Month: February 2021

Eat broccoli sprouts for depression

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

This 2021 rodent study investigated sulforaphane effects on depression:

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

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

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

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

Nrf2-induced BDNF transcription in a model of depression.

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

In conclusion:

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

https://www.nature.com/articles/s41398-021-01261-6 “Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents”

Part 2 curates three papers that cited this study.

Eat broccoli sprouts for arthritis

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

This 2021 rodent study investigated sulforaphane’s adaptive immune system effects on arthritis:

“Sulforaphane reduced clinical and histologic scores of collagen-induced arthritis mice. Anti-arthritic and anti-inflammatory effects of sulforaphane were due to suppression of differentiation of naïve cells into plasma cells and GC [germinal center] B cells.

This is the first report that sulforaphane exerts an anti-arthritic effect by regulating B-cell differentiation. Because plasma cells are not affected by conventional immunosuppressive drugs such as steroids, cyclophosphamide, and B-cell-depleting agents, our finding that sulforaphane suppresses their differentiation into plasma cells is encouraging and suggests that plasma cell-targeted treatment strategies for rheumatoid arthritis may be effective.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886167/ “The anti-arthritis effect of sulforaphane, an activator of Nrf2, is associated with inhibition of both B cell differentiation and the production of inflammatory cytokines”

Although not directly stated, it appeared that this study had 15 sulforaphane treatment subjects from the same experiments being run 3 times on 5 subjects. The above graphic was repeated with the other two less-significant findings in supplementary data.

Hooray for the People of Texas!

gettingwell4 Just me

One anecdote from “vacationing” in the Dallas area last week:

I waited until temperatures were above 15° F to forage for food. The closest grocery store had the same situation as my hotel: no electricity all morning. It somehow had electricity for cash registers, but not for overhead lighting. People walked around using their phone’s flashlight feature for illumination.

A lady offered me her cart as I entered and she left. Many bare shelves. I got items to satisfy my gut microbiota (canned artichokes, canned hearts of palm, store-recipe grain bars, standard rolled oats). And Pinot Noir.

I stood in line with ~200 other shoppers in Grand Prairie, Texas for forty-five minutes. While the store manager verified that I was at least 21 years old, store-wide electricity came back on! I hadn’t heard squeals and sighs of delight like that for a while. 🙂

Reflected on respect for people and property as I drove back to my hotel, I didn’t see any:

  • Police;
  • Grocery store security; or
  • Stealing.

I had a civilization experience instead. Not like Portland, Minneapolis, Seattle, San Francisco, DC, Kenosha…

For those who care about such things, I’ll guess that grocery store’s customers’ racial mix was 25% Hispanic, 30% Black, 35% White, 10% Asian.

An aftershock anecdote from this morning: I saw three people drop out of an airport terminal’s Starbucks line when the barista announced it was cash-only.

My coffee cost $3, rounded up at the tip jar. Please be prepared.

Adaptive and innate immunity

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

Two 2021 reviews presented aspects of human immune systems:

“The adaptive immune system’s challenge is to protect the host through generation and differentiation of pathogen‐specific short‐lived effector T cells, while in parallel developing long‐lived memory cells to control future encounters with the same pathogen.

The system highly relies on self‐renewal of naïve and memory T cells, which is robust, but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential.

Less than 20% of nascent T cells are produced from the thymus in young adults, which dwindles to less than 1% after the age of 50 years. Even in young adults, the majority of T cells are produced in the periphery. A pickup in proliferation has been described in late life, possibly as a consequence of increased cell death and evolving lymphopenia.

One challenge of the aging process is to replenish cells while keeping integrity of the organ. The dynamic lymphoid system employs a vast number of T cells (>1011) and maintains a balance between cell production, death, and differentiation.

Enormous TCR ( T cell receptor) diversity is required to be able to respond to the universe of possible peptides (>209). Only T cell generation in the thymus can add new TCR specificities. Homoeostatic proliferation at best maintains diversity, >108 unique TCRs in a given adult.

Antigen-specific memory T cells adopt several fates with age:

  • Decrease in stem-like memory T cells;
  • Increase in NK (natural killer) cell-like TEMRA (terminally differentiated effector T cells);
  • Increase in exhausted T cells;
  • Increase in short-lived effector memory T cells; and
  • Decrease in tissue-residing T memory cells.

Virtual memory T cells without prior experience of antigen encounter also increase with age.”

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.15770 “Hallmarks of the aging T cell system”

“Trained immunity is characterized by long‐term functional reprogramming of innate immune cells following challenge with pathogens or microbial ligands during infection or vaccination. This cellular reprogramming leads to increased responsiveness upon re‐stimulation, and is mediated through epigenetic and metabolic modifications.

Trained immunity has been shown to last for at least 3 months and up to 1 year, while heterologous protection against infections can last for at least 5 years. These long-term effects are mediated through reprogramming of myeloid progenitor cells in bone marrow, which in turn generate myeloid cells with a trained immunity phenotype.

Molecular mechanisms underlying trained immunity, for example induced by β‐glucan or Bacille Calmette‐Guérin (BCG) vaccination, can be investigated by using and integrating different layers of information, including genome, epigenome, transcriptome, proteome, metabolome, microbiome, immune cell phenotyping and function. Interplay between epigenetic and metabolic reprogramming is necessary for induction of trained immunity, as certain metabolites have a direct effect on enzymes involved in epigenetic remodeling.

High-throughput methods allow researchers to use an unbiased approach examining many potential genes or markers in relation to health and disease, rather than examining a limited number of candidate genes or markers.

One strength of integrating multiple levels of data is an increased power to identify key regulatory molecular networks driving trained immunity. For example, results obtained from one level (i.e. genes) can be used to reduce the number of traits to test in a second level (i.e. proteins), thereby increasing power.

One important pitfall when it comes to designing effective omics studies, is sample size. With a large number of markers measured, and the relatively small contributing effect size of individual analytes, the risks of both type 1 and 2 errors are high without sufficient sample sizes for both discovery and validation cohorts.”

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.202048882 “Resolving trained immunity with systems biology”

Eat broccoli sprouts to prevent lung infections

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

A 2021 rodent study investigated lung infections:

“Mycobacterium avium complex (MAC) is the most common cause of pulmonary nontuberculous mycobacteria disease worldwide. It is thought that both environmental exposure and host susceptibility are required for the establishment of pulmonary MAC disease, because pulmonary MAC diseases are most commonly observed in slender, postmenopausal women without a clearly recognized immunodeficiency.

Host factors that regulate MAC susceptibility have not been elucidated until now. The Nrf2 system is activated in alveolar macrophages, the most important cells during MAC infection, as both the main reservoir of infection and bacillus-killing cells.

Treatment with sulforaphane (SFN) decreases Mycobacterium growth upregulating the expression of Nramp1 (natural resistance-associated macrophage protein 1, a susceptibility gene for pulmonary nontuberculous mycobacteria disease) and HO-1 (heme oxygenase 1). Mycobacterial counts in the lung, liver, and spleen were reduced after SFN treatment.

These results indicate that Nramp1 and HO-1, regulated by Nrf2, are essential in defending against MAC infection due to the promotion of phagolysosome fusion and granuloma formation, respectively. Nrf2 is thought to be a critical determinant of host resistance to MAC infection.”

https://mbio.asm.org/content/12/1/e01947-20 “Nrf2 Regulates Granuloma Formation and Macrophage Activation during Mycobacterium avium Infection via Mediating Nramp1 and HO-1 Expressions”

One step short of greatness

gettingwell4 2-3 stars Required further work, Cortisol, Epigenetics, Immune system, Neurochemicals, Stress, Testosterone

A 2021 rodent study investigated dietary effects of organic and conventional farming practices:

“We report results from a two-generation, dietary intervention study with male Wistar rats to identify the effects of feeds made from organic and conventional crops on growth, hormonal, and immune system parameters that are known to affect the risk of a number of chronic, non-communicable diseases in animals and humans.

Conventional, pesticide-based crop protection resulted in significantly lower fiber, polyphenol, flavonoid, and lutein, but higher lipid, aldicarb [a pesticide], and diquat [a herbicide] concentrations in animal feeds.

Conventional, mineral nitrogen, phosphorus and potassium (NPK)-based fertilization resulted in significantly lower polyphenol, but higher cadmium and protein concentrations in feeds.

Growth and other physiological parameters were only monitored for 9 weeks after weaning. It was therefore not possible to determine whether and to what extent:

  1. Differences in feed composition;
  2. Dietary intakes of compounds previously linked to obesity and chronic diseases; and/or
  3. Changes in endocrine and immune parameters in rats raised on feed crops treated with mineral fertilizers and/or pesticides,

would have resulted in higher levels of weight gain and/or diseases linked to obesity, endocrine disruption and/or changes in immune system activity/responsiveness.”

https://www.mdpi.com/2072-6643/13/2/377/htm “Feed Composition Differences Resulting from Organic and Conventional Farming Practices Affect Physiological Parameters in Wistar Rats—Results from a Factorial, Two-Generation Dietary Intervention Trial”

I’m always fascinated when researchers intentionally stop one step short of greatness.

It seems a main purpose of this study was to justify a 2013 study by these researchers on pretty much the same subject. The current study had a defined F0 generation, and four different F1 generations and F2 generations.

This study stopped without continuing to any F3 generations.

  • The F1 F2 OPOF line in the above graphic’s first column didn’t eat chow produced with either synthetic chemical pesticides or conventional fertilizers.
  • This line could have continued on to transgenerational great-grand offspring who would have had no direct exposure to the F0 generation’s conventionally fertilized and “protected” crop diet.
  • By continuing, these researchers could have found out what transgenerationally inherited effects on the F3 generation there may be from the F0 generation eating a conventionally-produced diet.
  • Anything found in this line’s F3 great-grand offspring may have applied to humans.

Do we ever consider our great-grandchildren?

A PhD in oats

gettingwell4 2-3 stars Required further work

The lead researcher of Eat oat sprouts for AVAs‘s second study made their PhD thesis freely available. It’s still informative 13 years later:

“The main objective of this research project was to obtain new knowledge on how to treat raw oat material of oat-based products in order to sustain or even increase levels of endogenous phenolic compounds, with emphasis on avenanthramides, in the final food product. Germination of oats proved to be a potential processing method for use on oats since it is relatively easy to perform, although time-consuming.”

Which of these may be better for you? 44.1 grams of 4-day-old hulless oat sprouts at the top:

Or 53.2 g of 3-day-old hulled oat sprouts at the bottom?

They both started from 20.0 g seeds, and germinated the same way up through three days. 20 grams was over 1,300 hulled oat seeds, and close to 700 hulless oat seeds.

3-day-old hulled oat sprouts taste better, have a higher germination rate, and supply more quantity of their nutrients by weight. Characteristics of hulls from the thesis:

“The hull constitutes on average approximately 25% of the total grain weight. Protein, oil, starch and water-soluble carbohydrate levels are overall relatively low.

A large number of bioactive phenolic compounds can be found, among them p-coumaric acid, ferulic acid, vanillic acid, tricin and avenanthramides. Hull constituents remain unaffected during germination.

Activity of β-glucanase increases during germination of oats, resulting in almost total degradation of β-glucan. Since β-glucan is known to have health beneficial effects in humans, degradation during germination is not desirable if oats are intended for use in food products rather than for brewing.”

I’m not going to deal with hulls. Humans can’t digest oat hulls anyway.

A case for 4-day-old hulless oat sprouts:

“Germination of oats can be a good method to sustain or increase avenanthramides and other potentially health beneficial phenolic compounds. Levels of avenanthramides can increase during germination, sometimes to a high degree.

There was no indication that the increase in avenanthramide content had reached a plateau for any cultivars at 120 h of germination, indicating that further increase could take place.

Total protein content in oats increases slightly during germination. Even though the increase is small, it is important, since essential amino acids lysine and tryptophan increase and therefore improve nutritional value.

Lipid content in oats decreases slightly during germination while content of free fatty acids increases, although there are differences between cultivars as well as between hulled and hulless cultivars.”

Eat oat sprouts for AVAs

gettingwell4 2-3 stars Required further work

Here are three oat studies, two of them specifically on oat sprouts. The first from 2019 was cited in Don’t brew oat sprouts – eat them! for oat sprouts having “up to 25-fold increase” in avenanthramides (AVAs):

“Oat seeds were germinated, extracted, and analysed, finding 28 unique AVAs. AVAs 2p, 2c, and 2f, which are commonly described as the major AVAs, represented less than 20% of total content in seedlings.

The germinator program was: soak for 20 h at 20 °C (aeration 1 min every 10 min), followed by germination for 72 h at 25 °C (RH ≥ 99%). After the first 72 h of germination, oat seedlings were incubated for another 96 h at 30 °C (RH 70–80%).

AVA content was boosted by germination, resulting in around 25 times larger quantities found in oat seedlings.

Previous studies also showed an increase in AVA content upon germination, but to a lesser extent than in our current experiment. It used different growth conditions, namely a shorter soaking time (10–14 vs. 20 h) and their seed germination phase was performed at lower temperature and different duration (120 h at 16 °C or 72 h at 20 °C vs 96 h at 30 °C).

Additionally, they quantified AVAs 2p, 2c, 2f, and 3f but also observed a large number of unknown peaks in the UV 340 nm chromatogram. Based on the wide variety of AVAs annotated in our work, many of these peaks probably corresponded to other AVAs, but they were not identified and quantified as such.”

https://www.sciencedirect.com/science/article/pii/S0308814618319411 “Mass spectrometric characterisation of avenanthramides and enhancing their production by germination of oat (Avena sativa)”

No measurements were taken at three days when germination parameters changed. These researchers didn’t bother to take any samples between Hours 0 and 168. This lack of germination-stage evidence limited findings’ utility to other researchers.

Was this study designed to create a headline rather than useful germination-stage information? Why obliquely and directly fault another study in the Abstract, Results and Discussion, and Conclusion sections for being performed more than a decade earlier, without subsequent advancements in science and technology?

Contrast this study’s design with 2020 Oat sprouts analysis which took measurements under 18 different conditions (hulled / dehulled seeds of two oat varieties, for 1-to-9 days, at 12-to-20°C). Those researchers produced evidence to support many further studies, such as:

“Presence / absence of hull might determine different effects of germination conditions on α-amylase, protease, and lipase activities.”

The referenced disparaged 2007 study:

“..investigated the effect of a steeping and germination process, using a pilot plant malting system, on content of AVAs and other phenolic compounds. This was performed to gain a more collective and comparative picture of what happens to phenolic compounds in the oat kernel during germination.

Steeping and germination was performed at two different temperatures, 16 and 20°C. Three closely related North American covered oat cultivars were steeped to 45% moisture, which took 10, 12, and 14 h for Vista, Gem, and Dane, respectively.

After steeping, oat grains were drained and samples were germinated at 16°C for 120 h or at 20°C for 72 h (due to a machine breakdown, the 20°C experiment had to be stopped at 72 h of germination). Sampling during germination was carried out at set hours (for 16°C at 12, 24, 48, 72, 96 and 120 h and for 20°C at 12, 24, 48 and 72 h).

Chromatogram of AVAs and other phenols from cultivar Dane (16°C treatment). Peaks for AVAs 2c, 2p, 2f and 3f are identified. Unknown peaks are numbered in order of appearance (from 1-21). For isolation and identification of AVA 3f the commercial product SPC-flakes, purchased in a health food shop, was used.

An increase in AVA content of germinated seeds, as compared to raw grains, was observed for Dane (125%, p < 0.001) and for Vista (29%, p = 0.007). HHT [avenanthramide-synthesizing enzyme] activity increased 62% (p = 0.014) in Dane, whereas no change was detected in Vista and Gem. This increase started early in germination to reach its maximum at 96 h of germination.

Effects of temperature on AVAs 2c, 2p and 2f, and activities of HHT and PO, was less important than time of steeping, or time of germination, or cultivar. However, almost all unknown compounds were affected by temperature, indicating the importance of this factor.”

https://www.sciencedirect.com/science/article/abs/pii/S0733521007001762 “Avenanthramide content and related enzyme activities in oats as affected by steeping and germination” (not freely available)

This study’s HHT (avenanthramide-synthesizing enzyme) maximum-at-96-hours finding may be what I tasted in Sprouting hulless oats, where that variety’s sprouts improved their sweetness and enzymes between Days 3 and 4. Did an extra day improve AVA content?

So their pilot malting system broke down. They had to get an analysis standard from a health food store. And there were many unknowns due to 2007 science and technology.

Despite difficulties, germination-stage samples produced evidence and analyses other people could use more than a decade later.

A 2020 study cited the first study for basic, not headline, information:

“There are various potential mechanisms for AVAs anti-inflammatory effects, including inhibition of lipoxygenases (LOX), which catalyse oxygenation of polyunsaturated fatty acids into potent signal molecules involved in inflammatory processes.

It was found that AVAs comprising caffeic or sinapic acid exhibited significant lipoxygenase inhibition (60–90%), whereas low or no inhibition was observed with AVAs containing p-coumaric or ferulic acid.

Corresponding free cinnamic acids, AVA analogue Tranilast® and LOX inhibitor trans-resveratrol were included for comparison. Trans-resveratrol showed inhibition, whereas no difference in inhibition was seen on comparing AVAs with their free corresponding cinnamic acids, which implies that the anthranilic acid part of the avenanthramide molecule does not affect inhibition.

Whether dietary AVAs at intake levels normally achieved through consumption of oat products exert LOX inhibitory activity in vivo, and thereby inhibit production of pro-inflammatory compounds, remains to be elucidated. In this context it may also be of importance to emphasize that lipid content in groats of various oat cultivars is comparably high (49–135 g kg−1) and that LA [linoleic acid (C18:2, n-6)] and ALA [α-linolenic acid (C18:3, n-3)] comprise about 40% and 1%, respectively, of fatty acids.

Consumption of oats has been linked to a decreased risk of several chronic diseases, and AVAs contribute to protective effects. This study suggests that avenanthramides comprising caffeic acid or sinapic acid partly exert their antioxidant and anti-inflammatory effects via lipoxygenase inhibition.”

https://www.sciencedirect.com/science/article/pii/S2405844020311488 “Avenanthramides as lipoxygenase inhibitors”

Tampa’s Riverwalk

Don’t brew oat sprouts – eat them!

gettingwell4 4-5 stars Advanced knowledge, Dopamine, Neurochemicals , ,

This 2020 study chemically analyzed four grains and their brew-processing products:

“Side-stream products of malting, particularly rootlet, are currently treated as animal feed. Instead of ending up in final products (e.g., malt and beer), a substantial portion of phytochemicals end up in side streams.

Rootlets are being increasingly investigated to overcome their bitter taste and to unleash their potential. Adding the fact that side-stream products produced in high quantity are also rich in protein, their nutritional value may be too high to justify usage as feed rather than food.

Grains were steeped for 26 to 30 h with a wet–dry–wet steeping program. Oats were wet steeped for 4 h at 13 °C before and after 18 h of dry steeping at 15 °C.

All grains were germinated for 6 days at 15 °C, after which they were dried with a gentle kilning program to a final temperature of 83 °C and moisture of 4%. Rootlets were separated from malt after drying.

Statistically significant changes occurred in abundance of all 285 annotated phytochemicals during malting, when comparing whole grain with malted grain or rootlet. In oats, cumulative levels of avenanthramides increased by 2.6-fold in the malted grain compared to intact whole grain. Up to 25-fold increase has been reported previously after a slightly longer germination.

Phenolamides cumulative levels in oats increased in both malted grain (11-fold) and rootlet (50-fold). Cumulative flavonoid levels were nearly 3-fold higher in malted grain and rootlet compared to whole grain.

Avenanthramides and phenolamides had much lower extractability into the water extract and wort.

To our knowledge, this is the first time avenanthramides are reported from any other species than oats, suggesting that the synthesis pathway for avenanthramides evolved before oats diverged from the other cereals. Furthermore, benzoxazinoids are herein reported for the first time in oats.

Several previously uncharacterized saponins were found in oats in addition to the previously known avenacins and avenacosides. However, because of limited reference data currently available, their identity could not be determined beyond compound class and molecular formula in this study.

Plants can synthetize up to hundreds of thousands of secondary metabolites, and current spectral databases only contain a fraction of them to allow identification. Compounds found in this study do not represent the complete range of phytochemicals existing in cereals.”

https://www.nature.com/articles/s41538-020-00081-0 “Side-stream products of malting: a neglected source of phytochemicals”

Twice a day for six weeks I’ve eaten oat sprouts 3-to-6-days old from two species and three varieties. I’ve never noticed any “bitter taste” of rootlets mentioned.

Maybe “a final temperature of 83 °C and moisture of 4%” had something to do with it? Oat sprouts I ate never got above 25°C, and I doubt their moisture content was < 80%.

Maybe “Oats were wet steeped for 4 h at 13 °C before and after 18 h of dry steeping at 15 °C” gave oat sprouts a bitter taste? I process oat sprout batches the same way I do broccoli sprout batches. A new batch soaks to start germination every 12 hours, then is rinsed three times every 24 hours on a 6 hours – 6 hours – 12 hours cycle. Temperature in my kitchen is 21°C (70°F) because it’s winter outside.

The above graphic is a heat map of 29 studied C-type avenanthramides. Don’t know why 26 known A-type avenanthramides described in Eat oats today! weren’t analyzed. The second study of Sprouting oats stated:

“There is a higher concentration of A-type AVAs [avenanthramides] than C-type AVAs in sprouted oats.”

Reference 33’s “up to 25-fold increase” is curated in Eat oat sprouts for AVAs.

Go with the Alzheimer’s Disease evidence

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

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

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

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

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

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

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

Characteristics of AD microbial profiles changed from butyrate producers, such as Faecalibacterium, into lactate producers, such as Bifidobacterium. These alterations contributed to shifts in metabolic pathways from butyrate to lactate, which might have participated in pathogenesis of AD. Specific roles of AD-associated signatures and their functions should be explored in further studies.”

https://www.frontiersin.org/articles/10.3389/fcell.2020.634069/full “Structural and Functional Dysbiosis of Fecal Microbiota in Chinese Patients With Alzheimer’s Disease”

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

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

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

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

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

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

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

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

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

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

Treat your gut microbiota as one of your organs

gettingwell4 4-5 stars Advanced knowledge, Brainstem, Cerebellum, Cerebrum, Epigenetics, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Serotonin, Stress , , , , ,

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

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

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

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

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

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

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

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

https://www.hindawi.com/journals/cjidmm/2021/6658674/ “Gut Microbiota-Derived Metabolites in the Development of Diseases”

A second paper provided more details about SCFAs:

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

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

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

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

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

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

The gut-host signal axis may be more resistant to such intervention by microbial SCFAs, so this method should be tested for ≥3 months. In addition, due to inter-individual variability in microbiota and metabolism, factors that may directly affect host substrate and energy metabolism, such as diet and physical activity, should be standardized or at least assessed.”

https://www.hindawi.com/journals/cjidmm/2021/6632266/ “Modulation of Short-Chain Fatty Acids as Potential Therapy Method for Type 2 Diabetes Mellitus”

Increasing soluble fiber intake with inulin

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

From a 2015 USDA technical report:

“Inulin is a naturally-occurring carbohydrate found in roots of chicory and many other food plants. Oligofructose is derived from inulin.

Inulin is a polymer chain of multiple fructose molecules with a glucose molecule at one end. Length of the fructose chain of inulin can range from 2–60 fructose molecules.

Inulin is mostly indigestible by human enzymes due to its shape, but is digestible by microbes in the large intestine. It can serve as a prebiotic, a nutrient source for microflora in the human digestive system.”

From a 2021 review Friend or foe? The roles of inulin-type fructans (not freely available):

“Inulin-type fructans are a mixture of inulin, oligofructose and fructooligosaccharide (FOS). They aren’t absorbed in the stomach and small intestine. They can be completely fermented by bacteria in the large intestine.

They treat digestive diseases, metabolic syndrome, immune system and inflammatory diseases, endothelial dysfunction, and prevent infection and cancer.

A 2010 gastrointestinal tolerance of chicory inulin products study indicated that 10 g/day of native inulin or 5 g/day of oligofructose were well-tolerated in healthy, young adults. Over this dose would induce mild gastrointestinal symptoms.”

I bought this last month:

From the manufacturer:

“A powdered food ingredient based on chicory inulin with a high level of oligofructose 1 (DP2-DP10). This product is characterized by a high solubility.

Inulin from chicory is a polydisperse mixture of linear fructose polymers with mostly a terminal glucose unit, coupled by means of beta (2-1) bonds. The number of units (degree of polymerization) can vary between 2 and 60.

It is a fine, white powder with 30% the sweetness of sucrose. It has >=85% inulin/oligofructose and <15% fructose, glucose, sucrose. It has 2.2 kcal/gram and a glycemic response of 20.”

From the vendor:

“You pay for the product… not the product packaging! Each teaspoon (tsp) delivers 2g fiber.

Inulin is hygroscopic so will take on moisture, especially in humid environments. Store in a dry place and remove as much air from the pouch as able before resealing after each use. Alternately, you could store in several smaller air-tight containers. This will limit exposure to possible humidity. Room temperature or cooler is ideal.”

It tastes like cotton candy. 🙂 Its first use was to replace 2 grams of soluble fiber I got from eating 56 grams of noodles:

Probably won’t reorder FOS when I run out. I’ve taken 1.5 grams FOS every day for 16 years.

Eat broccoli sprouts for your kidneys

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

Starting Year 7 of curating research with a 2021 review of kidney disease and sulforaphane:

“Many chronic kidney disease (CKD) patients progress to end-stage kidney disease – the ultimate in failed prevention. While increased oxidative stress is a major molecular underpinning of CKD progression, no treatment modality specifically targeting oxidative stress has been established clinically.

Pathophysiologic effects occur when there is an imbalance between oxidation and reduction – an altered redox state in which excess free radicals react with other molecules, including lipids, proteins, and nuclear DNA. Mitochondrial DNA is also susceptible to oxidative damage.

All mechanisms discussed above have been shown to be present in CKD. When levels of antioxidant agents such as SOD, CAT, GPx/glutathione, and NRF2 are reduced, harmful effects of oxidation and generation of ROS cannot be appropriately mitigated.

Data suggest continued SFN [sulforaphane] administration is needed to maintain activation of the NRF2 pathway to confer protection against oxidative damage of diabetes. Renal protective effect of SFN has been demonstrated in many other models of kidney injury.

SFN may have therapeutic potential in kidney disease by stimulating the NRF2 pathway.”

https://www.mdpi.com/2072-6643/13/1/266/htm “Eat Your Broccoli: Oxidative Stress, NRF2, and Sulforaphane in Chronic Kidney Disease”

Didn’t see where these researchers intended to perform a suggested “clinical study to assess the effect of SFN in CKD.” Keep reading before experimentally treating patients, please. Targets they missed included:

  • Parameters of myrosinase hydrolizing glucoraphanin;
  • “Consumption of broccoli strains with more glucoraphanin leads to higher plasma levels of SFN” and
  • “It follows that SFN could also pose similar adverse effects, particularly if taken in an isolated preparation.”

Also missing from this kidney review were connections to broccoli sprouts’ effectiveness in preventing bladder disease. Isothiocyanate metabolites accumulate in the bladder.

I came across this paper from it citing Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. I curated it due to informatively citing Microwave broccoli to increase sulforaphane levels.