Young gut, young eyes

I’ll highlight this 2022 rodent study findings of effects on eye health:

“We tested the hypothesis that manipulating intestinal microbiota influences development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Using fecal microbiota transplantation, we exchanged intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice.

Transfer of aged donor microbiota into young mice accelerates age-associated central nervous system inflammation, retinal inflammation, and cytokine signaling. It promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability.

These detrimental effects can be reversed by transfer of young donor microbiota.

young and aged fmt

We provide the first direct evidence that aged intestinal microbiota drives retinal inflammation, and regulates expression of the functional visual protein RPE65. RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion. Mutations or loss of function are associated with retinitis pigmentosa, and are implicated in age-related macular degeneration.

Our finding that age-associated decline in host retinal RPE65 expression is induced by an aged donor microbiota, and conversely is rescued by young donor microbiota transfer, suggests age-associated gut microbiota functions or products regulate visual function.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-01243-w “Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain”


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Exercise substitutes?

Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)


A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

  • Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.
  • Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.
  • Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.
  • It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).
  • Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”


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Blood pressure and brain age

This 2021 human study investigated associations between blood pressure and MRI measurements:

“We estimated how a validated measure of brain health related to changes in BP over a period of 12 years. The main findings of this study were:

  • All BP measures were associated with older BrainAGE;
  • Associations were stronger in men than women;
  • Associations were not only detected in hypertensive individuals but across the whole BP range; and
  • Individuals with optimal blood pressure (110/70) presented with the lowest BrainAGE.

These findings support the view that maintaining blood pressure in an optimal range (SBP < 115, DBP < 75) across the lifespan starting before mid-life (i.e., in early adulthood and before) is essential to maintain good cerebral health.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523821/ “Optimal Blood Pressure Keeps Our Brains Younger”


I’m making progress on a New Year’s resolution. Here’s how I started 2022:

bp 2021

Current readings show both lower averages and variability:

bp 2022

~12% decreases in average systolic (111 – 126)/126 and diastolic (69 – 78)/78 pressures over 135 days. 🙂 I measure blood pressure every day right after I wake up.

What caused these decreases? Continuing what I was already doing. The top factor is probably that at lunch every day I take 600 mcg of Vitamin K2 MK-7 along with a gram of flax oil.

I started taking K2 this time last year per Vitamin K2 – What can it do? Apparently its effects are gradual and develop slowly. Vitamin K2 and hypertension may also be relevant.

I came across this study from its mention in today’s video:

Coffee improves information’s signal-to-noise ratio

This 2022 rodent study investigated caffeine’s effects:

“A majority of molecular and neurophysiological studies explored the impact of acute rather than repeated exposure to caffeine. We show that, in bulk tissue analysis, chronic caffeine treatment reduced metabolic processes related to lipids, mitochondria, and translation in mouse hippocampus. In sharp contrast to what was observed in bulk tissue, we found that caffeine induced a neuronal autonomous epigenomic response related to synaptic plasticity activation.

149371-JCI-RG-RV-3_ga_591026

Regular caffeine intake exerts a long-term effect on neuronal activity/plasticity in the adult brain, lowering metabolic-related processes, and simultaneously finely tuning activity-dependent regulations. In non-neuronal cells, caffeine decreases activities under basal conditions, and improves signal-to-noise ratio during information encoding in brain circuits, contributing to bolster salience of information.

Overall, our data prompt the novel concept that regular caffeine intake promotes a more efficient ability of the brain to encode experience-related events. By coordinating epigenomic changes in neuronal and non-neuronal cells, regular caffeine intake promotes a fine-tuning of metabolism in resting conditions.”

https://www.jci.org/articles/view/149371 “Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription”


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Eat broccoli sprouts for stress

This 2022 review subject was aspects of sulforaphane regulating stress:

“Sulforaphane (SFN) shows great versatility in turning on different cellular responses. This isothiocyanate acts as a master regulator of cellular homeostasis due to its antioxidant response and cytoplasmic, mitochondrial, and endoplasmic reticulum (ER) protein modulation. SFN acts as an effective strategy to counteract oxidative stress, apoptosis, and ER stress, among others as seen in different injury models.

The ER is a complex membrane system, involved in several cellular processes including lipid synthesis and distribution, and Ca2+ storage and signaling. The ER is highly dynamic and changes according to cellular demand (e.g., hypoxia, mitochondrial dysfunction, or oxidative stress), leading to accumulation of unfolded or misfolded proteins in ER lumen, known as ER stress.

ER stress is buffered by unfolded protein response (UPR) activation, a homeostatic signaling network that orchestrates recovery of ER function by decreasing the burden of misfolded proteins. If stress signals continue it could lead to apoptosis activation.

Studies highlight a close interrelationship between ER stress and oxidative stress, two events driven by the accumulation of reactive oxygen species. Responses to stress inevitably perpetuate, and act as a vicious cycle that triggers development of different pathologies, such as cardiovascular diseases, neurodegenerative diseases, and others.

The PERK/Nrf2 pathway communicates oxidative stress and ER stress:

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SFN couples oxidative and ER stress to promote cellular redox homeostasis. Further studies in animal and human models are required to elucidate pathways and proteins involved in differential responses orchestrated by SFN, emphasizing that responses will depend on cell type and kind of pathology, as well as SFN concentration.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320522002545 “Role of sulforaphane in endoplasmic reticulum homeostasis through regulation of the antioxidant response” (not freely available) Thanks to Dr. Alejandro Silva for providing a copy.


Every hand’s a winner, and every hand’s a loser has more on UPR.

Brain changes

This 2022 human study investigated healthy young adult brain changes using MRI and epigenetic clock technologies:

“We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. It is largely unknown how accelerated epigenetic age affects multiple cortical features among young adults from 19 to 49 years. Prior findings imply not only that these dynamic changes reveal different aspects of cortical aging, but also that chronological age itself is not a reliable factor to understand the process of cortical aging.

accelerated epigenetic age vs brain features

Seventy-nine young healthy individuals participated in this study. Findings of our study should be interpreted within the context of relatively small sample size, without older adults, and with epigenetic age assessed from saliva.

Additional and unique regional changes due to advanced and accelerated epigenetic age, compared to chronological age-related changes, suggest that epigenetic age could be a viable biomarker of cortical aging. Longitudinal and cross-sectional studies with a larger sample and wider age range are necessary to characterize ongoing effects of epigenetic cortical aging, not only for healthy but also for pathological aging.”

https://doi.org/10.1093/cercor/bhac043 “The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults” (not freely available) Thanks to Dr. Yong Jeon Cheong for providing a copy.

Young immune system, young brain

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:

  1. Dysfunction of mitochondria;
  2. Accumulation of oxidatively damaged proteins, nucleic acids, and lipids in brain cells;
  3. Disorders of energy metabolism;
  4. Impaired ‘waste disposal’ mechanism (autophagosome and proteasome functionality);
  5. Impaired signal transduction of adaptive stress response;
  6. Impaired DNA repair;
  7. Abnormal neural network activity;
  8. Imbalance of neuronal Ca2+ processing;
  9. Stem cell exhaustion; and
  10. Increased inflammation.

mrna brain expression

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”


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Vitamin D and pain

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.

vitamin d and pain

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.

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All about AGEs

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.

file:///D:/MYFILES/ELSEVIER/FCT/00112987/FINALXML/GRAPHICS/NATI

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

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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Signaling pathways and aging

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’.”

MET minutes

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?

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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Epigenetic clocks and entropy

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”


PXL_20220322_191309272

Gut microbiota knowledge through 2021

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.