Take acetyl-L-carnitine for early-life trauma

This 2021 rodent study traumatized female mice during their last 20% of pregnancy, with effects that included:

  • Prenatally stressed pups raised by stressed mothers had normal cognitive function, but depressive-like behavior and social impairment;
  • Prenatally stressed pups raised by control mothers did not reverse behavioral deficits; and
  • Control pups raised by stressed mothers displayed prenatally stressed pups’ behavioral phenotypes.

Acetyl-L-carnitine (ALCAR) protected against and reversed depressive-like behavior induced by prenatal trauma:

alcar regime

ALCAR was supplemented in drinking water of s → S mice either from weaning to adulthood (3–8 weeks), or for one week in adulthood (7–8 weeks). ALCAR supplementation from weaning rendered s → S mice resistant to developing depressive-like behavior.

ALCAR supplementation for 1 week during adulthood rescued depressive-like behavior. One week after ALCAR cessation, however, the anti-depressant effect of ALCAR was diminished.

Intergenerational trauma induces social deficits and depressive-like behavior through divergent and convergent mechanisms of both in utero and early-life parenting environments:

  • We establish 2-HG [2-hydroxyglutaric acid, a hypoxia and mitochondrial dysfunction marker, and an epigenetic modifier] as an early predictive biomarker for trauma-induced behavioral deficits; and
  • Demonstrate that early pharmacological correction of mitochondria metabolism dysfunction by ALCAR can permanently reverse behavioral deficits.”

https://www.nature.com/articles/s42003-021-02255-2 “Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction”


Previously curated studies cited were:

This study had an effusive endorsement of acetyl-L-carnitine in its Discussion section, ending with:

“This has the potential to change lives of millions of people who suffer from major depression or have risk of developing this disabling disorder, particularly those in which depression arose from prenatal traumatic stress.”

I take a gram daily. Don’t know about prenatal trauma, but I’m certain what happened during my early childhood.

I asked both these researchers and those of Reference 70 for their estimates of a human equivalent to “0.3% ALCAR in drinking water.” Will update with their replies.


PXL_20210704_095621886

Basal cognition

To follow up Electroceuticals, a 2021 article by Dr. Michael Levin:

“A key philosophical idea, borrowed from computer science, is substrate independence. Components of a living system can carry out appropriate, clearly specified cognitive functions.

Cognitive processes in embryogenesis and regeneration:

rstb20200458f01

    • (a) An egg will reliably give rise to a species-specific anatomical outcome.
    • (b) This process is usually described as a feed-forward system where activity of gene-regulatory networks (GRNs) within cells results in expression of effector proteins that, via structural properties of proteins and physical forces, will result in the emergence of complex shape. This class of models (bottom-up process driven by self-organization and parallel activity of large numbers of local agents) is difficult to apply to several biological phenomena. Regulative development can alter subsequent steps to reach the correct anatomical goal state despite drastic deviations of the starting state.
    • (c) For example, mammalian embryos can be divided in half, giving rise to perfectly normal monozygotic twins, each of which has regenerated the missing cell mass.
    • (d) Mammalian embryos can also be combined, giving rise to a normal embryo in which no parts are duplicated.
    • (e) Such capabilities suggest that pattern control is fundamentally a homeostatic process—a closed-loop system using feedback to minimize error (distance) between a current shape and a target morphology. Although these kinds of decision-making models are commonplace in engineering, they are only recently beginning to be employed in biology. This kind of pattern-homeostatic process must store a setpoint that serves as a stop condition; however, as with most types of memory, it can be specifically modified by experience.
    • (f) In the phenomenon of trophic memory, damage created at a specific point on the branched structure of deer antlers is recalled as ectopic branch points in subsequent years’ antler regeneration. This reveals ability of cells at the scalp to remember spatial location of specific damage events and alter cell behaviour to adjust the resulting pattern appropriately—a pattern memory that stretches across months of time and considerable spatial distance and is able to modify low-level (cellular) growth rules to construct a pre-determined stored pattern that differs from genome-default for this species.
    • (g) A similar capability was recently shown in a molecularly tractable model system, in which genetically normal planarian flatworms were bioelectrically reprogrammed to regenerate two-headed animals when cut in subsequent rounds of asexual reproduction in plain water.
    • (h) The decision making revealed by cells, tissues and organs in these examples of dynamic remodelling toward specific target states could be implemented by cybernetic processes at various positions along a scale of proto-cognitive complexity.

A challenge for the field of basal cognition is to reveal gradualism of cellular properties underwriting this critical biological function to leverage an understanding of clear phase transitions observed in cognitive capacities. The origin and development of nervous systems is so far the most dramatic example.”

https://royalsocietypublishing.org/doi/10.1098/rstb.2020.0458 “Uncovering cognitive similarities and differences, conservation and innovation”


Why aren’t more resources being directed toward these research efforts? Glad to see that at least one co-founder of Microsoft, Paul Allen, posthumously used his billions to sponsor science for human good.

Electroceuticals

To follow up A top-down view of biological goal-directed mechanisms, 2020 and 2021 presentations by Dr. Michael Levin of Tufts University:

“We want to able to design a living form at the level of anatomy, and have the system compile it down into a set of low level instructions that you would have to give to the cellular collective to make it do this. What we would like to do is to offload all that complexity onto cells, and control this  whole thing with inputs, experiences, or stimuli.

What evolution does is to exploit bioelectricity to implement networks that store these patterns, patterns that serve as memories and goal states.”


electroceuticals


Appreciate Dr. Levin sticking with his findings for three decades now. Credit my son for refreshing my memory.

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.”

https://heart.bmj.com/content/106/9/691 “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.”

https://www.sciencedirect.com/science/article/pii/S2213231721000161 “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.”

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13123 “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.

PXL_20210606_095517049

I came across this subject in today’s video:

The next phase of reversing aging and immunosenescent trends

Dr. Greg Fahy earlier this week provided an update on the November 2020 TRIIM-X follow-on to the September 2019 TRIIM curated in Reversal of aging and immunosenescent trends. Emphasis was on reproducibility:

23:45 Dr. Steve Horvath reanalyzed TRIIM for the plasma portion of Levine’s PhenoAge epigenetic clock. Results were congruent with four other epigenetic clocks showing a 2.5 year reduction of biological age.

39:20 TRIIM-X preliminary results started with C-Reactive protein.

43:05 No backsliding in epigenetic age deceleration between TRIIM and TRIIM-X!

continued epigenetic age deceleration

55:07 Q & A session starts with how TRIIM-X controls for supplements. Answers for resveratrol and calorie restriction, emphasizing that CR doesn’t reverse aging.

1:10 TRIIM-X took photos of subjects’ hair at baseline!


Great update! The last 20 minutes emphasized a need for capital in aging research. TRIIM-X has another 1.5 years to go, and other aging research projects needing funding were mentioned.

Don’t know what happened to the unmentioned 3000 IU vitamin D and 50 mg zinc recommendations of TRIIM. So I asked. Dr. Fahy replied:

“They are still there! Just not mentioned!”

Thought briefly about enrolling in TRIIM-X, but there’s no way anyone but me gets to experiment with my body.

Dietary fibers and the aged microbiome

This 2021 rodent study investigated effects of four different types of dietary fiber on two different types of aged human microbiota:

Individual differences in gut microbiota may influence host metabolic responses to dietary fiber in humans. Dietary fibers are edible carbohydrates resistant to host digestive enzymes, and not broken down or absorbed in the small intestine.

We colonized genetically identical germ-free mice with two distinct human fecal communities and fed them isocaloric diets containing different types of fiber. We used fecal specimens from a cohort of previously analyzed samples obtained from adults in their mid-seventies.

We used 10% dietary fiber and 35% kcal derived from fat as comparable to the intake level of dietary fiber in US adults:

four diets

All mice had the same assorted fiber diet for two weeks. Mice were then switched to one of four diets described above: cellulose, inulin, pectin, and assorted fiber, and maintained in these diets for another 4 weeks.

There was a ~ 4-fold range in levels of cecal butyrate among the eight groups despite all animals consuming the same diet [before switching]. Butyrate is known to vary widely among humans and has been linked with beneficial health effects on the host:

SCFA individual differences

We chose inulin and pectin as the former is commonly used as a prebiotic, while the latter has been proven to support growth of a wide variety of gut microbes, and it is commonly used as a dietary supplement. We also chose these two dietary fibers due to their distinct structures, including differences in basic units, linkages, and degree of polymerization.

Assorted fiber diet had the same total amount of dietary fiber as treatment groups used in this study, but with more diversity in fermentable substrates, which we reasoned would support engraftment of taxa relevant to all dietary treatments. Inclusion of this group in the experimental phase also served as a control to inform whether this diet used during colonization drove major differences.

Diet and its interaction with gut community showed a significant effect on serum glucose levels. While pectin diet had an overall beneficial effect on metabolic phenotypes relative to non-fermentable cellulose for SubA-colonized mice, this diet was less favorable for SubB-colonized animals, which showed the strongest benefits on inulin fiber.

In inulin diet, mice inoculated with SubB showed decreased adiposity, decreased liver triglycerides (TG) and lower serum levels of fasting glucose relative to animals colonized with SubA. In contrast, pectin-fed mice colonized with SubB accumulated more fat mass relative to SubA-colonized counterparts, whereas serum glucose and liver TG were comparable between the two community groups.

Mice colonized with SubB showed significantly lower levels of adiposity than those colonized with SubA in the assorted fiber diet, whereas serum glucose and liver TG were comparable.

We found that these two transplanted communities elicited divergent metabolic epigenetic and transcriptional responses to the same dietary fiber. Furthermore, differences between mice colonized with these two communities varied depending on type of fiber consumed.

Populations contain a significant amount of genetic variation derived from their largely individual associated microbiomes. Dissecting effects of gut microbial vs. host genetic variation while controlling environmental exposure is practically impossible to achieve in human studies.

One-size-fits-all approaches to promote health are unlikely to elicit consistent effects across individuals. Identifying gut microbial biomarkers associated with beneficial responses to common interventions may help to stratify subjects into more effective personalized treatments.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-021-01061-6 “Gut microbiome variation modulates the effects of dietary fiber on host metabolism”


1. This study nailed it! You are what you eat, and The future of your brain is in your gut right now.

2. Group differences in cecal butyrate in the second graphic were instructive. But what really needed to be analyzed was each individual subject’s responses within the eight groups, and each individual’s characteristics.

What did or didn’t matter to each individual could then be applied and analyzed to what did or didn’t matter to its group. Researchers need to flip from a top-down statistics-package approach, to a bottoms-up individual paradigm for evidence.

3. Haven’t mentioned Increasing soluble fiber intake with inulin recently. I eat the labeled 2.5 grams serving. More than that runs into a 10 g “Over this dose would induce mild gastrointestinal symptoms” threshold.

I eat a half-dozen cloves of garlic in daily AGE-less chicken vegetable soup. Garlic contains ≈ 16% inulin, contributing 4-5 g inulin.

4. My dietary fiber intake of current practices is well beyond this study’s all-category 10% with broccoli, red cabbage, mustard, and oat sprouts. Several times more than our human ancestors’ dietary fiber 100 g/day if Switch on your Nrf2 signaling pathway measurements are correct?

Trying to make my gut microbiota happy, expecting that they’ll reciprocally respond. Dietary fat content is < 10 %.

An outstanding review of Vitamin K deficiency and disease

This 2019 review focused on one Vitamin K-deficiency biomarker. All parts I’ve quoted are outside the liver, so Vitamin K deficiency ≈ Vitamin K2 deficiency.

This is a hard read with many technical details, but sometimes that’s how researchers do it:

“Active MGP (matrix Gla protein), once released into extracellular space, acts as a local inhibitor of calcification. Widespread expression of MGP points to a role of MGP that by far exceeds its well-known function as local inhibitor of calcification.

Recent research confirmed this concept, usually by measuring plasma dp-ucMGP (desphospho-uncarboxylated MGP), a biomarker reflecting poor vitamin K status:

1160fig02

Vitamin K plays a pivotal role in maintaining bone health. Increasing evidence also implicates MGP in maintaining bone health.

In the Health, Aging and Body Composition study, 791 older community-dwelling adults underwent magnetic resonance imaging to measure bilateral knee structural features. The highest [25%] compared with the lowest fourth of the dp-ucMGP distribution had higher odds of having:

  • Meniscus damage;
  • Osteophytes;
  • Bone marrow lesions; and
  • Subarticular cysts.

Regarding Vitamin K supplementation:

  • Studies showed a dose-dependent decrease in circulating dp-ucMGP with an 86% decrease already observed after 4 weeks of substitution by 360 μg menaquinone-7 [in 50 hemodialysis patients];
  • In a randomized double-blind trial of 244 postmenopausal women followed up for 3 years, arterial stiffness as captured by aortic pulse wave velocity or stiffness index β, decreased in intervention compared with control group.

These results should be considered as hypothesis-generating in view of small sample size, and because there were no between-group differences in vitamin K–induced changes in elastic properties of the carotid artery.

Plasma dp-ucMGP levels ranging from 1.4 to 4.6 μg/L were optimal in terms of risk of mortality and macrovascular cardiovascular illness (4.6 μg/L threshold corresponding to the 65th percentile of dp-ucMGP distribution).

Vitamin K supplementation before irreversible organ damage sets in might find its application in prevention of a wide range of disabling diseases. Circulating dp-ucMGP levels might be measured over time to track risk of vascular complications.”

https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.119.12412 “Vitamin K–Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity”


I usually don’t give 5+ stars to reviews. This one was different.

Yes, there could be factors other than this one Vitamin K deficiency biomarker involved in study findings. Sure, these coauthors cited their own studies. Its overall purpose, though, was to inform readers.

I’ll summarize this paper as providing evidence for a biomarker of Vitamin K2 deficiency being implicated in the development and progression of many diseases.

Red cabbage effects on gut microbiota

A tremendous 2021 study involving the group who published Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts:

“The aim was to evaluate the influence of red cabbage extracts on bioaccessibility of their isothiocyanates, and their effect on intestinal microbiota using a dynamic model of human digestion treated with the gut microbiome of obese adults.

Plant plasma membrane vesicles as delivery systems for bioactive compounds has been studied. Diverse types of plant membrane vesicles could be good candidates for this purpose, such as extracellular vesicles, which are spheroids of cytosolic material surrounded by a lipid bilayer, or extracted plasma membrane from fresh plant tissue.

As an example of the latter, we used cauliflower plasma membrane vesicles, which are proteoliposomes with a high proportion of unsaturated fatty acids. There could be an interaction between plant aquaporins found in our vesicles and isothiocyanates present in red cabbage aqueous extract, which could have increased stability.

In this way, plasma membrane vesicles may act as stabilizing carriers and feeding agents for enzymes and bile salts rather than an encapsulating agent per se. However, this aspect should be further studied.

red cabbage sfn, i3c, iberin

In the transversal colon reactor, butyric acid production by gut microbiota had a 3-fold increase after 14-day treatment for free red cabbage aqueous extract when compared to stabilization period. A 3.5-fold increase was observed when using nanonencapsulated extract.

Regarding the descending colon, a 2-fold increase in butyric acid was produced after 14 days of treatment with free red cabbage aqueous extract. A 4-fold increase was observed in production after treatment with nanoencapsulated extract.

Propionic and acetic acids were studied, but no changes were observed. The fact that encapsulated red cabbage extract provided a higher production of butyric acid pointed to future developments for design of a functional ingredient or food product for management of overweightness and obesity.”

https://www.mdpi.com/2304-8158/10/5/1038/htm “The Influence of Red Cabbage Extract Nanoencapsulated with Brassica Plasma Membrane Vesicles on the Gut Microbiome of Obese Volunteers”


This study demonstrated that iberin was initially the third highest isothiocyanate of red cabbage after glucosinolate hydrolysis. Iberin surpassed sulforaphane to become the predominant isothiocyanate – in both free and nanoencapsulated forms – when it reached the lower colon, where most of our gut microbiota reside.

As noted in Tailoring measurements for broccoli sprouts, study findings of mature plants don’t necessarily apply to their sprouts. Lab analyses of broccoli sprout compounds used 9-day-old red cabbage sprouts to measure iberin (3MSOP-ITC in Figure 5). Haven’t found recent studies on iberin’s effects on gut microbiota and intestinal epithelial cells.

This study showed “a 3 to 4-fold increase in production of butyric acid with encapsulated extract treatment.” Keep leading the way. 🙂

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.

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-020-00920-y “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.”

https://pubs.acs.org/doi/10.1021/acs.jafc.0c03170 “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.

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.”

https://elifesciences.org/articles/62048 “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”

A bat epigenetic clock

This 2021 study subject was bats:

“Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity.

Hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that:

  • Age-related methylation change is influenced by developmental processes, while
  • Longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that
  • Bat longevity results from augmented immune response and cancer suppression.

Molossus molossus [a short-lived species] age genes are not enriched for immunity genes or genes that frequently mutated in cancer. However, M. molossus longevity genes exhibit significant overlap with genes involved in immunity and genes frequently mutated in human tumors.

Similar overlap patterns among immunity, longevity, and tumor-mutated genes also exist for long-lived bats.

Two species’ genetic adaptations for tumor suppression have been described to help explain their extreme longevity. Bats also have genetic mechanisms that enable strong antiviral immune responses without inducing damaging inflammatory reactions that may enable them to tolerate high levels of viral exposure.

Our results are consistent with an epigenetic clock theory of aging that connects beneficial developmental and cell maintenance processes to detrimental processes causing tissue dysfunction.”

https://www.nature.com/articles/s41467-021-21900-2 “DNA methylation predicts age and provides insight into exceptional longevity of bats”


The founder of the epigenetic clock has been busy, coauthoring more published studies than there have been weeks in this year! I’ve read five other 2021 studies he’s coauthored on dogs, horses, mammals (2), and humans in DNA methylation biomarker for cumulative lead exposure is associated with Parkinson’s disease. This one stood out for its “longevity results from augmented immune response and cancer suppression” findings.

If we’re interested in longevity, this clarity can direct efforts to both improve our immune systems and avoid problems like cancer. Symptoms may be subclinical, but that doesn’t provide adequate rationale to not address causes.

Peer review comments and responses were informative:

Reviewer #1 – “Developing an aging clock that works for a diverse set of bat species is a spectacular achievement.”

Reviewer #2 – “This is a tour de force study.”

Replies to Reviewer #3:

“Difference in recorded lifespans between three long-lived species and two short-lived species that we used to identify longevity DMPs [differentially methylated positions] is 20 years or more, even though they have similar body sizes (20-40 g). The three long-lived species [maximum ages 29.9, 30.5, and 37.1 years] also represent three different phylogenetic lineages.

CpG sites that undergo hypomethylation with age do so largely at random. In contrast, sites that undergo hypermethylation with age are highly nonrandom, and as has been noted before, are near genes associated with development. So yes, we believe there are predictable methylation changes with age.”

Choosing your future with β-glucan

This 2020 rodent study investigated yeast cell wall β-glucan effects on bacterial infections:

“β-glucan is a potent inducer of epigenetic and functional reprogramming of innate immune cells, a process called trained immunity, resulting in an enhanced host response against secondary infections. We investigate whether β-glucan exposure confers protection against pulmonary Mycobacterium tuberculosis (Mtb) infection.

  • β-glucan induces trained immunity via histone modifications. β-glucan-induced trained immunity confers protection against virulent Mtb via the IL-1 signaling pathway.
  • β-glucan-induced trained immunity enhances production of proinflammatory cytokines in human monocytes challenged with heat-killed Mtb. Increase in cytokine production capacity was the result of epigenetic reprogramming and mediated via the PI3K/Akt/mTOR pathway.

Most important, β-glucan-treated mice infected with Mtb demonstrated remarkably enhanced survival, which was dependent on IL-1 signaling.

survival Mtb

β-glucan epigenetically reprograms human monocytes, leading to a phenotype characterized by a unique IL-1 signature and anti-mycobacterial properties. β-glucan-treated mice were protected against pulmonary Mtb infection.

While both β-glucan and BCG [Bacillus Calmette-Guerin tuberculosis vaccine] reprogram HSCs to induce trained immunity, BCG reprogramming of HSCs was dependent on IFNγ signaling. β-glucan reprogramming of HSCs was mediated via IL-1 signaling, which was also required for protection against Mtb infection.

Considering safety of β-glucan in a human clinical trial, our results strongly suggest potential clinical implications of β-glucan for both prophylactic and therapeutic use in TB.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30587-8 “β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1″


My comment “many of these findings also apply to yeast cell wall β-glucan treatments” in Long-lasting benefits of a common vaccine lacked clarity. This post provides part of that evidence.

So where do you choose to be? In an 80% survival group who were administered β-glucan before they encountered a serious infection? Or in a < 20% survival group who didn’t take β-glucan?

Which is better for resolving a health situation before it becomes a problem?

  • Roll the dice, and hope for luck / providence?
  • Do nothing constructive, and depend on interventions after a problem occurs?
  • Take responsibility for your own one precious life?

PXL_20210327_111214712

Harnessing endogenous defenses with broccoli sprouts

This 2019 article was by the author of Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. It isn’t widely available, so I’ll quote liberally:

“Demand for solutions to digestive health issues is accelerating, especially since both scientific literature and popular press dedicate significant resources to promoting awareness of what has come to be known as ‘gut health’. In considering available therapies and the possibility that a somewhat different approach may more comprehensively optimise function of the gut ecosystem, a number of questions which do not yet have satisfactory answers are ponderable dilemmas:

  1. If diet alone can dramatically shift composition of the microbiome within 24 hours, what do we expect of a probiotic supplement?
  2. + Even though probiotics as food or supplements demonstrate favourable clinical outcomes, they typically don’t colonise the gut. How do we expect them to restore diversity and lost species to the gut microbiome after antibiotics? If no trace of an administered probiotic organism can be found a few weeks later, is there any sustained benefit?
  3. Presence of obesity and other diseases is indirectly proportional to diversity of microbial organisms inhabiting the human gut. What can we expect of a few selected probiotic strains in helping to solve this problem?
  4. No antimicrobial approach selectively destroys a pathogen without impacting commensals to some degree. If we select a tool to eradicate gut pathogens, pathobionts or rogue commensals, how do we avoid damaging protective commensals with which we live symbiotically?
  5. The value of using a probiotic supplement after antibiotic therapy to recolonise the gut is uncertain. A 2018 multi-centre study showed that probiotic supplementation after antibiotics delayed gut microbiome reconstitution by around five months.
  6. If the gut can harbour around 1,000 different species, why do we expect a probiotic supplement harbouring just a few species to favourably modify a human microbiome?
  7. If Lactobacilli make up <0.1% of total microbes, why do we so readily choose them as probiotic supplements?
  8. If L-glutamine is a preferred energy source for the small intestine and not the colon, why is it used almost universally in gut repair programmes regardless of the affected region?

Removal of gluten and administration of probiotics have lesser impact than endogenous factors like elevated HbA1c:

Shift emphasis closer to optimising colonocyte metabolism as the primary driver of dysbiosis in the colon. Since these mechanisms within the human gut ecosystem already exist, intervene at this level, as distinct from using antimicrobials and exogenous probiotic strains to influence host cell function.

Phytonutrients that potently activate these core processes have been identified and are sufficiently bioavailable to achieve this end. Restoring homeostasis to intestinal epithelial cells can be readily justified as a key initial step.

Sulforaphane is a potent inducer of hundreds of genes associated with cellular defences mechanisms. In this context, these genes include those that code for antioxidant and phase II detoxification enzymes, glutathione and metallothionein.

Sulforaphane exhibits other more specific gut and immune-related effects. As the most potent single food-derived activator of Nrf2, sulforaphane is capable of upregulating protective genes in colonocytes and other cells.

A growing body of work has identified the colonocyte as the driver of dysbiosis. Targeting colonocyte function provides an alternative to targeting microbes for remediation of dysbiosis.

https://www.researchgate.net/publication/336578800_Restoring_Gut_Ecology_Harnessing_the_Inbuilt_Defence_Mechanisms_of_the_Gut_Epithelium “Restoring Gut Ecology: Harnessing the Inbuilt Defence Mechanisms of the Gut Epithelium” (registration required)


If you can’t access this paper, read The future of your brain is in your gut right now. If you can’t access that paper, listen to Switch on your Nrf2 signaling pathway.

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.”

https://www.sciencedirect.com/science/article/pii/B9780128205938000148 “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.