Epigenetics

All about AGEs

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

My 900th 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.

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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

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

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.”

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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 Ly6Clow 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.”

Microsoft PowerPoint - graphical abstract_revised

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.”

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Reversibility of AGEs concentrations

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress

This 2021 rodent study investigated dietary advanced glycation end products (AGEs):

“There is increasing evidence in humans and animals that consumption of dietary AGEs contribute to AGEs measured in plasma and organs and that a diet high in dietary AGEs in humans has negative biological effects, such as low-grade inflammation, endothelial dysfunction, and insulin resistance. However:

  • It is currently unknown whether AGE accumulation in tissues and the negative biological effects associated with a high AGE diet are reversible; and
  • How dietary AGEs are involved in the aforementioned biological effects remains poorly understood.

We hypothesized that mice fed a high dietary AGE diet for 10 weeks would show increased blood and tissue AGEs, increased inflammatory markers, and different microbiota composition as compared to mice fed a standard dietary AGE diet. In addition, we studied whether changes following the high dietary AGE diet were reversible by implementing a switch after 5-weeks of high dietary AGE diet to the standard dietary AGE diet for 5 subsequent weeks.

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To obtain a high AGE diet, a standard rodent chow was baked at 160 ◦C for two hours. Free- and protein-bound AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were analyzed in plasma, liver, and kidney. Additionally, free-, protein-bound AGEs, and AGE precursor oxoaldehydes methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3DG) were analysed in animal diets.

Inflammatory z-score consists of TNF-α, IFN-γ, KC/GRO, IL-6, and IL-10:

inflammatory z scores

A high AGE-diet led to an increase of AGEs in plasma, kidney, and liver, and to more inflammation, and modification of gut microbiota. These effects were reversed or discontinued by a diet lower in AGEs.

Our observations of reversible AGE accumulation in kidney and liver may not be extrapolated to other organs. Likewise, our findings in mice cannot be directly extrapolated to humans, as species differences exist in for example metabolic rate and dietary habits, as also in gut microbiota composition.”

https://www.sciencedirect.com/science/article/abs/pii/S0963996921004464 “Dietary advanced glycation end products (AGEs) increase their concentration in plasma and tissues, result in inflammation and modulate gut microbial composition in mice; evidence for reversibility” (not freely available)

This study started with 9-week-old mice and lasted eleven weeks, the human equivalents of which are ages 20 to 30 years. Study measurements weren’t intended to detect all potential symptoms of high-AGE diets. The lead author followed up with All about AGEs.

AGEs’ reversibility in older humans is one of my operative hypotheses:

  • I haven’t cooked or eaten high AGE precursor or AGEs food at home in the past three years.
  • The highest AGE item I’ve eaten at restaurants has been fish tacos.
  • I’m not hyperglycemic, and don’t expect that further AGE accumulation from either exogenous or endogenous sources has occurred.

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State-dependent memory

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Anterior cingulate cortex, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress, Thalamus , , ,

This 2021 review by two coauthors of What can cause memories that are accessible only when returning to the original brain state? provided evidence for alternative interpretations of memory experiments:

“Memory consolidation hypotheses postulate a long series of various and time consuming elaborate processes that come to protect memory from disruption after various periods of time. For more than fifty years, consolidation hypotheses led to the idea that:

  1. Memories are fragile and can easily be disrupted; and
  2. Memories require several hours to be encoded (Cellular Consolidation), and extensive periods of time (days to weeks and even months and years), to be definitely stabilized (Systems Consolidation).

Although these views rely on well substantiated findings, their interpretation can be called into question.

An alternative position is that amnesia reflects retrieval difficulties due to contextual changes. This simple explanation is able to account for most, if not all, results obtained in consolidation studies.

memory state dependency

Systems Consolidation can be explained in terms of a form of state-dependency.

Recent memory remains detailed, context-specific (in animals), and vivid (in humans) and very susceptible to contextual changes. With the passage of time, memories become less precise, and retention performance less and less affected by contextual changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0149763421005510 “Revisiting systems consolidation and the concept of consolidation” (not freely available)

I came across this review while trying to understand why a 2022 rodent study felt wrong. That study followed the standard memory paradigm, and I appreciate its lead author providing a copy since it wasn’t otherwise available.

But those researchers boxed themselves in with consolidation explanations for findings. They used drugs to change subjects’ memories’ contexts between training and testing. They didn’t see that tested memories were dependent on subjects’ initial brain states.

This review cited a paper abstracted in Resiliency in stress responses, namely Neurobiological mechanisms of state-dependent learning.

Crab for lunch

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Signaling pathways and aging

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

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.

erk1-2 pathway

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.

Grip+Strength

Longevity+study+(02.09.2021)-modificado-2

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

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

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.

METminutes

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.

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Are blood epigenetic clock measurements optimal?

gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Epigenetics, Immune system, Lower brain , , , , ,

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).

men age faster

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”

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Biological age and zinc

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

This 2022 human study investigated zinc’s influence in modulating DNA methylation patterns:

“The purpose of this study was to identify epigenetic variables related to serum Zn (ZnS) levels and Zn daily ingestion (ZnDI) in a case-control cohort. Individuals were selected and classified according to their body mass index into two groups: control group of 11 women without obesity, and study group composed of 10 women with obesity. Inclusion criteria were women aged 18–50 years with stable body weight for at least 6 months.

Novel Zinc-Related Differentially Methylated Regions in Leukocyt

A negative correlation of ZnS with epigenetic age acceleration residual suggested that the higher the ZnS levels, the lower the aging rate:

serum zinc

Our results regarding Zn homeostasis in women with obesity suggested regulation by other mechanisms besides ingestion:

  • Zn-associated differentially methylated regions may exert downstream effects on inflammation, macronutrient metabolism, and DNA/cellular process repair.
  • Hypomethylation of the PM20D1 gene could interconnect DNA methylation and nutritional status.”

https://www.frontiersin.org/articles/10.3389/fnut.2022.785281/full “Novel Zinc-Related Differentially Methylated Regions in Leukocytes of Women With and Without Obesity”

This study emphasized that nutrients aren’t the whole story on health. We also have to be in metabolic zones where our diet and nutrient choices can achieve desired effects.

Subjects’ selection criteria (BMI) was more than double the control group’s. Sometimes people’s lives show others what not to do with their own.

Epigenetic clocks and entropy

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

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.

entropy associations

(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”

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Vascular memory

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Primal Therapy, Stress , ,

This 2022 rodent study investigated effects of inducing hypertension for two weeks:

“Hypertension is conventionally associated with a neurohormonal activation from the sympathetic nervous and the renin-angiotensin-aldosterone systems. Angiotensin II (AngII) is a potent regulator of blood pressure, and is also a key player in hypertension development.

An initial 2-week exposure to AngII induced profound changes in cardiac and vascular remodeling, including endothelial activation, vascular inflammation and oxidant stress, all of which were maintained up to 3 weeks after AngII withdrawal. This phenotype was sustained despite early normalization of blood pressure after AngII withdrawal.

Our RNAseq pathway analysis suggests involvement of epigenetic regulators involved in methylation, such as PRC2. PRC2 complex catalyzes trimethylation of histone H3 on lysine 27 (H3K27me3), a histone mark necessary for maintaining transcriptional repression during multicellular development.

H3K27me3 AngII

Cell type-specific patterns of H3K27me3 are crucial for preserving cell identity. Consistent with this analysis, we observed a significant increase in H3K27me3 epigenetic mark in aortic tissue, intriguingly, only in both memory conditions.

Transient exposure to Ang II produces prolonged vascular remodeling with robust ACTA2 downregulation, associated with epigenetic imprinting, supporting a memory effect despite stimulus withdrawal. Future characterization of underlying AngII-dependent signaling might unveil new targets for its therapeutic modulation and reversal of this adverse legacy effect.”

https://www.frontiersin.org/articles/10.3389/fcvm.2022.854361/full “Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of Vascular Memory”

These subjects’ ages were equivalent to a 20-year-old human:

  • How much earlier could our vascular system retain events we experienced such as epigenetic H3K27me3 increases? Teenaged, late childhood, early childhood, infancy, fetal parts of our lives?
  • How long would these vascular system memories and their continued signaling linger?
  • What experiences could change these long-lasting memories?

Icy fire

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Selecting broccoli varieties

gettingwell4 5+ stars Premium, Epigenetics

This 2022 study evaluated 14 broccoli varieties grown in the same conditions for their floret compounds:

“Glucosinolate (GSL) profile and content in 11 inbred broccoli lines and three commercial cultivars were analyzed. Hydrolysate content, myrosinase activity, and nitrile formation rate were also determined.

Sulforaphane – an isothiocyanate (ITC) hydrolysate of glucoraphanin – content showed relatively higher value in the following order: 5404 > 5410 > 5407 > 5411, although glucoraphanin content was lower in those lines:

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No significant relationship was found between myrosinase activity and total hydrolysate content, except in line 5310, which had the lowest myrosinase activity and the lowest total hydrolysate content. There was no significant correlation between myrosinase activities and sulforaphane.

We found a clear difference in selecting functional broccoli by considering only the GSL content or hydrolysates.

  • Even if total GSL content and individual GSL content were high, ITC content could not be produced at a high level.
  • When GSL content is high, if nitrile formation rate was also high, more nitrile than ITC would be produced.

Low nitrile formation rate and higher hydrolysate content should be considered when selecting functional broccoli lines with high GSL content.”

https://www.sciencedirect.com/science/article/pii/S0304423822001108 “Selection of broccoli (Brassica oleracea var. italica) on composition and content of glucosinolates and hydrolysates”

As 3-day-old broccoli sprouts have the optimal yields, Lab analyses of broccoli sprout compounds, Tailoring measurements for broccoli sprouts, and this study found, there weren’t many potential health benefits based solely on broccoli varieties’ glucoraphanin contents. But genotypes had a greater effect than did environmental influences, and seed / sprout / stalk / floret beneficial contents differed.

There are opportunities for vendors to showcase healthier broccoli products. Growing, harvesting, and storage conditions will make that expensive to test and certify, though.

As A follow-on study to 3-day-old broccoli sprouts have the optimal yields, Enhancing sulforaphane content, and Microwave broccoli to increase sulforaphane levels showed, there are ways to improve myrosinase activity and isothiocyanate yield. I do these easy actions every day while growing 3-day-old sprouts from unknown broccoli varieties. Waiting for evidence to compel changing that.

Strange birds

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Epigenetic components for evaluating a person’s physical fitness

gettingwell4 4-5 stars Advanced knowledge, Epigenetics ,

This 2022 human study incorporated DNA methylation measures of four physical fitness parameters into a new epigenetic clock:

“Our work introduces new DNAm biomarkers for fitness parameters of gait speed (walking speed), hand grip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max). These DNAm biomarkers represent new tools for researchers with access to blood samples and interest in epigenetic components to fitness.

Our DNAm biomarker fitness parameter biomarkers are not intended to replace true physical fitness measurements. Instead, these DNAm biomarker estimates provide an epigenetic component to evaluating a person’s physical fitness. This biomarker integrates the established DNAm prediction of mortality risk GrimAge.

DNAmFitAge provides an easily interpretable tool to relate physical fitness to biological age. Adjusting DNAmFitAge for chronological age generates a novel measure of epigenetic age acceleration, FitAgeAcceleration, which is informative for physical activity level, mortality risk, coronary heart disease risk, comorbidities, and disease-free status across several large validation datasets.

ttd

The age-adjusted version FitAgeAcceleration provides a novel measure of epigenetic age acceleration explained through physical fitness. This research demonstrates biological age can be estimated using DNAm fitness parameter biomarkers which are dependent on exercise lifestyle.”

https://www.medrxiv.org/content/10.1101/2022.03.21.22272043v1.full-text “DNAmFitAge: Biological Age Indicator Incorporating Physical Fitness”

I walk quickly on the beach almost every day at > 3 mph. I occasionally see younger people eclipse my gait speed, which makes me try harder. 🙂

Year Two of Changing to a youthful phenotype with sprouts

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

1. I’ve eaten clinically-relevant doses of sulforaphane every day for 104 weeks now with microwaved 3-day-old broccoli, red cabbage, and mustard sprouts. That’s 8+ times longer than any sulforaphane clinical trial.

I continue to:

  • Eat Avena nuda oats for breakfast;
  • Eat 3-day-old hulled Avena sativa oat sprouts twice a day;
  • Eat AGE-less chicken vegetable soup twice a day;
  • Take supplements that promote healthspan twice a day;
  • Exercise at least 30 minutes daily;
  • Take yeast cell wall β-glucan daily, with nothing else an hour before or after; and
  • Avoid undue stress by working from home 40 hours a week in my 25th year as a professional software developer.

I’ve experienced many positive effects described in studies. Researchers keep exploring new aspects of their fields, and I look forward to more evidence on youthening during Year Three.

2. I’m not especially scientific or maniacal about the above practices, other than weighing sprouting seeds. I pay attention to people who measure everything, but won’t turn my life into a series of unfeeling experiments. As Dr. Arthur Janov said:

“What is the point of life if we cannot feel and love others? Without feeling, life becomes empty and sterile. It, above all, loses its meaning.”

3. Beginning last month, our world was subjected to yet another wave of propaganda, with predictable oppression of those who reported obvious lies and distortions. Previously exposed agendas took a back seat to regain their venom, as their effects waned in herding people toward personally devastating cliffs.

Meme perpetrators don’t care about you or me. Spending our time on their ideas, beliefs, and behaviors takes us further away from dealing with our individually motivating causes and individual truths, with real consequences: a wasted life.

Value your own one precious life. Winter is over, spring is here.

PXL_20220322_191200562

Gut microbiota knowledge through 2021

gettingwell4 2-3 stars Required further work, Amygdala, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress , , , , , , ,

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

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:

top 5 phylum 2-2022

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

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

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.

rcs ages ales

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.

sfn vs mg

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.

op lumbar vertebrae

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”