The amino acid ergothioneine

A trio of papers on ergothioneine starts with a 2019 human study. 3,236 people without cardiovascular disease and diabetes mellitus ages 57.4±6.0 were measured for 112 metabolites, then followed-up after 20+ years:

“We identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.

overall mortality and ergothioneine

Ergothioneine exists in many dietary sources and has especially high levels in mushrooms, tempeh, and garlic. Ergothioneine has previously been associated with a higher intake of vegetables, seafood and with a lower intake of solid fats and added sugar as well as associated with healthy food patterns.” “Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease”

I came across this study by its citation in a 2021 review:

“The body has evolved to rely on highly abundant low molecular weight thiols such as glutathione to maintain redox homeostasis but also play other important roles including xenobiotic detoxification and signalling. Some of these thiols may also be derived from diet, such as the trimethyl-betaine derivative of histidine, ergothioneine (ET).

image description

ET can be found in most (if not all) tissues, with differential rates of accumulation, owing to differing expression of the transporter. High expression of the transporter, and hence high levels of ET, is observed in certain cells (e.g. blood cells, bone marrow, ocular tissues, brain) that are likely predisposed to oxidative stress, although other tissues can accumulate high levels of ET with sustained administration. This has been suggested to be an adaptive physiological response to elevate ET in the damaged tissue and thereby limit further injury.” “Ergothioneine, recent developments”

The coauthors of this review were also coauthors of a 2018 review:

“Ergothioneine is avidly taken up from the diet by humans and other animals through a transporter, OCTN1. Ergothioneine is not rapidly metabolised, or excreted in urine, and has powerful antioxidant and cytoprotective properties.

ergothioneine in foods

Effects of dietary ET supplementation on oxidative damage in young healthy adults found a trend to a decrease in oxidative damage, as detected in plasma and urine using several established biomarkers of oxidative damage, but no major decreases. This could arguably be a useful property of ET: not interfering with important roles of ROS/RNS in healthy tissues, but coming into play when oxidative damage becomes excessive due to tissue injury, toxin exposure or disease, and ET is then accumulated.” “Ergothioneine – a diet-derived antioxidant with therapeutic potential”

I’m upping a half-pound of mushrooms every day to 3/4 lb. (340 g). Don’t think I could eat more garlic than the current six cloves.


I came across this subject in today’s video:

Your bones influence your brain

This 2020 review subject was brain-bone crosstalk:

“Multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis. Skeletal diseases display impaired brain development and function.

Along with brain and bone pathologies, trauma events highlight strong interaction of both organs. While brain-derived molecules affecting bone include central regulators – transmitters of the sympathetic, parasympathetic and sensory nervous system – bone-derived mediators altering brain function are released from bone cells and marrow.


Osteoblast-derived hormone osteocalcin (OCN) exerts neuroprotective effects. Studies revealed a bidirectional dependence of brain and bone through bone cell-derived modulators that directly affect behavioral and cognitive function.

The main bone-derived mediator affecting the brain is OCN, which is exclusively synthesized by osteoblasts. OCN was recently discovered to transverse the BBB to enter the CNS, where it promotes spatial learning and memory while preventing anxiety-like behavior or even depression.

Cognitive function and circulating levels of OCN are proposed to inversely correlate with age. Maternal osteocalcin regulates embryonic brain development by enhancing monoamine neurotransmitters and their synthesis.

Clinical observations provide key evidence for a bidirectional communication between brain and bone tissue, which is strongly supported by experimental studies that unraveled underlying mechanistic pathways and identified molecular mediators involved in this crosstalk.” “Crosstalk of Brain and Bone-Clinical Observations and Their Molecular Bases”

The first paper of Vitamin K2 – What can it do? said:

Osteocalcin γ-carboxylation is the main mechanism of action through which Vitamin K2 improves bone health.”

This paper didn’t mention Matrix Gla Protein (MGP) carboxylation, and said a contrary:

“Undercarboxylated, bioactive OCN, initially considered as an inhibitor of bone mineralization, participates in systemic body regulation and homeostasis.”

The 2019 paper cited was Osteocalcin‑GPRC6A: An update of its clinical and biological multi‑organic interactions (Review):

“Osteocalcin is a small protein present in two forms: Carboxylated (cOC) and undercarboxylated (ucOC). Only ucOC can signal as a hormone while cOC cannot.”

It went on to downplay cOC, and also didn’t mention MGP carboxylation.

I think it’s a question of balance. cOC stays in your bones. Carboxylated MGP influences calcium to go into your bones instead of your blood vessel walls. Two good things.

Eat oats and regain cognitive normalcy

This 2020 rodent study investigated effects of different diets:

“The present study aimed to evaluate effects of β-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD). After long-term supplementation for 15 weeks, β-glucan prevented HFFD-induced cognitive impairment, assessed behaviorally by object location, novel object recognition, and nesting building tests:

  • Long-term β-glucan supplementation suppressed microglia activation and inflammation in hippocampus of HFFD-fed mice;
  • β-glucan attenuated deleterious engulfment of synapses by activation of microglia seen in HFFD mice;
  • β-glucan significantly prevented upregulation of TNF-α, IL-1β, and IL-6 mRNA expression in hippocampus; and
  • A broad-spectrum antibiotic intervention abrogated β-glucan-induced improvement in cognitive function, highlighting the essential role of gut microbiota to mediate cognitive function and behavior.

We found that short-term β-glucan supplementation did not change cognitive behavior in HFFD fed mice. HFFD feeding for 7 days dramatically changed gut microbial profile, with β-glucan-fed mice clustered apart from HFFD-fed mice sample, suggesting:

  • Quick changes in gut microbiota are induced by short-term β-glucan consumption and
  • Possible causality of gut microbiota profile on cognition.

7% β-glucan 7% nondigestible fiber

β-glucan supplementation increased place discrimination ratio in object location test compared with HFFD mice; however, there was no significant difference in total exploration time with objects during test phases between the two groups. Higher place discrimination index in β-glucan supplementation group was not due to better general performance, but increased recognition memory.

Results provide consistent evidence linking increased β-glucan intake to improved:

  • Gut microbiota profile;
  • Intestinal barrier function;
  • Reduced endotoxemia; and
  • Enhanced cognitive function via more optimized synaptic and signaling pathways in critical brain areas.

It is speculative that β-glucan improvement of gut microbiota composition, but not necessarily diversity per se, may be most critical for improved cognition. Enhanced consumption of β-glucan-rich foods is an easily implementable nutritional strategy to attenuate diet-induced cognitive decline. “β-glucan attenuates cognitive impairment via the gut-brain axis in diet-induced obese mice”

This study did well by elaborating It’s the fiber, not the fat and Eat oats to prevent diabetes related findings. How many humans eat themselves into essentially the same situation as this HFFD group with no gut-microbiota-friendly dietary fiber?

Experiments were with β-glucan 1,3/1,4 found in oats. β-glucan 1,3/1,6 has separate effects, especially on innate immunity.

It’s a coin toss on whether observed cognitive improvement was due to 7% β-glucan soluble fiber, 7% indigestible fiber, or both. I do both, beginning with Avena nuda oats for breakfast.

Red cabbage pigments and the brain

This 2020 sheep study measured red cabbage anthocyanin concentrations:

“Study aim was to determine whether strongly bioactive hydrophilic red cabbage anthocyanins cross the blood-cerebrospinal fluid barrier (blood-CSF barrier) and whether there is a selectivity of this barrier towards these compounds.

The blood-CSF barrier, apart from the vascular blood-brain barrier, is the second important barrier. Despite very tight connections between endothelial cells of blood vessels of the choroid plexus, blood-CSF barrier allows selective passing of substances from blood to CSF, which is considered as a medium actively involved in transport of information to nerve cells.

Uncharged, lipophilic, and small-sized substances (≤ 600 Da) can cross the brain barriers without major obstacles thanks to diffusion. The rate of these substances’ penetration into brain tissue is directly proportional to their lipid solubility, and inversely proportional to particle size. Hydrophilic substances require special carriers.

The average percentage level of native anthocyanins over the whole experiment was almost 39.5%, while their metabolites constituted just over 60.5%. However, the proportion of native forms vs. metabolites did not develop identically:

  1. Early term (0.5-4 hrs) was distinguished by native derivatives (> 76%).
  2. Second period (4.5 h) had a similar contribution of native anthocyanins (49.85%) and their metabolites (50.15%).
  3. Third interval (5.0-10 h) more than 87% of anthocyanins were metabolites.

For comparison, a human experiment showed only one period with maximum blood plasma anthocyanins concentration (2 h) after red cabbage consumption.

Only one of 17 native anthocyanins found in blood plasma was detected in CSF. Eleven of 17 metabolites found in blood were identified in CSF.

sheep csf cyanins

Due to their hydrophilic nature and considerable size (≥ 611 Da), there seems to be no possibility to use diffusion for permeation of red cabbage anthocyanins through the blood-CSF barrier. These pigments may pass through this barrier only by the use of special carriers. Other mechanisms of anthocyanins permeation through blood-CSF barrier cannot be eliminated.

Two maximal values of total anthocyanins concentration appeared in both blood and CSF. When the pool of cyanidin compounds available in blood became depleted, the decline of total anthocyanin concentration in CSF was also noted.

Nonacylated cyanidin derivatives penetrated the blood-CSF barrier, but acylated cyanidin derivatives did not. A significantly higher proportion of cyanidin sulfate forms in CSF (31%) compared to blood plasma (9%).

Further targeted studies are needed to determine which paths of permeation via blood-CSF barrier are actually responsible for anthocyanins passing, as well as what mechanisms are present during these processes. In addition, it is worth remembering that low molecular weight compounds formed mainly by colonic microbiota are very important metabolites of anthocyanins, and could be relevant in the context of permeation through brain barriers.” “The Blood–Cerebrospinal Fluid Barrier Is Selective for Red Cabbage Anthocyanins and Their Metabolites” (not freely available)

Don’t understand why this study hasn’t been cited even once. These researchers’ methods could be performed with broccoli and other red cabbage compounds.

One aspect of research on short-chain fatty acids

To further understand An overlooked gut microbiota product, a 2018 rodent study found:

“Microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, neuroimmune regulation, and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood

SCFAs are primarily derived from fermentation of dietary fibres, and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress.

Administration of SCFAs to mice undergoing psychosocial stress alleviated enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability.

experimental design

SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress.” “Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations”

One way researchers advance science is to relate aspects of their findings to previous studies. That approach works, but may miss items that weren’t covered in previous research.

This study fed specific quantities of three SCFAs – acetate, butyrate, and propionate – apparently due to previous research findings. If other SCFAs produced by gut microbiota were ignored – like crotonate (aka unsaturated butyrate) – how would that approach advance science?

I found this study from its citation in Harnessing endogenous defenses with broccoli sprouts.

Every hand’s a winner, and every hand’s a loser

Another great blog post Know When To Fold ‘Em by Dr. Paul Clayton:

“Newly formed proteins entering the endoplasmic reticulum must be correctly folded to achieve their final form and function. This is a complex procedure with a failure rate of over 80%.

When metabolism is sufficiently skewed, accuracy of protein folding in the endoplasmic reticulum falls below an already low baseline of 20%. Accumulation of misfolded or unfolded proteins in the endoplasmic reticulum then triggers stress.

Integrated Stress Response (ISR) is something that cells do when they are affected by major stressors:

  • ISR turns down global protein synthesis, which is designed to kill virally infected or cancerous cells. If it kills the cancer cell or virally infected cell, that is the end of it.
  • If the stressor is in the heat / hypoxia / nutrient group, however, ISR effectively puts a cell into dark mode until hard times are over. Once the stressor has passed, a cell can then start to recover and return to homeostatic health.
  • But if the stressor is sustained, a low-grade ISR continues to smolder away, causing long-term impairment locally and ultimately systemically. Accumulation of misfolded or unfolded proteins activates ISR, leading to a down-regulation of protein synthesis, and increasing protein folding and degradation of unfolded proteins.

This is analogous to inflammation. Acute inflammatory responses to a pathogen or to tissue damage are entirely adaptive, and essential. Chronic inflammation, on the other hand, causes local and eventually systemic damage if left unchecked for long enough.”

A 2020 rodent study was cited for “reversing age-related cognitive decline”:

“This suggests that the aged brain has not permanently lost cognitive capacities. Rather, cognitive resources are still there, but have been somehow blocked, trapped by a vicious cycle of cellular stress.

Our work with ISR inhibition demonstrates a way to break that cycle, and restore cognitive abilities that had become walled off over time.

stress response inhibitor effects

If these findings in mice translate into human physiology, they offer hope and a tangible strategy to sustain cognitive ability as we age.” “Small molecule cognitive enhancer reverses age-related memory decline in mice”

I’m curious as to why sulforaphane hasn’t been mentioned even once in Dr. Paul Clayton’s blog, which started three years ago. Do hundreds of sulforaphane studies performed in this century not contribute to his perspective? Polyphenols are mentioned a dozen times, yet they are 1% bioavailable compared with 80% “small molecule” sulforaphane.

Advice from the song depends on your definition of money:

“Know when to walk away
Know when to run
Never count your money
When you’re sitting at the table”

Let β-glucan train your brain

This 2021 rodent study investigated yeast cell wall β-glucan’s effects on the brain’s immune system:

“Innate immune memory can manifest in two different ways, [1] immune training and [2] immune tolerance, which means [1] an enhanced or [2] suppressed immune response towards a secondary challenge. Lipopolysaccharide (LPS) and β-glucan (BG) are two commonly used ligands to induce immune training and tolerance.

Microglia, the innate immune cells of the central nervous system, can adopt diverse phenotypes and functions in health and disease. In our previous study, we have shown that LPS preconditioning induces immune tolerance in microglia.

Compared to LPS, relatively little is known about effects of BG on microglia. In this study, we report for the first time that systemic administration of BG activates microglia in vivo, and that BG preconditioning induces immune training in microglia.


Our results show that BG activated microglia without inducing significant cytokine expression.

BG- and LPS-preconditioning both induced immune training in microglia two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning induced immune tolerance in microglia where BG-induced immune training was no longer detected.” “Systemic administration of β-glucan induces immune training in microglia”

One solution to “BG-induced immune training was no longer detected” after 7 days is to take β-glucan every day. I haven’t seen studies that found β-glucan induced immune tolerance, i.e. “suppressed immune response towards a secondary challenge.”

I take allergy medicine twice a day. Switched over to a different β-glucan vendor and dose per Year One of Changing to a youthful phenotype with broccoli sprouts.

I take 1 gram of Glucan 300 capsules without eating anything an hour before or an hour afterwards. I’ve only been doing it for a week, though, and haven’t been able to separate out β-glucan effects on seasonal allergies. I’ll try stopping allergy medicine when pollen stops coating my car.

Swarming a spring sea trout run. Ospreys outcompeted gulls for breakfast.

Our first 1000 days

This 2021 review subject was a measurable aspect of our early lives:

“The first 1000 days from conception are a sensitive period for human development programming. During this period, environmental exposures may result in long-lasting epigenetic imprints that contribute to future developmental trajectories.

The present review reports on effects of adverse and protective environmental conditions occurring on glucocorticoid receptor gene (NR3C1) regulation in humans. Thirty-four studies were included.

The hypothalamic-pituitary-adrenal (HPA) axis is key in regulating mobilization of energy. It is involved in stress reactivity and regulation, and it supports development of behavioral, cognitive, and socio-emotional domains.

The NR3C1 gene encodes for specific glucocorticoid receptors (GRs) in the mammalian brain, and it is epigenetically regulated by environmental exposures.

When mixed stressful conditions were not differentiated for their effects on NR3C1 methylation, no significant results were obtained, which speaks in favor of specificity of epigenetic vestiges of different adverse conditions. Specific maternal behaviors and caregiving actions – such as breastfeeding, sensitive and contingent interactive behavior, and gentle touch – consistently correlated with decreased NR3C1 methylation.

If the neuroendocrine system of a developing fetus and infant is particularly sensitive to environmental stimulations, this model may provide the epigenetic basis to inform promotion of family-centered prevention, treatment, and supportive interventions for at-risk conditions. A more ambiguous picture emerged for later effects of NR3C1 methylation on developmental outcomes during infancy and childhood, suggesting that future research should favor epigenome-wide approaches to long-term epigenetic programming in humans.” “Glucocorticoid receptor gene (NR3C1) methylation during the first thousand days: Environmental exposures and developmental outcomes” (not freely available). Thanks to Dr. Livio Provenci for providing a copy.

I respectfully disagree with recommendations for an EWAS approach during infancy and childhood. What happened to each of us wasn’t necessarily applicable to a group. Group statistics may make interesting research topics, but they won’t change anything for each individual.

Regarding treatment, our individual experiences and needs during our first 1000 days should be repeatedly sensed and felt in order to be therapeutic. Those memories are embedded in our needs because cognitive aspects of our brains weren’t developed then.

To become curative, we first sense and feel early needs and experiences. Later, we understand their contributions and continuations in our emotions, behavior, and thinking.

And then we can start to change who we were made into.


This 2021 review subject was circadian signaling in the digestive system:

“The circadian system controls diurnal rhythms in gastrointestinal digestion, absorption, motility, hormones, barrier function, and gut microbiota. The master clock, located in the suprachiasmatic nucleus (SCN) region of the hypothalamus, is synchronized or entrained by the light–dark cycle and, in turn, synchronizes clocks present in peripheral tissues and organs.

Rhythmic clock gene expression can be observed in almost every cell outside the SCN. These rhythms persist in culture, indicating that these cells also contain an endogenous circadian clock system.

Processes in the gastrointestinal tract and its accessory digestive organs display 24-hour rhythmicity:

Clock disruption has been associated with disturbances in gut motility. In an 8-day randomized crossover study, in which 14 healthy young adults were subjected to simulated day-shift or night-shift sleeping schedules, circadian misalignment increased postprandial hunger hormone ghrelin levels by 10.4%.

Leptin, a satiety hormone produced by white adipose tissue, peaks at night in human plasma. A volunteer ate and slept at all phases of the circadian cycle by scheduling seven recurring 28-hour ‘days’ in dim light and eating four isocaloric meals every ‘day’. Plasma leptin levels followed the forced 28-hour behavioural cycle, while their endogenous 24-hour rhythm was lost. However, since meal timing can entrain the circadian system, this forced desynchrony study could not exclude a potential role of the circadian system.

Another constant routine protocol study with 20 healthy participants showed that rhythms in plasma lipids differed substantially between individuals, suggesting the existence of different circadian metabolic phenotypes.

Composition, function, and absolute abundance of gut microbiota oscillate diurnally. For example, microbial pathways involved in cell growth, DNA repair and energy metabolism peaked during the dark phase, while detoxification, environmental sensing and motility peaked during the day.

It is unclear how phase information is communicated to gut microbiota. However, human commensal bacterium Enterobacter aerogenes showed an endogenous, temperature-compensated 24-hour pattern of swarming and motility in response to melatonin, suggesting that the host circadian system might regulate microbiota by entraining bacterial clocks.

With increasing popularity of time-restricted eating as a dietary intervention, which entrains peripheral clocks of the gastrointestinal tract, studies investigating circadian clocks in the human digestive system are highly needed. Additionally, further research is needed to comprehend shifts in temporal relationships between different gut hormones during chronodisruption.” “Circadian clocks in the digestive system” (not freely available). Thanks to Dr. Inge Depoortere for providing a copy.

This review included many more human examples. I mainly quoted gut interactions.

A long time ago I was successively stationed on four submarines. An 18-hour schedule while underwater for weeks and months wiped out my circadian rhythms.

The U.S. Navy got around to studying 18-hour schedule effects this century. In 2014, submarine Commanding Officers were reportedly authorized to switch their crews to a 24-hour schedule.

Surface! Surface! Surface!

Eat broccoli sprouts for depression

This 2021 rodent study investigated sulforaphane effects on depression:

“Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by:

  • Activating BDNF;
  • Inhibiting expression of its transcriptional repressors (HDAC2 [histone deacetylase 2, a negative regulator of neuroplasticity], mSin3A, and MeCP2); and
  • Revising abnormal synaptic transmission.

In a mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the medial prefrontal cortex and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, protein levels of BDNF transcriptional repressors in CSDS-susceptible mice were higher than those of control and CSDS-resilient mice.

These data suggest that Nrf2 activation increases expression of Bdnf and decreases expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.

Nrf2-induced BDNF transcription in a model of depression.

  • Stress inhibits Nrf2 expression, which inhibits BDNF transcriptional and leads to abnormal synaptic transmission, causing depression-like behaviors in mice.
  • SFN induces BDNF transcription by activating Nrf2 and correcting abnormal synaptic transmission, resulting in antidepressant-like effects.

In conclusion:

  1. Nrf2 regulates transcription of Bdnf by binding to its exon I promoter.
  2. Inhibition of Nrf2-induced Bdnf transcription may play a role in the pathophysiology of depression.
  3. Activation of Nrf2-induced Bdnf transcription promoted antidepressant-like effects.
  4. Alterations in crosstalk between Nrf2 and BDNF may contribute to resilience versus susceptibility after stress.” “Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents”

Go with the Alzheimer’s Disease evidence

This 2021 study investigated gut microbiota differences between 100 AD patients and 71 age- and gender-matched controls:

“Structural changes in fecal microbiota were evident in Chinese AD patients, with decreased alpha-diversity indices and altered beta-diversity ones, evidence of structurally dysbiotic AD microbiota.

Interestingly, traditionally beneficial bacteria, such as Bifidobacterium and Akkermansia, increase in these AD patients while Faecalibacterium and Roseburia decrease significantly. Different species of Bifidobacterium may have different effects that can explain why Bifidobacterium spp. are commonly associated with healthy and diverse microbiota but sometimes also isolated in other conditions. We needed to re-examine the therapeutic potential of Bifidobacterium in terms of maintaining cognitive function and treating dementia.

Surprisingly, our data indicate that Akkermansia was among the most abundant genera in AD-associated fecal microbiota. Similar to Bifidobacterium, Akkermansia was negatively correlated with clinical indicators of AD, such as MMSE, WAIS, and Barthel, and anti-inflammatory cytokines such as IFN-γ.

Based on our present observations, Akkermansia cannot always be considered a potentially beneficial bacterium. It might be harmful for the gut–brain axis in the context of AD development in the elderly.

Aging is associated with an over-stimulation of both innate and adaptive immune systems, resulting in a low-grade, chronic state of inflammation defined as inflammaging. This can increase gut permeability and bacterial translocation.

Characteristics of AD microbial profiles changed from butyrate producers, such as Faecalibacterium, into lactate producers, such as Bifidobacterium. These alterations contributed to shifts in metabolic pathways from butyrate to lactate, which might have participated in pathogenesis of AD. Specific roles of AD-associated signatures and their functions should be explored in further studies.” “Structural and Functional Dysbiosis of Fecal Microbiota in Chinese Patients With Alzheimer’s Disease”

The control group’s 73-year-olds were better off than AD patients. How were they compared with their previous life stages?

Since we’re all aging, how do we each prepare ourselves? I’ll return to evidence including 2020 A rejuvenation therapy and sulforaphane, recently amplified in Part 2 of Switch on your Nrf2 signaling pathway:

“A link between inflammation and aging is the finding that inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that reduces production of gonadotropin-releasing hormone (GnRH) by neurons.

The case is particularly interesting when we realize that the aging phenotype can only be maintained by continuous activation of NF-κB. So here we have a multi-level interaction:

  1. Activation of NF-κB leads to
  2. Cellular aging, leading to
  3. Diminished production of GnRH, which then
  4. Acts (through cells with a receptor for it, or indirectly as a result of changes to GnRH-receptor-possessing cells) to decrease lifespan.

Cell energetics is not the solution, and will never lead to a solution because it makes the assumption that cells age. Cells take on the age-phenotype the body gives them.

Aging is not a defect – it’s a programmed progressive process, a continuation of development with the body doing more to kill itself with advancing years. Progressive life-states where each succeeding life-stage has a higher mortality (there are rare exceptions).

Cellular aging is externally controlled (cell non-autonomous). None of those remedies that slow ‘cell aging’ (basically all anti-aging medicines) can significantly extend anything but old age.

For change at the epigenomic/cellular level to travel up the biological hierarchy from cells to organ systems seems to take time. But the process can be repeated indefinitely (so far as we know).”

We may express concern about others. But each of us should also take responsibility for our own one precious life.

Treat your gut microbiota as one of your organs

Two 2021 reviews covered gut microbiota. The first was gut microbial origins of metabolites produced from our diets, and mutual effects:

“Gut microbiota has emerged as a virtual endocrine organ, producing multiple compounds that maintain homeostasis and influence function of the human body. Host diets regulate composition of gut microbiota and microbiota-derived metabolites, which causes a crosstalk between host and microbiome.

There are bacteria with different functions in the intestinal tract, and they perform their own duties. Some of them provide specialized support for other functional bacteria or intestinal cells.

Short-chain fatty acids (SCFAs) are metabolites of dietary fibers metabolized by intestinal microorganisms. Acetate, propionate, and butyrate are the most abundant (≥95%) SCFAs. They are present in an approximate molar ratio of 3 : 1 : 1 in the colon.

95% of produced SCFAs are rapidly absorbed by colonocytes. SCFAs are not distributed evenly; they are decreased from proximal to distal colon.

Changing the distribution of intestinal flora and thus distribution of metabolites may have a great effect in treatment of diseases because there is a concentration threshold for acetate’s different impacts on the host. Butyrate has a particularly important role as the preferred energy source for the colonic epithelium, and a proposed role in providing protection against colon cancer and colitis.

There is a connection between acetate and butyrate distinctly, which suggests significance of this metabolite transformation for microbiota survival. The significance may even play an important role in disease development.

  • SCFAs can modulate progression of inflammatory diseases by inhibiting HDAC activity.
  • They decrease cytokines such as IL-6 and TNF-α.
  • Their inhibition of HDAC may work through modulating NF-κB activity via controlling DNA transcription.” “Gut Microbiota-Derived Metabolites in the Development of Diseases”

A second paper provided more details about SCFAs:

“SCFAs not only have an essential role in intestinal health, but also enter systemic circulation as signaling molecules affecting host metabolism. We summarize effects of SCFAs on glucose and energy homeostasis, and mechanisms through which SCFAs regulate function of metabolically active organs.

Butyrate is the primary energy source for colonocytes, and propionate is a gluconeogenic substrate. After being absorbed by colonocytes, SCFAs are used as substrates in mitochondrial β-oxidation and the citric acid cycle to generate energy. SCFAs that are not metabolized in colonocytes are transported to the liver.

  • Uptake of propionate and butyrate in the liver is significant, whereas acetate uptake in the liver is negligible.
  • Only 40%, 10%, and 5% of microbial acetate, propionate, and butyrate, respectively, reach systemic circulation.
  • In the brain, acetate is used as an important energy source for astrocytes.

Butyrate-mediated inhibition of HDAC increases Nrf2 expression, which has been shown to lead to an increase of its downstream targets to protect against oxidative stress and inflammation. Deacetylase inhibition induced by butyrate also enhances mitochondrial activity.

SCFAs affect the gut-brain axis by regulating secretion of metabolic hormones, induction of intestinal gluconeogenesis (IGN), stimulation of vagal afferent neurons, and regulation of the central nervous system. The hunger-curbing effect of the portal glucose signal induced by IGN involves activation of afferents from the spinal cord and specific neurons in the parabrachial nucleus, rather than afferents from vagal nerves.

Clinical studies have indicated a causal role for SCFAs in metabolic health. A novel targeting method for colonic delivery of SCFAs should be developed to achieve more consistent and reliable dosing.

The gut-host signal axis may be more resistant to such intervention by microbial SCFAs, so this method should be tested for ≥3 months. In addition, due to inter-individual variability in microbiota and metabolism, factors that may directly affect host substrate and energy metabolism, such as diet and physical activity, should be standardized or at least assessed.” “Modulation of Short-Chain Fatty Acids as Potential Therapy Method for Type 2 Diabetes Mellitus”

Mid-life gut microbiota crisis

This 2019 rodent study investigated diet, stress, and behavioral relationships:

“Gut microbiome has emerged as being essential for brain health in ageing. We show that prebiotic supplementation with FOS-Inulin [a complex short- and long-chain prebiotic, oligofructose-enriched inulin] is capable of:

  • Dampening age-associated systemic inflammation; and
  • A profound yet differential alteration of gut microbiota composition in both young adult and middle-aged mice.

Middle-aged mice exhibited an increased influx of inflammatory monocytes into the brain. However, neuroinflammation at this stage was not significant enough to manifest in major cognitive impairments.

A much longer exposure to prebiotics might be needed to achieve significant effects, suggesting that supplementation may have to start earlier to be effectively preventative before alterations in the brain occur. This is particularly evident for behaviour.

Targeting gut microbiota, as we have done with a prebiotic, can affect the brain and subsequent behaviour through a variety of potential pathways including SCFAs [short-chain fatty acids], amino acids and immune pathways. All of these are interconnected. Future studies are needed to better deconvolve [figure out] such pathways in eliciting beneficial effects of inulin.

Modulatory effects of prebiotic supplementation on monocyte infiltration into the brain and accompanied regulation of age-related microglia activation highlight a potential pathway by which prebiotics can modulate peripheral immune response and alter neuroinflammation in ageing. Our data suggest a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function.” “Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome” (not freely available)

This study’s experiments subjected young and middle-aged mice to eight stress tests. I appreciated efforts to trace causes to behavioral effects, since behavior provided stronger evidence.

I’m in neither life stage investigated by this study. Still, per Reducing insoluble fiber, I’ll start taking inulin next week. See Increasing soluble fiber intake with inulin.

I came across this study through its citation in How will you feel?

Inauguration day

The future of your brain is in your gut right now

A 2020 paper by the author of Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease:

“The gut and brain communicate bidirectionally via several pathways which include:

  1. Neural via the vagus nerve;
  2. Endocrine via the HPA axis;
  3. Neurotransmitters, some of which are synthesized by microbes;
  4. Immune via cytokines; and
  5. Metabolic via microbially generated short-chain fatty acids.

How does nature maintain the gut-microbiome-brain axis? Mechanisms to maintain homeostasis of intestinal epithelial cells and their underlying cells are a key consideration.

The symbiotic relationship that exists between microbiota and the human host is evident when considering nutrient requirements of each. The host provides food for microbes, which consume that food to produce metabolites necessary for health of the host.

Consider function of the human nervous system, not in isolation but in integration with the gastrointestinal ecosystem of the host, in expectation of a favorable impact on human health and behavior.” “Chapter 14 – The gut microbiome: its role in brain health” (not freely available)

Always more questions:

  1. What did you put into your gut today?
  2. What type of internal environment did it support?
  3. What “favorable impact on human health and behavior” do you expect from today’s intake?
  4. How will you feel?
  5. Will you let evidence guide feeding your gut environment?

See Harnessing endogenous defenses with broccoli sprouts for further elaboration. See Switch on your Nrf2 signaling pathway for an interview with these papers’ author.

How will you feel?

Consider this a partial repost of Moral Fiber:

“We are all self-reproducing bioreactors. We provide an environment for trillions of microbes, most of which cannot survive for long without the food, shelter and a place to breed that we provide.

They inhabit us so thoroughly that not a single tissue in our body is sterile. Our microbiome affects our development, character, mood and health, and we affect it via our diet, medications and mood states.

The microbiome:

  • Affects our thinking and our mood;
  • Influences how we develop;
  • Molds our personalities;
  • Our sociability;
  • Our responses to fear and pain;
  • Our proneness to brain disease; and
  • May be as or more important in these respects than our genetic makeup.

Dysbiosis has become prevalent due to removal of prebiotic fibers from today’s ultra-processed foods. I believe that dietary shift has created a generation of humans less able to sustain or receive love.

They suffer from reduced motivation and lower impulse control. They are more anxious, more depressed, more selfish, more polarized, and therefore more susceptible to the corrosive politics of identity.

Other recent blog posts by Dr. Paul Clayton and team include Skin in The Game and Kenosha Kids.

Image from Thomas Cole : The Consummation, The Course of the Empire (1836) Canvas Gallery Wrapped Giclee Wall Art Print (D4060)