The oligosaccharide stachyose

June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neural plasticity

Two 2022 stachyose papers to follow on to Don’t take Beano if you’re stressed, which studied raffinose. Stachyose is in the raffinose oligosaccharide group with similar characteristics, and its content is usually larger in legumes. First is a rodent study:

“Stress can activate the hypothalamic–pituitary–adrenal (HPA) axis and elevate glucocorticoids in the body (cortisol in humans and corticosterone in rodents). Glucocorticoid receptors are abundant in the hippocampus, and play an important role in stress-induced cognition alteration.

Corticosterone is often used to model cognitive impairment induced by stress. Long-term potentiation (LTP) deficit and cognitive impairment always coexist in stress models, and LTP impairment is often considered as one mechanism for stress-induced cognitive deficits.

N-methyl-D-aspartate (NMDA) receptors play critical roles both in normal synaptic functions and excitotoxicity in the central nervous system. D-serine, a coactivator of NMDA receptors, plays an important role in brain function.

In this study, we focused on effects of stachyose, on LTP impairment by corticosterone, gut flora, and the D-serine pathway.

Data in this study showed that 7-consecutive-day intragastric (i.g.) administration of stachyose had protective effect. There was little effect via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration.

To disturb gut flora, a combination of non-absorbable antibiotics (ATB) were applied. Results showed that ATB canceled the protective effect of stachyose without affecting LTP in control and corticosterone-treated mice, suggesting that stachyose may display its protective effects against LTP impairment by corticosterone via gut flora.

Further study is needed to uncover the relation between gut flora and the D-serine metabolic pathway.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.799244/full “Stachyose Alleviates Corticosterone-Induced Long-Term Potentiation Impairment via the Gut–Brain Axis”

One of this study’s references was Eat oats and regain cognitive normalcy.

A stachyose clinical trial is expected to complete this month:

“In the stachyose intervention group, each person took 5 g of stachyose daily before breakfast. Administration method was 100 ml of drinking water dissolved and taken orally for two months. Each person in the placebo control group took the same amount of maltodextrin daily. Stool samples of the 36 subjects were collected weekly.

Primary outcome measures:

Expression of microRNA; and

Structure of gut microbiota.”

https://clinicaltrials.gov/ct2/show/NCT05392348 “Regulatory Effect of Stachyose on Gut Microbiota and microRNA Expression in Human”

The misnomer of nonessential amino acids

June 4, 2022June 4, 2022 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Brainstem, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Control group, Embryo development, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

Three papers, starting with a 2022 review:

“Ideal diets must provide all physiologically and nutritionally essential amino acids (AAs).

Proposed optimal ratios and amounts of true digestible AAs in diets during different phases of growth and production. Because dynamic requirements of animals for dietary AAs are influenced by a plethora of factors, data below as well as the literature serve only as references to guide feeding practices and nutritional research.

Nutritionists should move beyond the ‘ideal protein’ concept to consider optimum ratios and amounts of all proteinogenic AAs in diets for mammals, birds, and aquatic animals, and, in the case of carnivores, also taurine. This will help formulate effectively low-protein diets for livestock (including swine and high-producing dairy cattle), poultry, fish, and crustaceans, as well as zoo and companion animals.”

https://journals.sagepub.com/doi/10.1177/15353702221082658 “The ‘ideal protein’ concept is not ideal in animal nutrition”

A second 2022 review focused on serine:

“The main dietary source of L-serine is protein, in which L-serine content ranges between 2 and 5%. At the daily intake of ~1 g protein per kg of body weight, the amount of serine obtained from food ranges between 1.4 and 3.5 g (13.2–33.0 mmol) per day in an adult.

Mechanisms of potential benefits of supplementing L-serine include increased synthesis of sphingolipids, decreased synthesis of 1-deoxysphingolipids, decrease in homocysteine levels, and increased synthesis of cysteine and its metabolites, including glutathione. L-serine supplementation has been suggested as a rational therapeutic approach in several disorders, particularly primary disorders of L-serine synthesis, neurodegenerative disorders, and diabetic neuropathy.

Unfortunately, the number of clinical studies evaluating dietary supplementation of L-serine as a possible therapy is small. Studies examining therapeutic effects of L-serine in CNS injury and chronic renal diseases, in which it is supposed that L-serine weakens glutamate neurotoxicity and lowers homocysteine levels, respectively, are missing.”

https://www.mdpi.com/2072-6643/14/9/1987/htm “Serine Metabolism in Health and Disease and as a Conditionally Essential Amino Acid”

A 2021 review subject was D-serine, L-serine’s D-isoform:

“The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-serine is necessary for activation of NMDAR and in maintenance of long-term potentiation, and is involved in brain development, neuronal connectivity, synaptic plasticity, and regulation of learning and memory.

The source of D-amino acids in mammals was historically attributed to diet or intestinal bacteria until racemization of L-serine by serine racemase was identified as the endogenous source of D-serine. The enzyme responsible for catabolism (breakdown) of D-serine is D-amino acid oxidase; this enzyme is most abundant in cerebellum and brainstem, areas with low levels of D-serine.

Activation of the NMDAR co-agonist-binding site by D-serine and glycine is mandatory for induction of synaptic plasticity. D-serine acts primarily at synaptic NMDARs whereas glycine acts primarily at extrasynaptic NMDARs.

In normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2021.754032/full “An Overview of the Involvement of D-Serine in Cognitive Impairment in Normal Aging and Dementia”

Young gut, young eyes

May 17, 2022May 17, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Corpus callosum, Genetic factors, Neural plasticity, Neurodegenerative disease

I’ll highlight this 2022 rodent study findings of effects on eye health:

“We tested the hypothesis that manipulating intestinal microbiota influences development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Using fecal microbiota transplantation, we exchanged intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice.

Transfer of aged donor microbiota into young mice accelerates age-associated central nervous system inflammation, retinal inflammation, and cytokine signaling. It promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability.

These detrimental effects can be reversed by transfer of young donor microbiota.

We provide the first direct evidence that aged intestinal microbiota drives retinal inflammation, and regulates expression of the functional visual protein RPE65. RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion. Mutations or loss of function are associated with retinitis pigmentosa, and are implicated in age-related macular degeneration.

Our finding that age-associated decline in host retinal RPE65 expression is induced by an aged donor microbiota, and conversely is rescued by young donor microbiota transfer, suggests age-associated gut microbiota functions or products regulate visual function.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-01243-w “Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain”

Exercise substitutes?

May 16, 2022September 11, 2022 gettingwell4 2-3 stars Required further work, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Genetic factors, Infants, Neurodegenerative disease

Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)

A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.

Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.

Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.

It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).

Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”

Coffee improves information’s signal-to-noise ratio

May 14, 2022May 16, 2022 gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Cerebrum, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals Brain neurons, Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

This 2022 rodent study investigated caffeine’s effects:

“A majority of molecular and neurophysiological studies explored the impact of acute rather than repeated exposure to caffeine. We show that, in bulk tissue analysis, chronic caffeine treatment reduced metabolic processes related to lipids, mitochondria, and translation in mouse hippocampus. In sharp contrast to what was observed in bulk tissue, we found that caffeine induced a neuronal autonomous epigenomic response related to synaptic plasticity activation.

Regular caffeine intake exerts a long-term effect on neuronal activity/plasticity in the adult brain, lowering metabolic-related processes, and simultaneously finely tuning activity-dependent regulations. In non-neuronal cells, caffeine decreases activities under basal conditions, and improves signal-to-noise ratio during information encoding in brain circuits, contributing to bolster salience of information.

Overall, our data prompt the novel concept that regular caffeine intake promotes a more efficient ability of the brain to encode experience-related events. By coordinating epigenomic changes in neuronal and non-neuronal cells, regular caffeine intake promotes a fine-tuning of metabolism in resting conditions.”

https://www.jci.org/articles/view/149371 “Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription”

Brain changes

May 11, 2022May 11, 2022 gettingwell4 4-5 stars Advanced knowledge, Anterior cingulate cortex, Brain development, Brain hemispheres, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory DNA methylation, Genetic factors, Neurodegenerative disease, Prefrontal cortex

This 2022 human study investigated healthy young adult brain changes using MRI and epigenetic clock technologies:

“We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. It is largely unknown how accelerated epigenetic age affects multiple cortical features among young adults from 19 to 49 years. Prior findings imply not only that these dynamic changes reveal different aspects of cortical aging, but also that chronological age itself is not a reliable factor to understand the process of cortical aging.

Seventy-nine young healthy individuals participated in this study. Findings of our study should be interpreted within the context of relatively small sample size, without older adults, and with epigenetic age assessed from saliva.

Additional and unique regional changes due to advanced and accelerated epigenetic age, compared to chronological age-related changes, suggest that epigenetic age could be a viable biomarker of cortical aging. Longitudinal and cross-sectional studies with a larger sample and wider age range are necessary to characterize ongoing effects of epigenetic cortical aging, not only for healthy but also for pathological aging.”

https://doi.org/10.1093/cercor/bhac043 “The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults” (not freely available) Thanks to Dr. Yong Jeon Cheong for providing a copy.

Young immune system, young brain

May 6, 2022May 6, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Genetic factors, Neurodegenerative disease

This 2022 study investigated brain aging:

“We aimed to explore key genes underlying cognitively normal brain aging and its potential molecular mechanisms. Cellular and molecular mechanisms of brain aging are complex and mainly include:

Dysfunction of mitochondria;

Accumulation of oxidatively damaged proteins, nucleic acids, and lipids in brain cells;

Disorders of energy metabolism;

Impaired ‘waste disposal’ mechanism (autophagosome and proteasome functionality);

Impaired signal transduction of adaptive stress response;

Impaired DNA repair;

Abnormal neural network activity;

Imbalance of neuronal Ca²⁺ processing;

Stem cell exhaustion; and

Increased inflammation.

Expression of CD44, CD93, and CD163 mRNA detected by qPCR in hippocampal tissue of cognitively normal aged and young mice.

Underlying molecular mechanisms for maintaining healthy brain aging are related to decline of immune-inflammatory responses. CD44, CD93, and CD 163 are potential biomarkers.”

https://www.frontiersin.org/articles/10.3389/fnagi.2022.833402/full “Identification of Key Biomarkers and Pathways for Maintaining Cognitively Normal Brain Aging Based on Integrated Bioinformatics Analysis”

Reinvigorated

May 3, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory Genetic factors

A follow-on to Beginning of the cure for aging:

“So, I rubbed a small sample of E5 on my right hand and after three days the results were visible. The skin on the treated hand is visibly thicker and lighter. Certainly not a definitive test, but wow, my hand looks decades younger. Dr. Harold Katcher

Hi all,

I applied a little bit of an old freeze-dried prep – there’s no trick here Jay (how could there be), my right-hand looks 30 years younger, even my veins are narrower and less prominent, (I wonder if they’ve let go of their calcification) they also seem less visible because the skin appears thicker

Obviously, the experiment needs to be tried on many people, but I’m certain their reaction will be the same as mine. The interesting thing is, as you noted Jay that the E5 used was essentially just the precipitate, (so therefore crude), but if only for external use, it would not have to meet the same criteria for use as something used internally.

I’m looking at my hands right now and am amazed, a real miracle. I suppose it will fade (as my blood contains pro-aging factors) – but surprisingly, we now have real evidence that E5 works on people. Yesterday Kavita said it doesn’t look like both hands could belong to the same person).

I only applied a small bit to the upper surface of my right hand, nothing more. It was actually historic.

Best to all, Harold

One thing I remember about my father’s parents was spots on their hands and forearms. As a child, I didn’t understand how that happened. After growing up in Miami, and visiting dermatologists 2-3 times a year decades later, it’s apparent.

All about AGEs

April 25, 2022April 27, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Neurochemicals, Serotonin, Stress Control group, Neurodegenerative disease

My 900^th curation is a 2022 review by the lead author of Reversibility of AGEs concentrations that fleshed out details of advanced glycation end products (AGEs) topics:

“This review aims to provide a state-of-the-art overview of the toxicokinetics and toxicodynamics of endogenously formed and exogenous dietary AGEs and their precursors. AGEs are a heterogenous group of:

Low molecular mass (LMM) glycation products formed by reaction with a free amino acid residue and/or to dicarbonyl precursors; and

High molecular mass (HMM) glycation products formed by reaction with a protein-bound amino acid residue, including cross-linked products (i.e. when two amino acid residues are involved instead of one).

Cross-linking of body proteins results in:

Altered structure and function of the proteins;

Proteins are less easily degraded;

An increase in stiffness in tissues that are rich in these proteins, including arterial, lung tissue, joints, and extracellular matrix. Stiffness in these tissues has been associated with diseases including hypertension, cataracts, dementia, atherosclerosis, glomerulosclerosis, emphysema, and joint pain.

In endogenous formation of AGEs and their precursors, the same pathways as exogenous proceed via non-enzymatic reactions, although they occur at lower rates due to the lower physiological temperatures. In addition, specific endogenous AGE formation pathways include glycolysis and the polyol pathway active under hyperglycemic conditions.

Considering heterogeneity of glycation products, as also reflected in different ADME outcomes, AGEs and their precursors cannot be grouped together. Specific, individual information is required for a proper evaluation, especially considering ADME properties.

The role of exogenous HMM AGEs and precursors seems to be restricted by limited bioavailability to local effects on the intestine including its microbiota, unless being degraded to their LMM form. An important role is probably left for reactive (endogenously formed) dicarbonyl AGE precursors and as a consequence the endogenously formed AGEs.

The direct contribution of reactive dicarbonyl precursors to dicarbonyl stress and their indirect contribution to endogenous HMM AGE formation and subsequent AGE receptor activation remain to be further studied.”

https://www.sciencedirect.com/science/article/pii/S0278691522001855 “Differences in kinetics and dynamics of endogenous versus exogenous advanced glycation end products (AGEs) and their precursors”

State-dependent memory

April 22, 2022 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Anterior cingulate cortex, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress, Thalamus Control group, Infants, Neural plasticity, Prefrontal cortex

This 2021 review by two coauthors of What can cause memories that are accessible only when returning to the original brain state? provided evidence for alternative interpretations of memory experiments:

“Memory consolidation hypotheses postulate a long series of various and time consuming elaborate processes that come to protect memory from disruption after various periods of time. For more than fifty years, consolidation hypotheses led to the idea that:

Memories are fragile and can easily be disrupted; and

Memories require several hours to be encoded (Cellular Consolidation), and extensive periods of time (days to weeks and even months and years), to be definitely stabilized (Systems Consolidation).

Although these views rely on well substantiated findings, their interpretation can be called into question.

An alternative position is that amnesia reflects retrieval difficulties due to contextual changes. This simple explanation is able to account for most, if not all, results obtained in consolidation studies.

Systems Consolidation can be explained in terms of a form of state-dependency.

Recent memory remains detailed, context-specific (in animals), and vivid (in humans) and very susceptible to contextual changes. With the passage of time, memories become less precise, and retention performance less and less affected by contextual changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763421005510 “Revisiting systems consolidation and the concept of consolidation” (not freely available)

I came across this review while trying to understand why a 2022 rodent study felt wrong. That study followed the standard memory paradigm, and I appreciate its lead author providing a copy since it wasn’t otherwise available.

But those researchers boxed themselves in with consolidation explanations for findings. They used drugs to change subjects’ memories’ contexts between training and testing. They didn’t see that tested memories were dependent on subjects’ initial brain states.

This review cited a paper abstracted in Resiliency in stress responses, namely Neurobiological mechanisms of state-dependent learning.

Crab for lunch

MET minutes

April 16, 2022April 17, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory Control group, Genetic factors, Neurodegenerative disease

This 2022 meta-analysis investigated the relationship between cognition and exercise expressed in MET minutes (metabolic equivalent for task, a unit that estimates amount of energy used during physical activity compared to resting metabolism):

“44 studies (4793 participants aged 50 years or over) were included. There was a non-linear, dose-response association between overall exercise and cognition.

We found no minimal threshold for beneficial effect of exercise on cognition. The estimated minimal exercise dose associated with clinically relevant changes in cognition was 724 METs-min per week, and doses beyond 1200 METs-min per week provided less clear benefits.

Obesity status was the main moderator of effects of exercise on cognition. Our results suggest that overweight/obese older adults may benefit from lower exercise levels than recommended for the general population.

Exercise is one of the few interventions shown to prevent and treat dementia or cognitive decline in older adults.”

https://www.sciencedirect.com/science/article/pii/S1568163722000332 “Optimal dose and type of exercise to improve cognitive function in older adults: A systematic review and bayesian model-based network meta-analysis of RCTs”

Similar to Biological age and zinc, this study found that our metabolic zones determine how our choices can achieve desired effects.

There’s no substitute for exercise. Take responsibility for your one precious life: nobody else exercises for you.

Came home this afternoon after my daily walk on the beach, thinking about how – in a way – this honored ancestors. We are the products of who they were and what they did to survive.

Vascular memory

April 8, 2022December 17, 2023 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Primal Therapy, Stress Control group, Embryo development, Infants

This 2022 rodent study investigated effects of inducing hypertension for two weeks:

“Hypertension is conventionally associated with a neurohormonal activation from the sympathetic nervous and the renin-angiotensin-aldosterone systems. Angiotensin II (AngII) is a potent regulator of blood pressure, and is also a key player in hypertension development.

An initial 2-week exposure to AngII induced profound changes in cardiac and vascular remodeling, including endothelial activation, vascular inflammation and oxidant stress, all of which were maintained up to 3 weeks after AngII withdrawal. This phenotype was sustained despite early normalization of blood pressure after AngII withdrawal.

Our RNAseq pathway analysis suggests involvement of epigenetic regulators involved in methylation, such as PRC2. PRC2 complex catalyzes trimethylation of histone H3 on lysine 27 (H3K27me3), a histone mark necessary for maintaining transcriptional repression during multicellular development.

Cell type-specific patterns of H3K27me3 are crucial for preserving cell identity. Consistent with this analysis, we observed a significant increase in H3K27me3 epigenetic mark in aortic tissue, intriguingly, only in both memory conditions.

Transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting, supporting a memory effect despite stimulus withdrawal. Future characterization of underlying AngII-dependent signaling might unveil new targets for its therapeutic modulation and reversal of this adverse legacy effect.”

https://www.frontiersin.org/articles/10.3389/fcvm.2022.854361/full “Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of Vascular Memory”

These subjects’ ages were equivalent to a 20-year-old human:

How much earlier could our vascular system retain events we experienced such as epigenetic H3K27me3 increases? Teenaged, late childhood, early childhood, infancy, fetal parts of our lives?
How long would these vascular system memories and their continued signaling linger?
What experiences could change these long-lasting memories?

Icy fire

Gut microbiota knowledge through 2021

March 21, 2022January 3, 2023 gettingwell4 2-3 stars Required further work, Amygdala, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Infants, Neurodegenerative disease, Prefrontal cortex, Reciprocity

I’ll curate this 2022 review of what’s known and unknown about our trillions of gut microbiota through its topic headings:

“Most microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases.

A. Understanding the Microbiome Composition and Factors That Shape Its Diversity
Effect of Diet Composition on the Microbiome Diversity

Macronutrients and Microbiome Diversity

Nutrient and Mineral Supplements and Microbiome Diversity

Stress

Drugs

Race and Host Genetics

Aging

Lifestyle

Exercise

Smoking

Urbanization

B. Understanding the Microbiome Function and Its Association With Onset and Progression of Many Diseases

Microbiome Association With Inflammatory and Metabolic Disorders

Chronic Inflammation in GIT and Beyond

Development of Malignant Tumors

Obesity

Coronary Artery Disease

Respiratory Diseases

Microbiome Role in Psychiatric, Behavioral, and Emotional Disorders

Anxiety

Depression

Sleep

Fear Response

Autism

Alzheimer and Dementia

C. Understanding the Microbiome Function as Mediated by Secreted Molecules

D. Conclusion and Future Directions – A pioneering study aimed to computationally predict functions of microbes on earth estimates the presence of 35.5 million functions in bacteria of which only 0.02% are known. Our knowledge of its functions and how they mediate health and diseases is preliminary.”

https://www.frontiersin.org/articles/10.3389/fmicb.2022.825338 “Recent Advances in Understanding the Structure and Function of the Human Microbiome”

I took another test last month at the 14-month point of treating my gut microbiota better. Compared with the 7-month top level measurements, what stood out was an increase in relative abundance from 1% to 7% in the Verrucomicrophia phylum that pretty much exclusively comprises species Akkermansia muciniphilia in humans:

This review termed Akkermansia muciniphilia relative increases as beneficial. Go with the Alzheimer’s Disease evidence didn’t.

Preventing human infections with dietary fibers inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But I already eat much more fiber than our human ancestors’ estimated 100 grams of fiber every day, so lack of fiber definitely didn’t cause this relative increase.

Resistant starch therapy observed:

“Relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders increase in relative abundance to a greater extent.”

I’ll wait for further evidence while taking responsibility for my own one precious life.

Didn’t agree with this review’s statements regarding microbial associations with fear. These reviewers framed such associations as if gut microbiota in the present had stronger influences on an individual’s fear responses than did any of the individual’s earlier experiences. No way.

I came across this review by it citing The microbiome: An emerging key player in aging and longevity, which was Reference 25 of Dr. Paul Clayton’s blog post What are You Thinking?

Also didn’t agree with some of the doctor’s post:

Heterochronic parabiosis of young and old animals is wildly different from fecal transfer. Can’t really compare them to any level of detail.
Using a rodent young-to-old fecal microbiota transplant study to imply the same effects would happen in humans? Humans don’t live in controlled environments, so why would a young human individual’s gut microbiota necessarily have healthier effects than an old individual’s?
Another example was the penultimate paragraph: “By adding a mix of prebiotic fibers to your diet and maintaining a more youthful and less inflammatory microbiome you will have less inflammation, less endotoxaemia and less inflammageing. You will therefore live healthier and longer.” I’m okay with the first sentence. Equivalating the first sentence to both healthspan and lifespan increases in the second sentence wasn’t supported by any of the 45 cited references.

Reversing hair greying

March 7, 2022January 29, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Stress, Telomeres DNA methylation, Genetic factors

I’ll highlight this 2021 human study’s findings regarding stress:

“We profiled hair pigmentation patterns (HPPs) along individual human hair shafts, producing quantifiable physical timescales of rapid greying transitions. White/grey hairs that naturally regain pigmentation across sex, ethnicities, ages, and body regions, quantitatively define reversibility of greying in humans.

A systematic survey of two-colored hairs on the scalp of a 35-year-old Caucasian male with auburn hair color over a 2-day period yielded five two-colored hair shafts (HSs) from the frontal and temporal scalp regions. Unexpectedly, all HSs exhibited reversal. HPP analysis further showed that all HSs underwent reversal of greying around the same time period.

A retrospective assessment of psychosocial stress levels using a time-anchored visual analog scale (participants rate and link specific life events with start and end dates) was then compared to HPPs. Reversal of greying for all hairs coincided closely with decline in stress and a 1-month period of lowest stress over the past year (0 on a scale of 0–10) following a 2-week vacation.

We were also able to examine a two-colored hair characterized by an unusual pattern of complete HS greying followed by rapid and complete reversal plucked from the scalp of a 30-year-old Asian female participant with black hair. HPP analysis of this HS showed a white segment representing approximately 2 cm.

Quantitative life stress assessment revealed a specific 2-month period associated with an objective life stressor (marital conflict and separation, concluded with relocation) where the participant rated her perceived stress as highest (9–10 out of 10) over the past year. The increase in stress corresponded in time with complete but reversible hair greying.

We document a complete switch-on/off phenomena during a single anagen cycle. Proteomic features of hair greying directly implicate multiple metabolic pathways that are both reversible in nature and sensitive to stress-related neuroendocrine factors.

This new method to quantitatively map recent life history in HPPs provides an opportunity to longitudinally examine the influence of recent life exposures on human biology. Additional prospective studies with larger sample sizes are needed to confirm robust reproducibility and generalizability of our findings.”

https://elifesciences.org/articles/67437 “Quantitative mapping of human hair greying and reversal in relation to life stress”

See Reversing hair greying, Part 2 for selected papers through 2024 that cited this study.

Signaling pathways and disordered proteins

March 4, 2022March 7, 2022 gettingwell4 2-3 stars Required further work, Cortisol, Epigenetics, Glutamate, Immune system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neural plasticity

This 2022 review explored the title subject:

“Cell signaling imposes many demands on proteins that comprise these pathways, including abilities to form active and inactive states, and to engage in multiple protein interactions. Signaling often requires amplifying signals, regulating or tuning responses to signals, combining information sourced from multiple pathways, all while ensuring process fidelity.

Sensitivity, adaptability, and tunability are possible, in part, due to inclusion of intrinsically disordered regions in many proteins involved in cell signaling. This review highlights the critical role of intrinsically disordered proteins for signaling:

In widely diverse organisms (animals, plants, bacteria, fungi);

In every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine); and

At each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process.

Function of the glucocorticoid receptor is regulated in part by its intrinsically disordered C-terminal tail. Prior to activation, the glucocorticoid receptor resides in cytosol:

Intrinsic disorder in the glucocorticoid receptor not only enables multiple allosteric regulatory interactions to impact function, but also allows deployment of different surfaces of the protein to enable binding to many different sets of macromolecules, and regulation of these interactions via mRNA splicing and phosphorylation.

Combinations of alternative translation initiation and alternative mRNA splicing result in production of multiple glucocorticoid receptor isoforms from one gene. Various isoforms exhibit distinctive tissue distribution patterns and altered transcriptional regulatory profiles.

Greater than 90% of transcription factors either contain intrinsically disordered regions of proteins or are entirely intrinsically disordered. The many advantages conferred by disorder to cell signaling cascades means that:

Understanding signaling required definition of roles disorder plays in each pathway;

Many more examples of disordered proteins in cell signaling pathways are likely to be discovered; and

More mechanisms by which disorder functions remain to be elucidated.”

https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00821-7 “Intrinsically disordered proteins play diverse roles in cell signaling”

Cells in vivo seldom act on their own impetus. I would have liked discussion – or at least mention – of bidirectional signals between genes / cells / tissues / organs / organism / environment. This review’s topic of cell signaling pathways excluded “interactions of complex, interconnected systems spanning hierarchical levels” as explored in An environmental signaling paradigm of aging.