Limbic system

A healthspan improvement

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hippocampus, Immune system, Limbic system, Stress ,

Two 2022 publishments, starting with an excerpt from an informative interview with the Director of one of the three Interventions Testing Program centers:

“A paper submitted this week is one in which we tried a combination of rapamycin plus acarbose. Rapamycin works very well in male and female mice, while acarbose works significantly in both sexes but has a much stronger effect in males.

What we found in males is that when you give rapamycin and acarbose together, you do better than either rapamycin by itself or acarbose by itself. That combination of drugs together gives male survival a 29% boost.

That’s the largest percentage increase we’ve seen in males or females. This combination is the best thing we’ve ever had for either sex.

When you give acarbose and rapamycin together to females, they don’t do any better or any worse than on rapamycin alone. This is not too surprising because acarbose gives only a small effect in females. We expected it wouldn’t have a big boost over rapamycin alone in female animals, and that’s what we found.”

https://www.lifespan.io/news/prof-richard-miller-on-the-intervention-testing-program/

The study mentioned above:

“C57BL/6 mice were fed a cocktail diet containing one-half the dose of each drug compared to full dose cocktail diet and control diet. Half-dose drug cocktail was just as effective as full dose in preventing age-related cognitive impairment, but was less effective in other physical performance tests. Half-dose cocktail also had no effect on reducing pathological lesions.

Rapamycin was the major contributor for the cocktail’s effect on suppressing cognitive impairment. Decreased neuronal activation and impaired cognitive performance during aging occurs in both humans and rodents. Chronic mTOR attenuation by rapamycin has shown benefits of restoring deficits in neurovascular coupling response and cerebrovascular dysfunction in aging rodent models.

C57BL/6 female mice fed chow with acarbose performed equally well in grip strength as females fed chow with cocktail. That this sex-dependent result in strength performance was not seen in cocktail treated mice suggests that rapamycin and phenylbutyrate contributed in some way.

grip strength

HET3 4-way cross is a useful strain to help validate effects of the cocktail on aging parameters in C57BL/6 mice. HET3 mice were tested in the same manner, age, and timing as C57BL/6 mice, but only with the drug cocktail compared to control chow.

grip strength het3 mice

Grip strength force was normalized by body weight measured on the testing date so that peak force was expressed relative to body weight.

The drug cocktail was very effective in delaying progression of age-related pathology in all organs examined. We view this as a vital component of the study since mice were treated for only three months.

Administration of a cocktail has a major advantage over any individual drug tested in this study. A combination of three drugs previously shown to enhance lifespan and health span in mice is able to delay aging phenotypes more effectively and more robustly than any individual drug in the cocktail when started at middle age and given for a short period of time.”

https://www.nature.com/articles/s41598-022-11229-1 “Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice”

It makes evolutionary sense for male mice to benefit more from anti-aging treatments than females.  Per How well do single-mother rodent studies inform us about human fathers?

“The Rattus and Mus genera used in almost all rodent research aren’t part of the 6% in which fathers also provide offspring care.”

There probably isn’t an evolutionary advantage for male mice to live much longer after sperm donation. Female mice don’t cache sperm.

It’s similar to studies in which treatments only benefited subjects who started out deficient. This interview hinted at how females’ healthspans and lifespans were already evolutionarily protected, with only male mice benefiting from 17α-estradiol treatment.

Female protection may have limits in humans. For example, most whale species don’t experience menopause. In those that do, like Orca, menopause is thought to be evolutionarily determined in order to keep females’ children from competing for resources with females’ grandchildren and great-grandchildren. That’s a hypothesis, though, as those species’ male lifespans aren’t adequately measured.

Rodent research and development on interventions and doses continues. 37 months is a human equivalent to this study’s 3-month treatment. What will effective anti-aging treatments be for humans?

More strange birds

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Young immune system, young brain

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress , , ,

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”

PXL_20220506_184430747

Thyroid function

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Hypothalamus, Immune system, Limbic system , , , ,

This 2022 review subject was thyroid function changes:

“Circulating concentrations of thyrotropin (TSH) and thyroxine (T4) are tightly regulated. Each individual has setpoints for TSH and free T4 which are genetically determined, and subject to environmental and epigenetic influence.

What is normal for one individual may not be normal for another, even within conventional definitions of euthyroidism. Notably, circulating TSH exists in several different isoforms with varying degrees of glycosylation, sialylation, and sulfonation which affect tissue availability and bioactivity. This is not reflected in immunoreactive TSH concentrations determined by routine laboratory assays.

enm-2022-1463f2

TSH and free T4 relationship analyzed by age in 120,403 patients who were not taking thyroxine treatment. Median TSH for each free T4 integer value (in pmol/ L) was calculated, then plotted as 20-year age bands in adults. Dotted horizontal and vertical lines mark the TSH reference range (0.4 to 4.0 mU/L) and free T4 reference range (10 to 20 pmol/L), respectively.

Mild TSH elevation in older people does not predict adverse health outcomes. In fact, higher TSH is associated with greater life expectancy, including extreme longevity.

In older people, TSH increases with aging without an accompanying fall in free T4. Clinical guidelines now recommend against routine levothyroxine treatment in older people with mild subclinical hypothyroidism.”

https://e-enm.org/journal/view.php?doi=10.3803/EnM.2022.1463 “Thyroid Function across the Lifespan: Do Age-Related Changes Matter?”

PXL_20220427_190457415

State-dependent memory

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Anterior cingulate cortex, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress, Thalamus , , ,

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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Gut microbiota knowledge through 2021

gettingwell4 2-3 stars Required further work, Amygdala, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress , , , , , , ,

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

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:

top 5 phylum 2-2022

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

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

Resistant starch therapy observed:

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

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

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

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

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

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

Reversing hair greying

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Stress, Telomeres ,

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

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

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

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

vacay

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

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

separation

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

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

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

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

Eat broccoli sprouts for depression, Part 2

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 , , , , ,

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

gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Neurochemicals, Stress, Telomeres , , ,

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”

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.

Gut signals

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hypothalamus, Immune system, Limbic system , , ,

I’ll highlight signaling pathway aspects of this 2022 review:

“The gut bacterial community plays an important role in regulation of multiple aspects of metabolic disorders. This regulation depends, among other things, on production of a wide variety of metabolites by microbiota and on their interactions with receptors on host cells that can activate or inhibit signalling pathways, and either be beneficial and detrimental to the host’s health.

Colonocytes and endocrine cells express a variety of receptors able to sense and transmit signals from the microbial environment:

gutjnl-2021-326789-F4.large

  • TLRs cover a wide range of both external stimuli (PAMPs) and internal signals derived from tissue damage. Their activation induces antigen-presenting cell activation, thereby bridging innate and adaptive immune responses, and stimulates signalling cascades as an attempt to fend off microbial invaders or repair damaged tissue.
  • The endocannabinoid signalling system appears to play a key role in regulating energy, glucose, and lipid metabolism but also in immunity, inflammation, and more recently in microbiota-host interactions.
  • Although the primary function of bile acids (BAs) is to regulate digestion and absorption of cholesterol, triglycerides, and fat-soluble vitamins, it has been recently recognised that BAs also serve an endocrine function as they act as signalling molecules. BAs have been shown to modulate epithelial cell proliferation, gene expression, lipid, glucose, and energy metabolism by activating several receptors. Because of their signalling capacities and the fact that BAs are chemically transformed by gut microbiota, BAs can be considered as microbiota-derived signalling metabolites.
  • Numerous AhR ligands exist including environmental triggers, nutrition-derived signals, various phytochemicals, and bacterial metabolites such as tryptophan.

Most signalling metabolites can be produced by large numbers of different gut bacteria, and hence have limited specificity.”

https://gut.bmj.com/content/early/2022/01/31/gutjnl-2021-326789.long “Gut microbiome and health: mechanistic insights”

Gut microbiota’s positive epigenetic effects

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , ,

Three papers with the first a 2021 review:

“Gut microbiota along with their metabolites are involved in health and disease through multiple epigenetic mechanisms including:

  • Affecting transporter activities, e.g. DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs);
  • Providing methyl donors to participate in DNA methylation and histone modifications; and
  • miRNAs that can lead to gene transcriptional modifications.

ijms-22-06933-g003

These mechanisms can participate in a variety of biological processes such as:

  • Maturation of intestinal epithelial cells (IECs);
  • Maintenance of intestinal homeostasis;
  • Inflammatory response;
  • Development of metabolic disorders; and
  • Prevention of colon cancer.”

https://www.mdpi.com/1422-0067/22/13/6933/htm “Dissecting the Interplay Mechanism between Epigenetics and Gut Microbiota: Health Maintenance and Disease Prevention”

A second 2022 review added subjects such as crotonate (aka unsaturated butyrate):

“Studies are carving out potential roles for additional histone modifications, such as crotonylation and ethylation, in facilitating crosstalk between microbiota and host. Lysine crotonylation is a relatively less studied histone modification that is often enriched at active promoters and enhancers in mammalian cells.

While addition or removal of crotonyl motifs can be catalyzed by specialized histone crotonyltransferases and decrotonylases, HATs and HDACs have also been reported to exhibit histone crotonyl-modifying activity. Microbiota stimulate multiple types of histone modifications and regulate activity of histone-modifying enzymes to calibrate local and extra-intestinal chromatin landscapes.”

https://www.tandfonline.com/doi/full/10.1080/19490976.2021.2022407 “Epigenetic regulation by gut microbiota”

A third 2021 review added subjects such as broccoli sprout compounds’ epigenetic effects:

“Glucosinolates are converted into isothiocyanates (ITCs) by bacteria that regulate host epigenetics. Levels of ITCs produced following broccoli consumption are highly dependent on the functional capacity of individual microbiomes, as much interindividual variability exists in gut microbiota composition and function in humans.

Sulforaphane inhibits HDAC activity both in vitro and in vivo, and protects against tumor development. Microbial-mediated production of ITCs represents a strong diet-microbe interaction that has a direct impact on host epigenome and health.”

https://www.sciencedirect.com/science/article/pii/S0955286321000516 “The interplay between diet, gut microbes, and host epigenetics in health and disease”

Clearing the channel

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Nrf2 and circadian rhythm

gettingwell4 4-5 stars Advanced knowledge, Hypothalamus, Limbic system, Stress ,

This 2021 rodent study investigated aging’s effects:

“We investigated aging consequences on temporal patterns of antioxidant defenses, molecular clock machinery, and blood pressure.

We observed circadian rhythms of catalase (CAT) and glutathione peroxidase (GPx) mRNA expression, as well as ultradian rhythms of Nrf2 mRNA levels, in the hearts of young adult rats. We also found circadian oscillations of CAT and GPx enzymatic activities, reduced glutathione (GSH), and BMAL1 protein.

Aging abolished rhythms of CAT and GPx enzymatic activities, phase-shifted rhythm acrophases of GSH and BMAL1 protein levels, and turned circadian the ultradian oscillation of Nrf2 expression.

aging changes Nrf2 oscillation

Moreover, aging phase-shifted the circadian pattern of systolic blood pressure. In conclusion, aging modifies temporal organization of antioxidant defenses and blood pressure, probably as a consequence of disruption in the circadian rhythm of the clock’s transcriptional regulator, BMAL1, in heart.”

https://doi.org/10.1007/s10522-021-09938-7 “Aging disrupts the temporal organization of antioxidant defenses in the heart of male rats and phase shifts circadian rhythms of systolic blood pressure” (not freely available)

A human equivalent to this study’s 3-month-old young adult group is around 19 years. The older group’s 22-month age is roughly equivalent to a 68-year-old human.

Couldn’t say whether Nrf2 oscillations flattening out with age is specific to heart tissue, or is a more general trend. I’m pretty sure that humans have to make good things happen while aging, because bad things are pre-programmed.

I came across this study from a citation trail of a comment to Eat broccoli sprouts for your workouts. I didn’t curate the mentioned study because one of its coauthors tainted it by designing and supervising Problematic rodent sulforaphane studies.

How would you answer the comment’s question?

Repairs needed: The story of 2021

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Defend yourself with taurine

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Locus coeruleus, Lower brain, Neurochemicals, Stress , ,

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.”

antioxidants-10-01876-g001-550

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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Gut microbiota vs. disease risks

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress , , ,

This 2021 review subject was risk relationships between diseases from the perspective of gut microbiota:

“There is a significant inverse relationship between the onset of Alzheimer’s disease/Parkinson’s disease (AD/PD) and cancer, but the mechanism is still unclear. Considering that intestinal flora can connect them, we briefly introduced the relationship among AD/PD, cancer, and intestinal flora, studied metabolites or components of the intestinal flora, and the role of intestinal barriers and intestinal hormones in AD/PD and cancer.

According to existing evidence:

  • Bifidobacterium and Lactobacillus positively affect AD/PD and cancer;
  • Ruminococcaceae, Prevotellaceae, and Prevotella significantly improve on AD/PD but harm cancer; and
  • Blautia has universal anticancer ability, but it may aggravate AD pathology.

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This may partially explain the antagonistic relationship between neurodegenerative diseases and cancer. When some individuals suffer from one disease, their intestinal flora change to obtain a stronger resistance to the other disease than healthy individuals, which is consistent with statistical data.”

https://www.sciencedirect.com/science/article/pii/S0753332221011276 “Composition of intestinal flora affects the risk relationship between Alzheimer’s disease/Parkinson’s disease and cancer”

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Immune system aging

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres , , , , , , ,

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.

aging immune system

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.

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Offspring brain effects from maternal adversity

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Stress , , , , , ,

This 2021 rodent study investigated conception through weaning effects on offspring from stressing their mothers:

“We investigated consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. We analyzed patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females, and found sex-dependent and sex-concordant influences of these insults.

The pair-fed (PF) group in the PAE model is a standard control for effects of alcohol in reducing food intake. However, compared to the PAE group that, albeit eating less, eats ad libitum, pair-feeding is a treatment in itself, with PF dams receiving a restricted ration, which results in both hunger and a disrupted feeding schedule. These stress-related effects could potentially parallel or model food scarcity or food insecurity in human populations.

We observed more DMRs (Differentially Methylated Regions) that showed decreased DNAm rather than increased DNAm in PF animals, suggesting that food-related stress may interfere with one-carbon metabolism and the pathways that deposit methylation on DNA. We also identified a sex-concordant DMR that showed decreased DNAm in PF animals in the glucocorticoid receptor Nr3c1, which plays a key role in stress responsivity and may reflect a reprogramming of the stress response.

This result is in line with previous studies that have shown that pair-feeding is a considerable stressor on dams, with lasting consequences on development, behavior, and physiology of their offspring. Altered DNAm of this key HPA axis gene may reflect broader alterations to stress response systems, which may in turn, influence programming of numerous physiological systems linked to the stress response, including immune function, metabolic processes, and circadian rhythms.

In PAE and PF animals compared to controls, we identified 26 biological pathways that were enriched in females, including those involved in cellular stress and metabolism, and 10 biological pathways enriched in males, which were mainly involved in metabolic processes. These findings suggest that PAE and restricted feeding, both of which act in many respects as prenatal stressors, may influence some common biological pathways, which may explain some of the occasional overlap between their resulting phenotypes.

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This study highlights the complex network of neurobiological pathways that respond to prenatal adversity/stressors and that modulate differential effects of early life insults on functional and health outcomes. Study of these exposures provides a unique opportunity to investigate sex-specific effects of prenatal adversity on epigenetic patterns, as possible biological mechanisms underlying sex-specific responses to prenatal insults are understudied and remain largely unknown.”

https://www.mdpi.com/2073-4425/12/11/1773/htm “Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress”

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