Young immune system, young brain

May 6, 2022May 6, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Stress Brain neurons, Control group, Genetic factors, Neurodegenerative disease

This 2022 study investigated brain aging:

“We aimed to explore key genes underlying cognitively normal brain aging and its potential molecular mechanisms. Cellular and molecular mechanisms of brain aging are complex and mainly include:

Dysfunction of mitochondria;

Accumulation of oxidatively damaged proteins, nucleic acids, and lipids in brain cells;

Disorders of energy metabolism;

Impaired ‘waste disposal’ mechanism (autophagosome and proteasome functionality);

Impaired signal transduction of adaptive stress response;

Impaired DNA repair;

Abnormal neural network activity;

Imbalance of neuronal Ca²⁺ processing;

Stem cell exhaustion; and

Increased inflammation.

Expression of CD44, CD93, and CD163 mRNA detected by qPCR in hippocampal tissue of cognitively normal aged and young mice.

Underlying molecular mechanisms for maintaining healthy brain aging are related to decline of immune-inflammatory responses. CD44, CD93, and CD 163 are potential biomarkers.”

https://www.frontiersin.org/articles/10.3389/fnagi.2022.833402/full “Identification of Key Biomarkers and Pathways for Maintaining Cognitively Normal Brain Aging Based on Integrated Bioinformatics Analysis”

Vitamin D and pain

May 2, 2022May 2, 2022 gettingwell4 2-3 stars Required further work, Epigenetics Control group, DNA methylation, Genetic factors, Neurodegenerative disease

This 2022 human study investigated epigenetic clock associations:

“We assessed the potential relationship of Vitamin D’s effects on pain intensity and disability through associations in epigenetic aging in individuals with and without knee osteoarthritis (KOA). We hypothesized that associations between Vitamin D levels with pain intensity and interference in persons with KOA would be significantly mediated by epigenetic aging.

As a whole, the sample had a mean Vitamin D serum level of 26.7 ng/mL (± 12.8 ng/mL). The mean AgeAccelGrim was 2.4 years (± 5.6 years). There were no significant differences in Vitamin D levels between sex, race, and study site categories.

There was a significant difference in Vitamin D levels between the pain groups, with individuals in the High Impact Pain group showing significantly lower mean levels of Vitamin D (24.01 ng/mL) compared to the Low Impact Pain (28.30 ng/mL) and No Pain (27.30 ng/mL) groups.

Data from this study highlight the important role that Vitamin D plays within the genomic environment, as well as in relation to health outcomes including pain intensity and disability.”

https://link.springer.com/article/10.1007/s12603-022-1758-z “Accelerated Epigenetic Aging Mediates the Association between Vitamin D Levels and Knee Pain in Community-Dwelling Individuals” (not freely available)

It’s good to see a study relating biological age to nutrition status. I didn’t see much discussion of other obvious factors involved in either pain or biological age in their limitations paragraph.

Subjects’ Vitamin D 26.7 ng/mL ± 12.8 ng/mL status indicated that most didn’t spend a few cents every day for their own one precious life. And Vitamin D supplementation wasn’t an exclusion criterion.

The local fire and rescue squad came last Friday to take away a younger neighbor’s body who died overnight. Last I talked with them, they were at least 50 pounds overweight and never exercised. Expressed condolences to their spouse, but wasn’t shocked.

I don’t live in a community-dwelling situation (old people who live on their own as opposed to those taken care of in nursing homes) like this study’s subjects. My youngest neighbors are in their twenties.

Nature hasn’t cared about our lives after our early teens, because we survived long enough to reproduce. What happens in our lives after puberty is largely up to each individual.

All about AGEs

April 25, 2022April 27, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Neurochemicals, Serotonin, Stress Control group, Neurodegenerative disease

My 900^th curation is a 2022 review by the lead author of Reversibility of AGEs concentrations that fleshed out details of advanced glycation end products (AGEs) topics:

“This review aims to provide a state-of-the-art overview of the toxicokinetics and toxicodynamics of endogenously formed and exogenous dietary AGEs and their precursors. AGEs are a heterogenous group of:

Low molecular mass (LMM) glycation products formed by reaction with a free amino acid residue and/or to dicarbonyl precursors; and

High molecular mass (HMM) glycation products formed by reaction with a protein-bound amino acid residue, including cross-linked products (i.e. when two amino acid residues are involved instead of one).

Cross-linking of body proteins results in:

Altered structure and function of the proteins;

Proteins are less easily degraded;

An increase in stiffness in tissues that are rich in these proteins, including arterial, lung tissue, joints, and extracellular matrix. Stiffness in these tissues has been associated with diseases including hypertension, cataracts, dementia, atherosclerosis, glomerulosclerosis, emphysema, and joint pain.

In endogenous formation of AGEs and their precursors, the same pathways as exogenous proceed via non-enzymatic reactions, although they occur at lower rates due to the lower physiological temperatures. In addition, specific endogenous AGE formation pathways include glycolysis and the polyol pathway active under hyperglycemic conditions.

Considering heterogeneity of glycation products, as also reflected in different ADME outcomes, AGEs and their precursors cannot be grouped together. Specific, individual information is required for a proper evaluation, especially considering ADME properties.

The role of exogenous HMM AGEs and precursors seems to be restricted by limited bioavailability to local effects on the intestine including its microbiota, unless being degraded to their LMM form. An important role is probably left for reactive (endogenously formed) dicarbonyl AGE precursors and as a consequence the endogenously formed AGEs.

The direct contribution of reactive dicarbonyl precursors to dicarbonyl stress and their indirect contribution to endogenous HMM AGE formation and subsequent AGE receptor activation remain to be further studied.”

https://www.sciencedirect.com/science/article/pii/S0278691522001855 “Differences in kinetics and dynamics of endogenous versus exogenous advanced glycation end products (AGEs) and their precursors”

Recent glucosamine research

April 24, 2022September 27, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group, Genetic factors, Neurodegenerative disease

Prompted by a conversation in Year Two of Changing to a youthful phenotype with sprouts, here are sixteen 2022 papers published in the last 45 days involving glucosamine. There are more researchers alive today than in the sum of human history, and they are compelled to publish.

Human research

https://www.sciencedirect.com/science/article/pii/S0378874122002860 “The efficacy and safety of Jinwu Gutong capsule in the treatment of knee osteoarthritis: A meta-analysis of randomized controlled trials”

“The Jinwu Gutong (JWGT) capsule is a Chinese patent medicine that is widely used in the treatment of knee osteoarthritis (KOA) and osteoporosis in China and is considered to have the potential for good clinical efficacy. The application of JWGT combined with NSAIDs, hyaluronic acid, or glucosamine can significantly improve the clinical efficacy of the latter agents in KOA treatment.”

https://link.springer.com/article/10.1007/s00330-022-08772-w “Breast cancer imaging with glucosamine CEST (chemical exchange saturation transfer) MRI: first human experience” (not freely available)

“This study aims to evaluate the feasibility of imaging breast cancer with glucosamine (GlcN) CEST MRI technique to distinguish between tumor and surrounding tissue, compared to the conventional MRI method. The results of this initial feasibility study indicate the potential of GlcN CEST MRI to diagnose breast cancer in a clinical setup.”

https://link.springer.com/article/10.1007/s10067-022-06105-2 “The comparison of curcuminoid formulations or its combination with conventional therapies versus conventional therapies alone for knee osteoarthritis” (not freely available)

“Curcuminoid formulations or its combination with conventional therapies has been used for the treatment of knee osteoarthritis. Evidence is limited due to small-sized clinical trials. This study aims to evaluate the efficacy of curcuminoid formulations or its combination with conventional therapies for KOA.”

Animal, chemical, and microbiota research

https://academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjac016/6548195 “Regulation of the urea cycle by CPS1 O-GlcNAcylation in response to dietary restriction and aging”

“O-linked N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of intracellular proteins is a dynamic process broadly implicated in age-related disease, yet it remains uncharacterized whether and how O-GlcNAcylation contributes to the natural aging process. Our results identify CPS1 O-GlcNAcylation as a key nutrient-sensing regulatory step in the urea cycle during aging and dietary restriction, implying a role for mitochondrial O-GlcNAcylation in nutritional regulation of longevity.”

https://www.mdpi.com/2076-2607/10/3/626/htm “Laccase-Catalyzed Derivatization of Aminoglycoside Antibiotics and Glucosamine”

“The increasing demand for new and effective antibiotics requires intelligent strategies to obtain a wide range of potential candidates. The products protected mice against infection with Staphylococcus aureus, which was lethal to the control animals. The results underline the great potential of laccases in obtaining new biologically active compounds, in this case new antibiotic candidates from the class of aminoglycosides.”

https://iopscience.iop.org/article/10.1088/1748-605X/ac61fa “Gelatin-glucosamine hydrochloride/crosslinked-cyclodextrin metal-organic frameworks@IBU composite hydrogel long-term sustained drug delivery system for osteoarthritis treatment” (not freely available)

“Osteoarthritis (OA) is a disease of articular cartilage degradation and inflammation of the joint capsule. Combining anti-inflammatory therapy with nutritional supplement is an effective means for the treatment of OA. Mechanical properties, sustained drug release behavior, and good biocompatibility of G-GH/CL-CD-MOF@IBU composite hydrogel showed that it has potential application in OA treatment of long-term sustained nutritional supplement and anti-inflammatory synchronously.”

https://pubs.rsc.org/en/content/articlelanding/2022/FO/D1FO04086C “Glucosamine enhances proliferation, barrier, and anti-oxidative functions in porcine trophectoderm cells”

“Trophectoderm (TE) is the first epithelium that appears during mammalian embryogenesis, and is a polarized transporting single cell layer that comprises the wall of the blastocyst. Previous studies have revealed the functional roles of glucose (Gluc), fructose (Fruc), and glutamine (Gln), which play a positive role in porcine trophectoderm (pTr) cell proliferation and migration, suggesting the importance of nutrients for normal development of the conceptus and implantation.

This work was conducted to test the hypothesis that glucosamine (GlcN), which is synthesized from Gln and Fruc-6-phosphate through the hexosamine biosynthesis pathway, can stimulate proliferation and sustain the barrier and anti-oxidative functions of pTr cells. GlcN plays an important role in promoting proliferation and stimulating the mTOR cell signaling pathway, as well as ameliorating oxidative stress and augmenting barrier functions in pTr cells.”

https://pubs.acs.org/doi/10.1021/acschemneuro.2c00057 “O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies”

“Neurodegenerative proteinopathies are characterized by the intracellular formation of insoluble and toxic protein aggregates in the brain that are closely linked to disease progression. O-GlcNAcase prevents the removal of O-linked N-acetyl-d-glucosamine moieties from intracellular proteins and has emerged as an attractive therapeutic approach to prevent the formation of tau pathology.”

https://onlinelibrary.wiley.com/doi/10.1002/ctm2.762 “Glucosamine facilitates cardiac ischemic recovery via recruiting Ly6C^low monocytes in a STAT1 and O-GlcNAcylation-dependent fashion”

“Glucosamine (GlcN, 2-amino-2-deoxy-d-glucose) is a freely available and commonly used dietary supplement for human cartilage health, which hexosamine biosynthesis pathway and induces protein O-GlcNAcylation. GlcN early therapy (GlcN/E), which initiated 1 day before myocardial infarction (MI), effectively facilitated cardiac ischemic recovery. More importantly, short-term GlcN therapy initiated even 3 days post-MI (GlcN/L) was also sufficient to induce clear cardiac protection, suggesting that both GlcN/E and GlcN/L therapies effectively ameliorate post-MI cardiac dysfunction and scar formation.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007349/ “Filling gaps in bacterial catabolic pathways with computation and high-throughput genetics”

“For many microbes, we know little about them beyond their genome sequences. We built an automated tool to identify gaps: transporters or enzymes that should be present, to explain how a bacterium uses a carbon source, but could not be found in the genome. By comparing these gaps to large-scale genetic data for 29 bacteria, we identified hundreds of novel transporters and enzymes, and a new metabolic pathway for consuming glucosamine.”

https://www.sciencedirect.com/science/article/pii/S0031942222000991 “Ingadosides A-C, acacic acid-type saponins from Inga sapindoides with potent inhibitory activity against downy mildew”

“As part of a project aiming at the discovery of environmentally friendly alternatives to copper in organic agriculture, a 96% ethanolic extract from the leaves of Inga sapindoides showed potent inhibitory activity against grapevine downy mildew. I. sapindoides, a tree which is often cultivated for shading coffee plantations in Central America, may represent a sustainable source of fungicidal products to be used in the replacement of copper.”

https://www.sciencedirect.com/science/article/abs/pii/S0378111922002840 “Aerobic exercise combined with glucosamine hydrochloride capsules inhibited the apoptosis of chondrocytes in rabbit knee osteoarthritis by affecting TRPV5 expression”

“This study aimed to investigate the effect of aerobic exercise combined with glucosamine on the apoptosis of chondrocytes of rabbit knee osteoarthritis by affecting the expression of TRPV5. Aerobic exercise combined with glucosamine hydrochloride capsules inhibited the apoptosis of chondrocytes in rabbit KOA by affecting the expression of TRPV5.”

https://pubs.rsc.org/en/content/articlelanding/2022/BM/D2BM00280A “Smart erythrocyte-hitchhiking insulin delivery system for prolonged automatic blood glucose control”

“Long and automatic control of blood glucose levels in diabetic patients could solve the problems caused by frequent insulin injections. Herein, we exploited the protection potential of erythrocytes by a ‘hitchhiking’ strategy to significantly prolong the blood circulation time of a specifically-designed smart hitchhiking insulin delivery system (SHIDS). In the SHIDS, insulin, glucose oxidase, and catalase were co-loaded into nanoparticles formed by modified chitosan. The free glucosamines in chitosan anchor glucose transporters on the surface of erythrocytes, allowing erythrocyte-hitchhiking in the blood flow.”

https://www.sciencedirect.com/science/article/abs/pii/S0308814621027825 “Maillard-reacted peptides from glucosamine-induced glycation exhibit a pronounced salt taste-enhancing effect” (not freely available)

“Reducing salt intake, as one of the most cost-effective approaches, is congruent with improved population health. Maillard-reacted peptides exhibited a significant salt taste-enhancing effect, which may be attributed to the glucosamine-induced glycation. The current study provides a theoretical basis for preparation of salt taste-enhancing peptides and their future application to reduce salt content of formulated foods.”

https://academic.oup.com/glycob/advance-article-abstract/doi/10.1093/glycob/cwac027/6572163 “Peptidoglycan from Akkermansia muciniphila Muc T: chemical structure and immunostimulatory properties of muropeptides” (not freely available)

“Akkermansia muciniphila is an intestinal symbiont known to improve the gut barrier function in mice and humans. Our results provide new insights into the diversity of cell envelope structures of key gut microbiota members and their role in steering host-microbiome interactions.”

Reviews

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008999/ “Ruminal bacteria lipopolysaccharides: an immunological and microbial outlook”

“Lipopolysaccharides (LPS) are outer membrane components of Gram-negative bacteria made of three regions: the O-antigen; the core oligosaccharide; and a glucosamine disaccharide linked to hydroxy fatty acids, which is named lipid A. this review identifies numerous areas for future research, including setting the basis for future modeling and simulation of host microbiome interactions in ruminants.”

Signaling pathways and aging

April 17, 2022February 8, 2023 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system Control group, DNA methylation, Genetic factors, Neurodegenerative disease

This 2022 study investigated biological mechanisms of aging:

“Age-related multimorbidity, the presence of more than one age-related disease (ARD) in an individual, poses a major and increasing challenge. Open questions are whether mechanisms of aging can explain ARD co-occurrence in patients, and whether intervention into these mechanisms could prevent or treat multiple ARDs simultaneously.

Five signaling pathways/ cascades were significantly enriched across protein lists for all nine aging hallmarks. These pathways are likely to play a key role in the etiology of ARDs.

Among these five signaling pathways, three were involved in the innate and/ or adaptive immune response. Underlying genes were derived from ARDs comprising metabolic syndrome disorders, autoimmune disorders, and cancers, highlighting the immune response across multiple ARDs.

The ‘intrinsic apoptotic signaling pathway in response to DNA damage by a p53 class mediator’ was also significantly enriched across all aging hallmark protein lists. Underlying genes were derived from multiple cancers and metabolic syndrome disorders.

The ERK1/2 pathway regulates many processes including cell survival, metabolism, and inflammation and was significantly enriched across all aging hallmark protein lists. Underlying genes were derived from 22 aging hallmark-associated ARDs.

Our study provides evidence for the role of aging hallmarks in the etiology of human ARD multimorbidities and ARDs with incompletely understood pathogenesis. We also raise the possibility that multiple ARDs may be prevented by targeting common signaling pathways.”

https://onlinelibrary.wiley.com/doi/10.1111/acel.13524 “Biological mechanisms of aging predict age-related disease co-occurrence in patients”

I’ll assume that this study finding the importance of innate and adaptive immunity, intrinsic apoptotic, and ERK1/2 signaling pathways in aging was incorporated into A rejuvenation therapy and sulforaphane treatment. Its lead laboratory researcher Dr. Harold Katcher said in interviews that the treatment was formulated from existing research findings.

Its first follow-on lifespan study is going well (4/30/2022 update). 7 6 of 8 treated subjects are alive, compared with 5 4 of 8 control group subjects.

Subjects’ age at the follow-on study’s February 2021 start was 24 months. They are 38-months-old now, and rat maximum lifespan is 45 months, so there should be preliminary results in 2022.

Regarding healthspan, grip strength in treated subjects after a fourth dose was recently measured at 2.6 times control subjects.

Other health measurements are body weight, and TNF-α and IL-6 cytokines.

A second follow-on study uses 18-month-old subjects of both sexes. The initial study was all males, and the first follow-on study is all females.

This second follow-on treatment group will be dosed at 45-day intervals vs. 90-day intervals of the first two studies. Human equivalent doses would be once every 4 years vs. every 8 years.

The treatment works per Beginning of the cure for aging and Reinvigorated. This second follow-on study is research and development to approximate optimal treatment times by age and possibly sex. The idea per Week 37 of Changing to a youthful phenotype with broccoli sprouts is that “by the second rejuvenation you’re already starting at ‘young’.”

Update #2 6/17/2022

Update #3 2/8/2023

MET minutes

April 16, 2022April 17, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory Control group, Genetic factors, Neurodegenerative disease

This 2022 meta-analysis investigated the relationship between cognition and exercise expressed in MET minutes (metabolic equivalent for task, a unit that estimates amount of energy used during physical activity compared to resting metabolism):

“44 studies (4793 participants aged 50 years or over) were included. There was a non-linear, dose-response association between overall exercise and cognition.

We found no minimal threshold for beneficial effect of exercise on cognition. The estimated minimal exercise dose associated with clinically relevant changes in cognition was 724 METs-min per week, and doses beyond 1200 METs-min per week provided less clear benefits.

Obesity status was the main moderator of effects of exercise on cognition. Our results suggest that overweight/obese older adults may benefit from lower exercise levels than recommended for the general population.

Exercise is one of the few interventions shown to prevent and treat dementia or cognitive decline in older adults.”

https://www.sciencedirect.com/science/article/pii/S1568163722000332 “Optimal dose and type of exercise to improve cognitive function in older adults: A systematic review and bayesian model-based network meta-analysis of RCTs”

Similar to Biological age and zinc, this study found that our metabolic zones determine how our choices can achieve desired effects.

There’s no substitute for exercise. Take responsibility for your one precious life: nobody else exercises for you.

Came home this afternoon after my daily walk on the beach, thinking about how – in a way – this honored ancestors. We are the products of who they were and what they did to survive.

Are blood epigenetic clock measurements optimal?

April 15, 2022April 16, 2022 gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Epigenetics, Immune system, Lower brain Brain neurons, Control group, DNA methylation, Genetic factors, Neurodegenerative disease, Prefrontal cortex

This 2022 human study investigated tissue-specific epigenetic clock measurements:

“We used DNA methylation data representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen, and pituitary gland) to quantify the extent to which epigenetic age acceleration (EAA) in one tissue correlates with EAA in another tissue.

Epigenetic age was moderately correlated across tissues:

Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. Blood did not correlate with epigenetic age of liver.

EAA in liver was weakly correlated with EAA in kidney, adipose, lung, and bone marrow.

Hypertension was associated with EAA in several tissues, consistent with multiorgan impacts of this illness.

HIV infection was associated with positive age acceleration in kidney and spleen.

Men were found to exhibit higher EAA than women across all tissues when analyzed together. Significant results were also observed in individual tissues (muscle, spleen, and lymph nodes).

Blood alone will often fail to detect EAA in other tissues. It will be advisable to profile several sources of DNA (including blood, buccal cells, adipose, and skin) to get a comprehensive picture of the epigenetic aging state of an individual.”

https://link.springer.com/article/10.1007/s11357-022-00560-0 “HIV, pathology and epigenetic age acceleration in different human tissues”

Epigenetic clocks and entropy

April 10, 2022April 16, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Control group, DNA methylation, Embryo development, Genetic factors, Neurodegenerative disease

Two epigenetic clock papers, starting with a 2022 rodent study:

“We tested performance of new pan-tissue and liver-specific epigenetic mouse clocks, evaluating how these related to metabolic states, genotype-dependent life expectancy, and methylome entropy.

Entropy, a measure of noise and information loss, increases as a function of time and age. In context of the methylome, higher entropy represents a tendency for the highly organized hypo- and hypermethylated landscape to erode towards a more hemi-methylated [discordant] state.

This increase in disorder, particularly across CpGs that are highly conserved, could have important functional consequences. Entropy of age-gain CpGs was increased by high fat diet, and predicted strain lifespan.

Overall, we find that mice belonging to longer-lived BXD strains had a more youthful methylome with lower entropy at age-gain CpGs. Entropy of age-loss CpGs on the other hand, was related to body weight.

(h) Residual plot (adjusted for age, diet, BWF [final body weight], glucose, cholesterol, and batch) shows an inverse association between entropy at age-gain sites, and lifespan. (i) A similar residual plot shows the association between BWF and age-loss entropy.

The rate of noise accumulation, an aspect of epigenomic aging, can vary between individuals. Resilience or susceptibility to higher noise may be partly modulated by diet as well as genetic factors.

Convergence of evidence from genetic and gene expression analyses indicates that genes involved in metabolism and energy balance contribute to age-dependent restructuring of the methylome, which in turn forms the basis of epigenetic clocks.”

https://elifesciences.org/articles/75244 “Genetic loci and metabolic states associated with murine epigenetic aging”

Reference 28 was a 2021 human study cited for “identified the APOE locus as the strongest GWAS hit for two measures of biological age acceleration”

“We observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains.

Our study reaffirms that aging patterns are heterogeneous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition. Understanding personalized aging susceptibility phenotypes has important implications for primary and secondary disease interventions.”

https://onlinelibrary.wiley.com/doi/10.1111/acel.13376 “Genetic associations for two biological age measures point to distinct aging phenotypes”

Gut microbiota knowledge through 2021

March 21, 2022January 3, 2023 gettingwell4 2-3 stars Required further work, Amygdala, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Infants, Neurodegenerative disease, Prefrontal cortex, Reciprocity

I’ll curate this 2022 review of what’s known and unknown about our trillions of gut microbiota through its topic headings:

“Most microbial taxa and species of the human microbiome are still unknown. Without revealing the identity of these microbes as a first step, we cannot appreciate their role in human health and diseases.

A. Understanding the Microbiome Composition and Factors That Shape Its Diversity
Effect of Diet Composition on the Microbiome Diversity

Macronutrients and Microbiome Diversity

Nutrient and Mineral Supplements and Microbiome Diversity

Stress

Drugs

Race and Host Genetics

Aging

Lifestyle

Exercise

Smoking

Urbanization

B. Understanding the Microbiome Function and Its Association With Onset and Progression of Many Diseases

Microbiome Association With Inflammatory and Metabolic Disorders

Chronic Inflammation in GIT and Beyond

Development of Malignant Tumors

Obesity

Coronary Artery Disease

Respiratory Diseases

Microbiome Role in Psychiatric, Behavioral, and Emotional Disorders

Anxiety

Depression

Sleep

Fear Response

Autism

Alzheimer and Dementia

C. Understanding the Microbiome Function as Mediated by Secreted Molecules

D. Conclusion and Future Directions – A pioneering study aimed to computationally predict functions of microbes on earth estimates the presence of 35.5 million functions in bacteria of which only 0.02% are known. Our knowledge of its functions and how they mediate health and diseases is preliminary.”

https://www.frontiersin.org/articles/10.3389/fmicb.2022.825338 “Recent Advances in Understanding the Structure and Function of the Human Microbiome”

I took another test last month at the 14-month point of treating my gut microbiota better. Compared with the 7-month top level measurements, what stood out was an increase in relative abundance from 1% to 7% in the Verrucomicrophia phylum that pretty much exclusively comprises species Akkermansia muciniphilia in humans:

This review termed Akkermansia muciniphilia relative increases as beneficial. Go with the Alzheimer’s Disease evidence didn’t.

Preventing human infections with dietary fibers inferred that insufficient dietary fiber may disproportionately increase abundance of this species. But I already eat much more fiber than our human ancestors’ estimated 100 grams of fiber every day, so lack of fiber definitely didn’t cause this relative increase.

Resistant starch therapy observed:

“Relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders increase in relative abundance to a greater extent.”

I’ll wait for further evidence while taking responsibility for my own one precious life.

Didn’t agree with this review’s statements regarding microbial associations with fear. These reviewers framed such associations as if gut microbiota in the present had stronger influences on an individual’s fear responses than did any of the individual’s earlier experiences. No way.

I came across this review by it citing The microbiome: An emerging key player in aging and longevity, which was Reference 25 of Dr. Paul Clayton’s blog post What are You Thinking?

Also didn’t agree with some of the doctor’s post:

Heterochronic parabiosis of young and old animals is wildly different from fecal transfer. Can’t really compare them to any level of detail.
Using a rodent young-to-old fecal microbiota transplant study to imply the same effects would happen in humans? Humans don’t live in controlled environments, so why would a young human individual’s gut microbiota necessarily have healthier effects than an old individual’s?
Another example was the penultimate paragraph: “By adding a mix of prebiotic fibers to your diet and maintaining a more youthful and less inflammatory microbiome you will have less inflammation, less endotoxaemia and less inflammageing. You will therefore live healthier and longer.” I’m okay with the first sentence. Equivalating the first sentence to both healthspan and lifespan increases in the second sentence wasn’t supported by any of the 45 cited references.

Advanced glycation / lipoxidation end products

March 16, 2022March 18, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Brain neurons, Control group, DNA methylation, Genetic factors, Neurodegenerative disease

Three papers on what can be expected from AGEs, beginning with a 2022 review:

“Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. In addition to causing damage directly, the RCS adducts advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs) elicit chronic inflammation through receptor-mediated mechanisms.

Endogenously formed RCS and AGEs/ALEs accumulation induced by hyperglycemia, hyperlipidemia, and oxidative stress have been long recognized as critical factors in pathogenesis of cardiovascular, renal, and eye complications. The role of dietary glyco/lipotoxins in vascular complications is debated, as the metabolic fate of most ingested AGEs/ALEs and RCS remains unknown, and their contribution to systemic carbonyl stress is uncertain.

Plasma glucose spikes after a meal rich in readily absorbable carbohydrates, particularly in association with an unfavorable lipid composition, may promote proinflammatory and pro-oxidant responses by inducing a transient increase in RCS levels and consequent AGE formation. As protein-bound AGEs are not easily eliminated from the body, they can eventually accumulate in vascular and metabolic tissues because of repeated cycles of nutrient-induced carbonyl stress, favoring establishment of systemic low chronic inflammation.

Post-challenge glucose excursions are associated with a transient increase in circulating RCS levels, particularly in diabetic and prediabetic individuals. Diet-induced weight loss is associated with decreases in postprandial carbonyl stress in obese subjects. Data on lean and metabolically healthy individuals are limited.”

https://www.mdpi.com/2072-6643/14/5/1061/htm “Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet”

I understand that researchers feel obligated to end papers with suggestions for future research. It’s a little irritating, though, when these are pie-in-the-sky.

People who wait for endogenous vs. exogenous AGE / ALE questions to be answered in their lifetimes are at risk for giving themselves diseases.

A second paper is a 2021 human cell study:

“Sulforaphane (SFN) found in cruciferous vegetables is a potent activator of the Nrf2 transcription factor, the master regulator of redox biology in mammalian cells. Nrf2 modulates expression of several antioxidant enzymes, such as γ-glutamylcysteine ligase (γ-GCL). This is the rate-limiting step in synthesis of the major non-enzymatic antioxidant glutathione (GSH). Silencing of Nrf2 or inhibition of GSH synthesis abolished SFN-promoted mitochondrial protection in cells exposed to methylglyoxal (MG), a pro-oxidant agent whose levels are high in several human diseases.

MG is a reactive dicarbonyl presenting both endogenous (e.g. glycolysis) and exogenous (e.g. food cooking) sources. MG induces neurotoxicity, at least in part, by affecting mitochondrial function, including a decline in oxidative phosphorylation (OXPHOS) system activity, bioenergetics failure, and redox disturbances.

We found that SFN prevented MG-induced OXPHOS dysfunction and mitochondrial redox impairment. SFN protected mitochondria of MG-challenged cells by a mechanism involving the Nrf2/γ-GCL/GSH axis.”

https://link.springer.com/article/10.1007/s11064-020-03204-x “The Isothiocyanate Sulforaphane Depends on the Nrf2/γ‑GCL/GSH Axis to Prevent Mitochondrial Dysfunction in Cells Exposed to Methylglyoxal” (not freely available)

Although this study’s 5 µM sulforaphane treatment is achievable in human plasma, that level isn’t sustainable for 24 hours as the study did in vitro. Would sulforaphane’s in vivo effects likewise prevent methylglyoxal from inducing AGEs?

A third paper is a 2022 human study:

“AGEs have been widely reported to play an important role in osteoporosis (OP). We investigated the effect of AGEs on osteoblast function and underlying mechanisms.

Levels of bone mineral density (BMD), serum AGEs, and fasting blood glucose (FBG) were measured in patients with OP and healthy individuals:

Patients with OP had a higher level of serum AGEs and FBG compared with healthy individuals.

The level of serum AGEs in patients with OP was negatively correlated with BMD, but was positively correlated with FBG.

AGEs and serum from patients with OP markedly inhibited hFOB1.19 osteoblast cell proliferation, alkaline phosphatase production, and mineralized nodule formation.

Apoptosis and ferroptosis were significantly promoted by AGEs and serum from patients with OP.

Serum from OP patients with T2DM caused stronger effect than that from OP patients with normal FBG.

Collectively, AGEs could disrupt functions of osteoblasts by inducing cell ferroptosis, thus contributing to OP.”

https://www.spandidos-publications.com/10.3892/mmr.2022.12656 “Advanced glycation end products promote osteoporosis by inducing ferroptosis in osteoblasts”

Vitamin K forms

March 2, 2022May 20, 2023 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress Brain neurons, Control group, Genetic factors, Neurodegenerative disease

Two papers on Vitamin K, beginning with a 2021 review:

“Vitamin K is involved in many biological processes. Menaquinones (MK) [Vitamin K₂] and phylloquinone [Vitamin K₁] vary in biological activity, showing different bioavailability, half-life, and transport mechanisms.

The effective dose to decrease uncarboxylated osteocalcin was six times lower for MK-7 than for MK-4. Similarly, MK-7 affected blood coagulation system at dose three to four times lower than vitamin K₁.

Both vitamin K₁ and MK-7 inhibited decline in bone mineral density. However, benefits for occurrence of cardiovascular diseases have been observed only for long-chain menaquinones. There are currently no guidelines for recommended doses and forms of vitamin K in prevention of osteoporosis, atherosclerosis, and other cardiovascular disorders.”

https://www.mdpi.com/2304-8158/10/12/3136/htm “Relationship between Structure and Biological Activity of Various Vitamin K Forms”

This first paper cited a 2019 meta-analysis for:

“Vitamin K₂ supplementation is a preventative measure rather than an osteoporosis treatment.

Meta-analysis of various interventions for improving BMD revealed that vitamin K₂ can increase lumbar spine BMD. It ranked sixth among eighteen different single or combined interventions including Ca, vitamin D, estrogen, isoflavone and exercise.

Effect size for change in bone mineral density (BMD) using forest plots. LS, lumbar spine; D, vitamin D; Est, oestrogen; Ex, exercise; K, vitamin K; Iso, isoflavone; FN, femoral neck.

Lumbar spine:

Ca, vitamin D, vitamin K, oestrogen, exercise, Ca + vitamin D, vitamin D + vitamin K, and vitamin D + oestrogen were associated with significantly beneficial effects relative to no treatment.

Ca, vitamin D, oestrogen, and Ca + vitamin D were associated with beneficial effects compared with placebo.

Vitamin D + vitamin K was associated with positive effect with Ca.

Oestrogen, vitamin D + vitamin K, and vitamin D + oestrogen were associated with beneficial effect compared with vitamin D.

Ca + vitamin D + exercise had a beneficial effect compared with Ca + vitamin D.

Ca + oestrogen, and isoflavone + exercise were related to negative effects relative to oestrogen.

Femoral neck:

Ca, exercise, and vitamin D + oestrogen were associated with significant beneficial intervention effects relative to no treatment.

The present study demonstrated that many interventions were valuable for improving BMD in the LS and FN of postmenopausal women. It confirmed the need for postmenopausal women to improve BMD through preventive measures such as nutrients or oestrogen.

It also confirmed that different single or combined preventions can affect BMD at different sites in different orders. This reveals to medical and health workers and postmenopausal women which methods can be selected preferentially to prevent bone loss.”

https://doi.org/10.1017/S0007114519002290 “Impact of calcium, vitamin D, vitamin K, oestrogen, isoflavone and exercise on bone mineral density for osteoporosis prevention in postmenopausal women: a network meta-analysis”

Amazingly oblivious that this freely-available second 2019 paper has been cited only by this first paper. What recent literature is more relevant to postmenopausal women’s health?

CD38 and balance

February 14, 2022July 19, 2023 gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Neurochemicals, Stress, Telomeres Brain neurons, Control group, Genetic factors, Neurodegenerative disease

I’ll highlight this 2022 review’s relationships between inflammation and cluster of differentiation 38:

“We review the nicotinamide adenine dinucleotide (NAD) catabolizing enzyme CD38, which plays critical roles in pathogenesis of diseases related to infection, inflammation, fibrosis, metabolism, and aging.

NAD is a cofactor of paramount importance for an array of cellular processes related to mitochondrial function and metabolism, redox reactions, signaling, cell division, inflammation, and DNA repair. Dysregulation of NAD is associated with multiple diseases. Since CD38 is the main NADase in mammalian tissues, its contribution to pathological processes has been explored in multiple disease models.

CD38 is upregulated in a cell-dependent manner by several stimuli in the presence of pro-inflammatory or secreted senescence factors or in response to a bacterial infection, retinoic acid, or gonadal steroids. CD38 is stimulated in a cell-specific manner by lipopolysaccharide, tumor necrosis factor alpha, interleukin-6, and interferon-γ.

CD38 plays a critical role in inflammation, migration, and immunometabolism, but equally important is resolution of the inflammatory response which left unchecked leads to loss of self-tolerance, tissue infiltration of lymphocytes, and circulation of autoantibodies.

Depending upon context, CD38 can either promote or protect against an autoimmune response.

Chronic mucosal inflammation and tissue damage characteristic of inflammatory bowel disease predisposes IBD patients to development of colorectal cancer, and the risks increase with duration, extent, and severity of inflammation.

Pulmonary fibrosis occurs in the presence of unresolved inflammation and dysregulated tissue repair, and results from an array of injurious stimuli including infection, toxicant exposure, adverse effects of drugs, and autoimmune response.

Modulating CD38 and NAD levels in kidney disease may provide therapeutic approaches for prevention of inflammatory conditions of the kidney.

Inflammation as well as evidence of senescence are present in pathophysiology of chronic liver diseases that progress to cirrhosis.

Inflammation-associated metabolic diseases impair vascular function. Chronic inflammation can lead to vascular senescence and dysfunction.

One cause of NAD decline during aging is due to increase of NAD breakdown in the presence of increased CD38 expression and activity on immune cells, thus linking inflammaging with tissue NAD decline. Other sources of NAD decline include increased DNA-damage requiring PARP1 activation, and decreased NAMPT levels leading to diminished NAD synthesis through the salvage pathway.

Inflammation is among the major risk factors that predispose organisms to age-associated diseases. During aging, accumulation of senescent cells creates an environment rich in proinflammatory signals, leading to ‘inflammaging.’ Metabolically active cells lose their replicative capacity by entering an irreversible quiescent state, and are considered both a cause and a consequence of inflammaging.

Recent findings uncover a major role of CD38 in inflammation and senescence, showing that age-related NAD⁺ decline and the sterile inflammation of aging are partially mediated by a senescence / senescence associated secretory phenotype (SASP)-induced accumulation of CD38⁺ inflammatory cells in tissues. Given the clear association between the phenomenon of inflammaging, senescence, and CD38, as well as the impact of CD38 on degradation of NAD and the NAD precursor NMN, future studies should focus on CD38 as a druggable target in viral illnesses.”

https://journals.physiology.org/doi/abs/10.1152/ajpcell.00451.2021 “The CD38 glycohydrolase and the NAD sink: implications for pathological conditions”

We extend good-vs.-bad thinking to nature. Does that paradigm explain much, though?

All pieces of a puzzle are important. Otherwise, evolution would have eliminated what wasn’t necessary for its purposes.

Restoring balance to an earlier phenotype suits my purposes. Don’t want to eliminate inflammatory responses, but instead, calm them down so that they’re evoked appropriately.

Studying AGEs and neurodegeneration

February 13, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress Brain neurons, Control group, Genetic factors, Neurodegenerative disease, Unconscious feelings, Unconscious memories

This 2022 review suggested more effective ways to conduct in vitro studies of advanced glycation end products (AGEs) and neurodegenerative diseases:

“The main goal of this review was to present and discuss in vitro models that were applied or have the potential to be used in research on AGEs and ND.

We introduced and explained current knowledge on AGEs regarding their formation and accumulation in humans.

We presented existing evidence linking involvement of AGEs in ND and explained basic concepts of brain physiology and immunology affected by AGEs.

We presented and discussed available in vitro models to study AGE-mediated neurodegeneration by dividing them into sections from simple models. These have been applied to more complex models that have not been yet applied in the field of AGEs, but offer opportunities.

We gathered advisable in vitro tools based on their relevance to three primary endpoints that AGEs can impact brain pathophysiology and their characteristics and suitability to mimic ND pathophysiology.

Several studies have indicated intracellular formation of AGEs by microglia or neurons, but identification of intracellular AGEs in those cases is made by immunoassays, which have received much criticism regarding their reliability to identify and quantify AGEs. Concerns about these techniques are mostly related to undefined specificity and affinity of anti-AGE antibodies.

The source of observed AGE accumulation in the brain of patients (dietary or endogenous) is not yet fully understood. For that reason, studies on AGE digestion and absorption (i.e., in vitro digestion models) are crucial to understanding the type of dietary AGEs that will circulate and cross the BBB to reach the brain.

On the other hand, endogenous AGEs can also be formed due to increased glucose levels derived from a high glycemic diet. Highly reactive molecules in the brain can contribute to locally produced AGEs extracellularly or intracellularly.

Clinical studies mainly focus on the fate and metabolism of dietary AGEs. Exposure based on consumption of certain foods is difficult to translate to a concentration that cells are going to be exposed to. The complexity and multiple sources of protein glycation require application of in vitro models to understand potential contribution to neurodegeneration.”

https://www.mdpi.com/2072-6643/14/2/363/htm “In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration”

While we’re waiting for research to catch up, we can hedge neurodegenerative disease bets by:

Not spiking our blood glucose levels;
Avoiding foods with medium and high levels of AGEs;
Giving our gut microbiota the intake they need instead of what our unconscious programming dictates; and
Maintaining youthful activities.

Lifespan Uber Correlation

January 21, 2022January 21, 2022 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebellum, Cerebrum, Epigenetics, Immune system, Lower brain Control group, DNA methylation, Embryo development, Genetic factors, Neurodegenerative disease, Prefrontal cortex

This 2022 study developed new epigenetic clocks:

“Maximum lifespan is deemed to be a stable trait in species. The rate of biological function decline (i.e., aging) would be expected to correlate inversely with maximum species lifespan. Although aging and maximum lifespan are intimately intertwined, they nevertheless appear in some investigations to be distinct processes.

Some cytosines conserved across mammals exhibit age-related methylation changes so consistent that they were used to successfully develop cross-species age predictors. In a similar vein, methylation levels of some conserved cytosines correlate highly with species lifespan, leading to the development of highly accurate lifespan predictors. Surprisingly, little to no commonality is found between these two sets of cytosines.

We correlated the intra-species age correlation with maximum lifespan across mammalian species. We refer to this correlation of correlations as Lifespan Uber Correlation (LUC).

We overlapped genes from the LUC signature with genes found in human genome-wide association studies (GWAS) of various pathologies and conditions. With all due caution, we report that some genes from the LUC signature were those highlighted by GWAS to be associated with type II diabetes, stroke, chronic kidney disease, and breast cancer.

We used the subset of CpGs found to be significant in our LUC to build age estimators (epigenetic clocks). We demonstrated that these clocks are able to capture effects of interventions that are known to alter age as well as lifespan, such as caloric restriction, growth hormone receptor knockout, and high-fat diet.

We found that Bcl11b heterozygous knockout mice exhibited an increased epigenetic age in the striatum. BCL11B is a zinc finger protein with a wide range of functions, including development of the brain, immune system, and cardiac system.

This gene is also implicated in several human diseases including, but not limited to, Huntington disease, Alzheimer’s diseases, HIV, and T-cell malignancies. BCL11B plays an important role in adult neurogenesis, but is less studied in the context of lifespan disparities in mammals.

Bcl11b knockout affected both DNA methylation and mRNA expression of LUC genes. Our current study does not inform us about the potential role of Bcl11b in aging processes during adulthood since observed patterns could be attributed to developmental defects.

We are characterizing other genetic and non-genetic interventions that perturb the LUC clocks. These we will feature in a separate report that will uncover biological processes regulated by LUC cytosines and their associated genes.”

https://www.biorxiv.org/content/10.1101/2022.01.16.476530v1 “Divergent age-related methylation patterns in long and short-lived mammals”

Defend yourself with taurine

December 28, 2021 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Locus coeruleus, Lower brain, Neurochemicals, Stress Brain neurons, Control group, Neurodegenerative disease

This densely packed 2021 review subject was taurine:

“Taurine (Tau), a sulphur-containing non-proteinogenic β-amino acid, has a special place as an important natural modulator of antioxidant defence networks:

Direct antioxidant effect of Tau due to scavenging free radicals is limited, and could be expected only in a few tissues (heart and eye) with comparatively high concentrations.

Maintaining optimal Tau status of mitochondria controls free radical production.

Indirect antioxidant activities of Tau due to modulating transcription factors leading to upregulation of the antioxidant defence network are likely to be major molecular mechanisms of Tau’s antioxidant and anti-inflammatory activities.

A range of toxicological models clearly show protective antioxidant-related effects of Tau.”

https://www.mdpi.com/2076-3921/10/12/1876/htm “Taurine as a Natural Antioxidant: From Direct Antioxidant Effects to Protective Action in Various Toxicological Models”