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Brain restoration with plasmalogens

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

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

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

1. Nutritional Supplementation Strategy

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

2. Advanced MRI Technologies

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

3. Reversing Brain Shrinkage

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

Specific increased adaptations in brain measurements over 17 months included:

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

No changes:

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

Decreased adaptations in brain measurements included:

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

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

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

etable 3

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

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

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

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

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

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

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

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

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

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.

Eat broccoli sprouts for your high intensity interval training

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This 2023 human study investigated broccoli sprouts and HIIT:

“In the present study we applied a program of 7 consecutive days of exercise with High intensity interval training (HIIT) and twice daily administration of a glucosinolate rich sprout drink (GRS) or a placebo drink (PLA) in a double-blinded, placebo controlled, cross-over fashion. The intent was to challenge subjects’ adaptive capacity and antioxidative defence, and determine if administration of GRS in combination with exercise could activate Nrf2, enhance physical performance, and protect against potential negative effects of excessive exercise.

Broccoli raab sprouts and alfalfa sprouts (placebo) were grown in a commercial sprout growing facility, and harvested on day 5. Sprouts were homogenized in water with a ratio of 75 g of sprouts to 180 mL of water, then immediately frozen to −80° C.

Upon consumption, drinks were quickly thawed, and 50 mL apple juice concentrate was added for improved taste and masking, together with 0.75 g brown mustard seed powder containing myrosinase to facilitate conversion of glucosinolates to isothiocyanates. Broccoli sprouts contained 1.145 ± 0.035 mmol of total glucosinolates per 75 g fresh weight.

hypoglycemia

  • Markedly reduced hypoglycemia suggests that factors beyond carbohydrate intake and energy balance, such as oxidative stress, might play a pivotal role in glucose regulation. This highlights the complexity of metabolic responses to strenuous exercise, and indicates the need for further investigations.
  • Overall adaptations to acute oxidative stress induced by exercise and GRS were towards diminished oxidative stress and improved physical performance.
  • An unexpected finding in this study was that blood lactate concentrations during submaximal exercise were lower after GRS compared to PLA. Lower lactate accumulation seen after a period of training is often attributed to either an increased oxygen delivery or improved mitochondrial capacity. We did not find any significant differences in either VO2max or mitochondrial function or capacity, indicating that other, unknown mechanisms were at play.

We showed that incorporating supplementation with GRS-rich broccoli sprouts into a 7-day intense training regimen in a cohort of healthy subjects:

  1. Mitigates several markers of oxidative stress;
  2. Improves blood glucose profile; and
  3. Enhances exercise-induced adaptations.”

https://www.sciencedirect.com/science/article/pii/S2213231723002744 “Glucosinolate-rich broccoli sprouts protect against oxidative stress and improve adaptations to intense exercise training”

This study was excellent. Other human studies it cited were less so.

Reference 17 was cited for 30 mg sulforaphane. It was actually 30 mg glucoraphanin per Eat broccoli sprouts for your workouts.

Reference 18 was also cited for 30 mg sulforaphane. That study’s Materials and methods section wasn’t forthcoming on how the sulforaphane was manufactured or obtained, though, which created reproducibility issues.

PXL_20230907_105152720

Part 2 of Harnessing endogenous defenses with broccoli sprouts

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The author of this 2023 paper expanded Part 1 to include further clinical evidence and four human case studies. I’ll highlight just a few items because it’s quite detailed:

“Accumulating evidence for the crucifer-derived bioactive molecule sulforaphane (SFN) in upstream cellular defence mechanisms highlights its potential as a therapeutic candidate in targeting functional gastrointestinal conditions, as well as systemic disorders. This article catalogues evolution of and rationale for a hypothesis that multifunctional sulforaphane can be utilised as the initial step in restoring ecology of the gut ecosystem.

It can do this primarily by targeting functions of intestinal epithelial cells. In many cases where primary presenting symptoms are related to aberrant intestinal function, complete or partial resolution also occurred in seemingly unrelated conditions such as inflammatory skin diseases, multiple food intolerances, histamine-like allergic reactions, and neuro-psychological disorders.

Although SFN was the primary and initial intervention, clinicians recommended that their patients consume a mixed diet of minimally processed foods rich in vegetables and other sources of phytochemicals. It was also clear that dietary recommendations alone were not capable of making changes that occurred when SFN was added.

ijms-24-13448-g004

In seeking an effective gateway for addressing digestive, immune, cardiometabolic and other chronic disease, this hypothesis proposes an approach that harnesses the endogenous processes of human cells. These processes focus on restoring homeostasis to the gut, its underlying immune network, and the companion microbiota, with the collective potential to beneficially impact all gut–organ axes.”

https://www.mdpi.com/1422-0067/24/17/13448 “The Rationale for Sulforaphane Favourably Influencing Gut Homeostasis and Gut–Organ Dysfunction: A Clinician’s Hypothesis”

The author proposed this paper as a working hypothesis to be scientifically correct. Would a null hypothesis be along the lines of “I’ll eat a clinically relevant dose of broccoli sprouts every day for twelve weeks, and nothing will change”?

Case study #1 had a timing parallel with my experiences per:

“She was able to tolerate 20 mg SFN daily after several weeks; the dose was increased to 40 mg daily by 6 weeks.”

I doubled my dose at Week 6. All case studies documented transformative experiences, but they weren’t the same types that shortly followed for me.

Taurine’s effects on healthspan and lifespan

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A 2023 human / primate / rodent / worm study with 56 coauthors exhaustively investigated taurine effects:

“We measured the blood concentration of taurine during aging and investigated the effect of taurine supplementation on healthspan and lifespan in several species.

  • In C57Bl/6J wild-type (WT) mice, serum taurine concentrations declined from 132.3 ± 14.2 ng/ml at 4 weeks to 40.2 ± 7.1 ng/ml at 56 weeks.
  • In 15-year-old monkeys, serum taurine concentrations were 85% lower than in 5-year-old monkeys.
  • Taurine concentrations in elderly humans were decreased by more than 80% compared with concentration in serum of younger individuals.

Regardless of their sex, taurine-fed mice survived longer than control mice. The median lifespan increase was 10 to 12%, and life expectancy at 28 months increased by 18 to 25%.

Improved survival of taurine-fed mice was not a consequence of low survival of control animals or differences in diet. Taurine deficiency is a driver of aging in mice because its reversal increases lifespan.

lifespan extension starting taurine in middle age

We investigated the health of taurine-fed middle-aged mice and found an improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system, indicating an overall increase in healthspan. Taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammation.

An association analysis of metabolite clinical risk factors in humans showed that lower taurine, hypotaurine, and N-acetyltaurine concentrations were associated with adverse health, such as increased abdominal obesity, hypertension, inflammation, and prevalence of type 2 diabetes. We found that a bout of exercise increased concentrations of taurine metabolites in blood, which might partially underlie antiaging effects of exercise.

Taurine abundance decreases during aging. A reversal of this decline through taurine supplementation increases healthspan and lifespan in mice and worms, and healthspan in monkeys.”

https://www.science.org/doi/10.1126/science.abn9257 “Taurine deficiency as a driver of aging”

One area curiously not investigated in this study was that taurine supplementation freed up cysteine to do things other than synthesize taurine, like synthesize glutathione, an idea in Treating psychopathological symptoms will somehow resolve causes? An introductory article brought up this point:

“One of the most studied mechanisms of action for taurine is an increase in antioxidant capacity. Although oxidative damage is not clearly linked to mammalian lifespan, it plays a role in many age-associated pathologies.

Taurine is a poor scavenger of reactive oxygen species, with the exception of hypochlorite, which it detoxifies to N-chlorotaurine. N-Chlorotaurine is anti-inflammatory and induces expression of antioxidant enzymes in mice and humans.

Taurine supplementation might also cause an increase in levels of its precursors, including the antioxidants hypotaurine and cysteine. An interesting corollary is that up-regulating endogenous taurine synthesis would have the opposite result—consuming hypotaurine and cysteine.”

https://www.science.org/doi/10.1126/science.adi3025 “Taurine linked with healthy aging”

A human equivalent taurine dose is (1 g x .081) x 70 kg = 5.67 grams. Dose tests from supplementary data were:

“Dose and frequency of taurine administration was selected based on a pilot study, which showed that when given once daily to middle-aged WT mice, this regimen increased peak blood taurine concentrations to baseline concentrations in young (4-week-old) mice.”

taurine dose

I’ve taken 2 grams every day for the past three years, and will now bump that up to 5 grams. My diet doesn’t regularly include any foods high in taurine.

I recommend reading the study rather than commentaries. Its publisher did a very good job of linking figures so that images can be viewed, then the reader returned to the right context.

Gatekeepers are out in full force on this study, and their viewpoints are probably what you’ll see first, to include unevidenced statements like “the study’s main authors cautioned the public not to self-dose with the supplement” and the above introductory article’s unreferenced “equivalent doses used in the study by Singh et al. would be very high in humans.” Pretty pathetic that such ‘authorities’ are even publicized after recent years of deliberately misleading the world about science and medicine.

This study and all commentaries called for clinical trials that are NOT going to happen:

  • 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.

Take responsibility for your own one precious life. See Part 2 for a sample of citing papers.

PXL_20230601_181526429

Measuring gut microbiota, Part 2

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A 2023 porcine study expanded Part 1’s coverage to include stomach and small intestine microbiota:

“Identification of individual intestinal microbes affecting phenotypes and diseases depends on statistical analyses between these two main variables. Because the phenotypes or diseases are typically well-defined, success of statistical analyses on these studies depend on precise elucidation of gut microbiome composition.

This work with genetically homogenous sibling pigs grown in a cohoused condition to minimize experimental errors showed that composition of the gut microbiome constantly changed in response to local environmental changes of the GI tract. Pigs are omnivorous and have the most similar digestive mechanisms to humans.

The stomach and small intestine microbiomes – which are rich in nutrients – were very different from the large intestine and feces microbiomes in terms of both composition and diversity. Firmicutes, Proteobacteria, Actinobacteria, Cyanobacteria, and Fusobacteria phyla were relatively more dominant in the stomach and small intestine than the large intestine and feces. Bacteroidetes was more heavily dominated in the large intestine and feces.

Sampling locations within the GI tract were determined based on their anatomical feature: stomach, duodenum (small intestine_1), jejunum (small intestine_2 ~ small intestine_5), ileum (small intestine_6), cecum (large intestine_1), colon (large intestine_2 ~ large intestine_6), and rectum (large intestine_7).

diversity

The gut microbiome between locations within an individual was significantly different, while individual differences at the same locations of the GI tract were not as significant. Fecal microbiome was more closely related to the gut microbiome in large intestine than stomach or small intestine.

Intestinal bacteria in terms of both species number and their prevalence were dramatically increased as intestinal matter transited from the stomach to the large intestine. Cooccurrence network analysis showed the gradual adaptation of intestinal microbiota from stomach to large intestine:

  • At the same time, the highly dense and diverse bacteria in the large intestine were closely related to each other.
  • Fecal microbiome did not represent any microbiome at the 14 locations.

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

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

https://www.hindawi.com/journals/cmi/2023/6868417/ “Fecal Microbiome Does Not Represent Whole Gut Microbiome”

This study showed that pig stomach and small intestine microbiota had few associations with fecal microbiota samples. Part 1 showed that only 6% of large intestine microbiota genes producing a secondary metabolite were found in human fecal samples.

What’s the point of poop microbiota studies when those microbiota don’t fairly represent ANY preceding gut microbiota, either overall or in actionable stages?

I don’t endorse this study’s Conclusions section suggestions of “endoscopic methods” because it ignores iatrogenic injuries and deaths. I’ll continue to give my trillion+ microbiota partners what they need, and expect reciprocity.

PXL_20230529_163229866.MP

Measuring gut microbiota, Part 1

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A 2023 paper combined results of two clinical trials focused on large intestine microbiota:

“Our current understanding of the gut microbiome places it at the center of multiple physiological processes, and establishes its relevance to many facets of health and disease. Microbiome databases are based upon stool samples or invasively-acquired colon samples obtained during procedures such as colonoscopy.

We present data from two prospective clinical studies describing significant differences between the stool microbiome and inner-colonic microbiome collected during FDA-cleared defecation-inducing, gravity-fed, and high-volume colonic lavage. We examined several microbiome characteristics, including microbial diversity, community differential abundance, and composition of biosynthetic gene clusters (BGCs).

BGCs are locally clustered groups of two or more genes that encode a biosynthetic pathway that produces a secondary metabolite:

  • 6% of identified BGCs were common to stool and pooled inner-colonic effluent samples, 25% were expressed only in stool, and 69% were unique to effluent samples.
  • When effluent-specific BGCs were divided according to colon areas, 25% were found in Effluent-1 (left descending colon), 21% in Effluent-2 (transverse colon), and 11% in Effluent-3 (right ascending colon).

gr4

Taxonomic and phylogenetic differences between inner-colonic effluent and stool samples increased gradually when approaching the proximal colon and small intestine:

  • Comparing the left colon to stool showed that 22 species were significantly enriched while only five species were significantly more abundant in stool.
  • A comparison between the transverse colon and stool revealed 76 species that were significantly more differentially abundant, while stool had 10 differentially abundant species.
  • The most significant differentially abundant species were found by comparing the right colon (closest to the small intestine) to stool, with 96 species differently enriched while stool had 20 species significantly enriched.

Individuals are far more distinct in their inner-colonic microbial community than in their stool samples. Microbiota are relatively similar across patients when examining stool samples, while expression of rare microbial strains is more specific to each individual.

Analyzing both stool and inner-colonic effluents can provide more information on the gut microbiome.”

https://www.cell.com/heliyon/fulltext/S2405-8440(23)00809-5 “The gut microbiome–Does stool represent right?”

Continued in Part 2.

PXL_20230529_162603190.MP

Physical fitness and epigenetic clocks

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This 2023 human study of 144 men average age 68 investigated relationships among physical fitness measurements and three epigenetic clocks:

“We investigated relationships between physical fitness and age-adjusted values from residuals of the regression of DNAm aging clocks to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of physical fitness variables to DNAmAgeAccel in the presence of other lifestyle factors.

  • Volume of oxygen (VO2/kg) at ventilatory threshold and at Peak, fat free mass, calf circumference, serum HDL-C, daily intake of carbohydrates, iron, copper, vitamin C, and β-carotene were negatively related with DNAmAgeAccel.
  • Body fat, visceral fat area, and serum TG were positively related to DNAmAgeAccel.

figure 4

Frequent alcohol consumption and past- and current-smoking status were associated with accelerated DNAmAgeAccel, while a morning lifestyle was associated with deceleration of it. Multiple regression analysis suggested that – rather than physical fitness – serum triglycerides, carbohydrate intake, and smoking status were significantly associated with DNAmAgeAccel.

In conclusion, the contribution of cardiorespiratory fitness to DNAmAgeAccel was relatively low compared to lifestyle factors such as smoking. However, this study reveals a negative relationship between cardiorespiratory fitness and DNAmAgeAccel in older men.”

https://www.medrxiv.org/content/10.1101/2023.04.12.23288187v1.full-text “Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based aging clocks in older men: WASEDA’S Health Study”

PXL_20230330_191228773

Remembering life before birth

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This 2023 primate study investigated the body’s capability to remember prenatal experiences influencing later life:

“Maternal stressors and other environmental factors affect the developing embryo and fetus in ways that lead to increased susceptibility for chronic disease in later life. Developmental programming of chronic low-grade inflammation plays an important role in onset and progression of these diseases.

Establishing innate immune cell memory involves increased glycolysis, reduced oxidative phosphorylation, and expression of transcription factors which prime for pro-inflammatory activity. This memory relies on propagation of epigenetic modifications that develop in hematopoietic stem and progenitor cells (HSPCs), which can be passed on to progeny immune cells (i.e., macrophages).

These changes persist with altered epigenetic regulation for years after weaning – even when offspring are fed a conventional diet – predisposing offspring to inflammatory disease across their lifespans.

cell memory

Several factors may initiate metabolomic reprogramming in fetal HSPCs:

  • We found increased chromatin accessibility of gene regulatory regions and RNA signatures supporting activation of factors with a major role in regulating macrophage inflammatory activation, including FOS/JUN, NF-κB, C/EBPβ, and STAT6.
  • Our prior work demonstrated a persistently altered histone code in liver tissue from juvenile animals.
  • Maternal diet-supplied lipids, including oleic acid, in hematopoietic tissues may play an important role in priming inflammation and metabolism in fetal HSPCs and bone marrow-derived macrophages with postnatal persistence.

Striking changes in fetal bone marrow and liver HSPCs observed here suggest that the primary driver for developmental programming of inflammation takes place in utero. However, we cannot rule out that exposure to maternal diet during lactation postnatally triggers shifts in microbiome composition or function contributing to inflammation.

Components of maternal diet, rather than maternal obesity per se, are a modifiable risk factor with potential to alter developmental programming of offspring immune systems.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00404-7 “Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring”

And there are other ways we remember everything that happened then and along the way. Big clues are in our out-of-context responses to present day events.

PXL_20230326_104753766

Week 148 of Changing to a youthful phenotype with sprouts

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Ending the week with a thorough 2023 study of microwaving broccoli in a bag:

“Appropriate processing and cooking technologies can effectively improve the content of bioactive compounds in vegetables. Effects of microwave bag cooking on broccoli floret quality attributes, glucosinolates (GLSs) content and hydrolysate production were investigated in this study.

Microwave bag cooking preserved the color of florets, enhanced total phenolic and flavonoid content, as well as total chlorophyll and ascorbic acid content. The majority of microorganisms were inactivated. Floret structure was greatly altered, enhancing antioxidant capacity and promoting release of GLSs and myrosinase activity.

Fresh broccoli (Brassica oleracea L. var. italica) was purchased from a local market. Broccoli balls with uniform size, no pests and no mechanical damage were selected for the experiment. Broccoli was washed with deionized water and dried naturally before being cut at about 1 cm below the flower head. The microwave bag was filled with 25 g florets and sealed with a heat sealer.

To the best of our knowledge, microwave bag cooking was evaluated for the first time to explore effects on sulforaphane (SFN) and indole-3-carbinol (I3C) content. Microwave bag cooking at 400 W for 10 s resulted in the highest SFN content (870.18 ± 19.14 μg/g), which was about 3.99 times that of untreated florets.

sfn content

Microwave bag cooking at 800 W for 10 s resulted in the highest I3C content, which was 6.16 times that of untreated florets.

i3c content

Our findings demonstrated that I3C in supplements or vegetables also degraded quickly under various processing conditions, such as thermal processing, and that DIM and LTr1 were not only produced in acidic conditions. This filled a gap in the literature regarding effects of vegetable processing, particularly thermal treatment, on content of glucobrassicin degradation products. In brief, under suitable conditions of microwave bag cooking, content of indole hydrolyzate I3C can be significantly increased, whereas content of dimerization and trimerization products did not change as significantly as I3C.

This work demonstrated that microwave bag cooking was a quick and easy cooking method that could preserve potential health benefits of broccoli florets while also satisfying the needs of modern consumers.”

https://www.sciencedirect.com/science/article/abs/pii/S0963996922014594 “Microwave bag cooking affects the quality, glucosinolates content and hydrolysate production of broccoli florets” (not freely available) Thanks to Professor Lei Zheng for providing a copy.

Can’t replicate this study’s cooking method completely. Ziploc bags are microwavable but a little different than heat-sealed bags. I also grow a broccoli / red cabbage / mustard sprout mix.

Using 25 grams of the mix and 40% power on my 1000W microwave for 10 seconds produced a sharper taste than did the method I’ve used. Scooping the mix out of a quart bag was messy.

I put the next 25 grams on a microwavable plate that snugly fit into a sealed bag. 80% power on a 1000W microwave for 10 seconds definitely tastes more cooked.

PXL_20230212_131346050

I’ll alternate between 400W and 800W for a while to see which one I prefer. It’s as quick and easy as claimed.

PXL_20230209_212821487

Environmental signaling rescues aging muscle stem cells

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This 2023 rodent study applied An environmental signaling paradigm of aging concepts to muscle stem cells:

“The stem cell niche environment represents an important therapeutic target to enhance tissue regeneration in aging. We decoupled age-related cell-intrinsic effects, niche-mediated cell-extrinsic effects, and changes in population dynamics of muscle stem cells (MuSCs) and two key muscle-resident cells in young and aged mice.

in vivo model

We showed that:

  1. Age-related reduction in MuSCs is not stochastic.
  2. Despite differences in transcriptomes of MuSC clusters, the effect of age on gene expression is largely uniform, suggesting that the niche environment has a fundamental role in age-related changes in MuSC gene expression.
  3. A significant fraction of changes in the transcriptome of aging MuSCs can be reversed by exposure to the young muscle environment, i.e. are niche-responsive. Given the high percentage [46.6% at a stringent cutoff of s-value < 0.05] of reversibility in gene expression, our findings indicate that age-related changes in the niche are principal drivers of resulting alterations in the MuSC transcriptome.
  4. Aging is correlated with changes at the level of chromatin accessibility and DNA methylation in MuSCs.

Plasticity of the MuSC transcriptome suggests that modulating the niche environment can be a powerful tool to restore stem cell-mediated endogenous muscle regeneration in aging. Consequently, as opposed to focusing solely on MuSCs themselves to mitigate effects of aging on MuSCs, bioengineering of the niche in its entirety may be a viable therapeutic option.”

https://www.nature.com/articles/s41467-023-36265-x “Transcriptional reprogramming of skeletal muscle stem cells by the niche environment”

This study destroyed extremely well-funded directed research efforts that detract from science, especially those promoting irreversibility of epigenetic changes (but: Rockefeller) and randomness of pro-aging programming (but: Harvard).

These researchers showed they could do more with their ideas and careers than maintain an outdated and easily disproved status quo.

Eat broccoli sprouts to epigenetically regulate histones

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Five papers on beneficial effects from sulforaphane inhibiting histone deacetylases (HDACs), starting with a 2022 rodent cell study:

“Sulforaphane (SFN) has tissue specificity for subtypes of HDACs that are downregulated. For example:

  • In breast cancer cells, HDAC1-3 are inhibited by SFN to induce cell apoptosis;
  • In skin cells, HDAC1-4 are regulated by SFN [anti-skin cancer]; and
  • In the cochlea, SFN inhibits HDAC2, 4, and 5 [attenuates hearing loss].

In the present study, SFN significantly inhibited HDAC2, 3, and 5 expression and HDACs activity in cardiomyocytes, thereby increasing H3 acetylation levels in the Nrf2 promoter and upregulating Nrf2 expression. Mechanism by which SFN prevents Ang II-induced cardiomyocyte apoptosis:

  • Ang II activates oxidative stress by increasing ROS leading to inflammation, oxidative stress and fibrosis in cardiomyocytes.
  • SFN prevents Ang II-induced cardiomyocyte apoptosis by inhibiting HDACs to activate Nrf2 and downstream antioxidant genes.

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SFN activates Nrf2 by inhibiting HDACs expression and activation.”

https://www.aging-us.com/article/204247/text “Sulforaphane inhibits angiotensin II-induced cardiomyocyte apoptosis by acetylation modification of Nrf2”

A 2021 rodent study found:

“SFN significantly attenuated diabetes-induced renal fibrosis in vivo. SFN inhibited diabetes-induced increase in HDAC2 activity.

Bone morphologic protein 7 (BMP-7) has been shown to reduce renal fibrosis induced by transforming growth factor-beta1. SFN protects against diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7.”

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https://e-dmj.org/journal/view.php?doi=10.4093/dmj.2020.0168 “Sulforaphane Ameliorates Diabetes-Induced Renal Fibrosis through Epigenetic Up-Regulation of BMP-7”

A 2019 human osteosarcoma cell study found:

“SFN inhibits mTOR in a concentration- and time-dependent manner. This inhibition occurs in the presence or in the absence of NRF2.

SFN inhibits HDAC6 and decreases catalytic activity of AKT, which partially explains the mechanism by which SFN inhibits mTOR.”

https://www.sciencedirect.com/science/article/pii/S0944711319302284 “The isothiocyanate sulforaphane inhibits mTOR in an NRF2-independent manner”

A 2022 review cited a 2018 cell study:

“HDAC expression and activity are dysregulated in various diseases including asthma, chronic obstructive pulmonary disease, cancer, cardiac hypertrophy, and neurodegenerative and psychological disorders. HDAC inhibitors could be a potential therapeutic target for many diseases.

In hypertension, aortic stiffness is usually increased and vascular smooth muscle cells (VSMCs) contribute to vascular stiffness. We used VSMCs to test the degree of acetylation of histones in this study.

Sulforaphane weakly inhibited HDAC2 and effectively inhibited HDAC9.”

https://www.sciencedirect.com/science/article/pii/S0006295222002052 “Zinc-dependent histone deacetylases: Potential therapeutic targets for arterial hypertension”

https://www.sciencedirect.com/science/article/abs/pii/S0753332217364636 “Inhibition of class IIa histone deacetylase activity by gallic acid, sulforaphane, TMP269, and panobinostat” (not freely available)

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If you were given a lens to see clearly, would you accept it?

gettingwell4 5+ stars Premium, Amygdala, Brainstem, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress , , , , , , , ,

Two papers, starting with a 2022 rodent study of maternal behaviors’ effects on offspring physiologies:

“Early life adversity (ELA) is a major risk factor for development of pathology. Predictability of parental care may be a distinguishing feature of different forms of ELA.

We tested the hypothesis that changes in maternal behavior in mice would be contingent on the type of ELA experienced, directly comparing predictability of care in limited bedding and nesting (LBN) and maternal separation (MS) paradigms. We then tested whether predictability of ELA environment altered expression of corticotropin-releasing hormone (Crh), a sexually-dimorphic neuropeptide that regulates threat-related learning.

MS was associated with increased expression of Crh-related genes in males, but not females. LBN primarily increased expression of these genes in females, but not males.”

https://www.sciencedirect.com/science/article/pii/S2352289522000595 “Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala”

I came across this first study by it citing a republished version of 2005 epigenetic research from McGill University:

“Early experience permanently alters behavior and physiology. A critical question concerns the mechanism of these environmental programming effects.

We propose that epigenomic changes serve as an intermediate process that imprints dynamic environmental experiences on the fixed genome, resulting in stable alterations in phenotype. These findings demonstrate that structural modifications of DNA can be established through environmental programming and that – in spite of inherent stability of this epigenomic marker – it is dynamic and potentially reversible.”

https://www.tandfonline.com/doi/full/10.31887/DCNS.2005.7.2/mmeaney “Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome”

This post commemorates the five-year anniversary of Dr. Arthur Janov’s death. Its title is taken from my reaction to his comment on Beyond Belief: Symptoms of hopelessness. Search his blog for mentions of the second paper’s coauthors, Drs. Meaney and Szyf.

Our lives are substantially a product of our parents’ actualized and unsatisfied needs. Our children and their children are reflections of us with our problems (unfelt needs) or elucidations (felt needs).

What if the price we pay for avoiding and pressuring down our feelings is: A wasted life?

What if the grand hypothesis worth proving is: For one’s life to have meaning, each individual has to regain their feelings?

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Measuring epigenetic DNA causes

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This 2022 human cell study investigated DNA methylation and aging:

“Models based on DNA methylation can be used to predict the age of biological samples, but their interpretability is limited due to the lack of causal inferences. Neither existing epigenetic clocks nor DNA methylation changes are enriched in causal CpG sites. Causal CpGs include similar numbers of sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits.

One general approach for developing anti-aging interventions is to identify molecular changes during aging and use these changes as targets to modulate the aging process. A similar idea has also been applied to evaluate potential longevity interventions. However, this logic is intrinsically flawed, as correlation does not imply causation, and age-related changes are not necessarily causal to age-associated declines.

We developed a framework for integrating causal knowledge into epigenetic clock models and constructed DamAge and AdaptAge that measure age-related damaging and adaptive changes, respectively. DamAge acceleration is associated with various adverse conditions (e.g., mortality risk), whereas AdaptAge acceleration is related to beneficial adaptations.

causality clocks

We found that transcription factor (TF)-binding sites of BRD4 and CREB1 are enriched with CpG sites whose methylation levels promote healthy longevity, and TF-binding sites for HDAC1 are enriched with CpG sites whose methylation levels decrease healthy longevity.

  • BRD4 contributes to cell senescence and promotes inflammation, and higher DNA methylation at BRD4 binding sites may inhibit the downstream effects of BRD4 and promote healthy longevity.
  • CREB1 is related to type II diabetes and neurodegeneration, and mediates the effect of calorie restriction. Our data suggest that higher methylation at CREB1-binding sites may support its longevity effects.
  • HDAC1 is a histone deacetylase, and its activity increases with aging and may promote age-related phenotypes. Increased DNA methylation at HDAC1 binding sites may causally inhibit healthy longevity.

Our causality-informed clock models provide novel insights into the aging mechanisms and testing interventions that delay aging and reverse biological age.”

https://www.biorxiv.org/content/10.1101/2022.10.07.511382v1 “Causal Epigenetic Age Uncouples Damage and Adaptation”

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Minds of their own

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

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

Michael Levin - Cell Intelligence in Physiological and Morphological Spaces

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

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

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

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

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

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

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