All about walnuts’ effects

Five 2022 papers focusing on walnuts, starting with a comparison of eight tree nuts:

“The aim of the present study was to examine 8 different popular nuts – pecan, pine, hazelnuts, pistachio, almonds, cashew, walnuts, and macadamia. Total content of phenolic compounds in nuts ranged from 5.9 (pistachio) to 432.9 (walnuts) mg/100 g.

Walnuts had the highest content of polymeric procyanidins, which are of great interest as important compounds in nutrition and biological activity, as they exhibit antioxidant, anti-inflammatory, antimicrobial, cardio- and neuroprotective action. Walnuts are good sources of fatty acids, especially omega-3 and omega-6.”

https://www.sciencedirect.com/science/article/pii/S2590157522002164 “Nuts as functional foods: Variation of nutritional and phytochemical profiles and their in vitro bioactive properties”


A second study compared the same eight tree nuts plus Brazil nuts and peanuts:

“The highest total content of all analyzed flavonoids was determined in walnuts (114.861 µg/g) with epicatechin the most abundant, while the lowest was in almonds (1.717 µg/g). Epicatechin has antioxidant, anti-inflammatory, antitumor, and anti-diabetic properties. Epicatechin has beneficial effects on the nervous system, enhances muscle performance, and improves cardiac function.”

https://www.mdpi.com/1420-3049/27/14/4326/htm “The Content of Phenolic Compounds and Mineral Elements in Edible Nuts”


Next, two systematic reviews and meta-analyses of human studies:

“We carried out a systematic review of cohort studies and randomized controlled trials (RCTs) investigating walnut consumption, compared with no or lower walnut consumption, including those with subjects from within the general population and those with existing health conditions, published from 2017 to 5 May 2021.

  • Evidence published since 2017 is consistent with previous research suggesting that walnut consumption improves lipid profiles and is associated with reduced CVD risk.
  • Evidence pointing to effects on blood pressure, inflammation, hemostatic markers, and glucose metabolism remains conflicting.
  • Evidence from human studies showing that walnut consumption may benefit cognitive health, which is needed to corroborate findings from animal studies, is now beginning to accumulate.”

https://academic.oup.com/nutritionreviews/advance-article/doi/10.1093/nutrit/nuac040/6651942 “Walnut consumption and health outcomes with public health relevance – a systematic review of cohort studies and randomized controlled trials published from 2017 to present”


“We aimed to perform a systematic review and meta-analysis of RCTs to thoroughly assess data concerning effects of walnut intake on selected markers of inflammation and metabolic syndrome in mature adults. Our findings showed that:

  • Walnut-enriched diets significantly decreased TG, TC, and LDL-C concentrations, while HDL-C levels were not significantly affected.
  • No significant changes were noticed on anthropometric, cardiometabolic, and glycemic indices after higher walnut consumption.
  • Inflammatory biomarkers did not record statistically significant results.”

https://www.mdpi.com/2076-3921/11/7/1412/htm “Walnut Intake Interventions Targeting Biomarkers of Metabolic Syndrome and Inflammation in Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials”


Finishing with a rodent study that gave subjects diabetes with a high-fat diet, then mixed two concentrations of walnut extract in with the treatment groups’ chow:

“This study was conducted to evaluate the protective effect of Gimcheon 1ho cultivar walnut (GC) on cerebral disorder by insulin resistance, oxidative stress, and inflammation in HFD-induced diabetic disorder mice. After HFD feed was supplied for 12 weeks, samples were orally ingested for 4 weeks to GC20 and GC50 groups (20 and 50 mg/kg of body weight, respectively).

  • Administration of GC improved mitochondrial membrane potential function, and suppressed oxidative stress in the brain.
  • GC inhibited hepatic and cerebral lipid peroxidation and the formation of serum AGEs, and increased serum antioxidant activity to improve HFD-induced oxidative stress.
  • The HFD group showed significant memory impairment in behavioral tests. On the other hand, administration of GC showed improvement in spatial learning and memory function.

walnut brain effects

Based on these physiological activities, GC showed protective effects against HFD-induced diabetic dysfunctions through complex and diverse pathways.”

https://www.mdpi.com/1420-3049/27/16/5316/htm “Walnut Prevents Cognitive Impairment by Regulating the Synaptic and Mitochondrial Dysfunction via JNK Signaling and Apoptosis Pathway in High-Fat Diet-Induced C57BL/6 Mice”


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Minds of their own

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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Glucoraphanin is not sulforaphane

A poorly-conceived and intentionally-misrepresented human 2022 broccoli product study:

“We investigated whether a sulforaphane (SFN) [actually, sulforaphane precursor glucoraphanin] intake intervention improved cognitive performance and mood states in healthy older adults in a 12-week, double-blinded, randomized controlled trial.

The SFN group showed improvement in processing speed and a decrease in negative mood compared to the placebo group. However, there were no significant results in other biomarkers of oxidant stress, inflammation, or neural plasticity.

These results indicate that nutrition interventions using SFN can have positive effects on cognitive functioning and mood in healthy older adults.”

https://www.frontiersin.org/articles/10.3389/fnagi.2022.929628/full “Effects of sulforaphane intake on processing speed and negative moods in healthy older adults: Evidence from a randomized controlled trial”


Contrary to this study’s title, actual sulforaphane intake was not measured. The glucoraphanin product used in this study was the same item and daily dose as Eat broccoli sprouts for your workouts, which investigated effects with 19-to-23-year-old men. The treatment was taken all at once at an unspecified time of day rather than three times a day with young subjects.

These researchers knew from the 2012 study cited for dose that:

“Individual conversions of glucosinolates [like glucoraphanin] to isothiocyanates [like sulforaphane] varied enormously, from about 1% to more than 40% of dose. In contrast, administration of isothiocyanates (largely sulforaphane)-containing broccoli sprout extracts, resulted in uniformly high (70-90%) conversions to urinary dithiocarbamates.”

Young or old, a daily 30 mg glucoraphanin intake isn’t sufficient to fully activate human Nrf2 signaling pathways. A daily 17 mg sulforaphane intake could accomplish that.


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Broccoli sprouts and your brain

A 2022 review of Nrf2 signaling hilariously avoided mentioning sulforaphane, although of ~4,000 sulforaphane published articles, two were cited. I’ll curate it anyway to highlight referenced brain effects.

“A good stability of NRF2 activity is crucial to maintain redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, ageing, and ageing-related neurodegenerative diseases.

A functional NRF2 system is important to regulate both neuroinflammation, i.e., activation of microglia and astrocytes, and oxidative stress in the brain. NRF2 and NF-κB transcription factors regulate cellular responses to inflammation and oxidative stress in order to maintain brain homeostasis. Both pathways have been described to inhibit each other.

Nrf2 brain aging

Future challenges will be to establish novel therapies to:

  • Increase NRF2 activation in specific cell types and/or brain regions; and
  • Modulate NRF2 pathway in senescent cells.

Modulation of NRF2 signalling pathway by using specific food products [like unmentioned broccoli sprouts] and phytochemicals [like unmentioned sulforaphane], dietary supplements [like unmentioned Vitamin D3], drugs, and epigenetic modifiers, alone or in combination, will help to limit inflammatory diseases, ageing process, and subsequently ageing-related diseases.”

https://www.mdpi.com/2076-3921/11/8/1426/htm “Normal and Pathological NRF2 Signalling in the Central Nervous System”


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The goddess of rainbows

Two 2022 papers, starting with a review of irisin:

“This article is an overview of irisin generation, secretion, and tissue distribution. Its targeting of tissues or organs for prevention and treatment of chronic diseases is systematically summarized, with discussion of underlying molecular mechanisms.

Irisin is an exercise-induced myokine expressed as a bioactive peptide in multiple tissues and organs. Exercise and cold exposure are major inducers for its secretion.

Mechanistic studies confirm that irisin is closely correlated with lipid metabolism, insulin resistance, inflammation, ROS, endocrine, neurotrophic factors, cell regeneration and repairing, and central nervous system regulation. Irisin decreases with age, and is closely associated with a wide range of aging-related diseases.

A number of studies in elderly humans and animal models have shown that exercise can promote the body’s circulation and increase irisin levels in some tissues and organs. Resistance, aerobic, or combined exercise seem to play a positive role. However, exercise could not change serum irisin in some reported studies.

irisin human studies

There are large individual differences in exercise training in the elderly population. Since the half-life of irisin in the body is less than 1 h, it is necessary to pay attention to the time of blood sampling after a single exercise intervention. Some factors that impede detection of irisin levels in vivo include the half-life of irisin protein, sampling time, different tissues, and different health statuses before and after intervention.

It is worth noting that high-intensity exercise shows higher irisin levels even with the same energy expenditure during exercise. Precision studies of irisin in elderly subjects following exercise intervention need to be further clarified.”

https://www.sciencedirect.com/science/article/pii/S1568163722001222 “Irisin, An Exercise-induced Bioactive Peptide Beneficial for Health Promotion During Aging Process” (not freely available) Thanks to Dr. Ning Chen for providing a copy.


A second paper was a human study too recent to be cited by the first paper. I’ll highlight its irisin findings:

“We investigated the complex relationship among DNAm based biomarkers of aging, including DNAmFitAge, a variety of physiological functioning variables, blood serum measures including cholesterol, irisin level, and redox balance, and the microbiome on 303 healthy individuals aged between 33 and 88 years with a diverse level of physical fitness. Regular exercise was associated with younger biological age, better memory, and more protective blood serum levels.

Our research intends to show that regular physical exercise is related to microbiota and methylation differences which are both beneficial to aging and measurable. Our research provides the first investigation between microbiome derived metabolic pathways and DNAm based aging biomarkers.

Irisin levels decrease with age (0.23 average decrease for every 1 year older). We found age-related decreases in irisin levels were attenuated by exercise training. The link between irisin to GrimAge Acceleration and FitAge Acceleration is a novel observation.

HDL is positively associated with irisin. HDL and irisin have complex roles in physiology, and the positive relationship we observe between physical exercise and HDL and irisin align with protective effects seen between HDL and irisin with glucose homeostasis.

This work further supports the biological importance of irisin to the aging process. It is possible our research motivates interventions to boost irisin, like through physical exercise, as possible anti-aging therapies.”

https://www.medrxiv.org/content/10.1101/2022.07.22.22277842v1 “DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation


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Variable aging measurements

Two papers on aging measurements, starting with a 2022 human study:

“We collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration / neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging.

blsa participant ages

We demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity, and shorter survival.”

https://www.nature.com/articles/s43587-022-00243-7 “Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging”


I disagree with this study’s methodology.

1. Although it acknowledged individual variability, nothing was done to positively adjust to those facts. What could have been done per A review of biological variability was:

“Obtain a measurement of variability that is independent of the mean to ensure to not confound changes in variability with shifts in mean.”

2. A usual research practice is to take at least three measurements, and use their average as representative. That wasn’t done here, maybe because of time and expense considerations?

3. An important measurement for physical function was the time to finish a 400 meter walk. I walk more than ten times that almost every day. I use the first 400 meters as a warmup period while getting to the beach to walk eastward and enjoy the predawn light and water animal activity. I concentrate on gait speed during the last third while walking westward on a straightaway bike path.

This study would measure my gait speed as a sometimes old person during the first 400 meters, rather than a gait speed that usually approaches a young person’s during the last 400 meters. Even if I tried to walk my fastest right out of the gate, I wouldn’t be surprised to find a decade or two difference by this study’s measurements between a morning walk’s first and last 400 meter gait speeds.

4. An important cognitive function measurement was the Digital Symbol Substitution Test, apparently taken during subjects’ fasted state? Sometimes after exercising, I’m okay cognitively when starting work in a fasted state at 6:30 a.m., and other times I’m tired.

Two days ago during the last hour of work 1:30-2:30 p.m., I did outstanding work, four hours after eating whole oats for breakfast, and after drinking two coffees and three teas. I took time to put together pieces of puzzles into proper contexts for management’s attention. My bosses weren’t too pleased with the story it told, but it is what it is.

5. Are measurements of how you start what matters? Or is it how you finish, as is common in competitive sports?

This study would measure my cognitive function as a sometimes old person, rather than performance that approaches a young person’s later in the workday. For both physical and cognitive function, my abilities to ramp up and come close to young people’s capabilities are features that I work on, not random, inconvenient measurement variability.

6. Blood measurements were downgraded as having “limited coverage of the four phenotypic domains.” These were taken to fit into specific paradigms and epigenetic clocks. They predictably failed to show causality, as acknowledged with:

“Our analysis showed strong associations between global longitudinal phenotypic score and changes in physical and cognitive function. We did not have sufficient observations to fully separate these two dimensions over time, which would have strengthened the assumption of causality.”

Nowhere in this study was it hinted that all measurements were downstream effects of unmeasured causes. A follow-on study could reanalyze these subjects’ blood samples, MRI, and other measurements for originating upstream factors of signaling pathways and cascades per Signaling pathways and aging and An environmental signaling paradigm of aging.


Reference 35 of this first study was a 2021 human and rodent study that was tossed in as a limitation with:

“We might not have all of the relevant phenotypic measures (for example, more detailed immune profiles) for all participants.”

Its findings included:

“From the blood immunome of 1,001 individuals aged 8–96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians.

Canonical markers of acute infection such as IL-6 and tumor necrosis factor-α were not major contributors to iAge, indicating that, except for IL-1β, infection-driven inflammatory markers of the acute inflammatory response do not contribute to age-related chronic inflammation.

We conducted a follow-up study in an independent cohort of 97 extremely healthy adults (aged 25–90 years) matched for cardiovascular risk factors (including conserved levels of high-sensitivity C-reactive protein), selected from a total of 151 recruited participants using strict selection criteria. In this healthy cohort, inflammation markers were measured using a 48-plex cytokine panel. Only 6 circulating immune proteins were significantly correlated with age, with CXCL9 again the largest contributor to age-related inflammation.

CXCL9 is a T-cell chemoattractant induced by IFN-γ and is mostly produced by neutrophils, macrophages and endothelial cells (ECs). We find that CXCL9 is mainly produced by aged endothelium and predicts subclinical levels of cardiovascular aging in nominally healthy individuals.

We did not find any significant correlation between known disease risk factors reported in the study (BMI, smoking, dyslipidemia) and levels of CXCL9 gene or protein expression. We hypothesize that one root cause of CXCL9 overproduction is cellular aging per se, which can trigger metabolic dysfunction.

As ECs but not cardiomyocytes expressed the CXCL9 receptor, CXCR3, we hypothesize that this chemokine acts both in a paracrine fashion (when it is produced by macrophages to attract T cells to the site of injury) and in an autocrine fashion (when it is produced by the endothelium) creating a positive feedback loop. In this model, increasing doses of CXCL9 and expression of its receptor in these cells leads to cumulative deterioration of endothelial function in aging.

IFN-γ did not increase in expression in our cellular aging RNA-seq experiment, suggesting that there are triggers of CXCL9 (other than IFN-γ) that play a role in cellular senescence in the endothelium that are currently unknown. However, in our 1KIP study, IFN-γ was in fact the second-most important negative contributor to iAge, which could be explained by the cell-priming effect of cytokines, where the effect of a first cytokine alters the response to a different one.

iAge derived from immunological cytokines gives us an insight into the salient cytokines that are related to aging and disease. A notable difference compared to other clocks is that iAge is clearly actionable as shown by our experiments in CXCL9 where we can reverse aging phenotypes. More practical approaches range from altering a person’s exposomes (lifestyle) and/or the use of interventions to target CXCL9 and other biomarkers described here.

Our immune metric for human health can identify within healthy older adults with no clinical or laboratory evidence of cardiovascular disease, those at risk for early cardiovascular aging. We demonstrate that CXCL9 is a master regulator of vascular function and cellular senescence, which indicates that therapies targeting CXCL9 could be used to prevent age-related deterioration of the vascular system and other physiological systems as well.”

https://www.nature.com/articles/s43587-021-00082-y “An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging”


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Gut microbiota therapy

This June 2022 review cited twenty 2022 papers for relationships between Parkinson’s disease and gut microbiota:

“Clinical diagnosis of PD is based on typical motor symptoms, and novel diagnostic biomarkers have been developed such as imaging markers, and α-synuclein fluid and tissue markers. Multimorbidity of non-motor disorders heighten the risk of adverse outcomes for patients with PD, which usually appear 20 years before onset of motor symptoms.

The gut microbiota is intimately connected to occurrence, development, and progression of PD, especially in early stages. A better understanding of the microbiota–gut–brain axis in PD can provide an opportunity to monitor an individual’s health by manipulating gut microbiota composition.

Several approaches like administration of probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, FMT, and dietary modifications have been tried to mitigate dysbiosis-induced ill effects and alleviate PD progression.

fimmu-13-937555-g001

Epidemiological studies have reported that diet affects (positively or negatively) onset of neurodegenerative disorders. Evidence suggests that diet composition’s effects on brain health is not due to diet-induced inflammatory response, but because of its effects on the gut microbiome.

Dysbiotic gut microbiota (including altered microbial metabolites) may play crucial roles in PD via various mechanisms, such as:

  • Increased intestinal permeability;
  • Aggravated intestinal inflammation and neuroinflammation;
  • Abnormal aggregation of α-synuclein fibrils;
  • Imbalanced oxidative stress; and
  • Decreased neurotransmitters production.

Future studies are essential to further elucidate cause-effect relationships between gut microbiota and PD, improved PD therapeutic and diagnostic options, disease progression tracking, and patient stratification capabilities to deliver personalized treatment and optimize clinical trial designs.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.937555/full “Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease”


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Taurine week #6: Stress

Two 2022 rodent studies of taurine’s associations with long-term stress, starting with a chronic restraint stress model:

“We show that chronic restraint stress can lead to hyperalgesia accompanied by changes in gut microbiota that have significant gender differences. Corresponding changes of bacteria can further induce hyperalgesia and affect different serum metabolism in mice of the corresponding sex.

Different serum metabolites between pseudo-germ-free mice receiving fecal microbiota transplantation from the chronic restraint stress group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice.

Effects of gut microbiota transplantation on serum metabolomics of female host: Taurine and hypotaurine metabolism, tryptophan metabolism, serotonergic synapse, arachidonic acid metabolism, and choline metabolism in cancer were the five identified pathways in which these different metabolites were enriched.

1-s2.0-S1043661822000743-gr11_lrg

Taurine and hypotaurine play essential roles in anti-inflammation, anti-hypertension, anti-hyperglycemia, and analgesia. Taurine can be used as a diagnostic index for fibromyalgia syndrome and neuropathic pain.

These findings improve our understanding of sexual dimorphism in gut microbiota in stress-induced hyperalgesia and the effect of gut microbiota on blood metabolic traits. Follow-up research will investigate causal relationships between them.”

https://www.sciencedirect.com/science/article/pii/S1043661822000743 “Gut microbiota and its role in stress-induced hyperalgesia: Gender-specific responses linked to different changes in serum metabolites”

Human equivalents:

  • A 7-8 month-old mouse would be a 38-42 year-old human.
  • A 14-day stress period is about two years for humans.

A second study used a chronic social defeat stress model:

“The level of taurine in extracellular fluid of the cerebral medial prefrontal cortex (mPFC) was significantly reduced in mice with chronic social defeat stress (CSDS)-induced depression. We found that taurine supplementation effectively rescued immobility time during a tail suspension assay and improved social avoidance behaviors in CSDS mice.

Male C57BL/6 J mice (∼ 23 g) and male CD-1 mice aged 7–8 months (∼ 45 g) were used. CD-1 mice were screened for aggressive behavior during social interactions for three consecutive days before the start of the social defeat sessions. Experimental C57BL/6 J mice were subjected to physical interactions with a novel CD-1 mouse for 10 min once per day over 10 consecutive days.

We found significant reductions in taurine and betaine levels in mPFC interstitial fluid of CSDS mice compared with control mice.

csds taurine betaine

We additionally investigated levels of interstitial taurine in chronic restraint stress (CRS) mice, another depressive animal model. After 14 days of CRS treatment, mice showed typical depression-like behaviors, including decreased sucrose preference and increased immobility time. mPFC levels of interstitial taurine were also significantly decreased in CRS mice.

Taurine treatment protected CSDS mice from impairments in dendritic complexity, spine density, and proportions of different types of spines. Expression of N-methyl D-aspartate receptor subunit 2A, an important synaptic receptor, was largely restored in the mPFC of these mice after taurine supplementation.

These results demonstrated that taurine exerted an antidepressive effect by protecting cortical neurons from dendritic spine loss and synaptic protein deficits.”

https://link.springer.com/article/10.1007/s10571-022-01218-3 “Taurine Alleviates Chronic Social Defeat Stress-Induced Depression by Protecting Cortical Neurons from Dendritic Spine Loss”

Human equivalents:

  • A 7-8 month-old mouse would be a 38-42 year-old human.
  • A 500 mg/kg taurine dose injected intraperitoneally is (.081 x 500 mg) x 70KG = 2.835 g.
  • A 10-day stress period is about a year and a half for humans.

Don’t think aggressive humans would have to be twice as large to stress those around them. There may be choices other than enduring a year and a half of that.

The oligosaccharide stachyose

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.

tileshop.fcgi

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:

  1. Expression of microRNA; and
  2. Structure of gut microbiota.”

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


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The misnomer of nonessential amino acids

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.

10.1177_15353702221082658-table5

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”


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Young gut, young eyes

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.

young and aged fmt

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”


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Coffee improves information’s signal-to-noise ratio

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.

149371-JCI-RG-RV-3_ga_591026

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”


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State-dependent memory

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:

  1. Memories are fragile and can easily be disrupted; and
  2. 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.

memory state dependency

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

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Signaling pathways and disordered proteins

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:

glucocorticoid receptor

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:

  1. Understanding signaling required definition of roles disorder plays in each pathway;
  2. Many more examples of disordered proteins in cell signaling pathways are likely to be discovered; and
  3. 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.

Eat broccoli sprouts for depression, Part 2

Here are three papers that cited last year’s Part 1. First is a 2021 rodent study investigating a microRNA’s pro-depressive effects:

“Depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests.

Nrf2 CUMS

Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury.

Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit wolfram syndrome 1 (Wfs1) transcription.

We found that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors. We didn’t investigate the role of Nrf2 in other depression models (chronic social stress model and chronic restraint stress model) and important brain regions other than hippocampus, such as prefrontal cortex and nucleus accumbens. Accordingly, other depression models and brain regions need to be designed and explored to further validate the role of Nrf2 in depression in future studies.”

https://link.springer.com/article/10.1007/s10753-021-01554-4 “Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression‑Like Behaviors” (not freely available)

This study demonstrated that activating the Nrf2 pathway inhibited brain inflammation, cognitive dysfunction, and depression. Would modulating one microRNA and one gene in vivo without Nrf2 activation achieve similar results?


A 2021 review focused on the immune system’s role in depression:

“Major depressive disorder is one of the most common psychiatric illnesses. The mean age of patients with this disorder is 30.4 years, and the prevalence is twice higher in women than in men.

Activation of inflammatory pathways in the brain is considered to be an important producer of excitotoxicity and oxidative stress inducer that contributes to neuronal damage seen in the disorder. This activation is mainly due to pro-inflammatory cytokines activating the tryptophan-kynurenine (KP) pathway in microglial cells and astrocytes.

Elevated levels of cortisol exert an inhibitory feedback mechanism on its receptors in the hippocampus and hypothalamus, stopping stimulation of these structures to restore balance. When this balance is disrupted, hypercortisolemia directly stimulates extrahepatic enzyme 2,3-indolimine dioxygenase (IDO) located in various tissues (intestine, placenta, liver, and brain) and immune system macrophages and dendritic cells.

Elevation of IDO activities causes metabolism of 99% of available tryptophan in the KP pathway, substantially reducing serotonin synthesis, and producing reactive oxygen species and nitrogen radicals. The excitotoxicity generated produces tissue lesions, and activates the inflammatory response.”

https://academic.oup.com/ijnp/article/25/1/46/6415265 “Inflammatory Process and Immune System in Major Depressive Disorder”

This review highlighted that stress via cortisol and IDO may affect the brain and other parts of the body.


A 2022 review elaborated on Part 1’s findings of MeCP2 as a BDNF inhibitor:

“Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity.

Ability to cope with stressors relies upon activation of the hypothalamic–pituitary–adrenal (HPA) axis. MeCP2 has been shown to contribute to early life stress-dependent epigenetic programming of genes that enhance HPA-axis activity.

We describe known functions of MeCP2 as an epigenetic regulator, and provide evidence for its role in modulating synaptic plasticity via transcriptional regulation of BDNF or other proteins involved in synaptogenesis and synaptic strength like reelin. We conclude that MeCP2 is a promising target for development of novel, more efficacious therapeutics for treatment of stress-related disorders such as depression.”

https://www.mdpi.com/2073-4409/11/4/748/htm “The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression”


Osprey lunch

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