Taurine week #7: Brain

Finishing a week’s worth of 2022 taurine research with two reviews of taurine’s brain effects:

“We provide a overview of brain taurine homeostasis, and review mechanisms by which taurine can afford neuroprotection in individuals with obesity and diabetes. Alterations to taurine homeostasis can impact a number of biological processes such as osmolarity control, calcium homeostasis, and inhibitory neurotransmission, and have been reported in both metabolic and neurodegenerative disorders.

Models of neurodegenerative disorders show reduced brain taurine concentrations. On the other hand, models of insulin-dependent diabetes, insulin resistance, and diet-induced obesity display taurine accumulation in the hippocampus. Given cytoprotective actions of taurine, such accumulation of taurine might constitute a compensatory mechanism that attempts to prevent neurodegeneration.

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Taurine release is mainly mediated by volume-regulated anion channels (VRAC) that are activated by hypo-osmotic conditions and electrical activity. They can be stimulated via glutamate metabotropic (mGluR) and ionotropic receptors (mainly NMDA and AMPA), adenosine A1 receptors (A1R), and metabotropic ATP receptors (P2Y).

Taurine mediates its neuromodulatory effects by binding to GABAA, GABAB, and glycine receptors. While taurine binding to GABAA and GABAB is weaker than to GABA, taurine is a rather potent ligand of the glycine receptor. Reuptake of taurine occurs via taurine transporter TauT.

Cytoprotective actions of taurine contribute to brain health improvements in subjects with obesity and diabetes through various mechanisms that improve neuronal function, such as:

  • Modulating inhibitory neurotransmission, which promotes an excitatory–inhibitory balance;
  • Stimulating antioxidant systems; and
  • Stabilizing mitochondria energy production and Ca2+ homeostasis.”

https://www.mdpi.com/2072-6643/14/6/1292/htm “Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes”


A second review focused on taurine’s secondary bile acids produced by gut microbiota:

“Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. Hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases.

Biliary acids may influence each of the following three mechanisms through which interactions within the brain-gut-microbiota axis take place: neurological, immunological, and neuroendocrine. These microbial metabolites can act as direct neurotransmitters or neuromodulators, serving as key modulators of the brain-gut interactions.

The gut microbial community, through their capacity to produce bile acid metabolites distinct from the liver, can be thought of as an endocrine organ with potential to alter host physiology, perhaps to their own favour. Hydrophilic bile acids, currently regarded as important hormones, exert modulatory effects on gut microbiota composition to produce secondary bile acids which seem to bind a number of receptors with a higher affinity than primary biliary acids, expressed on many different cells.

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TUDCA regulates expression of genes involved in cell cycle regulation and apoptotic pathways, promoting neuronal survival. TUDCA:

  • Improves protein folding capacity through its chaperoning activity, in turn reducing protein aggregation and deposition;
  • Reduces reactive oxygen species production, leading to protection against mitochondrial dysfunction;
  • Ameliorates endoplasmic reticulum stress; and
  • Inhibits expression of pro-inflammatory cytokines, exerting an anti-neuroinflammatory effect.

Although Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and cerebral ischemia have different disease progressions, they share similar pathways which can be targeted by TUDCA. This makes this bile acid a potentially strong therapeutic option to be tested in human diseases. Clinical evidence collected so far has reported comprehensive data on ALS only.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166453/ “Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases”

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.

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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 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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Exercise substitutes?

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”


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Blood pressure and brain age

This 2021 human study investigated associations between blood pressure and MRI measurements:

“We estimated how a validated measure of brain health related to changes in BP over a period of 12 years. The main findings of this study were:

  • All BP measures were associated with older BrainAGE;
  • Associations were stronger in men than women;
  • Associations were not only detected in hypertensive individuals but across the whole BP range; and
  • Individuals with optimal blood pressure (110/70) presented with the lowest BrainAGE.

These findings support the view that maintaining blood pressure in an optimal range (SBP < 115, DBP < 75) across the lifespan starting before mid-life (i.e., in early adulthood and before) is essential to maintain good cerebral health.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523821/ “Optimal Blood Pressure Keeps Our Brains Younger”


I’m making progress on a New Year’s resolution. Here’s how I started 2022:

bp 2021

Current readings show both lower averages and variability:

bp 2022

~12% decreases in average systolic (111 – 126)/126 and diastolic (69 – 78)/78 pressures over 135 days. 🙂 I measure blood pressure every day right after I wake up.

What caused these decreases? Continuing what I was already doing. The top factor is probably that at lunch every day I take 600 mcg of Vitamin K2 MK-7 along with a gram of flax oil.

I started taking K2 this time last year per Vitamin K2 – What can it do? Apparently its effects are gradual and develop slowly. Vitamin K2 and hypertension may also be relevant.

I came across this study from its mention in today’s video:

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.

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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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Brain changes

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.

accelerated epigenetic age vs brain features

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

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:

  1. Dysfunction of mitochondria;
  2. Accumulation of oxidatively damaged proteins, nucleic acids, and lipids in brain cells;
  3. Disorders of energy metabolism;
  4. Impaired ‘waste disposal’ mechanism (autophagosome and proteasome functionality);
  5. Impaired signal transduction of adaptive stress response;
  6. Impaired DNA repair;
  7. Abnormal neural network activity;
  8. Imbalance of neuronal Ca2+ processing;
  9. Stem cell exhaustion; and
  10. Increased inflammation.

mrna brain expression

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”


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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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Year Two of Changing to a youthful phenotype with sprouts

1. I’ve eaten clinically-relevant doses of sulforaphane every day for 104 weeks now with microwaved 3-day-old broccoli, red cabbage, and mustard sprouts. That’s 8+ times longer than any sulforaphane clinical trial.

I continue to:

  • Eat Avena nuda oats for breakfast;
  • Eat 3-day-old hulled Avena sativa oat sprouts twice a day;
  • Eat AGE-less chicken vegetable soup twice a day;
  • Take supplements that promote healthspan twice a day;
  • Exercise at least 30 minutes daily;
  • Take yeast cell wall β-glucan daily, with nothing else an hour before or after; and
  • Avoid undue stress by working from home 40 hours a week in my 25th year as a professional software developer.

I’ve experienced many positive effects described in studies. Researchers keep exploring new aspects of their fields, and I look forward to more evidence on youthening during Year Three.

2. I’m not especially scientific or maniacal about the above practices, other than weighing sprouting seeds. I pay attention to people who measure everything, but won’t turn my life into a series of unfeeling experiments. As Dr. Arthur Janov said:

“What is the point of life if we cannot feel and love others? Without feeling, life becomes empty and sterile. It, above all, loses its meaning.”

3. Beginning last month, our world was subjected to yet another wave of propaganda, with predictable oppression of those who reported obvious lies and distortions. Previously exposed agendas took a back seat to regain their venom, as their effects waned in herding people toward personally devastating cliffs.

Meme perpetrators don’t care about you or me. Spending our time on their ideas, beliefs, and behaviors takes us further away from dealing with our individually motivating causes and individual truths, with real consequences: a wasted life.

Value your own one precious life. Winter is over, spring is here.

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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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CD38 and balance

I’ll highlight this 2022 review’s relationships between inflammation and cluster of differentiation 38:

“We review the nicotinamide adenine dinucleotide (NAD) catabolizing enzyme CD38, which plays critical roles in pathogenesis of diseases related to infection, inflammation, fibrosis, metabolism, and aging.

NAD is a cofactor of paramount importance for an array of cellular processes related to mitochondrial function and metabolism, redox reactions, signaling, cell division, inflammation, and DNA repair. Dysregulation of NAD is associated with multiple diseases. Since CD38 is the main NADase in mammalian tissues, its contribution to pathological processes has been explored in multiple disease models.

CD38 is upregulated in a cell-dependent manner by several stimuli in the presence of pro-inflammatory or secreted senescence factors or in response to a bacterial infection, retinoic acid, or gonadal steroids. CD38 is stimulated in a cell-specific manner by lipopolysaccharide, tumor necrosis factor alpha, interleukin-6, and interferon-γ.

dysregulated inflammation

CD38 plays a critical role in inflammation, migration, and immunometabolism, but equally important is resolution of the inflammatory response which left unchecked leads to loss of self-tolerance, tissue infiltration of lymphocytes, and circulation of autoantibodies.

  • Depending upon context, CD38 can either promote or protect against an autoimmune response.
  • Chronic mucosal inflammation and tissue damage characteristic of inflammatory bowel disease predisposes IBD patients to development of colorectal cancer, and the risks increase with duration, extent, and severity of inflammation.
  • Pulmonary fibrosis occurs in the presence of unresolved inflammation and dysregulated tissue repair, and results from an array of injurious stimuli including infection, toxicant exposure, adverse effects of drugs, and autoimmune response.
  • Modulating CD38 and NAD levels in kidney disease may provide therapeutic approaches for prevention of inflammatory conditions of the kidney.
  • Inflammation as well as evidence of senescence are present in pathophysiology of chronic liver diseases that progress to cirrhosis.
  • Inflammation-associated metabolic diseases impair vascular function. Chronic inflammation can lead to vascular senescence and dysfunction.

One cause of NAD decline during aging is due to increase of NAD breakdown in the presence of increased CD38 expression and activity on immune cells, thus linking inflammaging with tissue NAD decline. Other sources of NAD decline include increased DNA-damage requiring PARP1 activation, and decreased NAMPT levels leading to diminished NAD synthesis through the salvage pathway.

Inflammation is among the major risk factors that predispose organisms to age-associated diseases. During aging, accumulation of senescent cells creates an environment rich in proinflammatory signals, leading to ‘inflammaging.’ Metabolically active cells lose their replicative capacity by entering an irreversible quiescent state, and are considered both a cause and a consequence of inflammaging.

Recent findings uncover a major role of CD38 in inflammation and senescence, showing that age-related NAD+ decline and the sterile inflammation of aging are partially mediated by a senescence / senescence associated secretory phenotype (SASP)-induced accumulation of CD38+ inflammatory cells in tissues. Given the clear association between the phenomenon of inflammaging, senescence, and CD38, as well as the impact of CD38 on degradation of NAD and the NAD precursor NMN, future studies should focus on CD38 as a druggable target in viral illnesses.”

https://journals.physiology.org/doi/abs/10.1152/ajpcell.00451.2021 “The CD38 glycohydrolase and the NAD sink: implications for pathological conditions” (not freely available). Thanks to Dr. Julianna Zeidler for providing a copy.


We extend good-vs.-bad thinking to nature. Does that paradigm explain much, though?

All pieces of a puzzle are important. Otherwise, evolution would have eliminated what wasn’t necessary for its purposes.

Restoring balance to an earlier phenotype suits my purposes. Don’t want to eliminate inflammatory responses, but instead, calm them down so that they’re evoked appropriately.

Lifespan Uber Correlation

This 2022 study developed new epigenetic clocks:

“Maximum lifespan is deemed to be a stable trait in species. The rate of biological function decline (i.e., aging) would be expected to correlate inversely with maximum species lifespan. Although aging and maximum lifespan are intimately intertwined, they nevertheless appear in some investigations to be distinct processes.

Some cytosines conserved across mammals exhibit age-related methylation changes so consistent that they were used to successfully develop cross-species age predictors. In a similar vein, methylation levels of some conserved cytosines correlate highly with species lifespan, leading to the development of highly accurate lifespan predictors. Surprisingly, little to no commonality is found between these two sets of cytosines.

We correlated the intra-species age correlation with maximum lifespan across mammalian species. We refer to this correlation of correlations as Lifespan Uber Correlation (LUC).

We overlapped genes from the LUC signature with genes found in human genome-wide association studies (GWAS) of various pathologies and conditions. With all due caution, we report that some genes from the LUC signature were those highlighted by GWAS to be associated with type II diabetes, stroke, chronic kidney disease, and breast cancer.

Human aging genes vs mammalian LUC

We used the subset of CpGs found to be significant in our LUC to build age estimators (epigenetic clocks). We demonstrated that these clocks are able to capture effects of interventions that are known to alter age as well as lifespan, such as caloric restriction, growth hormone receptor knockout, and high-fat diet.

We found that Bcl11b heterozygous knockout mice exhibited an increased epigenetic age in the striatum. BCL11B is a zinc finger protein with a wide range of functions, including development of the brain, immune system, and cardiac system.

This gene is also implicated in several human diseases including, but not limited to, Huntington disease, Alzheimer’s diseases, HIV, and T-cell malignancies. BCL11B plays an important role in adult neurogenesis, but is less studied in the context of lifespan disparities in mammals.

Bcl11b knockout affected both DNA methylation and mRNA expression of LUC genes. Our current study does not inform us about the potential role of Bcl11b in aging processes during adulthood since observed patterns could be attributed to developmental defects.

We are characterizing other genetic and non-genetic interventions that perturb the LUC clocks. These we will feature in a separate report that will uncover biological processes regulated by LUC cytosines and their associated genes.”

https://www.biorxiv.org/content/10.1101/2022.01.16.476530v1 “Divergent age-related methylation patterns in long and short-lived mammals”


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Defend yourself with taurine

This densely packed 2021 review subject was taurine:

“Taurine (Tau), a sulphur-containing non-proteinogenic β-amino acid, has a special place as an important natural modulator of antioxidant defence networks:

  • Direct antioxidant effect of Tau due to scavenging free radicals is limited, and could be expected only in a few tissues (heart and eye) with comparatively high concentrations.
  • Maintaining optimal Tau status of mitochondria controls free radical production.
  • Indirect antioxidant activities of Tau due to modulating transcription factors leading to upregulation of the antioxidant defence network are likely to be major molecular mechanisms of Tau’s antioxidant and anti-inflammatory activities.
  • A range of toxicological models clearly show protective antioxidant-related effects of Tau.”

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https://www.mdpi.com/2076-3921/10/12/1876/htm “Taurine as a Natural Antioxidant: From Direct Antioxidant Effects to Protective Action in Various Toxicological Models”


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