 signaling.”

https://www.researchsquare.com/article/rs-3926942/v1 “Impaired Macroautophagy in Oligodendrocyte Precursor Cells Exacerbates Aging-related Cognitive Deficits via a Senescence Associated Signaling”

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Ergothioneine dosing, Part 2

gettingwell4 4-5 stars Advanced knowledge, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Telomeres , , ,

Continuing Part 1 with a 2024 rodent healthspan and lifespan study:

“We investigated the effects of daily oral supplementation of ergothioneine (ERGO) dissolved in drinking water on lifespan, frailty, and cognitive impairment in male mice from 7 weeks of age to the end of their lives. Ingestion of 4 ~ 5 mg/kg/day of ERGO remarkably extended the lifespan of male mice.

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The ERGO group showed significantly lower age-related declines in weight, fat mass, and average and maximum movement velocities at 88 weeks of age. This was compatible with dramatic suppression by ERGO of age-related increments in plasma biomarkers. ERGO also rescued age-related impairments in learning and memory ability.

Ingestion of ERGO may promote longevity and healthy aging in male mice, possibly through multiple biological mechanisms.”

https://link.springer.com/article/10.1007/s11357-024-01111-5 “Ergothioneine promotes longevity and healthy aging in male mice”

Subjects’ plasma ergothioneine levels of an estimated 4 ~ 5 mg/kg daily dose were:

11357_2024_1111_Fig3_HTML

A human equivalent daily dose is an estimated 22 mg to 28 mg (4 or 5 mg x .081 x 70 kg).

The third paper in Part 1 cited a 2017 clinical trial that provided 5 mg and 25 mg ergothioneine doses for 7 days, resulting in these plasma ergothioneine levels:

figure 3

The first paper of Part 1 referenced a 2020 human study where the dose was 5 mg/day for 12 weeks, but I don’t have access to it. It’s unclear whether humans could continually raise ergothioneine levels by daily consumption throughout our lives as did this rodent study.

A 2024 paper reviewed the importance of ergothioneine to humans:

“We propose that the diet-derived compound ergothioneine (ET) is an important nutrient in the human body, especially for maintenance of normal brain function, and that low body ET levels predispose humans to significantly increased risks of neurodegenerative and possibly other age-related diseases.

Work by multiple groups has established that low ET levels in humans are associated not only with cognitive impairment/AD but also with other age-related conditions, including frailty, Parkinson’s disease, vascular dementia, chronic renal disease, cardiovascular disease, and macular degeneration. Low ET levels also correlate with increased risk of developing preeclampsia in pregnant women [53].

Plasma ET levels from healthy (age-matched) vs unhealthy individuals in Singapore – Mild cognitive impairment (MCI); Alzheimer’s disease (AD); vascular dementia (VaD); Parkinson’s disease (PD); age-related macular degeneration (AMD):

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  • Does low ET cause or contribute to age-related neurodegeneration, or
  • Does disease cause low ET, or
  • Low ET and increased disease risk are both caused by something else, as yet unidentified?

Prevention of neurodegeneration is especially important, since by the time dementia is usually diagnosed damage to the brain is extensive and likely irreversible.”

https://www.sciencedirect.com/science/article/pii/S0891584924001357 “Are age-related neurodegenerative diseases caused by a lack of the diet-derived compound ergothioneine?”

Whether or not the healthy individuals ate mushrooms daily in the above graphic was lost while conglomerating multiple studies.

Note that scales of the above two human graphics are a thousand times smaller than the above rodent graphic. I thought that maybe the rodent study made a plasma ergothioneine calculation error, but didn’t see one in the provided Supplementary data.

Reference 53 of the second paper is a 2023 human study:

“We analysed early pregnancy samples from a cohort of 432 first time mothers. Of these 432 women, 97 went on to develop pre-term or term pre-eclampsia (PE).

If a threshold was set at the 90th percentile of the reference range in the control population (≥462 ng/ml), only one of these 97 women (1%) developed PE, versus 96/397 (24.2%) whose ergothioneine level was below this threshold. One possible interpretation of these findings, consistent with previous experiments in a reduced uterine perfusion model in rats, is that ergothioneine may indeed prove protective against PE in humans.”

https://portlandpress.com/bioscirep/article/43/7/BSR20230160/233119/Relationship-between-the-concentration-of “Relationship between the concentration of ergothioneine in plasma and the likelihood of developing pre-eclampsia”

Eyeballing the Healthy individuals in the above graphic, none of those 544 people were below this study’s 462 ng threshold.

A 2023 companion article analyzed the third paper’s unusual findings:

“These results suggest that there might be a dichotomized association between ergothioneine concentrations and preeclampsia; and only a high ergothioneine level over 90th percentile of the control population could be protective against preeclampsia.

Univariable results showed that ergothioneine had a significant non-linear association with preeclampsia and it would start to offer protective effect from 300 ng/ml onward. Analysis also confirmed that body mass index was significantly associated with an increased risk of preeclampsia.

A large observational study could strengthen the causal association between ergothioneine and preeclampsia. If confirmed, a randomized controlled trial (RCT) assessing whether ergothioneine supplementation can reduce risk of preeclampsia will be imminently feasible. Ideally, such RCT should compare placebo with a range of different doses of ergothioneine to identify the best or minimal effective dose, given its good safety records, including in pregnancy, with a no-observed-adverse-effect level (NOAEL) of 800 mg/kg body weight per day.”

https://portlandpress.com/bioscirep/article/43/8/BSR20231076/233395/Dose-related-relationship-between-ergothioneine “Dose-related relationship between ergothioneine concentrations and risk of preeclampsia”

My daily mushroom ergothioneine dose is around 7 mg, and I weigh about 70 kg. I don’t think a daily 800 mg/kg ergothioneine dose would be desirable for anybody, regardless of what experts say.

How many times have public health employees been wrong this decade? Would you bet your or your child’s health on their advice?

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Take acetyl-L-carnitine if you are healthy

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress , , , ,

Eight 2023 acetyl-L-carnitine / L-carnitine papers, starting with three healthy human studies:

“Thirty healthy volunteers aged between 19 and 52 years were divided randomly into two equal groups, one of which received 1000 mg of L-carnitine (LC) per day over a 12-week period. Total cholesterol and HDL-C increased significantly after supplementation. LC could be useful in impeding development of heart diseases in subjects with low HDL-C.”

https://journaljammr.com/index.php/JAMMR/article/view/5166 “L-Carnitine Increases High Density Lipoprotein-Cholesterol in Healthy Individuals: A Randomized Trial”

Rationale for dose selection wasn’t provided, and the possibility of limited results due to poor study design wasn’t mentioned.

“This study examined effects of 12 weeks of LC supplementation on bone mineral density (BMD) and selected blood markers involved in bone metabolism of postmenopausal women participating in a resistance training (RT) program. Participants’ diets were supplemented with either 1 g of LC-L-tartrate and 3 g of leucine per day (LC group) or 4 g of leucine per day as a placebo (PLA group), in a double-blind fashion.

Because the study protocol consisted of both exercise and supplementation, some favorable changes in the BMD could be expected. However, it was not possible to detect them in the short study period. No significant modification in BMDs of the spine, hip, and total skeleton and no differences between groups in one-repetition maximum could be due to the relatively short duration of the RT intervention.”

https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-023-00752-1 “Effect of a 3-month L-carnitine supplementation and resistance training program on circulating markers and bone mineral density in postmenopausal women: a randomized controlled trial”

Same comments as the first study regarding no rationale for dose selection, and no mention that limited results were possibly due to an inadequate dose.

In a letter to the editor, a researcher took issue with a study’s methodology:

“Based on finding that intravenous provision with carnitine alone does not increase muscle carnitine accretion, and on the above-reevaluated data, it appears that the basis for carnitine with caffeine being able to increase muscle carnitine levels, and thereby manipulation of muscle metabolism and exercise performance, is uncertain.

Carnitine bioavailability in any group would have been 9.5%. This assessment would be in line with previously recorded values of 5%–18% carnitine bioavailability. It is firmly believed that low carnitine bioavailability is attributable to the inability of kidneys to reabsorb carnitine when the threshold concentration for tubular reabsorption (about 40–60 μmol/L) has passed this value.

The authors’ proposed long-term use of carnitine supplementation as an aid to improve fat oxidation in type II diabetes also seems to lack provision.”

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15736 “LTE: Does caffeine truly raise muscle carnitine in humans?”

Two genetic studies:

“Our findings suggest that humans have lost a gene involved in carnitine biosynthesis. Hydroxytrimethyllysine aldolase (the second enzyme of carnitine biosynthesis) activity of serine hydroxymethyl transferase partially compensates for its function.”

https://www.researchsquare.com/article/rs-3295520/v1 “One substrate-many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse”

“Reported prevalence of primary carnitine deficiency (PCD) in the Faroe Islands of 1:300 is the highest in the world. The Faroese PCD patient cohort has been closely monitored and we now report results from a 10-year follow-up study of 139 PCD patients.

PCD is an autosomal recessive disorder that affects the function of organic cation transporter 2 (OCTN2) high-affinity carnitine transporters, that localizes to the cell membrane and transport carnitine actively inside the cell. Without proper functioning OCTN2 carnitine transporters, renal reabsorption of carnitine is impaired, and as a consequence, patients suffering from PCD have low plasma levels of carnitine. This can disturb cellular energy production and cause fatigue, but also in extreme cases lead to cellular dysfunction and severe symptoms of coma and sudden death.

PCD patients seem to adhere well to L-carnitine treatment, even though they have to ingest L-carnitine tablets at least three times a day. Overall mean L-carnitine dosage was 66.3 mg/kg/day.”

https://onlinelibrary.wiley.com/doi/10.1002/jmd2.12383 “Patients with primary carnitine deficiency treated with L-carnitine are alive and doing well—A 10-year follow-up in the Faroe Islands”

The average daily dose is (66.3 mg x 70 kg) = 4,641 mg. A third of this dose would be about 1.5 g.

The first study of Acetyl-L-carnitine dosing also suggested dosing L-carnitine three times a day because of 10-20% bioavailability.

A study with unhealthy humans:

“This retrospective study analyzed medical records of adult patients between March 2007 and April 2019, with presenting complaints of fatigue and lethargy. Acetyl-L-carnitine has physiological functions similar to L-carnitine but has higher bioavailability and antioxidant properties. This study confirmed that a triple combination therapy with γ-linolenic acid, V. vinifera extract, and acetyl-L-carnitine can improve arterial stiffness in patients.

Our study had some limitations:

  1. The study population may not be representative of the entire Korean adult population.
  2. The study did not have a medication-free control group. Instead, the comparison group comprised patients with medication compliance <80%.
  3. Drop-out rate of the triple-combination therapy (46.2%, 147/318) was relatively high, indicating the possibility of bias due to loss to follow-up.
  4. The study did not consider lifestyle factors such as smoking, diet, and physical activity level, which may affect arterial stiffness.
  5. The study did not examine interactions among drugs comprising the combination therapy, although all drugs are known to positively impact blood vessels.”

https://onlinelibrary.wiley.com/doi/10.1111/jch.14708 “Efficacy of γ-linolenic acid, Vitis vinifera extract, and acetyl-L-carnitine combination therapy for improving arterial stiffness in Korean adults: Real-world evidence”

This study’s acetyl-L-carnitine dose was 500 mg three times a day.

Wrapping up with two rodent studies:

“Acetyl L-carnitine (ALCAR) has proved useful in treatment of different types of chronic pain with excellent tolerability. The present work aimed at evaluating the anti-hyperalgesic efficacy of ALCAR in a model of persistent visceral pain associated with colitis.

The acetyl group in the ALCAR molecule can enhance cholinergic signalling by promoting synthesis of neurotransmitter acetylcholine, which plays an important role in both the enteric and central nervous systems. Acetylcholine signalling has significant antinociceptive effects in development of visceral pain, so it has been proposed as a therapeutic target.

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ALCAR significantly reduced establishment of visceral hyperalgesia in DNBS-treated animals, though the interventive protocol showed a greater efficacy than the preventive one.

  • The interventive protocol partially reduced colon damage in rats, counteracting enteric glia and spinal astrocyte activation resulting from colitis.
  • The preventive protocol effectively protected enteric neurons from inflammatory insult.

These findings suggest the putative usefulness of ALCAR as a food supplement for patients suffering from inflammatory bowel diseases.”

https://www.mdpi.com/1422-0067/24/19/14841 “Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System

This study cited multiple animal studies that found acetyl-L-carnitine was effective for different types of pain. I’ve taken it every day for nineteen years, and haven’t noticed that effect.

“Repetitive mild traumatic brain injuries (rmTBI) may contribute to development of neurodegenerative diseases through secondary injury pathways. Acetyl-L-carnitine (ALC) shows neuroprotection through anti-inflammatory effects, and via regulation of neuronal synaptic plasticity by counteracting post-trauma excitotoxicity. This study aimed to investigate mechanisms implicated in etiology of neurodegeneration in rmTBI mice treated with ALC.

ALC is an endogenously produced carnitine metabolite present in tissue and plasma, and readily crosses the blood brain barrier, unlike its unacetylated form. ALC is also a commonly available nutritional supplement, with a known safety profile, and had been well-studied for its role in aiding β-oxidation of long chain fatty acids in the mitochondria.

While some studies have shown promise for improving clinical and psychometric outcomes in individuals with probable Alzheimer’s disease (AD) and mild cognitive impairment, other studies that included participants with moderate AD progression were less conclusive. It may be that this lack of improvement is related to a therapeutic window of opportunity. Once neurodegenerative mechanisms have commenced, a reversal of these processes is not attainable.

There is currently a lack of evidence for safe therapeutics that can be administered long-term to reduce the risk of individuals developing cognitive and neuropsychological deficits after rmTBIs. Prophylactic ALC treatment in a paradigm of neurotrauma may be a way to maximize its therapeutic potential.

While brain structures display differential vulnerability to insult as evidenced by location specific postimpact disruption of key genes, this study shows correlative mRNA neurodegeneration and functional impairment that was ameliorated by ALC treatment in several key genes. ALC may mitigate damage inflicted in various secondary neurodegenerative cascades – confirmed by improvements in behavioral and cognitive function – and contribute to functional protection following rmTBI.”

https://www.frontiersin.org/articles/10.3389/fphar.2023.1254382/full “Repetitive mild traumatic brain injury-induced neurodegeneration and inflammation is attenuated by acetyl-L-carnitine in a preclinical model”

I read many traumatic brain injury papers earlier this year, but only curated two in Brain endothelial cells. I came away thinking that there’s no permanent recovery from TBIs, as just symptoms are effectively treated.

Most TBIs happen to old people who have diminished brain reserves. I didn’t see studies that factored in evidence of what happened earlier in injured people’s lives that created TBI susceptibility but wasn’t remembered.

Unlike other years, I haven’t watched any football this season. It’s unsettling that transient entertainment value continues to take precedence over permanent effects on players’ lives.

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What you expect may not be what you find

gettingwell4 2-3 stars Required further work, Acetylcholine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , , , ,

I’m halfway through a 90-day trial of plasmalogens coincident with improving peroxisomal function via resistance exercise and time-restricted eating. I haven’t curated related 2023 papers I’ve read concerning plasmalogens, peroxisomes, sphingolipids, ceramides, and mitochondrial interactions with these, mainly because I haven’t seen human-pertinent aspects similar to Dr. Goodenowe’s efforts.

The 2023 papers I’ve read have more to do with researcher incentives rather than actual human benefits. I’d guess that researchers care about these related subjects to the extent that they want to be the first to publish arcane details about them, like peroxisomes in the parotid salivary gland.

One area I expected to see a difference at the regimen’s beginning was in my peripheral nervous system Schwann cells. Instead, I had taste and smell improvements in my primary olfactory nervous system olfactory ensheathing cells, which are highly similar to Schwann cells. I was also happy to experience an immediate halt to my ulnar nerve elbow pain after what I interpret as ProdromeNeuro effects and perhaps coincident ProdromeGlia effects on items upstream of Schwann cells.

Here are three papers on Schwann cells that I haven’t yet seen as applicable to my current regimen, starting with a 2022 review:

“We summarise contributions of neurotransmitter receptors in regulation of morphogenetic events of glial cells, with particular attention paid to the role of acetylcholine receptors in Schwann cell physiology. This redundant and complex integrated regulation system could be explained as a mechanism of preserving glial cell physiology. In case of a single receptor signalling dysfunction, other neurotransmitters can overcome the deficit, preserving functions of glia and health of the nervous system.

Increased knowledge in medicinal chemistry and in bioinformatics accompanied by drug delivery studies might open a fascinating therapeutic perspective for cholinergic mimetics for treatment of several nervous system pathologies, and in reducing neuroinflammation both in the central and peripheral nervous systems.”

https://www.mdpi.com/2227-9059/11/1/41 “Emerging Roles of Cholinergic Receptors in Schwann Cell Development and Plasticity”

A 2023 study investigated the vagus nerve’s Schwann cells’ impact with gut function:

“The vagus nerve is the longest extrinsic cranial nerve in the body. It regulates gut physiology through the intrinsic nervous system (myenteric and submucosal plexus) and enteric glial cells interactions, which participate in controlling intestinal absorption, secretion, immune homeostasis, and motility.

Normal intestinal motility is critical for nutrition assimilation and several biological functions. The loss of normal gut function aggravates inflammation, oxidative stress, and other cellular stressors.”

https://bmcbiotechnol.biomedcentral.com/articles/10.1186/s12896-023-00781-x “A critical role for erythropoietin on vagus nerve Schwann cells in intestinal motility”

I haven’t curated a Buck Institute for Research on Aging sponsored study for a while, since their 2015 A study of how “age” itself wasn’t a causal factor for wound-healing differences detracted from science and their 2020 Linear thinking about biological age clocks wasted resources.

This 2023 rodent study couldn’t investigate anything outside of Buck’s limited paradigm’s echo chamber. This sponsor would rather break their arms patting themselves on their backs pretending they’re advancing science than fund relevant human research successes that do advance science:

“Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation.”

https://www.embopress.org/doi/full/10.15252/emmm.202317907 “Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury”

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Brain restoration with plasmalogens

gettingwell4 5+ stars Premium, Acetylcholine, Amygdala, Anterior cingulate cortex, Beliefs, Brain development, Brain hemispheres, Brainstem, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Thalamus , , , , , , , , , ,

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.

A smell and taste anecdote

gettingwell4 2-3 stars Required further work, Amygdala, Brainstem, Cerebrum, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress , , , ,

Two 2023 papers, starting with a study of smell and taste disorders:

“This study investigates the impact of etiology on the epidemiologic profile, disease severity, type of treatment, and therapy outcome in smell and taste disorders.

Hyposmia has a prevalence of about 15%, while approximately 5% of the population suffers from anosmia. Multiple innervation of the taste mucosa with fibers from the seventh, ninth, and tenth cranial nerves assures robustness of the gustatory system compared to smell.

Conservative therapy employs corticosteroids, antibiotics, vitamins and and minerals as well as functional rehabilitation by olfactory training. Data regarding outcome of therapy were only available for 71 (26.3%) of patients. Only the sinunasal etiology was significantly more likely to show improvement after therapy (27.4% show improvement vs. 9.6% show no improvement).”

https://link.springer.com/article/10.1007/s00405-023-07967-1 “Characteristics of smell and taste disorders depending on etiology: a retrospective study”

This study was a little light on describing effective treatments for smell and taste problems. For example, olfactory training was said to have good therapeutic response. Looking it up, though, it seems to be whatever each practitioner feels like doing.

A review introduced the subject of olfactory ensheathing cells:

“Olfactory ensheathing cells (OECs) are glial cells of the primary olfactory nervous system, which are composed of the olfactory nerve and outer nerve fiber layer of the olfactory bulb. The primary olfactory nervous system is unique in that it can constantly regenerate.

It is now possible to remove olfactory bulb tissue and olfactory mucosa (outermost layer and lamina propria, which belong to the central nervous system and peripheral nervous system, respectively), which also suggests the potential value of OECs therapy in central nervous system and peripheral nervous system diseases. OECs can survive and renew in the central nervous system, and have been widely used in nerve regeneration and tissue repair.

Schwann cells (SCs) form the myelin sheath of the peripheral nerve, protect and nourish neurons, and play an irreplaceable role in the repair of peripheral nerve injury. There is no transcriptional difference between OECs and SCs. OECs are highly similar to SCs, and express the biomarkers of SCs.

fimmu-14-1280186-g002

Functional mechanisms of OECs in the treatment of neurological diseases include neuroprotection, immune regulation, axon regeneration, improvement of nerve injury microenvironment and myelin regeneration, which also includes secreted bioactive factors. Results obtained in clinical trials are not very satisfactory, and the effectiveness of these cell-based therapies remains to be proved.”

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1280186/full “Potential therapeutic effect of olfactory ensheathing cells in neurological diseases: neurodegenerative diseases and peripheral nerve injuries”

Something interesting may have unexpectedly started with my 90-day trial of Prodrome Glia and Neuro products. Here’s an abbreviated look that omits my intermittent fasting and resistance exercise data:

day 7-15

Both product labels have a loading dose suggestion of 4-8 softgels (2 to 4 times the standard two-softgel dose) for 1-3 months. Two days after I started a Glia loading dose, my sense of smell, then sense of taste, were noticeably better.

I’ll guess that my primary olfactory nervous system glial cells are responding to these changes. At the beginning I thought that my peripheral nervous system Schwann cells might be affected regarding my left ulnar nerve. Since olfactory ensheathing cells are highly similar to Schwann cells, it doesn’t seem to be that much of a stretch to think that they could also be affected by my current regimen.

More testing is warranted, of course. I’ve had diminished smell and taste for decades, though. If the gardenias, roses, magnolias, honeysuckles, and other scents in past summers that had fainter scents than I remembered come across stronger, so much the better.

IMG_20200425_154336

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

Plasmalogens, Part 2

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This post compares Dr. Goodenowe’s clinical trial mentioned in Part 1 with other researchers’ human plasmalogen studies this decade. One of its findings was:

“Figure 1A illustrates that plasmalogen precursor DHA-AAG dose-dependently elevated both direct and indirect target species [DHA-PL, DHA-PE, and (LA + AA)-PL] and had no effect on levels of biochemically unrelated PE species index (LA + AA)-PE.

  • DHA-AAG had a greater elevating effect on its direct target, DHA-PL than its indirect targets.
  • The 1-month washout period resulted in decreased levels of both direct and indirect target species and no effect on unrelated PE species.

Figures 1A,B illustrate that DHA-AAG is converted to its direct and indirect target species in humans as predicted from animal studies on similar AAG plasmalogen precursors (Wood et al., 2011d).”

fcell-10-864842-g001A

Given this century’s background of numerous animal studies, there’s a need to know what translates to humans. Here are the three most recent human plasmalogen studies in descending order where I could access the full study:

2022

“Forty unmarried male students aged 18–22 years (20 in the plasmalogen group and 20 in the placebo group) were randomly allocated to either plasmalogen (2 mg per day) or placebo treatment of 4 weeks’ duration and ingested two capsules of 0.5 mg plasmalogen or placebo twice daily.

  • The primary efficacy outcome was the Total Mood Disturbance (TMD) T-score of POMS 2–Adult Short.
  • Secondary outcomes included the seven individual scales of POMS 2, other psychobehavioral measures (Athens Insomnia Scale and Uchida-Kraepelin test), physical performance test (shuttle run, grip muscle strength, and standing long jump), plasmalogen levels in plasma and erythrocytes, plasma levels of brain-derived neurotrophic factor (BDNF), urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), body mass index, and percent body fat.

Lipid composition of purified ether phospholipids from scallop is shown below. One capsule contained 0.48 mg of ethanolamine plasmalogen and 0.02 mg of choline plasmalogen. Plasmalogen and placebo capsules were prepared by a manufacturer (B&S Corporation, Tokyo).

fcell-10-894734-t001

There were no between-group differences in physical and laboratory measurements. It is suggested that orally administered plasmalogens alleviate negative mood states and sleep problems, and also enhance mental concentration.”

https://www.frontiersin.org/articles/10.3389/fcell.2022.894734/full “Orally Administered Plasmalogens Alleviate Negative Mood States and Enhance Mental Concentration: A Randomized, Double-Blind, Placebo-Controlled Trial”

There was no dose / response investigation, so there’s no data to corroborate that this 2 mg treatment produced these effects. It isn’t difficult to think of other factors that could influence the primary outcome of a 18-22 year-old unmarried male’s moods.

2020

“Effects of ascidian-derived plasmalogens on cognitive performance improvement were assessed in a randomized, double-blind, placebo-controlled study including Japanese adult volunteers age 45.6 ± 11.1 years with mild forgetfulness. An allocation controller who was not directly involved in the study equally, but randomly, assigned participants to either the intervention group (n＝33) or the placebo group (n＝33), based on normalized Cognitrax composite memory score (the primary outcome), sex, and age at time of screen. Participants were administered either one active capsule (200 mg medium-chain triglyceride (MCT) oil including ascidian plasmalogen oil) or placebo capsule (200 mg MCT oil) per day with water, any time during the day for 12 weeks.

Ascidian plasmalogen oil was extracted from ascidians (Halocynthia roretzi) and sold by NIHON PHARMACEUTICAL CO., LTD. Based on a previous study, 33％ of lipids contained in ascidians are phospholipids, 23％ of which are plasmalogens, and fatty acids of the sn-2 position of plasmalogens are mainly EPA, DHA, oleic acid, and arachidonic acid. The active capsule contains 1 mg plasmalogen.

Compared to the placebo group, the intervention group showed a significant increase score in composite memory (eight weeks: 3.0 ± 16.3 points, 12 weeks: 6.7 ± 17.5 points), which was defined as the sum of verbal and visual memory scores. These results indicate consumption of ascidian-derived plasmalogen maintains and enhances memory function.”

https://www.jstage.jst.go.jp/article/jos/69/12/69_ess20167/_article “The Impact of Ascidian (Halocynthia roretzi)-derived Plasmalogen on Cognitive Function in Healthy Humans: A Randomized, Double-blind, Placebo-controlled Trial”

Again no dose / response investigation, so no corroborating data. Standard deviations many times larger than a sample’s mean indicated wild variability (aka noise). Maybe intervention participants experienced memory loss (3.0 mean – 16.3 SD = -13.3; 6.7 mean – 17.5 SD = -10.8)? Yet statistics inferred a signal that allowed interpreting this treatment as producing meaningful positive changes in cognitive function.

“Ten Parkinson’s disease (PD) patients age 67.80 (7.41) years received oral administration of 1 mg/day of purified ether phospholipids derived from scallop for 24 weeks. Clinical symptoms and blood tests were checked at 0, 4, 12, 24, and 28 weeks. Blood levels of plasmalogens in patients with PD were compared with those of 39 age-matched normal controls.

B&S Corporation Co. Ltd. (Tokyo) was involved in provision of capsules containing ether phospholipids derived from scallop. Ethanolamine ether phospholipids (ePE) in plasma from PD and relative composition of ethanolamine plasmalogen (plsPE) of erythrocyte membrane in PD were significantly low as compared to those of age-matched normal controls.

Oral administration of purified ether phospholipids derived from scallop for 24 weeks increased plasma ePE and erythrocyte plsPE to almost normal levels, and concomitantly improved some clinical symptoms of patients with PD. Results indicate the efficacy of oral administration of purified ether phospholipids derived from scallop to some nonmotor symptoms of PD. Physiological mechanisms of the efficacy of purified ether phospholipid derived from scallop remained to be elucidated.”

https://www.hindawi.com/journals/pd/2020/2671070/ “Improvement of Blood Plasmalogens and Clinical Symptoms in Parkinson’s Disease by Oral Administration of Ether Phospholipids: A Preliminary Report

Again no dose / response investigation, so no corroborating data. These researchers asserted their 2017 study to be a plasmalogen gold standard, as did the other two above studies.

Here’s part of what Dr. Goodenowe said about that 2017 study in a 2019 review Plasmalogen deficiency and neuropathology in Alzheimer’s disease: Causation or coincidence?:

“They did not observe a significant elevation of plasma levels of plasmalogens in the treated group relative to the baseline. Lower dose of plasmalogens (1 mg twice daily) and the labile nature of the vinyl-ether bond might have limited absorption of the intact molecule and might have contributed to the lack of response in terms of plasmalogen levels in blood as well as the cognitive function. Reported instability of plasmalogens in acidic environments questions the stability of preformed plasmalogens in gastric juice during digestion which might reduce plasmalogen bioavailability.”

Also see Part 1’s explanation of why using age-matched controls in plasmalogen studies is ridiculous.

Continued in Part 3.

Plasmalogens, Part 1

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

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

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

plasmalogens and cognition

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Continued in Part 2.

Ergothioneine dosing

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Four 2023 papers that outlined or used different ergothioneine doses, starting with a human/rodent study:

“We found that cognitive function and hippocampal neurogenesis were lower in mice fed an ERGO-free diet than in those fed the control diet. Mice fed an ERGO-free diet were orally administered ERGO (0, 2, and 20 mg/kg) for two weeks which reversed these effects.

trkb ratio

Phosphorylated brain-derived neurotrophic factor receptor TrkB, the activated form of TrkB, was also detected in extracellular vesicles (EVs) derived from serum samples of 52 volunteers who had been orally administered ERGO-containing tablets (5 mg/day for 12 weeks). The ratio of serum EV-derived phosphorylated TrkB was significantly higher in the ERGO-treated group than in the placebo-treated group and was positively correlated with both serum ERGO concentrations and several cognitive domain scores from Cognitrax.

cognitrax

The ratio of p-TrkB to TrkB in serum EVs was proposed as a quantitative diagnostic marker of long-term ERGO-induced cognitive improvement.”

https://www.researchsquare.com/article/rs-2626422/v1 “TrkB phosphorylation in serum extracellular vesicles correlates with cognitive function enhanced by ergothioneine in humans”

Human equivalents of all rodent ergothioneine doses were higher than the 5 mg/day for 12 weeks 2020 human study, cited as Reference 21. I couldn’t access that paper, so here’s its Abstract:

Effect of ergothioneine on the cognitive function improvement in healthy volunteers and mild cognitive impairment subjects – a randomized, double-blind, parallel-group comparison study

“These results indicate that continuous intake of ergothioneine improves cognitive function in healthy subjects.”

A rodent study compared effects of a fermented product with 0.1 and 1.0 mg/g (human equivalent 6 mg (1 mg x .081) x  70 kg) ergothioneine doses:

“Our present study demonstrated for the first time the preventive effect of Rice-koji fermented extracts made by Aspergillus oryzae on anxiety, impaired recognition, and nociception using a psychophysically stressed model. Our results also demonstrated preventive effects of ergothioneine (EGT) on stress-induced anxiety- and pain-like behaviors.

Daily administration of High dose Rice-koji or 0.1 mg/kg EGT decreased anxiety- and pain-like behaviors. These findings suggest that inhibitory effects of Rice-koji on psychological stress might be mediated through the actions of EGT.”

https://www.mdpi.com/2072-6643/15/18/3989 “Preventive Roles of Rice-koji Extracts and Ergothioneine on Anxiety- and Pain-like Responses under Psychophysical Stress Conditions in Male Mice”

Here’s one of several reviews that cited a 2017 clinical trial (duplicately Reference 39 and 61 for some reason) of 5 and 25 mg ergothioneine doses:

“In this pharmacokinetic study, forty-five healthy humans received placebo, 5, or 25 mg encapsulated ergothioneine/d for 7 d and were followed up for an additional 4 weeks. Ergothioneine was rapidly absorbed and largely retained by the body, with large increases in plasma ergothioneine levels and only minimal increases (<4 %) in urinary excretion observed. While plasma levels of ergothioneine decreased when supplementation was withdrawn, levels in whole blood continued to increase in a dose–response fashion, reaching maximal levels 3 weeks after withdrawal of supplement, which were sustained at 4 weeks follow-up.

A large difference in basal concentrations of ergothioneine in whole blood was observed. Participants with the highest basal levels of ergothioneine also appeared to take up more of supplemented ergothioneine.”

https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/ergothioneine-an-underrecognised-dietary-micronutrient-required-for-healthy-ageing/92CED7FF201A9FB23BEAFF0D3EAD7316 “Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing?”

Wrapping up with a deep dive into seven mushroom varieties’ compounds:

“Mushrooms contain multiple essential nutrients and health-promoting bioactive compounds, including amino acid L-ergothioneine. We compared metabolomes of fresh raw white button, crimini, portabella, lion’s mane, maitake, oyster, and shiitake mushrooms using untargeted liquid chromatography mass spectrometry (LC/MS)-based metabolomics.

Results indicate significantly higher concentrations of L-ergothioneine in lion’s mane and oyster mushrooms compared to the remaining five mushroom varieties, which had concentrations ranging from 1.94 ± 0.55 to 5.26 ± 1.23 mg/100 g wet weight (mean ± SD). There was also variability in concentration of L-ergothioneine between mushroom varieties of the same farm. Different numbers denote significance (p < 0.05).

foods-12-02985-g008

Mushrooms and their bioactive extracts are considered functional foods. Mushrooms have several bioactive compounds, including polysaccharides, lectins, terpenoids, sterols, and alkaloids, among others, which may positively impact health.

Cell walls of mushrooms contain polysaccharides, including β-glucans and chitin, which positively affect health, through modulating the immune system and protecting the cardiovascular system through improvements in glucose and lipid metabolism. Effects on the cardiovascular system are also attributable to lovastatin and polyphenols, known for their lipid-lowering and antioxidant properties, respectively.

While the 1344 compounds in common among the seven mushroom varieties support some level of similarity, detection of hundreds of unique-to-mushroom-variety compounds and differences in amino acid profiles indicate that not all mushrooms are chemically comparable. Given detection of >400 unique-to-mushroom-variety compounds in lion’s mane, maitake, oyster, and shiitake mushrooms, we suggest further targeted investigations on compounds detected and potential health benefits.”

https://www.mdpi.com/2304-8158/12/16/2985 “Metabolomics Profiling of White Button, Crimini, Portabella, Lion’s Mane, Maitake, Oyster, and Shiitake Mushrooms Using Untargeted Metabolomics and Targeted Amino Acid Analysis”

I eat around 200 grams of mushrooms daily, having temporarily overridden the boredom of eating AGE-less chicken vegetable soup every day. I prep all the top package’s frozen umami bomb (283 grams) and half of the bottom’s fresh mushrooms (340 grams) into the soup:

PXL_20230921_193708552

It makes servings for three days, including one for prep day dinner. I’d guess from “concentrations ranging from 1.94 ± 0.55 to 5.26 ± 1.23 mg/100 g (mean ± SD)” that my daily mushroom ergothioneine dose is around 7 mg ((1.94 mg + 5.26 mg) / 2) = 3.6 mg per 100 grams x 2 (for 200 grams).

Continued in Part 2.

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

Take Vitamin K2 to protect against aluminum toxicity

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This 2023 rodent study investigated relationships of MK-7 menaquinone, aluminum trichloride, and brain health:

“A variety of endogenous and exogenous agents, such as metals and environmental toxins (aluminum, mercury, etc.), can contribute to neurodegeneration, which is of multifactorial clinical occurrence.

The current study showed that Alzheimer’s Disease (AD)-like condition was induced in mice by AlCl3 treatment affecting spatial and recognition memory. Neuropathological alterations included neuroinflammation, oxidative stress, an increase in brain amyloid β levels, and loss of hippocampal neurons.

Aluminium chloride (AlCl3; 100 mg/kg for 3 weeks orally) was administered to Swiss albino mice to induce neurodegeneration and Vitamin K2 (100 mcg/kg for 3 weeks orally) was applied as treatment. This was followed by behavioral studies to determine memory changes.

Antioxidants like glutathione and SOD were low compared to the control group, while oxidative stress marker MDA was elevated. BDNF levels increased in the Vitamin K2 treated animals, suggesting its neuroprotective functions.

k2 abstract

vitamin K2 BDNF

Vitamin K2 could partially reverse AlCl3-mediated cognitive decline. It increased hippocampal acetylcholine and BDNF levels while reducing oxidative stress, neuroinflammation, and β-amyloid deposition, protecting hippocampal neurons from AlCl3-mediated damage.“

https://link.springer.com/article/10.1007/s10787-023-01290-1 “Vitamin K2 protects against aluminium chloride-mediated neurodegeneration” (not freely available)

This study’s human equivalent Vitamin K2 dose is (100 mcg x .081) x 70 kg = 567 mcg. I’ve taken 600 mcg MK-7 every day for the past two years.

Found out last week that I’ve also been inadvertently dosing myself with aluminum every day. This is the underside of my former 3-year-old drip coffee maker with its cover removed:

PXL_20230813_172709641

I’m certain its aluminum tubing that heats reservoir water started to corrode a long time ago. Currently trying out methods of making aluminum-free coffee.

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.”

36 holes in your roof

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An August 2023 interview with Dr. Dale Bredesen, who has reversed Alheizmer’s disease in many people, which will never be acknowledged by the corrupt paradigm:

“How much do you want me to go into things that are relatively controversial and how much do you want me to stick with kind of the more standard line?

For Alzheimer’s we noticed initially there are 36 different potential contributors. You need to patch as many as possible to have an effect.

All of these things, your estradiol level, your progesterone level, pregnenolone, free T3, TSH, Vitamin D, testosterone, these things are all critical. They all feed into the equation.

You have over a hundred trillion contacts in your brain. Will you be able to keep them? Or do you not have what it takes to keep them, and you have to downsize?

The reality is Alzheimer’s disease should be a rare disease. If everybody would get on appropriate prevention or early reversal, we could make it a rare disease.”

https://brokenscience.org/podcasts-ep-5/ “Dale Bredesen – Reversing Alzheimer’s Fate”

See A therapy to reverse cognitive decline for previous curation of Dr. Bredesen’s work.

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”