Immune system

Nrf2 Week #6: Phytochemicals

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

This 2023 review explored Nrf2 relationships with plant chemicals:

“This review focuses on possible mechanisms of Nrf2 activation by natural phytochemicals in preventing or treating chronic diseases, and regulating oxidative stress. Excess oxidative stress is closely related to many kinds of chronic diseases, such as cardiovascular diseases, cancer, neurodegenerative diseases, diabetes, obesity, and other inflammatory diseases.

Mitochondrial dysfunction and hyperglycemia lead to the massive production of ROS, which triggers molecular damage, inflammation, ferroptosis, insulin resistance, and β-cell dysfunction.

antioxidants-12-00236-g001

Crosstalk between Keap1-Nrf2-ARE pathway and other signaling pathways endows it with high complexity and significance in the multi-function of phytochemicals. Limited human data makes an urgent need to open the new field of phytochemical-original supplement application in human chronic disease prevention.”

https://www.mdpi.com/2076-3921/12/2/236 “The Regulatory Effect of Phytochemicals on Chronic Diseases by Targeting Nrf2-ARE Signaling Pathway”

Top ten mentions, not including references:

  • 21 Sulforaphane
  • 16 Broccoli
  • 9 Curcumin
  • 5 Resveratrol
  • 5 Green tea catechins
  • 4 Luteolin
  • 3 Garlic
  • 3 Soy isoflavones
  • 3 Lycopene
  • 3 Quercetin

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Nrf2 Week #4: Aging

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

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

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

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

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

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

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

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

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

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

  • Rodents with high Nrf2 activity have a longer lifespan than rodents with low activity.
  • Genetic knockout of Nrf2 usually leads to the increased senescent phenotype in a variety of animal organs and tissues, and also reduces lifespan of female mice.
  • There are also opposite examples, where Nrf2 knockout in aging mice reduced iron ions deposition in the brain, lowered the level of oxidative damage in the striatum, and also alleviated age-related motor dysfunction.

10541_2022_2401_Fig2

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

  • No experiments that use Nrf2 chemical inducers as anti-aging drugs have been performed so far.
  • Nrf2 is not involved in life extension caused by caloric restriction.
  • Epigenetic clocks do not reveal transcription factors activity of which changes with aging.

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

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

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Nrf2 Week #1: Targeting

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

It’s been a while since I curated Nrf2 research. Read almost a dozen relevant 2023 papers last week. Let’s begin with an opinion paper by a highly qualified researcher:

“The inducible transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) regulates expression of several hundred genes encoding proteins with antioxidant, anti-inflammatory, drug metabolising, and other homeostatic functions. Through its transcriptional targets, NRF2 activation orchestrates a comprehensive and long-lasting protection that allows adaptation and survival under diverse forms of cellular and organismal stress.

We highlight three NRF2 activators that have progressed furthest in clinical development. Overall outcomes of clinical trials with sulforaphane-rich preparations have strengthened preclinical evidence that sulforaphane has the potential to prevent toxic and neoplastic effects of environmental carcinogens, as well as to ameliorate conditions characterised by chronic oxidative, metabolic, and inflammatory stress.

Anti-inflammatory effects of most electrophilic NRF2 activators are partly NRF2-independent, and include inhibition of other inflammatory mediators. The majority of non-electrophilic PPI inhibitors are less potent in activating NRF2 in cellular systems than the electrophilic sulforaphane.

It remains to be shown that measurement of NRF2 activation in blood samples can reflect modulation of the pathway in target tissues. The field has yet to reach a consensus on the best approach for monitoring NRF2 activation in humans, including selection of the optimal panel of gene/protein targets.

Even after a single dose of an NRF2 activator, increased levels of the actual protectors (i.e., the downstream transcriptional targets of NRF2) persist over long periods of time (days), exceeding the half-life (hours) of the drug.

target disease

In certain contexts, the role of NRF2 is complex and cell-type-specific, for example, in mouse models of atherosclerosis. Considering that NRF2 activation functions to:

  • Restore cellular redox and protein homeostasis;
  • Preserve mitochondrial function; and
  • Inhibit inflammation.

Perhaps the most logical disease areas are neurological conditions where all of these processes contribute to survival of neurons and astrocytes, as well as metabolic disease and cancer prevention.”

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(22)00277-2 “Advances and challenges in therapeutic targeting of NRF2”

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Don’t eat yourself into disease, Part 2

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

This blog’s 1000th curation is a 2023 rodent study associating gut microbiota, behavior, memory, and food reward:

“Energy intake and energy expenditure is regulated by the hypothalamus, and is referred to as homeostatic regulation of food intake. The reward system is the non-homeostatic regulation of food intake – pleasure-related consumption of foods enriched in fat and sugar. The pleasure is encoded by dopamine release from dopaminergic neurons projecting from the ventral tegmental area to the striatum, the nucleus accumbens, and the prefrontal cortex.

Food reward can be divided into three components – liking, wanting, and learning:

  • Liking refers to food hedonic value;
  • Wanting to the motivational process to seek out and consume certain foods; and
  • Learning to reinforcing conditioning behavior associated with food intake stimulus.

We confirmed that obese mice have a dysregulation of the learning and the wanting components of  food reward. Our previous data showed that the liking component was transferable through fecal material transplantation.

We demonstrated that gut microbes play a role in the regulation of food reward, and could be responsible for compulsive behavior and excessive motivation to obtain sucrose pellets. Moreover, obese gut microbes affected dopaminergic and opioid markers involved in reward system.

We identified 33HPP (produced exclusively by gut bacteria) as particularly increased in mice recipients of gut microbes from obese mice. We were able to demonstrate its effects as key mediator of the gut-brain axis controlling the reward response to palatable food.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-023-01526-w “Obese-associated gut microbes and derived phenolic metabolite as mediators of excessive motivation for food reward”

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No exit

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Immune system, Memory, Neurochemicals, Stress, Telomeres ,

This 2023 rodent study investigated aging processes and gut microbiota in crowded conditions:

“Our study provides clear evidence that high-density crowding accelerates the aging process of Brandt’s voles. We also found that ‘high-density microbiota’ promote the aging-related phenotype in voles.

Because we minimized effects of direct fighting on mortality of voles, observed changes in lifespan in this study should mostly represent the natural aging processes of voles.

high-density survival

High density increased the level of stress hormone corticosterone, which disrupted gut microbiota composition by:

  • Decreasing abundance of anti-aging or anti-inflammatory bacterial species; and
  • Increasing the proportion of pathogenic bacteria.

This caused an increase in DNA oxidation and inflammation through upregulation of NF-kB and COX-2 pathways.

Although high-density relief and butyric acid administration interventions could reverse aging-related processes of adult voles, it remains unclear whether they could reverse the aging process in terms of lifespan.

Our results suggest that gut microbiota play a significant role in mediating aging-related processes of voles under high-density conditions, and can be used as a potential therapeutic target for treating stress-related diseases in humans.”

https://onlinelibrary.wiley.com/doi/10.1002/advs.202205346 “Gut Microbiota is Associated with Aging-Related Processes of a Small Mammal Species under High-Density Crowding Stress”

I came across this study by it citing Reversing hair greying for effects of stress interventions.

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Remembering life before birth

gettingwell4 5+ stars Premium, Epigenetics, Immune system, Memory, Stress , , , ,

This 2023 primate study investigated the body’s capability to remember prenatal experiences influencing later life:

“Maternal stressors and other environmental factors affect the developing embryo and fetus in ways that lead to increased susceptibility for chronic disease in later life. Developmental programming of chronic low-grade inflammation plays an important role in onset and progression of these diseases.

Establishing innate immune cell memory involves increased glycolysis, reduced oxidative phosphorylation, and expression of transcription factors which prime for pro-inflammatory activity. This memory relies on propagation of epigenetic modifications that develop in hematopoietic stem and progenitor cells (HSPCs), which can be passed on to progeny immune cells (i.e., macrophages).

These changes persist with altered epigenetic regulation for years after weaning – even when offspring are fed a conventional diet – predisposing offspring to inflammatory disease across their lifespans.

cell memory

Several factors may initiate metabolomic reprogramming in fetal HSPCs:

  • We found increased chromatin accessibility of gene regulatory regions and RNA signatures supporting activation of factors with a major role in regulating macrophage inflammatory activation, including FOS/JUN, NF-κB, C/EBPβ, and STAT6.
  • Our prior work demonstrated a persistently altered histone code in liver tissue from juvenile animals.
  • Maternal diet-supplied lipids, including oleic acid, in hematopoietic tissues may play an important role in priming inflammation and metabolism in fetal HSPCs and bone marrow-derived macrophages with postnatal persistence.

Striking changes in fetal bone marrow and liver HSPCs observed here suggest that the primary driver for developmental programming of inflammation takes place in utero. However, we cannot rule out that exposure to maternal diet during lactation postnatally triggers shifts in microbiome composition or function contributing to inflammation.

Components of maternal diet, rather than maternal obesity per se, are a modifiable risk factor with potential to alter developmental programming of offspring immune systems.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00404-7 “Maternal diet alters long-term innate immune cell memory in fetal and juvenile hematopoietic stem and progenitor cells in nonhuman primate offspring”

And there are other ways we remember everything that happened then and along the way. Big clues are in our out-of-context responses to present day events.

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Year Three of Changing to a youthful phenotype with sprouts

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

1. I’ve continued daily practices from Year Two with microwaved 3-day-old broccoli, red cabbage, and mustard sprouts for 13 times longer now than any sulforaphane clinical trial. I haven’t had another three-year period in my life where I wasn’t sick even once!

The main difference over the past year is that I eat AGE-less chicken vegetable soup 3-4 times a week rather than twice a day. That was just too boring, plus I stopped eating lunch. My other dinners are often steamed vegetables and seafood.

2. I frame the above and following tactics as part of a strategy of delaying evolutionarily-determined programs from doing more to kill my body every year:

  • Eat 16-hour sprouted Avena nuda oats for breakfast to give my trillion+ gut microbiota what they need;
  • Eat 3-day-old hulled Avena sativa oat sprouts twice a day to provide antioxidants in another form, avenanthramides;
  • Eat AGE-less chicken vegetable soup 3-4 times a week to prevent diet-induced problems;
  • Take supplements that promote healthspan twice a day;
  • Exercise at least 30 minutes daily;
  • Take yeast cell wall β-glucan daily, with nothing else an hour before or after; and
  • Avoid undue stress by working from home 40 hours a week in my 26th year as a professional software developer.

These tactics’ main components activate AMPK, Nrf2, and associated signaling pathways, and inhibit pro-inflammatory pathways such as NF-κB.

But fixing inflammation doesn’t repair all existing damage. I wonder what could have been physically resolved if I had started thirty+ years earlier.

3. One place I take clues from are successful anti-aging animal research efforts such as a study reviewed here earlier this month. Last curated in Improve your internal environment, improve its constituents’ functions, it used plasma fraction treatment. Plasma fraction eclipsed a caloric restriction treatment’s previous record for maximum species lifespan by 5%.

This type of research clearly isn’t a priority for official sponsors to fund, though. Take responsibility for your own one precious life.

Eat broccoli sprouts to protect your lungs

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

This 2023 human cell study investigated sulforaphane’s effects on tuberculosis infections:

“Basic research efforts on tuberculosis (TB) immunotherapy are currently only the tip of the iceberg. This study highlights the association between autophagy-related genes and immune infiltration in TB, an infectious pathogen that has been around for tens of thousands of years.

Sulforaphane (SFN) is readily absorbed into the bloodstream by the intestine due to its lipophilic nature. Experiments in this study TB patient cells showed that SFN could promote autophagy in macrophages infected with Mycobacterium abscessus (Mab). Intracellular bacterial load of macrophages was associated with SFN-enhanced cellular autophagic processes.

1-s2.0-S156757692300276X-gr4

The relationship between autophagy and immune cells is complex, and recurrence of tuberculosis is significantly influenced by intracellular mycobacteria of macrophages. Macrophages have longer lifespans than neutrophils, and provide shelter for mycobacteria as they are better suited than neutrophils to establish strategies for targeting autophagy.

This is one of the reasons why autophagy in macrophages was the focus of this study. Appropriate autophagy is beneficial for the body and controls Mtb replication, but autophagic programmed cell death can activate tissues to produce an excessive inflammatory response, resulting in severe damage to lung tissues.

Autophagy-related genes regulated by SFN have good diagnostic potential, with FOXO1 potentially serving as a target for TB immunotherapy. Downstream targets of FOXO1 include important pro-inflammatory signaling molecules such as IL-1β and TNF-α, which are important for control of mycobacterium.”

https://www.sciencedirect.com/science/article/pii/S156757692300276X “Identifying autophagy-related genes as potential targets for immunotherapy in tuberculosis”

Take yeast cell wall β-glucan, too, and train your immune system.

Oat β-glucan effects

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

Three papers on oat β-glucan’s effects in humans, starting with a 2023 study that compared different doses:

“Two randomized, double-blind, controlled studies were conducted with asymptomatic subjects between 20 and 40 years of age, male or female, normal weight or overweight.

In the first study – a crossover trial comprising two days of testing (β-glucan and control) separated by at least one week – 14 subjects ingested a breakfast with or without β-glucan from oats (5.2 g). Results indicate that acute intake of 5 g β-glucan slows transit time and decreases hunger sensation and postprandial glycaemia without affecting bile-acid synthesis. These changes were associated with decreased plasma insulin, C-peptide, and ghrelin, and increased plasma gastric inhibitory polypeptide  and pancreatic polypeptide.

In the second study, 32 subjects were distributed into 2 groups to ingest daily foods with (3 g/day) or without β-glucan for 3 weeks. Results indicate a regular daily intake of 3 g β-glucan is not sufficient to have an effect on fecal microbiota composition, suggesting that health-promoting effects at 3 g/d are probably due more to their physiological effect in the proximal part of the gastrointestinal tract than to their prebiotic effect in the colon.”

https://www.mdpi.com/2304-8158/12/4/700 “Modulation of Postprandial Plasma Concentrations of Digestive Hormones and Gut Microbiota by Foods Containing Oat ß-Glucans in Healthy Volunteers”

I’ll use a 2021 study Rapid Determination of β-Glucan Content of Hulled and Naked Oats Using near Infrared Spectroscopy Combined with Chemometrics to estimate my daily β-glucan intake. Those researchers tested 100 varieties of Avena nuda that varied between 3.12% and 5.22% β-glucan. My intake from 82 g (dry weight) of hulless oats (cinnamon sprinkled for taste) is probably between (82 g x .0312) = 3 g and (82 g x .0522) = 4 g.

They also tested 79 varieties of hulled Avena sativa that varied between 3.1% and 5.5% β-glucan. Oat sprouts analysis tested a Avena sativa variety where the β-glucan content decreased from 3.48% to 2.10% over four days of sprouting, a 40% reduction.

My daily β-glucan intake from 40 g (dry weight) of three-day-old hulled oat sprouts is probably 1 g [(40 g x .031) x .6 = 1 g and (40 g x .055) x .6 = 1 g]. That’s okay, because oat sprouts have other benefits per Oat sprouts analysis and Advantages of 3-day-old oat sprouts over oat grains.

My daily oat β-glucan intake is 4 – 5 grams. I’ve maintained that for two years, and don’t see any reason to stop.

A second 2023 paper from a clinical trial investigated effects of combining oat bran along with orange juice:

“Orange juice (OJ) is a rich dietary source of bioactive flavanones, and consuming OJ has been associated with beneficial effects including decreased inflammation and improved lipid profiles. However, dietary recommendations are to limit OJ consumption to one serving per day due to high sugar and low fiber content. Metabolic concerns are increased postprandial insulin response to a high sugar load which in individuals at risk may promote insulin resistance.

Consumption of 22 g oat bran containing 6 g of β-glucan together with 500 mL of OJ by healthy subjects impacts on OJ flavanone bioavailability with the 0-24 post-intake excretion of phase II metabolites, such as hesperetin-7-glucuronide, being reduced ~3-fold. This was not a consequence of bran affecting the rate of gastric transport, and underlying mechanisms behind reduced excretion of OJ flavanone metabolites remain a matter of conjecture.

The pool of bound phenolics in bran linked to polysaccharides appears not to be converted to free phenolics. It was rather principally a consequence of a bran-mediated increase in quantities of flavanones passing from the upper to the lower bowel where they were subjected to microbiota-mediated catabolism.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584923000515 “Bioavailability of orange juice (poly)phenols: β-glucan-rich oat bran decreases urinary excretion of flavanone phase II metabolites and enhances excretion of microbiota-derived phenolic catabolites” (not freely available) Thanks to Dr. José Manuel Moreno-Rojas for providing a copy.

This paper referenced a preliminary study by many of the same coauthors that found oat bran with 3 g of β-glucan didn’t have similar effects.

A 2022 meta-analysis investigated differences between whole oats and purified β-glucan:

“This systematic review and meta-analysis evaluated the impact of oats or β-glucan supplements on the lipid profile. Our findings show that both oat and isolated β-glucan interventions can improve lipid profiles, specifically total cholesterol and low density lipoprotein cholesterol (LDL) concentrations, and should be incorporated into one’s regular eating habits.

Interventions ranged from 14 to 84 days in length. Quantity of β-glucan ingested (oats and isolated β-glucan) ranged from 1.2 g/day to 11.2 g/day.

Limitations and additional considerations include:

  • We did not have enough studies that matched total fiber intake between intervention and control groups, and so could not evaluate if results were exclusively influenced by oat/isolated β-glucan supplementation, or if other types of dietary fiber would have a similar impact on lipidemia.
  • Mechanisms of changes in concentrations of triglycerides (TG) are linked to carbohydrates. An increase in availability of glucose in serum, resulting from absorption of carbohydrates, stimulates secretion of insulin and, as a result, synthesis of fatty acids in the liver is increased. Mixed results found in this and other meta-analyses regarding TG may be related to the fact that oats and isolated β-glucan were frequently administered through day-to-day processed foods which have sugar and other types of refined flour in their recipes.
  • Different oat cooking procedures, processing methods, and molecular weights modify viscosity and impact in cholesterol concentrations differently. Less processed oats appear to be more effective than processed oat products in improving lipidemia. Higher molecular weight is associated with increased viscosity, and greater reduction in LDL. Also, the process used to treat oats affects its molecular weight, and the highest viscosities were observed as a consequence of dry processes in comparison to ones that exhibit enzymatic activity.
  • Reducing saturated fat intake may be, in combination with increased viscous fiber intake from oats or isolated β-glucan, the most effective way to improve dyslipidemia. In future studies, amount and type of fat in diet should be evaluated and considered accordingly.”

http://dx.doi.org/10.1016/j.clnesp.2022.12.019 “The separate effects of whole oats and isolated beta-glucan on lipid profile: A systematic review and meta-analysis of randomized controlled trials” (not freely available)

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Peripheral vs. brain epigenetic measurements

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system , , ,

This 2023 human study investigated associations of peripheral and brain epigenetic measurements:

“Evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues are used, resulting in limited progress compared with other epigenetic studies.

Averaging data for each CpG across individuals, saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.87) and buccal–brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). However, cross-database correlations of correlation coefficients revealed relatively low brain vs. blood: r = 0.27, saliva: r = 0.18, and buccal: r = 0.24.

The majority of methylation in the brain is most likely not synchronized with methylation in the periphery. Despite this, variable CpGs that correlate in the brain and periphery, although in small numbers, may have biological relevance, and could be useful for inferring brain methylation from peripheral tissues.

This study has six major limitations.”

https://www.nature.com/articles/s41398-023-02370-0 “Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues”

Real science is messy. Hypotheses are experimentally reevaluated many, many times under varying conditions. I skip over studies where researchers don’t provide meaningful limitation clauses.

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Take inulin for your brain

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

This 2023 rodent study investigated effects of inulin on gut microbiota and brain inflammation:

“Microglia are the first immune responders in the brain. Their activation leading to neuroinflammation can promote homeostasis, but if unchecked can be pathological.

We evaluated anti-inflammatory effects of short-chain fatty acids (SCFAs) on lipopolysaccharide (LPS)-stimulated microglia from mice fed inulin, a soluble fiber fermented by intestinal microbiota to produce SCFAs, and SCFAs applied to primary microglia in vitro:

  • Feeding mice inulin increased SCFAs in the cecum and in plasma collected from the hepatic portal vein.
  • Microglia isolated from mice fed inulin and stimulated with LPS in vitro secreted less tumor necrosis factor α (TNF-α) compared to microglia from mice not given inulin.
  • Mice fed inulin and injected i.p with LPS ex vivo secretion of TNF-α by isolated microglia was lower than that secreted by microglia from mice not fed inulin and injected with LPS.

41598_2022_27086_Fig8_HTML

in vitro treatment of primary microglia with acetate and butyrate either alone or in combination downregulated microglia cytokine production, with effects being additive. SCFAs reduced histone deacetylase activity and nuclear factor-κB nuclear translocation after LPS treatment in vitro.

If SCFAs produced in the gut regulate microglia directly, it is likely through an epigenetic mechanism following diffusion.”

https://www.nature.com/articles/s41598-022-27086-x “Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids”

Mice typically eat 4-5 grams of chow daily. A human equivalent of this study’s 2.5% inulin treatment would be:

  • (5,000 mg x .025) = 125 mg;
  • (125 mg x .081) = 10.125 mg;
  • (10.125 mg x 70 kg) = 709 mg.

A daily intake of < 1 gram of inulin isn’t very much. I take < 10 grams.

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Ancient parasite DNA within us

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

Two 2023 papers on endogenous retroviruses (ERVs) and aging relationships, starting with the Introduction section of a comprehensive study:

“Several causal determinants of aging-related molecular changes have been identified, such as epigenetic alterations and stimulation of senescence-associated secretory phenotype (SASP) factors. Although the majority of these studies describe aging determinants originating primarily from protein-coding genes, the non-coding part of the genome has started to garner attention as well.

ERVs belonging to long terminal repeat (LTR) retrotransposons are a relic of ancient retroviral infection, fixed in the genome during evolution, comprising about 8% of the human genome. As a result of evolutionary pressure, most human ERVs (HERVs) accumulate mutations and deletions that prevent their replication and transposition function. However, some evolutionarily young subfamilies of HERV proviruses, such as the recently integrated HERVK, maintain open reading frames encoding proteins required for viral particle formation.

In this study, using cross-species models and multiple techniques, we revealed an uncharacterized role of endogenous retrovirus resurrection as a biomarker and driver for aging. Specifically, we identified endogenous retrovirus expression associated with cellular and tissue aging and that the accumulation of HERVK retrovirus-like particles (RVLPs) mediates the aging-promoting effects in recipient cells. More importantly, we can inhibit endogenous retrovirus-mediated pro-senescence effects to alleviate cellular senescence and tissue degeneration in vivo, suggesting possibilities for developing therapeutic strategies to treat aging-related disorders.”

https://www.cell.com/cell/fulltext/S0092-8674(22)01530-6 “Resurrection of endogenous retroviruses during aging reinforces senescence”

This first paper’s foreword summarized their many experiments and findings:

“The study found that HERVK transcripts, viral proteins, and RVLPs were highly activated in prematurely aged human mesenchymal progenitor cells (hPMCs). This was similarly observed in aged human primary fibroblasts and hPMCs. They also discovered that decreasing silencing epigenetic marks DNA methylation and H3K9me3 while increasing H3K36me3 enabled HERVK expression.

erv aging mechanism

These observations also raise several intriguing questions:

  • HERVK is occasionally activated and eventually suppressed under physiological conditions, for example, in human embryonic cells. It would be fascinating to probe the possibility of mimicking physiological conditions in order to turn off the positive feedback between HERVK and senescence.
  • ERVs are hallmarks of aging in different species, including human, primate, and mouse. Future quantification of the absolute physiological level of ERVs across a broad population of various ages might provide further insights into the relationship between ERVs and organismal age.”

https://academic.oup.com/lifemedi/advance-article/doi/10.1093/lifemedi/lnad001/6982772 “Endogenous retroviruses make aging go viral”

Previously curated papers on these subjects include:

A study of our evolutionary remnants

“Repressive epigenetic marks associated with ERVs, particularly LTRs, show a remarkable switch in silencing mechanisms, depending on evolutionary age:

  • Young LTRs tend to be CpG-rich and are mainly suppressed by DNA methylation, whereas
  • Intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation.
  • Evolutionarily old LTRs are more likely inactivated by accumulation of loss-of-function genetic mutations.”

Starving awakens ancient parasite DNA within us

Reality is sometimes stranger than what fiction writers dream up. 🙂

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Environmental signaling rescues aging muscle stem cells

gettingwell4 5+ stars Premium, Epigenetics, Immune system, Stress , ,

This 2023 rodent study applied An environmental signaling paradigm of aging concepts to muscle stem cells:

“The stem cell niche environment represents an important therapeutic target to enhance tissue regeneration in aging. We decoupled age-related cell-intrinsic effects, niche-mediated cell-extrinsic effects, and changes in population dynamics of muscle stem cells (MuSCs) and two key muscle-resident cells in young and aged mice.

in vivo model

We showed that:

  1. Age-related reduction in MuSCs is not stochastic.
  2. Despite differences in transcriptomes of MuSC clusters, the effect of age on gene expression is largely uniform, suggesting that the niche environment has a fundamental role in age-related changes in MuSC gene expression.
  3. A significant fraction of changes in the transcriptome of aging MuSCs can be reversed by exposure to the young muscle environment, i.e. are niche-responsive. Given the high percentage [46.6% at a stringent cutoff of s-value < 0.05] of reversibility in gene expression, our findings indicate that age-related changes in the niche are principal drivers of resulting alterations in the MuSC transcriptome.
  4. Aging is correlated with changes at the level of chromatin accessibility and DNA methylation in MuSCs.

Plasticity of the MuSC transcriptome suggests that modulating the niche environment can be a powerful tool to restore stem cell-mediated endogenous muscle regeneration in aging. Consequently, as opposed to focusing solely on MuSCs themselves to mitigate effects of aging on MuSCs, bioengineering of the niche in its entirety may be a viable therapeutic option.”

https://www.nature.com/articles/s41467-023-36265-x “Transcriptional reprogramming of skeletal muscle stem cells by the niche environment”

This study destroyed extremely well-funded directed research efforts that detract from science, especially those promoting irreversibility of epigenetic changes (but: Rockefeller) and randomness of pro-aging programming (but: Harvard).

These researchers showed they could do more with their ideas and careers than maintain an outdated and easily disproved status quo.

Blinded by their paradigm?

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Telomeres ,

This 2022 human study investigated another type of aging clock:

“The glycan clock of age, based entirely on immunoglobulin G (IgG) N-glycans, can predict biological age with high accuracy. Unlike DNA methylation, glycosylation of IgG does not predict chronological age with high accuracy.

Heritability analysis of plasma glycans revealed that the majority of traits have high heritability estimates, indicating a tight genetic control of glycosylation. To better understand genetic and environmental factors influencing glycan clock variation, we performed a heritability analysis on data from two cohorts included in the TwinsUK registry.

Glycosylation is a series of enzymatic reactions in which carbohydrates are attached to other molecules (e.g., proteins or lipids) resulting in formation of complex carbohydrates and glycoconjugates commonly referred to as ‘glycans.’ Glycosylation of IgG antibody is especially interesting as it dramatically affects its function, and acts as a molecular switch between pro- and anti-inflammatory immune responses.

Heritability of the glycan clock was estimated to decompose observed phenotypic variance into three latent sources of variation:

  • A—additive genetic variance [red] represents cumulative impact of genes;
  • C—shared/common environment variance [purple] results from influences to which both members of a twin pair are exposed; and
  • E—unique environment variance [green] is events occurring to one twin but not the other, and includes measurement error.

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Despite tight genetic control of the IgG glycome:

  • Heritability analysis of the glycan clock revealed only a moderate genetic contribution averaging around 39% [A, left side].
  • Including age of the individuals as a covariate in heritability analysis averaged 71% heritability estimates [B, right side].
  • Mean time difference was 7.5 years for points 1 and 2, and 6 years for points 2 and 3.

Observed increase in the genetic component could be a consequence of chronological age as a shared environmental variance characteristic for every individual and determined by their genetic makeup and epigenetic regulation.”

https://www.frontiersin.org/articles/10.3389/fcell.2022.982609/full “Heritability of the glycan clock of biological age”

Although A rejuvenation therapy and sulforaphane was cited, these researchers missed its central premise: Pro-aging epigenetic programming is directional and not purely random. Contrasting their above graphic’s heritability estimates of 39% with the age-regressed, right side’s average 71% could hardly have been more clear in illustrating this fact.

This study instead stated “Aging in general leads to epigenetic mediated deregulation of genes.” This weak sauce accompanied speculations such as “supports the notion that the glycan clock can be rejuvenated by simple lifestyle choices.”

Researchers almost always want to claim being first in finding x, y, or z. These researchers could have done that in this glycan clock study by highlighting an outstanding finding. So what happened?

An alternate explanation to their paradigm blinding them could be sponsor expectations, peer pressures, etc. I’ll ask them about it, and will update here with their response.

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Week 144 of Changing to a youthful phenotype with sprouts

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

Two papers, starting with a 2023 study that investigated the same red radish cultivar as Sulforaphene, a natural analog of sulforaphane:

“Availability of microgreen products is constantly rising, i.e., they are offered for sale in local farmers markets, specialty stores, and in chain grocery stores. Due to the low demands required for their cultivation and easily available LED settings, microgreens are increasingly grown on a small scale in homes and after harvesting, they are stored in kitchen refrigerators at 4 °C.

The aim of this study was to simulate such cultivation and storage conditions to examine antioxidant capacity of home-grown radish microgreens. Seven-day-old radish microgreens, grown under purple and white LED light, were harvested and stored at 4 °C for two weeks.

Measurements of total antioxidant capacity and bioactive substances were conducted on the harvesting day and on the 3rd, 7th, and 14th day of storage. All three radish cultivars (Raphanus sativus L.) with different leaf colorations:

  • Purple radish (R. sativus cult. China Rose, cvP);
  • Red radish (R. sativus cult. Sango, cvR); and
  • Green radish (Raphanus sativus var. longipinnatus, Japanese white or daikon radish, cvG)

were purchased commercially from a local supplier.

The highest contents of total soluble phenolics, proteins, and sugars, dry matter, and monomeric anthocyanin content, as well as higher overall antioxidant capacity determined in the red radish cultivar (cvR), distinguished this cultivar as the most desirable for human consumption regardless of the cultivation light spectrum.”

https://www.mdpi.com/2311-7524/9/1/76 “Antioxidant Capacity and Shelf Life of Radish Microgreens Affected by Growth Light and Cultivars”

A 2021 review summarized what was known about radishes up to then. Here’s part of its Discussion section:

“It is worth considering radish’s organoleptic characteristics since its particular flavor can influence its acceptability among consumers. The main compound associated with its characteristic pungent flavor is raphasatin, which we have found to be the most reported isothiocyanate produced from the breakdown of glucoraphasatin.

Glucoraphasatin ranked as one of the most concentrated glucosinolates in radish, particularly in its sprouts, but also present in other parts like roots and seeds. Pungency differs among radish cultivars, environmental growth factors, agronomic, and cooking practices.”

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https://www.sciencedirect.com/science/article/pii/S0924224421003058 “Nutritional and phytochemical characterization of radish (Raphanus sativus): A systematic review”

Seeds I’ve sprouted this year so far, left to right – red radish (Sango), broccoli, red cabbage (Red Acre), yellow mustard, oat (Avena sativa):

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Red radish had similar growth characteristics as broccoli. Started with 3.6 grams of seeds, which increased to 22.2 g after three days using the same soaking and rinsing protocol I use for other sprouts.

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The taste of red radish was too sharp for me to eat by themselves, so I combined them with my broccoli / red cabbage / mustard sprout mix. Bumped up microwaving time to 48 seconds in a 1000 W microwave while staying short of the 60°C (140°F) myrosinase cliff.

The whole mix still had a strong radish taste, though. It was as if two whole red radishes were sliced into a small salad.

Can’t add anything more to dampen that taste and expect beneficial compounds to be unaffected. From Week 19:

A 2018 Netherlands study Bioavailability of Isothiocyanates From Broccoli Sprouts in Protein, Lipid, and Fiber Gels found:

“Compared to the control broccoli sprout, incorporation of sprouts in gels led to lower bioavailability for preformed sulforaphane and iberin.”

IAW, eating protein, fats, and fiber along with microwaved broccoli sprouts wouldn’t help. A 2018 review with some of the same researchers Isothiocyanates from Brassica Vegetables-Effects of Processing, Cooking, Mastication, and Digestion offered one possible explanation for protein acting to lower broccoli sprout compounds’ bioavailability:

“In vitro studies show that ITCs can potentially react with amino acids, peptides, and proteins, and this reactivity may reduce the ITC bioavailability in protein‐rich foods. More in vivo studies should be performed to confirm the outcome obtained in vitro.”

Mixing in red radish sprouts also gave me an upset stomach five of the six mornings. So I won’t continue to sprout red radish.

That said, I’d definitely consider sprouting red radish again to accelerate isothiocyanate treatment of problems where symptoms are much worse than an upset stomach, such as:

  • Neurogenerative diseases with their cognitive decline;
  • Immune system disorders;
  • Bacterial and viral infections; and
  • Other damage caused by oxidative stress conditions in eyes, vascular system, kidney function, etc.

Piping in the New Year

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