Maintaining your myelin, Part 2

April 27, 2024April 27, 2024 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Corpus callosum, Neural plasticity, Neurodegenerative disease

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.

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”

Maintaining your myelin, Part 1

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

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

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

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

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

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

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

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

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

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

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

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

A 2024 review focused on myelin and oligodendrocyte plasticity:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Continued in Part 2.

Changing a cancerous phenotype

April 9, 2024April 11, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Epigenetics, Glutamate, Immune system, Neurochemicals, Stress Control group, Genetic factors, Neurodegenerative disease

A 2024 Dr. Goodenowe presentation to a professional audience. He ended the presentation by using his 86-year-old father as a case study of treatment to create an inhospitable environment for cancer.

1. Get the body ready

2. Starve the cancer and boost the immune system

3. Characteristics

4. 2019 sample biochemistry

5. 2023 biochemistry (compare HDL (33 vs. 80), see off-the-chart hsCRP, Hcy 16)

6. Treatment details #1

7. Treatment details #2

https://drgoodenowe.com/tfim-2024-recording-now-available/ “Breaking Cancer: The Biochemistry of Cancer Risk Assessment, Prevention, and Treatment—Real Knowledge That You Can Use In Your Practice”

Ergothioneine dosing, Part 2

March 17, 2024March 21, 2024 gettingwell4 4-5 stars Advanced knowledge, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Telomeres Brain neurons, Control group, Genetic factors, Neurodegenerative disease

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.

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:

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:

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):

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?

Sulforaphane’s effects on autism and liver disease

February 15, 2024 gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Glutamate, Immune system, Neurochemicals, Stress Control group, Embryo development

Here are two more papers that cited Precondition your defenses with broccoli sprouts, starting with a 2024 human / rodent study investigating gut microbiota / sulforaphane’s effects on autism:

“Sulforaphane (SFN) has been found to alleviate complications linked with several diseases by regulating gut microbiota (GM), while the effect of GM on SFN for autism spectrum disorders (ASD) has not been studied. We evaluated therapeutic effects of SFN on maternal immune activation (MIA)-induced ASD-like rat model and pediatric autism patients aged 4–7 years.

OSU-SO for social interactive OSU behavioral subscores, OSU-CO for non-verbal communicative OSU behavioral [significant] subscores, and OSU-ST for repetitive or ritualistic OSU behavioral subscores:

Although gut microbiota composition was significantly altered in SFN-treated ASD-like rats, alteration of GM was not evident in ASD patients after 12 weeks of SFN treatment. Limitations in this study:

Studies were conducted in male rats and boys only;

The sample size of our clinical study is relatively small [6 SFN-treated boys] and needs to be further expanded in the future; and

This study only uncovered a potential link between gut flora and the therapeutic effects of SFN on ASD.

SFN treatment alleviates social deficits in MIA-induced ASD-like rats and ASD patients, and improvements might be associated with gut microbiota.”

https://www.frontiersin.org/articles/10.3389/fnut.2023.1294057/full “Therapeutic efficacy of sulforaphane in autism spectrum disorders and its association with gut microbiota: animal model and human longitudinal studies”

The 2022 Efficacy of Sulforaphane in Treatment of Children with Autism Spectrum Disorder: A Randomized Double-Blind Placebo-Controlled Multi-center Trial (not freely available) was referenced for sulforaphane (actually, glucoraphanin with myrosinase enzyme) doses:

“Dosing was weight-based:

Two tablets/day for 10–29 lb;

Three tablets/day for 30–49 lb;

Four tablets/day for 50–69 lb.

An estimated delivery of approximately 24, 36, and 48 μmol of sulforaphane daily was expected in the respective SF dosage groups.”

Weights of the above μmol estimated dose amounts per https://pubchem.ncbi.nlm.nih.gov/compound/sulforaphane are 4.3, 6.4, and 8.5 mg, respectively. An average weight of a 4-year-old boy is 36 lbs / 16.3 kg, and a 7-year-old boy is 51.1 lbs / 23.2 kg.

This study’s maternal immune activation was done by injecting lipopolysaccharide into pregnant rats. Would injecting pregnant women with immune-activating substances have similar harmful effects on the fetus? We don’t have evidence because unbiased and unconflicted studies looking for such effects weren’t sponsored and/or published before immune-activating substances’ deployments.

A 2024 rodent study investigated sulforaphane’s effects on diabetic liver damage:

“We investigated whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes-induced hepatic ferroptosis, and the mechanisms involved. Results showed that diabetes-induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic molecules critical for:

Antioxidative defense (catalase, superoxide dismutases, thioredoxin reductase);

Iron metabolism (ferritin heavy chain (FTH1), ferroportin 1);

Glutathione (GSH) synthesis (cystine-glutamate antiporter system, cystathionase, glutamate-cysteine ligase catalitic subunit, glutamate-cysteine ligase modifier subunit, glutathione synthetase); and

GSH recycling – glutathione reductase (GR)

were reversed/increased by sulforaphane treatment.

Diabetes-induced increases in serum glucose and triglyceride levels were also significantly reduced by sulforaphane. Taken together, our results demonstrate a potent effect of SFN in inhibiting ferroptotic death of hepatocytes under diabetic conditions in vivo, thereby alleviating liver injury.

This is the first study to demonstrate the protective role of SFN against ferroptosis in the liver of diabetic mice. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes-related pathologies.”

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/biof.2042 “Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis”

Taurine’s effects on healthspan and lifespan, Part 2

January 10, 2024January 11, 2024 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Cortisol, Epigenetics, Hypothalamus, Limbic system, Memory, Neurochemicals, Stress Control group, DNA methylation, Genetic factors

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.

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.

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”

Take acetyl-L-carnitine if you are healthy

December 30, 2023December 30, 2023 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress Brain neurons, Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

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:

The study population may not be representative of the entire Korean adult population.

The study did not have a medication-free control group. Instead, the comparison group comprised patients with medication compliance <80%.

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.

The study did not consider lifestyle factors such as smoking, diet, and physical activity level, which may affect arterial stiffness.

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.

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.

What you expect may not be what you find

December 12, 2023December 12, 2023 gettingwell4 2-3 stars Required further work, Acetylcholine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Happiness, Neural plasticity, Neurodegenerative disease

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”

Building your plasmalogen savings account

December 8, 2023January 6, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Cerebrum, Dopamine, Epigenetics, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Brain neurons, Control group, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease

A webinar from earlier this week with Dr. Goodenowe, a clinical trial facilitator, and a physician:

From the Q&A segment:

“Is there a particular age where it’s recommended to test for plasmalogen levels? And what levels would be considered normal?

That’s a good question. That actually raises this whole concept of optimal health and this concept of aging.

The best way to think about it – we talked about this paycheck-to-paycheck situation, where as long as our bills are paid every day, technically we think we’re normal. But we still feel this sense of health anxiety – if you will – like we just don’t know if my car breaks down, or my water heater breaks down, do I have enough money to pay these events in my life?

That’s what health feels like to a lot of people, because they’re just kind of getting by. From a health perspective, they’re considered normal, but they have no reserve capacity, and they have no vitality in terms of health.

Plasmalogens are a type of molecule that you build a savings account of, over years, over decades. Your heart builds them up, your brain builds them up, and you slowly accumulate them. Then when you get an oxidative stress like what’s happening now in today’s world with all the covid and myocarditis and brain fog – a lot of these things are being caused because that reserve of plasmalogens has been depleted.

We want plasmalogens for a longevity perspective. There are other situations that can have low plasmalogens, other things can really knock your plasmalogens down.

So you want to start early, you want to build a savings account, and you want to maintain it. Maintain health and function, and create a sustained surplus for optimal health, for optimal neuromuscular performance.”

A good activity for bad weather days

November 26, 2023November 26, 2023 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Beliefs, Brain hemispheres, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Corpus callosum, DNA methylation, Genetic factors, Happiness, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

A free educational series recorded in 2021-2022 available at https://drgoodenowe.com/dr-goodenowes-educational-seminars/ takes the viewer through underlying research and principles of Dr. Goodenowe’s approach to health. It’s advertised as lasting four hours, but took me two days to view.

The series’ discussions and references are background material to better understand later presentations and interviews. Points of interest included:

Seminar B100 shows that the metabolomic profile of people who regularly eat broccoli is different than others.
B109 clarifies how peroxisomal function is improved through resistance exercise and intermittent fasting.
C103 and C104 show how plasmalogens act against neurodegeneration (Parkinson’s disease and multiple sclerosis).

Texts below videos are additional information, not transcripts. C101 text is historically informative.

The B200 ProdromeScan tutorial will take more study. But unlike Labcorp tests, ordering a ProdromeScan requires using a practitioner in Dr. Goodenowe’s network.

I sent the following to Prodrome customer service earlier this month:

Please add me to your approved list for ProdromeScan.

Customer service replied:

“We only add health professionals to an approved list, not individuals.”

I responded:

Good morning. I looked at the websites of doctors who are associated with Dr. Goodenowe who are near me. All of them are too compromised for me to establish a doctor / patient relationship. But I’m glad they left up their blog posts from earlier this decade so I could see who they really were before I reached out to them.

I request an exception to the policy.

Customer service replied:

“There is no exception that can be made to this policy. You need to be a patient of a certified practitioner.”

I’ll escalate my request before my 90-day trial of Prodrome Glia and Neuro products ends so I can get an appropriate metabolomic status. Right now, I won’t involve someone I can’t trust just to know my ProdromeScan information that’s additional to next week’s Labcorp tests.

My treatment-result metabolomic data is probably not mature today on Day 29 of ProdromeGlia and ProdromeNeuro supplementation, resistance exercise, and intermittent fasting. I otherwise wouldn’t have experienced these two events:

I’m happy that after starting normal ProdromeGlia and ProdromeNeuro doses at Day 1, then taking a ProdromeGlia loading dose starting from Day 11, my sense of smell and taste improved by Days 13-14.
Still jazzed that starting a ProdromeNeuro loading dose at Day 22 immediately resolved my left ulnar nerve pain that had been intermittently bothering me for over 5 years.

I have a quibble with the series’ recommendations for taking N-acetyl cysteine. Relevant views and research:

Switch on your Nrf2 signaling pathway pointed out:

“We use NAC in the lab all the time because it stops an Nrf2 activation. So that weak pro-oxidant signal that activates Nrf2, you switch it off by giving a dose of NAC. It’s a potent antioxidant in that right, but it’s blocking signalling. And that’s what I don’t like about its broad use.”

If someone bombs themself everyday with antioxidants, they’re doing nothing to improve training of their endogenous systems’ defensive functions. What happens when they stop bombing? One example was a 2022 human study that found GlyNAC-induced improvements dissolved back to baseline after supplements stopped.

Also, Precondition your defenses with broccoli sprouts highlighted NAC’s deleterious effects on autophagy and lysosome functions:

“TFEB activity is required for sulforaphane (SFN)-induced protection against both acute oxidant bursts and chronic oxidative stress. SFN-induced TFEB nuclear accumulation was completely blocked by pretreatment of cells by N-acetyl-cysteine (NAC), or by other commonly used antioxidants. NAC also blocked SFN-induced mRNA expression of TFEB target genes, as well as SFN-induced autophagosome formation.”

If a secondary goal of taking NAC per is also necessary for the formation of glutathione, taurine can do that without an antioxidant bomb. Taurine supplementation will free up cysteine to do things other than synthesize taurine, like synthesize glutathione.

Brain restoration with plasmalogens

November 20, 2023February 28, 2024 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 Brain neurons, Control group, Corpus callosum, Dr. Arthur Janov, Genetic factors, Levels of consciousness, Neural plasticity, Neurodegenerative disease, Prefrontal cortex, Unconscious feelings, Unconscious memories

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:

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

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:

“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:

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

No changes:

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

Decreased adaptations in brain measurements included:

White matter microstructure radial diffusivity -10%.
Amygdala connectivity to the anterior cingulate cortex to suppress / ignore / deny anxiety response.
Amygdala connectivity to the dorsal lateral prefrontal cortex.
Entorhinal cortex volume -14%.
Hippocampus volume -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:

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

November 13, 2023November 13, 2023 gettingwell4 2-3 stars Required further work, Amygdala, Brainstem, Cerebrum, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

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.

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:

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.

Eat broccoli sprouts to inhibit brain cancer

November 7, 2023November 11, 2023 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Neurochemicals, Stress Brain neurons, Control group, Genetic factors

This 2023 rodent study by Our model clinical trial group investigated effects of broccoli seeds, 8-day-old sprouts, 95-day-old florets, and pure sulforaphane on glioma:

“This study employs a C6 rat glioma model to assess chemoprotective potential of aqueous extracts from broccoli seeds, sprouts, and inflorescences, all rich in sulforaphane (SFN), and pure SFN as positive control.

In plant material, seeds and sprouts exhibited a heightened concentration of aliphatic-type glucosinolates (GSLs), while broccoli heads showcased a more substantial amount of indole group GSLs. Similar to the GSL trend, the highest concentration of phenolic compounds was evident in sprouts, succeeded by seeds, with broccoli heads exhibiting a subsequent lower content.

Within freeze-dried aqueous extracts obtained from plant material samples, seeds exhibited the most substantial SFN content, trailed by sprouts and inflorescences. This hierarchy aligns with precursor GSL content, specifically glucoraphanin (GRA). These outcomes imply that approximately 5% of GRA content converted into SFN.

Sinapic acid derivatives emerged as the primary category of phenolic compounds. Higher concentrations of these phenolic compounds were observed in inflorescences, succeeded by seeds, and lastly, broccoli sprouts.

Aqueous extracts from seeds, sprouts, and inflorescences were administered to rats over 30 days before the introduction of C6-glioma cells. This specific time frame corresponds to a critical risk factor and initiation of the tumor niche in humans. The objective was to assess whether this consumption could protect against tumor development.

Tumor volume within the control SS group significantly increased compared to the sprout group. Volume fluctuations observed in the seed and inflorescence groups did not demonstrate any statistically significant differences when compared to the control group.

Subjects administered with 0.1 mg/kg of SFN displayed a notable decrease in tumor growth. A stark contrast is evident when compared to the corresponding control group (control OO) and the 0.7 mg/kg SFN-treated group.

These findings substantiate the notion that elevated doses of the pure compound might potentially assume a pro-oxidant role, while lower doses hold promise in fostering an environment rich in antioxidants and conducive to chemoprotection.

All experimental groups developed gliomas. However, the group administered with aqueous extract of broccoli sprouts and the group treated with pure SFN at 0.1 mg/kg exhibited formation of diffuse low-grade gliomas. Conversely, the remaining groups exhibited malignant characteristics, and manifested development of thrombosed vessels.

Incorporating broccoli sprouts into one’s regular diet emerges as a highly promising strategy for averting onset of specific types of cancer. It is the most cost-effective option for society when contrasted with consumption of nutraceuticals. While achieving a standardized effective dose of SFN via food consumption, such as sprouts, poses challenges, forthcoming clinical studies are poised to determine an appropriate dosage for shaping human intervention trials.”

https://www.sciencedirect.com/science/article/pii/S0753332223015184 “The preventive effects of broccoli bioactives against cancer: Evidence from a validated rat glioma model”

This study’s Discussion section had a lot of hand waving regarding broccoli seeds’ failure to outperform broccoli sprouts despite its 1.06 mg/kg to 0.63 mg/kg sulforaphane advantage. Although not specifically referenced, hormetic effects described in Sulforaphane in the Goldilocks zone and subsequent studies probably account for pure sulforaphane’s dose / response findings that 0.1 mg/kg better inhibited glioma than did 0.7 mg/kg.

For those who think this post’s title is over-the-top:

Although eating non-patentable broccoli sprouts is safe and cheap, how many people will wait for clinical trials to determine whether these rodent findings translate to humans?
If today there was already human clinical trial evidence confirming translatable findings, how many people would still wait for incorruptible, morally upright, honest, and trusted medical authorities’ approvals?

Plasmalogens, Part 3

November 5, 2023March 31, 2024 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Brain hemispheres, Brainstem, Cerebellum, Cerebrum, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

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

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.”

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

November 3, 2023November 9, 2023 gettingwell4 2-3 stars Required further work, Acetylcholine, Dopamine, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neurodegenerative disease

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).”

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).

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.