Human agency vs. brain dysfunction

This 2021 human study used epigenetic clock technology to assess chronic inflammation as a driver of cognitive decline through its effects on brain structure:

“An epigenetic measure of C-reactive protein (DNAm CRP) was assembled for each participant. We found that higher inflammatory burden, indexed by DNAm CRP scores, associated with poor cognitive and neuroimaging brain health outcomes.

inflammation vs cognitive ability

DNAm CRP exhibited significantly larger associations with brain structural MRI metrics (including global grey and white matter atrophy, poorer white matter microstructure, and increased white matter hyperintensity burden) than serum CRP. Given that the 7 CpGs which make up DNAm CRP score reside in inflammation and vascular-related genes, these DNAm CRP-brain MRI associations may be capturing the impact of upstream inflammatory activity above and beyond that of serum CRP levels.

Our results indicate that some cognitive domains (processing speed) may be more mediated by brain structural consequences of chronic inflammation than others (verbal memory, visuospatial ability).

Our results add to the evidence base that DNAm-based predictors of inflammation may act as a quantifiable archive of longitudinal effects of these exposures – and other unaccounted for health and genetic profiles – that serum CRP levels fail to capture. By utilising an epigenetic inflammation measure, which integrates information from multiple immune-related CpG sites, we may provide a more reliable measure of chronic inflammation and thus a more comprehensive overview of consequences of chronic inflammation on brain structure and function.”

https://n.neurology.org/content/early/2021/11/17/WNL.0000000000012997.long “DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging”


These researchers essentially negated many of their findings by acknowledging:

“Although we endeavoured to remove participants with cognition-related pathology, these were screened via self-reported diagnoses, and we may be missing undiagnosed or subclinical incident neurodegenerative pathology.”

It wasn’t sufficient to claim in the Abstract section “Participants (N = 521) were cognitively normal, around 73 years of age” then include in the Discussion section a one-sentence limitation of relying on self-reports. Everyone defends themself against current and past realities and experiences.

Hard to imagine that objective measures such as the three comprising cognitive ability weren’t better screens. But then too many 73-year-old subjects may not have been “cognitively normal” and this study wouldn’t be adequately powered?

Can humans counteract inflammation? Non-communicable diseases? Smoking? Immune system degradation? Yes. No personal-agency actions were mentioned.

Also note this study’s social norming. The above-pictured 30-year-old female was busy at work, and subsequently hoisted a cat instead of a child in later years.

Take responsibility for your own one precious life.

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Do genes determine monogamy / polygamy?

This 2021 rodent study developed epigenetic clocks for deer mice:

“We have undertaken a genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior.

  • Analysis involved tails, whole brain, and liver samples that are not major target tissues for sex hormones. This implies that sex-specific patterns of methylation are inflicted early during development, and persist at adulthood.
  • Altitude-specific age-related changes are adjacent to genes that play a role in brain development, immune system functioning, and T-cell development.
  • Comparison of brain specimens between older P. leucopus and P. maniculatus indicated that in the latter, coordination of the unfolded protein response is compromised, and evidence of neurodegenerative pathology was obtained.
  • Our study involved three monogamous (P. californicus, P. polionotus, and P. eremicus) and two polygamous (P. maniculatus and P. leucopus) species. The most significant EWAS hits for monogamy included decreased methylation in Zeb2 intron, a key regulator of midbrain dopaminergic neuron development. These results derived from tail tissues, suggesting that inherent differences in bonding behavior instruct specific epigenetic changes in peripheral tissues that may be translated into distinct physiological outcomes. Whether this is due to differential regulation of specific neurohormonal circuits in response to hormones and neurotransmitters related to bonding, and what the exact physiological outputs are, remains to be determined.

Our study provided the first epigenetic clock for Peromyscus, and illustrated the hierarchical association between various biological variables in determining methylation profiles across different scales of biological organization.”

https://link.springer.com/article/10.1007/s11357-021-00472-5 “Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy”


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All about the betaine, Part 2

Continuing Part 1 by curating a partial outline of a 2021 review:

“This review focuses on the biological and beneficial effects of dietary betaine (trimethylglycine), a naturally occurring and crucial methyl donor.

Betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development.

  • Betaine Protects against Development of Alcohol-Induced Hepatic Steatosis
  • Betaine Protects against Detrimental Effects of HCV and Ethanol on Innate Immunity
  • Betaine Maintains Intestinal Epithelial Barrier Integrity
  • Betaine Maintains Adipose Function

biology-10-00456-g002

Human intervention studies showed no adverse effects with 4 g/day supplemental administration of betaine in healthy subjects. However, overweight subjects with metabolic syndrome showed a significant increase in total and LDL-cholesterol concentrations. These effects were not observed with 3 g/day of betaine administration.

We suggest betaine as a promising therapeutic for clinical use to treat these aforementioned diseases as well as other liver-/non-liver-related diseases and conditions.”

https://www.mdpi.com/2079-7737/10/6/456/htm “Beneficial Effects of Betaine: A Comprehensive Review”



This review cited a 2020 study Transgenerational Inheritance of Betaine-Induced Epigenetic Alterations in Estrogen-Responsive IGF-2/IGFBP2 Genes in Rat Hippocampus (not freely available):

“Hippocampal expression of aromatase, estrogen receptor α, and estrogen-related receptor β is downregulated in F1, together with estrogen-responsive insulin-like growth factor 2/insulin-like growth factor binding protein 2 (IGF-2/IGFBP2) genes. However, all these genes are upregulated in F2, which follows the same pattern of F0.

Imprinting control region of IGF-2 gene is hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all affected genes is hypermethylated in F1 but hypomethylated in F2 and F0.”

Intergenerational flip-flops of F0 phenotypes to opposite F1 phenotypes back to F0 phenotypes in the F2 generation can’t conclusively demonstrate transgenerational epigenetic inheritance of alterations due to betaine consumption during pregnancy. Those researchers had to continue on to a F3 female generation for transgenerational results, because F2 generation cells were present in F1 fetuses, and were potentially affected during pregnant F0 treatments.

I came across this paper through a citation chain initiated by Dr. Paul Clayton’s blog post Foie Gras:

“Thanks to our modern diet and lifestyle, nonalcoholic fatty liver disease (NAFLD) is now reckoned to affect an astonishing quarter of the world’s population.”

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Eat oats and inulin to reverse effects of circadian disruption

This 2021 rodent study induced metabolic syndrome with a high-fat diet and switching light-dark cycles every week for 14 weeks. While continuing to disrupt circadian rhythms for ten more weeks, most metabolic effects were reversed by adding either 5% β-glucan, 5% inulin, or .05% melatonin to subjects’ high-fat diet:

“Both prebiotics (oat β-glucan and chicory inulin) and melatonin significantly reversed circadian disruption-induced metabolic syndrome (CDIMS) and alteration of gut microbiota composition. Both prebiotics also reversed increase in body weight and liver weight-to-body weight ratio, and decrease in fasting plasma insulin. Only oat β-glucan reduced plasma leptin and alleviated glucose intolerance.

body weight

All dietary interventions enhanced species richness. In altering gut microbiota, oat β-glucan reversed populations of 7 bacterial genera and increased butyrate producers including Ruminococcaceae and Lachnospiraceae which enhance gut barrier protection and regulate glucose homeostasis.

Though melatonin cannot be fermented in the gut as prebiotics, oral administration of exogenous melatonin absorbed via melatonin receptors concentrated in the intestine has been demonstrated for its effects on shaping gut microbiota. There is currently no concrete mechanism explaining how melatonin affects gut microbial ecology. We postulate that the ability of melatonin to alleviate CDIMS is not governed by changes of SCFAs, but possibly a direct host effect which subsequently affects other metabolites such as bile acids.

In contrast with melatonin, oligomeric chicory inulin as a fermentable fiber mainly affects gut microbiota which affects the host indirectly. For polymeric oat β-glucan, our results suggested that it is probably a combination of both direct and indirect effects to the host, and this is a special property not yet evidenced in other polysaccharides.

Approximately 35% of human gut microbiota undergo temporal rhythmicity. We speculate that prebiotics may affect diurnal oscillations of gut microbiota, its capacity for energy harvest and production of metabolites, which subsequently affect host central circadian clocks through gut-microbiome-brain axis, in which gut microbes interact with central nervous system via nervous, endocrine, and immune signaling pathways.”

https://www.sciencedirect.com/science/article/abs/pii/S0144861721006032 “Circadian disruption-induced metabolic syndrome in mice is ameliorated by oat β-glucan mediated by gut microbiota” (not freely available)


Humans could avoid a high-fat diet, of course. My main experiences with circadian disruptions were 18-hour days of submarine life. That didn’t cause metabolic syndrome, just disorientation to the real world after surfacing.

The end of fig season

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Dementia blood factors

This 2021 human study performed blood metabolite analyses:

“Dementia is a collective term to describe various symptoms of cognitive impairment in a condition in which intelligence is irreversibly diminished due to acquired organic disorders of the brain, characterized by deterioration of memory, thinking, behavior, and the ability to perform daily activities.

In this study, we conducted nontargeted, comprehensive analysis of blood metabolites in dementia patients. Effort expended in this ‘no assumptions’ approach is often recompensed by identification of diagnostic compounds overlooked by targeted analysis.

The great variability of data in Figure 1 reflects genuine individual variation in metabolites, which were accurately detected by our metabolomic analysis. These data demonstrate that compounds having small to large individual variability are implicated in dementia.

dementia blood factors

7 group A compounds – plasma-enriched dementia factors – increased in dementia patients and might have a negative toxic impact on central nervous system (CNS) functions by themselves or their degradation products.

26 group B to E metabolites may be beneficial for the CNS, as their quantity all declined in dementia patients:

  • Red blood cell (RBC)-enriched group B metabolites all containing the trimethyl-ammonium ion may protect the CNS through their antioxidative and other activity.
  • Group C compounds, also RBC-enriched, have cellular functions implicated in energy, redox, and so forth, and may be important for maintaining CNS brain functions.
  • Group D’s 12 plasma compounds (amino acids, nucleosides, choline, and carnitine) – half of which had been reported as Alzheimer’s disease (AD)-related markers – may underpin actions of other metabolites for supply and degradation. Consistency of group D plasma metabolites as dementia markers but not group B and C RBC metabolites validated the method of searching dementia markers that we employed in the present study.
  • Group E compounds, caffeine and and its derivative dimethyl-xanthine, declined greatly in dementia subjects. Caffeine is an antagonist of adenosine, consistent with the present finding that adenosine belongs to group A compounds.

Twelve [groups B + C] of these 33 compounds are RBC-enriched, which has been scarcely reported. The majority of metabolites enriched in RBCs were not identified in previous studies.

Nine compounds possessing trimethylated ammonium ions are amphipathic compounds (with both hydrophilic and lipophilic properties) and form the basis of lipid polymorphism. All of them showed a sharp decline in abundance in dementia subjects.

amphipathic compounds

These amphipathic compounds may have similar roles, forming a higher-ordered, assembled structure. They might act as major neuroprotectants or antioxidants in the brain, and their levels are sensitive to both antioxidants and ROS.

We speculate the 7 group A compounds pathologically enhance or lead to severe dementia such as AD. This presumed dementia deterioration by group A factors is opposed if group B to E metabolites are sufficiently supplied.

However, group A markers were not found in frail subjects. If the change in group A is causal for dementia, then a cognitive cause in frailty may be distinct from that of dementia.”

https://www.pnas.org/content/118/37/e2022857118 “Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites”


Dementia subjects (ages 75-88) lived in an Okinawa hospital. Healthy elderly (ages 67-80) and young (ages 28-34) subjects lived in a neighboring village. Of the 24 subjects, 3 dementia and 1 healthy elderly were below a 18.5 to <25 BMI range, and none were above.

Get neuroprotectants working for you. Previous relevant curations included:

Epigenetic clocks so far in 2021

2021’s busiest researcher took time out this month to update progress on epigenetic clocks:

Hallmarks of aging aren’t all associated with epigenetic aging.

epigenetic aging vs. hallmarks of aging

Interventions that increase cellular lifespan aren’t all associated with epigenetic aging.

epigenetic aging vs. cellular lifespan

Many of his authored or coauthored 2021 papers developed human / mammalian species relative-age epigenetic clocks.

epigenetic clock mammalian maximum lifespan

Relative-age epigenetic clocks better predict human results from animal testing.

pan-mammalian epigenetic clock


Previously curated papers that were mentioned or relevant included:

Natural products vs. neurodegenerative diseases

I was recently asked about taking rapamycin for its effects on mTOR. I replied that diet could do the same thing. Here’s a 2021 review outlining such effects:

“As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt (Protein kinase B)/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials.

Growing evidence highlights the dysregulated PI3K/Akt/mTOR pathway and interconnected mediators in pathogenesis of NDDs. Side effects and drug-resistance of conventional neuroprotective agents urge the need for providing alternative therapies.

1-s2.0-S0944711321002075-ga1_lrg

Polyphenols, alkaloids, carotenoids, and terpenoids have shown to be capable of a great modulation of PI3K/Akt/mTOR in NDDs. Natural products potentially target various important oxidative/inflammatory/apoptotic/autophagic molecules/mediators, such as Bax, Bcl-2, p53, caspase-3, caspase-9, NF-κB, TNF-α, GSH, SOD, MAPK, GSK-3β, Nrf2/HO-1, JAK/STAT, CREB/BDNF, ERK1/2, and LC3 towards neuroprotection.

This is the first systematic and comprehensive review with a simultaneous focus on the critical role of PI3K/Akt/mTOR in NDDs and associated targeting by natural products.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711321002075 “Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration” (not freely available) Thanks to Dr. Sajad Fakhri for providing a copy.


Natural products mentioned in this review that I eat in everyday foods are listed below. The most effective ones are broccoli and red cabbage sprouts, and oats and oat sprouts:

  • Artichokes – luteolin;
  • Blackberries – anthocyanins;
  • Blueberries – anthocyanins, gallic acid, pterostilbene;
  • Broccoli and red cabbage sprouts – anthocyanins, kaempferol, luteolin, quercetin, sulforaphane;
  • Carrots – carotenoids;
  • Celery – apigenin, luteolin;
  • Green tea – epigallocatechin gallate;
  • Oats and oat sprouts – avenanthramides;
  • Strawberries – anthocyanins, fisetin;
  • Tomatoes – fisetin.

Four humpback whales

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All about vasopressin

This 2021 review subject was vasopressin:

“Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes, thereby implicated in pathomechanisms of many disorders. The most striking is its central effect in stress-axis regulation, as well as regulating many aspects of our behavior.

Arginine-vasopressin (AVP) is a nonapeptide that is synthesized mainly in the supraoptic, paraventricular (PVN), and suprachiasmatic nucleus of the hypothalamus. AVP cell groups of hypothalamus and midbrain were found to be glutamatergic, whereas those in regions derived from cerebral nuclei were mainly GABAergic.

In the PVN, AVP can be found together with corticotropin-releasing hormone (CRH), the main hypothalamic regulator of the HPA axis. The AVPergic system participates in regulation of several physiological processes, from stress hormone release through memory formation, thermo- and pain regulation, to social behavior.

vasopressin stress axis

AVP determines behavioral responses to environmental stimuli, and participates in development of social interactions, aggression, reproduction, parental behavior, and belonging. Alterations in AVPergic tone may be implicated in pathology of stress-related disorders (anxiety and depression), Alzheimer’s, posttraumatic stress disorder, as well as schizophrenia.

An increasing body of evidence confirms epigenetic contribution to changes in AVP or AVP receptor mRNA level, not only during the early perinatal period, but also in adulthood:

  • DNA methylation is more targeted on a single gene; and it is better characterized in relation to AVP;
  • Some hint for bidirectional interaction with histone acetylation was also described; and
  • miRNAs are implicated in the hormonal, peripheral role of AVP, and less is known about their interaction regarding behavioral alteration.”

https://www.mdpi.com/1422-0067/22/17/9415/htm “Epigenetic Modulation of Vasopressin Expression in Health and Disease”


Find your way, regardless of what the herd does.

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Take taurine for your mitochondria

This 2021 review summarized taurine’s beneficial effects on mitochondrial function:

“Taurine supplementation protects against pathologies associated with mitochondrial defects, such as aging, mitochondrial diseases, metabolic syndrome, cancer, cardiovascular diseases and neurological disorders. Potential mechanisms by which taurine exerts its antioxidant activity in maintaining mitochondria health include:

  1. Conjugates with uridine on mitochondrial tRNA to form a 5-taurinomethyluridine for proper synthesis of mitochondrial proteins (mechanism 1), which regulates the stability and functionality of respiratory chain complexes;
  2. Reduces superoxide generation by enhancing the activity of intracellular antioxidants (mechanism 2);
  3. Prevents calcium overload and prevents reduction in energy production and collapse of mitochondrial membrane potential (mechanism 3);
  4. Directly scavenges HOCl to form N-chlorotaurine in inhibiting a pro-inflammatory response (mechanism 4); and
  5. Inhibits mitochondria-mediated apoptosis by preventing caspase activation or by restoring the Bax/Bcl-2 ratio and preventing Bax translocation to the mitochondria to promote apoptosis.

taurine mechanisms

An analysis on pharmacokinetics of oral supplementation (4 g) in 8 healthy adults showed a baseline taurine content in a range of 30 μmol to 60 μmol. Plasma content increased to approximately 500 μmol 1.5 h after taurine intake. Plasma content subsequently decreased to baseline level 6.5 h after intake.

We discuss antioxidant action of taurine, particularly in relation to maintenance of mitochondria function. We describe human studies on taurine supplementation in several mitochondria-associated pathologies.”

https://www.mdpi.com/1420-3049/26/16/4913/html “The Role of Taurine in Mitochondria Health: More Than Just an Antioxidant”


I take a gram of taurine at breakfast and at dinner along with other supplements and 3-day-old Avena sativa oat sprouts. Don’t think my other foods’ combined taurine contents are more than one gram, because none are found in various top ten taurine-containing food lists.

As a reminder, your mitochondria came from your mother, except in rare cases.

Preventing human infections with dietary fibers

This 2020 review covered interactions of gut microbiota, intestinal mucus, and dietary fibers. I’ve outlined its headings and subheadings, and ended with its overview:

“I. Dietary fibers and human mucus-associated polysaccharides: can we make an analogy?

I.1 Brief overview of dietary fibers and mucus polysaccharides structures and properties

I.I.1 Dietary fibers

  • Dietary fiber intake and health effects

I.I.2 Intestinal mucus polysaccharides

  • Structure
  • Main functions

I.2 Similarities and differences between dietary fibers and mucus carbohydrates

  • Origin and metabolism
  • Structure

II. Interactions of dietary fibers and mucus-associated polysaccharides with human gut microbiota

II-1 Substrate accessibility and microbial niches

  • Dietary fibers
  • Mucus polysaccharides

II-2 Recognition and binding strategies

  • Dietary fibers
  • Mucus polysaccharides

II-3 Carbohydrate metabolism by human gut microbiota

II-3.1 Specialized carbohydrate-active enzymes

II-3.2 Vertical ecological relationships in carbohydrate degradation

  • Dietary fibers
  • Mucus polysaccharides

II-3.3 Horizontal ecological relationships in carbohydrate degradation

II.4 Effect of carbohydrates on gut microbiota composition and sources of variability

II.4.1 Well-known effect of dietary fibers on the gut microbiota

II.4.2 First evidences of a link between mucus polysaccharides and gut microbiota composition

III. Gut microbiota, dietary fibers and intestinal mucus: from health to diseases?

[no III.1]

III.2 Current evidences for the relationship between dietary fibers, mucus and intestinal-inflammatory related disorder

III.2.1 Obesity and metabolic-related disorders

  • Dietary fibers
  • Mucus polysaccharides

III.2.2 Inflammatory bowel diseases

  • Dietary fibers
  • Mucus polysaccharides

III.2.3 Colorectal cancer

  • Dietary fibers
  • Mucus polysaccharides

IV. How enteric pathogens can interact with mucus and dietary fibers in a complex microbial background?

IV.1 Mucus-associated polysaccharides: from interactions with enteric pathogens to a cue for their virulence?

IV.1.1 Pathogens binding to mucus

  • Binding structures
  • Sources of variations

IV.1.2 Mucus degradation by pathogens

  • Bacterial mucinases
  • Glycosyl hydrolases

IV.1.3 Mucus-based feeding of pathogens

  • Primary degraders or cross-feeding strategies
  • Importance of microbial background

IV.1.4 Pathogens and inflammation in a mucus-altered context

IV.1.5 Modulation of virulence genes by mucus degradation products

IV.2 How can dietary fiber modulate enteric pathogen virulence?

IV.2.1 Direct antagonistic effect of dietary fibers on pathogens

  • Bacteriostatic effect
  • Inhibition of cell adhesion
  • Inhibition of toxin binding and activity

IV.2.2 Indirect effect of dietary fibers through gut microbiota modulation

  • Modulation of microbiota composition
  • Modulation of gut microbiota activity

IV.2.3 Inhibition of pathogen interactions with mucus: a new mode of dietary fibers action?

  • Binding to mucus: dietary fibers acting as a decoy
  • Inhibition of mucus degradation by dietary fibers

V. Human in vitro gut models to decipher the role of dietary fibers and mucus in enteric infections: interest and limitations?

V.1 Main scientific challenges to be addressed

V.2 In vitro human gut models as a relevant alternative to in vivo studies

V.3 In vitro gut models to decipher key roles of digestive secretions, mucus and gut microbiota

V.4 Toward an integration of host responses

V.5 From health to disease conditions

dietary fibers prevent infections

Overview of the potential role of dietary fibers in preventing enteric infections. Reliable and converging data from scientific literature are represented with numbers in circles, while data more hypothetical needing further investigations are represented with numbers in squares.

  1. Some dietary fibers exhibit direct bacteriostatic effects against pathogens.
  2. Dietary fiber degradation leads to short-chain fatty acids (SCFAs) production that can modulate pathogens’ virulence.
  3. By presenting structure similarities with receptors, some dietary fibers can prevent pathogen adhesin binding to their receptors.
  4. By the same competition mechanism, dietary fibers can also prevent toxins binding to their receptors.
  5. Dietary fibers are able to promote gut microbiota diversity.
  6. Dietary fibers may promote growth of specific strains with probiotic properties and therefore exhibit anti-infectious properties.
  7. Suitable dietary fiber intake prevents microbiota’s switch to mucus consumption, limiting subsequent commensal microbiota encroachment and associated intestinal inflammation.
  8. Dietary fibers may prevent pathogen cross-feeding on mucus by limiting mucus degradation and/or by preserving diversity of competing bacterial species.
  9. By preventing mucus over-degradation by switcher microbes, dietary fibers can hamper pathogen progression close to the epithelial brush border, and further restrict subsequent inflammation.”

https://doi.org/10.1093/femsre/fuaa052 “Tripartite relationship between gut microbiota, intestinal mucus and dietary fibers: towards preventive strategies against enteric infections” (not freely available)


There were many links among gut microbiota studies previously curated. For example, Go with the Alzheimer’s Disease evidence found:

“Akkermansia cannot always be considered a potentially beneficial bacterium. It might be harmful for the gut–brain axis in the context of AD development in the elderly.”

The current review provided possible explanations:

“Akkermansia muciniphila could be considered as a species that fulfills a keystone function in mucin degradation. It is a good example of a mucus specialist.”

Points #7-9 of the above overview inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But Gut microbiota strains also found that effects may be found only below species at species’ strain levels.

These reviewers provided copies in places other than what’s linked above. Feel free to contact them for a copy.


Moon bandit

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No magic bullet, only magical thinking

Consider this a repost of Dr. Paul Clayton’s blog post The Drugs Don’t Work:

“The drug industry has enough funds to:

  • Rent politicians;
  • Subvert regulatory agencies;
  • Publish fake data in the most august peer-reviewed literature; and
  • Warp the output of medical schools everywhere.

Their products are a common cause of death. Every year, America’s aggressively modern approach to disease kills over 100,000 in-hospital patients, and twice that number of out-patients.

In 1900, a third of all deaths occurred in children under the age of 5. By 2000 this had fallen to 1.4%. The resulting 30-year increase in average life expectancy fed into the seductive and prevailing myth that we are all living longer; which is manifestly untrue. Improvements in sanitation were far more significant in pushing infections back than any medical developments.

There is currently no pharmaceutical cure for Alzheimer’s or Parkinsonism, nor can there be when these syndromes are in most cases driven by multiple metabolic distortions caused by today’s diet. The brain is so very complex, and it can go wrong in so many ways. The idea that we can find a magic bullet for either of these syndromes is ill-informed and philosophically mired in the past.

It is also dangerous. There is a significant sub-group of dementia sufferers whose conditions are driven and exacerbated by pharmaceuticals. Chronic use of a number of commonly prescribed drugs – and ironically, anti-Parkinson drugs – increases the risk of dementia by roughly 50%.

Big Pharma’s ability to subvert regulatory authorities is even more dangerous. The recent FDA approval of Biogen’s drug aducanumab is a scandal; not one member of the FDA Advisory Committee voted to approve this ineffective product, and three of them resigned in the aftermath of the FDA’s edict. This ‘anti-Alzheimer’s’ drug, which will earn Biogen $56,000 / patient / year, was licensed for financial reasons; it reduced amyloid plaque but was clinically ineffective.

So did the eagerly awaited gantenerumab and solanezumab. But they, too, failed to produce any significant clinical benefit.”


A knee-replacement patient enduring her daily workout

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Prevent your brain from shrinking

My 800th curation is a 2021 human diet and lifestyle study:

“Brain atrophy is correlated with risk of cognitive impairment, functional decline, and dementia. This study (a) examines the statistical association between brain volume (BV) and age for Tsimane, and (b) compares this association to that of 3 industrialized populations in the United States and Europe.

Tsimane forager-horticulturists of Bolivia have the lowest prevalence of coronary atherosclerosis of any studied population, and present few cardiovascular disease (CVD) risk factors. They have a high burden of infections and inflammation, reflected by biomarkers of chronic immune activation, including higher leukocytes counts, faster erythrocyte sedimentation rates, and higher levels of C-reactive protein, interleukin-6, and immunoglobulin-E than in Americans of all ages.

The Tsimane have endemic polyparasitism involving helminths and frequent gastrointestinal illness. Most morbidity and mortality in this population is due to infections.

brain volume

The Tsimane exhibit smaller age-related BV declines relative to industrialized populations, suggesting that their low CVD burden outweighs their high, infection-driven inflammatory risk. If:

  1. Cross-sectional data (which we believe are population-representative of Tsimane adults aged 40 and older) represent well the average life course of individuals; and
  2. The Tsimane are representative of the baseline case prior to urbanization;

these results suggest a ~70% increase in the rates of age-dependent BV decrease accompanying industrialized lifestyles.

Despite its limitations, this study suggests:

  • Brain atrophy may be slowed substantially by lifestyles associated with very low CVD risk; and
  • There is ample scope for interventions to improve brain health, even in the presence of chronically high systemic inflammation.

Lastly, the slow rate of age-dependent BV decrease in the Tsimane raises new questions about dementia, given the role of both infections and vascular factors in dementia risk.”

https://gurven.anth.ucsb.edu/sites/default/files/sitefiles/papers/irimiaetal2021.pdf “The indigenous South American Tsimane exhibit relatively modest decrease in brain volume with age despite high systemic inflammation”


I came across this study by its citation in Dr. Paul Clayton’s 2021 blog post We’ve got to get ourselves back to the garden.

Blood pressure and pain

A trio of papers, with the second and third citing a 2013 review:

“The relationship between pain and hypertension is potentially of great pathophysiological and clinical interest, but is poorly understood. Perception of acute pain initially plays an adaptive role, which results in prevention of tissue damage.

The consequence of ascending nociception is recruitment of segmental spinal reflexes through physiological neuronal connections:

  • In proportion to magnitude and duration of the stimulus, these spinal reflexes cause sympathetic nervous system activation, which increases peripheral resistances, heart rate, and stroke volume; and
  • The response also involves the neuroendocrine system, in particular, the hypothalamic-pituitary-adrenal axis, in addition to further activation of the sympathetic system by adrenal glands.

Persistent pain tends to become chronic and to increase BP values. After a long time, dysfunction of release of endogenous opioids results in a reduction of their analgesic effect. A vicious circle is established, where further pain leads to a reduction in pain tolerance, associated with decreased analgesia mediated by baroreceptors, in a kind of process of exhaustion.”

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.12145 “The Relationship Between Blood Pressure and Pain”


A second paper was a 2021 human experimental pain study:

“We investigated the effectiveness of physiological signals for automatic pain intensity estimation that can either substitute for, or complement patients’ self-reported information. Results indicate that for both subject-independent and subject-dependent scenarios, electrodermal activity (EDA) – which is also referred to as skin conductance (SC) or galvanic skin response – was the best signal for pain intensity estimation.

EDA gave mean absolute error (MAE) = 0.93 using only 3 time-series features:

  1. Time intervals between successive extreme events above the mean;
  2. Time intervals between successive extreme events below the mean; and
  3. Exponential fit to successive distances in 2-dimensional embedding space.

Although we obtained good results using 22 EDA features, we further explored to see if we could reach similar or better results with fewer EDA features. This plot highlights that by considering only the top 3 features, we obtained the same level of performance given by all 22 features together.

journal.pone.0254108.g002

This is the first study that achieved less than 1-unit error for continuous pain intensity estimation using only one physiological sensor’s 3 time-series feature, and a Support Vector Regression machine learning model. Considering that this is an encouraging result, we can estimate objective pain using only the EDA sensor, which needs neither a complex setup nor a complex computationally intense machine learning algorithm.

This study paves the way for developing a smart pain measurement wearable device that can change the quality of pain management significantly.”

https://doi.org/10.1371/journal.pone.0254108 “Exploration of physiological sensors, features, and machine learning models for pain intensity estimation”


A third paper was a 2020 human rotator cuff surgery study:

“Results of our study demonstrated that:

  • Pain during the early postoperative period;
  • Time until occurrence of a retear; and
  • Existence of hypertension

were correlated with severity of pain in patients with a retorn rotator cuff.

Pain was selected as the sole outcome parameter of this study because:

  • Pain is an important factor that compels patients to seek treatment for rotator cuff tears, along with functional disability;
  • Pain and subjective functional deficits are important factors that influence a surgeon’s decision to continue with treatment in cases of retearing; and
  • Analyzing pain severity can be a good way to determine patients’ overall satisfaction after rotator cuff repair.

However, pain is not always correlated with disease severity or tear size and vice versa. A lack of pain does not necessarily depend on integrity of the repaired tendon or constitute a good prognosis. In fact, patients with partial-thickness rotator cuff tears showed more pain than did those with full-thickness tears.

Existence of hypertension had a proportional relationship with pain at 12 months postoperatively in patients with retears. This can be interpreted as a suggestion that pain in patients with retears is not acute, but rather chronic, and may be connected to pain in the early postoperative period at 3 months. However, results of this study cannot explain benefits of controlling hypertension in alleviating pain in patients with retears.”

https://journals.sagepub.com/doi/10.1177/2325967120947414 “Factors Related to Pain in Patients With Retorn Rotator Cuffs: Early Postoperative Pain Predicts Pain at 12 Months Postoperatively”


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PTSD susceptibility?

This 2021 rodent study investigated post-traumatic stress disorder (PTSD) susceptibility:

“PTSD is an incapacitating trauma-related disorder, with no reliable therapy. We show distinct DNA methylation profiles of PTSD susceptibility in the nucleus accumbens (NAc). Data analysis revealed overall hypomethylation of different genomic CpG sites in susceptible animals.

Is it possible to treat PTSD by targeting epigenetic processes? Such an approach might reverse genomic underpinning of PTSD and serve as a cure.

To test plausibility of such an approach, a reliable animal (rat) model with high construct validity is needed. Previously, we reported one such model, which uses predator-associated trauma, and cue reminders to evoke recurring trauma. This simulates clinical PTSD symptoms including re-experiencing, avoidance, and hyperarousal.

Individual PTSD-like (susceptible) behavior is analyzed, enabling identification of susceptible animals separately from those that are non-PTSD-like (resilient). This model captures salient features of this disorder in humans, in which only a fraction of trauma victims develop PTSD, while others are resilient.

experimental model

Sprague–Dawley rats were exposed to trauma and to three subsequent trauma-associated reminders. Freezing behavior was measured under conditions of:

  • Exploration;
  • Social interaction (with a companion); and
  • Hyperarousal.

Controls were exposed to identical conditions except for the traumatic event.

PTSD-like behavior of each animal was compared with baseline and with the population. Two unambiguous sub-populations were identified, resilient and susceptible.

After exposure to trauma and its reminders, susceptible animals showed an increase from baseline in freezing behavior, and over time in all three behavioral tests, as opposed to resilient and control groups.

DMRs

Differentially methylated sites in susceptible and resilient animals compared to control group.

Although we focused in this study on DNA methylation changes that associate with susceptibility, we also report unique changes in DNA methylation that occur in resilient animals. Inhibition of critical genes that are downregulated in susceptible animals convert resilient animals to become susceptible.”

https://www.researchgate.net/publication/353192082_Reduction_of_DNMT3a_and_RORA_in_the_nucleus_accumbens_plays_a_causal_role_in_post-traumatic_stress_disorder-like_behavior_reversal_by_combinatorial_epigenetic_therapy “Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy” (registration required)


Rodents with the same genetics and environment displayed individual differences in their responses to traumatic events. Please provide evidence for that before venturing elsewhere.

Not sure why it took 3+ years for this study received in November 2017 to finally be published in July 2021. Sites other than https://doi.org/10.1038/s41380-021-01178-y are more transparent about their peer review and publication processes.

No causes for PTSD susceptibility were investigated. PTSD effects and symptoms aren’t causes, notwithstanding this study’s finding that:

“Our results support a causal role for the NAc as a critical brain region for expression of PTSD-like behaviors, and a role for programming genes by DNA methylation in the NAc in development of PTSD-like behaviors.”

Can’t say that I understand more about causes for PTSD susceptibility now than before I read this study. Researchers attaching significance to gene functional groups seemed like hypothesis-seeking efforts to overcome limited findings.

Will this study’s combination of a methyl donor with a Vitamin A metabolite address PTSD causes in humans? If it only temporarily alleviates symptoms, what lasting value will it have?


Several brain and body areas that store traumatic memories other than the nucleus accumbens were mentioned in The role of recall neurons in traumatic memories. A wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address each individual, their whole body, and their entire history.

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Osprey breakfast

Gut and brain health

This 2021 human review subject was interactions of gut health and disease with brain health and disease:

“Actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids (SCFAs), tryptophan, and bile acid metabolites / pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour.

Dietary fibres, proteins, and fats ingested by the host contain components which are metabolized by microbiota. SCFAs are produced from fermentation of fibres, and tryptophan-kynurenine (TRP-KYN) metabolites from dietary proteins. Primary bile acids derived from liver metabolism aid in lipid digestion, but can be deconjugated and bio-transformed into secondary bile acids.

1-s2.0-S0149763421001032-gr1

One of the greatest challenges with human microbiota studies is making inferences about composition of colonic microbiota from faeces. There are known differences between faecal and caecal microbiota composition in humans along with spatial variation across the gastrointestinal tract.

It is difficult to interpret microbiome-host associations without identifying the driving influence in such an interaction. Large cohort studies may require thousands of participants on order to reach 20 % explanatory power for a certain host-trait with specific microbiota-associated metrics (Shannon diversity, relative microbial abundance). Collection of metadata is important to allow for a better comparison between studies, and to identify differentially abundant microbes arising from confounding variables.”

https://www.sciencedirect.com/science/article/pii/S0149763421001032 “Mining Microbes for Mental Health: Determining the Role of Microbial Metabolic Pathways in Human Brain Health and Disease”


Don’t understand why these researchers handcuffed themselves by only using PubMed searches. For example, two papers were cited for:

“Conjugated and unconjugated bile acids, as well as taurine or glycine alone, are potential neuroactive ligands in humans.”

Compare scientific coverage of PubMed with Scopus:

  • 2017 paper: PubMed citations 39; Scopus citations 69.
  • 2019 paper: PubMed citations 69; Scopus citations 102.

Large numbers of papers intentionally missing from PubMed probably influenced this review’s findings, such as:

  1. “There are too few fibromyalgia and migraine microbiome-related studies to make definitive conclusions. However, one fibromyalgia study found altered microbial species associated with SCFA and tryptophan metabolism, as well as changes in serum levels of SCFAs. Similarly, the sole migraine-microbiota study reported an increased abundance of the kynurenine synthesis GBM (gut-brain module).
  2. Due to heterogeneity of stroke and vascular disease conditions, it is difficult to make substantial comparisons between studies. There is convincing evidence for involvement of specific microbial genera / species and a neurovascular condition in humans. However, taxa were linked to LPS biosynthesis rather than SCFA production.
  3. Several studies suggest lasting microbial changes in response to prenatal or postnatal stress, though these do not provide evidence for involvement of SCFA, tryptophan, or bile-acid modifying bacteria. Similar to stress, there are very few studies assessing impact of post-traumatic stress disorder on microbiota.”

These researchers took on a difficult task. Their study design could have been better.


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Wildlife

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