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.”

Train your gut microbiota with taurine

This 2021 rodent study found:

“We show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to expansion of taxa that utilize taurine.

Supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Taurine potentiates microbiota production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens.

fx1_lrg

This work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train microbiota, promoting its resistance to subsequent infection.”

https://www.cell.com/cell/fulltext/S0092-8674(20)31681-0 “Infection trains the host for microbiota-enhanced resistance to pathogens” (not freely available)


News coverage added:

“The studied infections induced host taurine production and expansion of taurine utilizers. Taurine was the trigger for activity of a class of bacteria that fight these infections.

The group’s data suggest that low levels of taurine allow pathogens to colonize the gut, but high levels produce enough hydrogen sulfide to prevent colonization. Taurine given to mice in drinking water prepared microbiota to prevent infection. However, when mice drank water containing bismuth subsalicylate, a common over-the-counter drug used to treat diarrhea and upset stomach, infection protection waned because bismuth inhibits hydrogen sulfide production.”

Can’t calculate a human equivalent dose without access to this study. I take 1 gram of taurine twice a day.

Per Treating psychopathological symptoms will somehow resolve causes? I resumed taurine supplementation last year after taking a year’s break. From that paper’s taurine section:

“Most studies that reported enhanced GSH [glutathione] in the brain following taurine treatment were performed under a chronic regimen and used in age-related disease models.

Such positive effects of taurine on GSH levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

If that paper’s hypothesis is correct, and the current study’s evidence is replicable, taurine supplementation is a win-win for both our brain and gut microbiota.


Sunrise minus 5 minutes

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.

dectin-1

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.”

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02103-4 “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.

PXL_20210405_103925702
Swarming a spring sea trout run. Ospreys outcompeted gulls for breakfast.

Eat broccoli sprouts for your heart

This 2021 rodent study investigated mechanisms of sulforaphane’s persistent cardiac protection:

“Sulforaphane (SFN) reduced Ang II‐induced CpG hypermethylation and promoted Ac‐H3 [histone H3 acetylation] accumulation in the Nrf2 promoter region, accompanied by inhibition of global DNMT [DNA methyltransferase] and HDAC [histone deacetylase] activity, and a decreased protein expression of key DNMT and HDAC enzymes.

jcmm16504-fig-0006-m

SFN reduces CpG methylation and promotes enrichment of Ac‐H3 in Nrf2 promoter by inhibiting DNMTs and HDACs. This partially contributes to long‐acting activation of cardiac Nrf2, thereby preventing Ang II‐induced cardiomyopathy.”

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.16504 “Sulforaphane prevents angiotensin II‐induced cardiomyopathy by activation of Nrf2 through epigenetic modification”


This study used the same dose of sulforaphane as Broccoli sprouts activate the AMPK pathway, but stopped at six months (equivalent to a 34-year-old human) rather than continuing to eight months (a 42-year-old human):

“0.5 mg/kg SFN in mice is converted to a human dose of 0.0405 mg/kg. In some clinical studies, the dose of SFN used to treat chronic diseases is usually higher.”

Findings highlighted:

  1. A disease condition existed in young adults that wasn’t severe enough for them to experience overt symptoms; and
  2. A disease condition could be reversed or prevented when its causes were addressed before it became a problem.

Studies such as one mentioned in Part 2 of Eat broccoli sprouts for your eyes showed that if one waited until a disease condition became a problem, capabilities to adequately address causes and prevent it may be lost. Do you want to be limited to addressing a disease’s symptoms once it gets bad enough to be noticeable?

Both studies found positive effects of sulforaphane in preventing cardiomyopathy. The 2020 study demonstrated in myocardial cells that sulforaphane’s activation of the AMPK pathway – which is upstream of the Nrf2 pathway – activated Nrf2:

“NRF2-mediated antioxidative effects can be activated via AMPK/AKT/GSK3β pathway, developing another pathway to confront cardiac oxidative damage.”

The current study similarly stated:

“Nrf2 can also be regulated independently of Keap1. Evidence indicates that SFN may indirectly activate Nrf2 by affecting activity of several upstream kinases.”


Both studies’ “human dose of 0.0405 mg/kg” were a minuscule 2.8 mg (.0405 mg/kg x 70 kg) human dose compared with my estimated daily 52 mg of sulforaphane from eating 65.5 grams of microwaved 3-day-old broccoli sprouts twice daily. Yet that small amount of sulforaphane was able to prevent a daily dose of angiotensin II from causing conditions that would lead to heart disease.

I linked this study yesterday in Reversing osteoporosis with Nrf2 as an example of similarities with exercise and eating broccoli sprouts. While activating my Nrf2 pathways this morning by walking four miles at sunrise, I came across a heron who tolerated me getting close to them:

PXL_20210407_110723070

It ate breakfast off a branch, and pecked morsels from the water if they hopped off.

Reversing osteoporosis with Nrf2

This 2021 rodent study made old females out of young females by removing their ovaries, which induced osteoporosis. They then demethylated the Nrf2 gene promoter with exercise, increasing its expression, which reversed osteoporosis:

“Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is an important epigenetic feature of osteoporosis (OP) pathogenesis.

Nrf2 promoter demethylation

Ovariectomized mice display increased femoral Dnmt1/3a/3b (Dnmts), Nrf2 promoter hypermethylation, and Nrf2 suppression, which promote oxidative stress (OS), osteoclastogenesis (OCG) and OP (dashed line).

Running exercise (RE, solid line) normalizes Dnmt aberrations, resulting in Nrf2 promoter demethylation, Nrf2 recovery and reduced femoral osteoporotic pathologies.

Nrf2 repression due to aberrant Dnmt elevations and associated promoter hypermethylation contributes significantly to epigenetic development of OP. RE effectively corrects epigenetic abnormalities and pathogenesis of OP.”

https://www.nature.com/articles/s41413-020-00128-8 “Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis”


Running an hour every day has effects on Nrf2 gene promoter expression similar to eating broccoli sprouts. A 2021 study Sulforaphane prevents angiotensin II‐induced cardiomyopathy by activation of Nrf2 through epigenetic modification found:

“SFN reduced Ang II‐induced CpG hypermethylation and promoted Ac‐H3 accumulation in the Nrf2 promoter region, accompanied by inhibition of global DNMT and HDAC activity, and a decreased protein expression of key DNMT and HDAC enzymes.”

A 2019 study Sulforaphane‑induced epigenetic regulation of Nrf2 expression by DNA methyltransferase in human Caco‑2 cells found:

“DNMT1 protein expression was inhibited by sulforaphane. Nrf2 promoter methylation decreased significantly in the sulforaphane group.

Sulforaphane may promote demethylation of the Nrf2 promoter region to increase activation of Nrf2.”


Per Week 6, my running days are over, though not walking, climbing, etc. Nrf2 activation with broccoli sprouts began after two weeks of self-quarantine more than a year ago.

Improving one’s own health provides sufficient rationale to act.

Oat β-glucan effects on colitis

This 2021 rodent study investigated oat β-glucan effects on colitis:

“In this study, we determined effects of consumption of low- and high-molar-mass oat beta-glucans on expression of selected markers of apoptosis and autophagy in colonocytes in TNBS colitis-induced rats. We analyzed expression of colon wall receptors, including TLRs and Dectin-1, which are involved in recognition of molecular patterns of pathogens in colon epithelial cells.

Rats were divided into two main groups: healthy control (H) and a TNBS (2,4,6-trinitrobenzosulfonic acid)-induced colitis (C) group, both including subgroups fed feed without beta-glucans (βG−) or feed supplemented with low- (βGl) or high-molar-mass oat beta-glucans (βGh) for 3, 7, or 21 days. Expression of autophagy (LC3B) and apoptosis (Caspase-3) markers, as well as Toll-like (TLRs) and Dectin-1 receptors in colon epithelial cells, was determined.

nutrients-13-00321-g001

1. [Autophagy] Autophagy contributes to adaptation of cells and maintenance of intracellular homeostasis enabling cells to survive under stressful conditions. The autophagy marker in colon wall and intestinal epithelial cells (IECs) investigated was expression of LC3B protein, which participates in formation and maturation of autophagosomes.

A decrease in this protein was found in colon wall after TNBS administration, which indicates intense repair processes of intestinal epithelium accompanying / preceding the period of Crohn’s disease (CD) remission. The above data indicate a significant effect of oat beta-glucans in restoring autophagy in inflamed IECs, and a stronger effect of oat beta-glucans with a high molar mass, which also increased activity of autophagy in colon tissue of control animals without colitis.

2. [Apoptosis] In early development of acute colitis, expression of Caspase-3, the executive enzyme of apoptosis, was very low. The highest expression of Caspase-3 protein was observed in control (HβGh+), feed supplemented with high-molar-mass oat beta-glucans.

  • After 7 days of TNBS administration, Caspase-3 expression in colitis-induced animals was approximately eight times higher than in control group, which indicates an increase in apoptosis in response to intestinal inflammation.
  • Consumption of feed supplemented with high-molar-mass oat beta-glucans by colitis animals resulted in approximately two times lower Caspase-3 expression after 7 days. Physical properties of high-molar-mass beta-glucans favor formation of a protective layer on inner wall of intestine, effectively supporting development of beneficial microbiota producing short-chain fatty acids.
  • Consumption of feed with low-molar-mass oat beta-glucans resulted in expression of this enzyme in colitis animals at a similar level as in control group.

This confirms significant effect of oat beta-glucans in reducing expression of Caspase-3 during ongoing inflammation, with low-molar-mass beta-glucans having a stronger effect.

3. [Dectin-1] Expression of Dectin-1 across all experimental time points was found to be reduced due to induced inflammation. We analyzed Dectin-1 expression in intestinal epithelial cells, not in colon wall or immune cells. Decrease in Dectin-1 expression in colonocytes noticed in our study may be related to disrupted intestinal barrier integrity by the ethanolic TNBS solution, that as a consequence, causes infiltration of pathogens / antigens into deeper layers of colon wall and allows their direct contact with cells of the immune system.

Results showed an increase in expression of Dectin-1 in inflamed IECs under influence of oat beta-glucans. A similar effect on expression of LC3B protein was noted, with oat beta-glucans of a high molar mass having a stronger effect.

4. [TNF-α] Concentration of TNF-α and other proinflammatory cytokines in colon wall of animals with TNBS-induced inflammation was significantly increased at all time points. Consumption of oat beta-glucans reduced concentration of these inflammatory factors.

The extrinsic pathway of apoptosis is induced by binding of this factor to the TNFR1a receptor. Increased autophagy in inflamed intestinal epithelium protected cells against TNF-α-induced apoptosis, which in turn helped to maintain integrity of the intestinal barrier and reduce inflammation.

5. [TLRs] After 3 days of TNBS administration, expression of TLR 4 and TLR 6 receptors in colonocytes was significantly lower in the colitis group receiving feed without beta-glucans as compared to control group. In the same group of rats (CβG−), TLR 5 expression was lower.

Decrease in expression of these receptors is mostly influenced by acute intestinal inflammation. Oat beta-glucans caused a significant increase in expression, especially TLR 5 and TLR 6, in inflamed IECs.

In summary, oat beta-glucans were found to alleviate the course of induced inflammation.”

https://www.mdpi.com/2072-6643/13/2/321/htm “Effects of Dietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs and Dectin-1 Signaling Pathways – Crohn’s Disease Model Study”


Eat oats to prevent inflammatory diseases:

“Oat beta-glucans with a high molar mass increased activity of autophagy in colon tissue of control animals without colitis.”

If we don’t do that, eat oats to treat inflammation:

“Confirms significant effect of oat beta-glucans in reducing expression of Caspase-3 during ongoing inflammation, with low-molar-mass beta-glucans having a stronger effect.”

I eat primarily low- and medium-molecular-weight oat β-glucan twice a day with 3-day-old hulled Avena sativa oat sprouts. For breakfast I eat primarily high-molecular-weight oat β-glucan in hulless Avena nuda oats soaked 12+ hours and microwaved 20 minutes at 80% power in a 1000W microwave.

An oats β-glucan clinical trial tested low-, medium-, and high-molecular-weight oat β-glucan in 14 people. It found:

Bioprocessing of oat bran with enzyme treatment, causing depolymerization of β-glucan, affects nutritional properties of bran and functional properties of β-glucan in human gastrointestinal tract.”

Neither study investigated gut microbiota. Pretty sure our hosted microorganisms had roles in both studies’ findings.

Gut microbiota topics

Here are thirty 2019 and 2020 papers related to Switch on your Nrf2 signaling pathway topics. Started gathering research on this particular theme three months ago.

There are more researchers alive today than in the sum of all history, and they’re publishing. I can’t keep up with the torrent of interesting papers.

on

2020 A prebiotic fructo-oligosaccharide promotes tight junction assembly in intestinal epithelial cells via an AMPK-dependent pathway

2019 Polyphenols and Intestinal Permeability: Rationale and Future Perspectives

2020 Prebiotic effect of dietary polyphenols: A systematic review

2019 Protease‐activated receptor signaling in intestinal permeability regulation

2020 Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

2019 Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

2020 The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals

2019 Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis

2019 Prebiotics, Probiotics, and Bacterial Infections

2020 Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

2020 Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor

2019 Involvement of Astrocytes in the Process of Metabolic Syndrome

2020 Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice (not freely available)

2019 Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1−/Δ7 mice

2020 Plasticity of Paneth cells and their ability to regulate intestinal stem cells

2020 Coagulopathy associated with COVID-19 – Perspectives & Preventive strategies using a biological response modifier Glucan

2020 Synergy between Cell Surface Glycosidases and Glycan-Binding Proteins Dictates the Utilization of Specific Beta(1,3)-Glucans by Human Gut Bacteroides

2020 Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

2020 Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

2019 Prebiotic supplementation in frail older people affects specific gut microbiota taxa but not global diversity

2020 Effectiveness of probiotics, prebiotics, and prebiotic‐like components in common functional foods

2020 Postbiotics-A Step Beyond Pre- and Probiotics

2019 Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential

2020 Postbiotics: Metabolites and mechanisms involved in microbiota-host interactions

2020 Postbiotics against Pathogens Commonly Involved in Pediatric Infectious Diseases

2019 Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis

2019 Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice

2020 Live and heat-killed cells of Lactobacillus plantarum Zhang-LL ease symptoms of chronic ulcerative colitis induced by dextran sulfate sodium in rats

2019 Health Benefits of Heat-Killed (Tyndallized) Probiotics: An Overview

2020 New Horizons in Microbiota and Metabolic Health Research (not freely available)