Nrf2 Week #4: Aging

May 24, 2023May 24, 2023 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Neurochemicals, Stress Control group, DNA methylation, Genetic factors

Two 2023 reviews of Nrf2 and aging, starting with Nrf2-mitochondria interactions:

“We discuss molecular mechanisms of interactions between Nrf2 and mitochondria that influence the rate of aging and lifespan. Nrf2 activity positively affects both mitochondrial dynamics and mitochondrial quality control.

Nrf2 influences mitochondrial function through regulation of nuclear genome-encoded mitochondrial proteins and changes in the balance of ROS or other metabolites. In turn, multiple regulatory proteins functionally associated with mitochondria affect Nrf2 activity and even form mutual regulatory loops with Nrf2. These loops enable fine-tuning of cellular redox balance and, possibly, of the cellular metabolism as a whole.

mtDNA-encoded signal peptides interact with nuclear regulatory systems, first of all, Nrf2, and are possibly involved in regulation of the aging rate. Interactions between regulatory cascades that link programs ensuring maintenance of cellular homeostasis and cellular responses to oxidative stress are a significant part of both aging and anti-aging programs.

Understanding these interactions will be of great help in searching for molecular targets to counteract aging-associated diseases and aging itself. Future research on Nrf2 signaling and ability of various substances that activate the Nrf2 pathway to prevent age-associated chronic diseases will provide further insight into the role of Nrf2 activation as a possible longevity-promoting intervention.”

https://link.springer.com/article/10.1134/S0006297922120057 “Transcription Factor Nrf2 and Mitochondria – Friends or Foes in the Regulation of Aging Rate” (not freely available) Thanks to Dr. Gregory A. Shilovsky for providing a copy.

The second review evaluated whether Nrf2 is a master regulator of aging:

“This paper briefly presents main mechanisms of mammalian aging and roles of inflammation and oxidative stress in this process. Mechanisms of Nrf2 activity regulation, its involvement in aging and development of the senescence-associated secretory phenotype are also discussed.

The age-related decrease in Nrf2 activity is of universal interspecies character:

Rodents with high Nrf2 activity have a longer lifespan than rodents with low activity.

Genetic knockout of Nrf2 usually leads to the increased senescent phenotype in a variety of animal organs and tissues, and also reduces lifespan of female mice.

There are also opposite examples, where Nrf2 knockout in aging mice reduced iron ions deposition in the brain, lowered the level of oxidative damage in the striatum, and also alleviated age-related motor dysfunction.

It would be incorrect to consider the effect of Nrf2 transcription factor at the organism level as exclusively antioxidant, anti-inflammatory, and, ultimately, anti-aging. Nrf2 controls many genes, products of which have complex, pleiotropic effects on the body:

No experiments that use Nrf2 chemical inducers as anti-aging drugs have been performed so far.

Nrf2 is not involved in life extension caused by caloric restriction.

Epigenetic clocks do not reveal transcription factors activity of which changes with aging.

Aging is accompanied by changes in gene expression profiles, which are tissue- and species-specific. These changes only to a small extent include genes controlled by Nrf2. At the moment, it cannot be concluded that Nrf2 is the master regulator of the aging process.”

https://link.springer.com/article/10.1134/S0006297922120045 “Does Nrf2 Play a Role of a Master Regulator of Mammalian Aging?”

Do broccoli sprouts treat gout and kidney stones?

November 12, 2022November 12, 2022 gettingwell4 2-3 stars Required further work, Epigenetics, Glutamate, Immune system, Neurochemicals, Stress Control group, DNA methylation, Genetic factors

This 2022 rodent study investigated glucoraphanin’s effects on reducing uric acid:

“Hyperuricemia is a chronic disease characterized by abnormally elevated serum uric acid levels. Sulforaphane could lower uric acid by decreasing urate synthesis and increasing renal urate excretion in hyperuricemic rats.

A hyperuricemia model was established by administering feedstuffs with 4% potassium oxonate and 20% yeast. Forty male Sprague–Dawley rats were randomly divided into the normal control, hyperuricemia, allopurinol, and sulforaphane groups. Animals were treated by oral gavage for six consecutive weeks, and then phenotypic parameters, metabolomic profiling, and metagenomic sequencing were performed.

We identified succinic acid and oxoglutaric acid as critical host-gut microbiome co-metabolites. Sulforaphane improved diversity of microbial ecosystems and functions, as well as metabolic control of the kidney. Sulforaphane exerted its renoprotective effect through epigenetic modification of Nrf2 and interaction between gut microbiota and epigenetic modification in hyperuricemic rats.

Limitations of this study include:

We used glucoraphanin bioactivated with myrosinase for our experiments. Future experiments may directly involve sulforaphane.

Bioinformatics analysis resulted in speculations that require further experimental testing.

Further investigation of interactions between microbiota and the host epigenome is still needed.”

https://www.sciencedirect.com/science/article/pii/S209012322200251X “Sulforaphane-driven reprogramming of gut microbiome and metabolome ameliorates the progression of hyperuricemia”

It was a stretch to label treatment subjects as the “sulforaphane group” by claiming “Glucoraphanin (10 mg/kg) was metabolized to SFN by myrosinase as described in previous studies.” Both this and the referenced 2014 study “(RS)-glucoraphanin purified from Tuscan black kale and bioactivated with myrosinase enzyme protects against cerebral ischemia/reperfusion injury in rats” measured glucoraphanin and myrosinase, but not sulforaphane.

A human equivalent to this study’s daily glucoraphanin intake of 10 mg / kg weight would be (.162 x 10 mg) x 70 kg = 113 mg. Whether 10 mg was dry or wet weight wasn’t disclosed.

If 10 mg was wet, 113 mg is a little more than twice our model clinical trial’s average glucoraphanin intake of 51 mg fresh weight from eating 30 grams / day of super sprouts. In April 2020’s Understanding a clinical trial’s broccoli sprout amount, a study coauthor said:

“We considered 30 g and 60 g to be 1/2 and 1 portion per day, respectively, of broccoli sprouts. When we carried out tests with consumers, previous to the bioavailability studies, higher amounts per day were not easy to consume and to get eaten by participants.”

Non-patentable boron benefits

August 14, 2022 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Cerebellum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Serotonin, Stress Brain neurons, Control group, Genetic factors, Infants, Neurodegenerative disease, Prefrontal cortex

To follow up Is boron important to health? I’ll highlight a 2022 review of boron intake:

“Boron is essential for activity of several metabolic enzymes, hormones, and micronutrients. It is important for growth and maintenance of bone, reduction in inflammatory biomarkers, and increasing levels of antioxidant enzymes.

The average person’s daily diet contains 1.5 to 3 milligrams of boron. Boron intakes of 1–3 mg/day have been shown to improve bone and brain health in adults when compared to intakes of 0.25–0.50 mg/day.

One week of 10 mg/d boron supplementation resulted in a 20% reduction in inflammatory biomarkers TNF-α, as well as significant reductions (nearly 50%) in plasma concentrations of hs-CRP and IL-6. Calcium fructoborate, a naturally occurring, plant-based boron-carbohydrate complex, had beneficial effects on osteoarthritis (OA) symptoms. A double-blind study in middle-aged patients with primary OA found that all groups except the placebo group saw a reduction in inflammatory biomarkers after 15 days of food supplementation with calcium fructoborate.

Dietary boron intake significantly improves brain function and cognitive functioning in humans. Electroencephalograms showed that boron pharmacological intervention after boron deficiency improved functioning in older men and women, such as less drowsiness and mental alertness, better psychomotor skills (for example, motor speed and dexterity), and better cognitive processing (e.g., attention and short-term memory). Boron compounds can help with both impaired recognition and spatial memory problems.

We discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. Boron reagents will play a significant role to improve dysbiosis.”

https://www.mdpi.com/1420-3049/27/11/3402/htm “The Role of Microbiome in Brain Development and Neurodegenerative Diseases”

Broccoli sprouts and your brain

August 9, 2022August 9, 2022 gettingwell4 0-1 star Wasted resources, Brain development, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress Brain neurons, DNA methylation, Embryo development, Genetic factors, Neural plasticity, Neurodegenerative disease

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.

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”

Taurine week #7: Brain

June 18, 2022June 18, 2022 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress, Thalamus Brain neurons, Control group, Embryo development, Genetic factors, Neurodegenerative disease, Prefrontal cortex

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.

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 GABA_A, GABA_B, and glycine receptors. While taurine binding to GABA_A and GABA_B 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.

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

June 17, 2022August 8, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Lower brain, Neurochemicals, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Neural plasticity, Prefrontal cortex

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.

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.

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.

Taurine week #2: Bile acids

June 14, 2022June 16, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Hypothalamus, Immune system, Limbic system, Neurochemicals, Testosterone Brain neurons, Control group, Genetic factors, Neurodegenerative disease

Two papers investigated taurine’s integration into bile acids, starting with a review:

“Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver, and stored in the gallbladder. BAs are released from the gallbladder into the small intestine via food intake to facilitate digestion and absorption of lipids and lipophilic vitamins by forming micelles in the small intestine.

After deconjugation by the gut microbiome, primary BAs are converted into secondary BAs. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine.

Some BAs reabsorbed from the intestine spill into systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues. Some BAs are not reabsorbed and bind to receptors in the terminal ileum.

BAs can affect cell-surface and intracellular membranes, including those of mitochondria and the endoplasmic reticulum. BAs are also hormones or signaling molecules, and can regulate BA, glucose, and lipid metabolism in various tissues, including the liver, pancreas, and both brown and white adipose tissue. BAs also affect the immune system.

BAs can affect the nervous system. More than 20 BAs have been detected in the brain of humans and rodents. The brain communicates with the gut and gut microbiome through BAs.”

https://www.mdpi.com/2076-2607/10/1/68/htm “Physiological Role of Bile Acids Modified by the Gut Microbiome”

Reference 56 was a human study:

“Centenarians (individuals aged 100 years and older) have a decreased susceptibility to ageing-associated illnesses, chronic inflammation, and infectious diseases. Centenarians have a distinct gut microbiome enriched in microorganisms that are capable of generating unique secondary bile acids.

We identified centenarian-specific gut microbiota signatures and defined bacterial species as well as genes and/or pathways that promote generation of isoLCA, 3-oxoLCA, 3-oxoalloLCA, and isoalloLCA. To our knowledge, isoalloLCA is one of the most potent antimicrobial agents that is selective against Gram-positive microorganisms, including multidrug-resistant pathogens, suggesting that it may contribute to maintenance of intestinal homeostasis by enhancing colonization-resistance mechanisms.”

https://www.nature.com/articles/s41586-021-03832-5 “Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians” (not freely available)

A few more papers will be coming on taurine and bile acids. I haven’t seen one investigate both taurine and glycine treatments to aid bile acid in achieving therapeutic results.

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”

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”

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.

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.

Eat broccoli sprouts for depression, Part 2

March 1, 2022January 3, 2023 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Neural plasticity, Prefrontal cortex

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 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

CD38 and balance

February 14, 2022February 14, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Neurochemicals, Stress, Telomeres Brain neurons, Control group, Genetic factors, Neurodegenerative disease

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.

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.

Immune system aging

December 19, 2021December 19, 2021 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres Brain neurons, Control group, Critical period, DNA methylation, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease

This 2021 review by three coauthors of Take responsibility for your one precious life – Trained innate immunity cast a wide net:

“Non-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. However, these mechanisms of memory generation and maintenance are compromised as organisms age.

This review discusses how immune function regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life. We aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory.

A comprehensive strategy is essential for human beings striving to lead long lives with healthy guts, functional brains, and free of severe infections.”

https://link.springer.com/article/10.1007/s12016-021-08905-x “Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics”

Attempts to cover a wide range of topics well are usually uneven. For example, older information in the DNA Methylation In Adaptive Immunity section was followed by a more recent Histone Modifications in Adaptive Immunity section.

This group specializes in tuberculosis vaccine trained immunity studies, and much of what they presented also applied to β-glucan trained immunity. A dozen previously curated papers were cited.

Saving bees by regulating epigenetics

November 13, 2021November 13, 2021 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Glutamate, Memory, Neurochemicals, Stress Control group, Genetic factors, Neural plasticity, Neurodegenerative disease

This 2021 study investigated an epigenetic treatment for bees forgetting about their hives:

“Over the last few decades, numbers of both wild and managed bee pollinators have been declining. Although reasons for this decline are under debate, it is highly likely that a combination of multiple stressors is to blame, in particular, deformed wing virus (DWV).

Histone deacetylase inhibitors (HDACi) are a class of compounds which prevent deacetylation of histones and therefore increase gene expression. The present study found that HDACi sodium butyrate (NaB) significantly increased survival and reversed the learning / memory impairment of DWV-infected bees. We demonstrated the mechanism of how epigenetic regulation can resume honeybees’ memory function.

When bees were infected with DWV, 50% of bees died by the end of day 2 and only 10% survived to the end of day 5.

When NaB was added to the diet prior to DWV infection, survival rate of DWV-infected bees (N/D group) remained >90% after 5 days.

Under laboratory rearing conditions, around 30% of control bees died over a period of 5 days.

When NaB was included in uninfected bees’ diet, less than 15% of bees died.

These results indicate that feeding bees with NaB could significantly increase survival with or without DWV infection.”

https://www.cell.com/iscience/fulltext/S2589-0042(21)01024-5 “Real-time monitoring of deformed wing virus-infected bee foraging behavior following histone deacetylase inhibitor treatment”

Interesting that these researchers didn’t attempt to eliminate either the virus cause of bee behavior or parasitical mites that carried the virus. They mainly depended on bees’ endogenous systems providing beneficial responses when stimulated.