Signaling pathways and aging

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

This 2022 study investigated biological mechanisms of aging:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Update #2 6/17/2022

Update #3 2/8/2023

MET minutes

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

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

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

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

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

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

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

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

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

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

Are blood epigenetic clock measurements optimal?

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

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

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

Epigenetic age was moderately correlated across tissues:

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

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

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

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

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

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

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

Epigenetic clocks and entropy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Selecting broccoli varieties

April 6, 2022 gettingwell4 5+ stars Premium, Epigenetics Genetic factors

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:

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

Epigenetic components for evaluating a person’s physical fitness

March 25, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics DNA methylation, Genetic factors

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.

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. 🙂

Gut microbiota knowledge through 2021

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

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

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

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

Macronutrients and Microbiome Diversity

Nutrient and Mineral Supplements and Microbiome Diversity

Stress

Drugs

Race and Host Genetics

Aging

Lifestyle

Exercise

Smoking

Urbanization

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

Microbiome Association With Inflammatory and Metabolic Disorders

Chronic Inflammation in GIT and Beyond

Development of Malignant Tumors

Obesity

Coronary Artery Disease

Respiratory Diseases

Microbiome Role in Psychiatric, Behavioral, and Emotional Disorders

Anxiety

Depression

Sleep

Fear Response

Autism

Alzheimer and Dementia

C. Understanding the Microbiome Function as Mediated by Secreted Molecules

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

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

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

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

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

Resistant starch therapy observed:

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

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

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

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

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

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

Advanced glycation / lipoxidation end products

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

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

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

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

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

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

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

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

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

A second paper is a 2021 human cell study:

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

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

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

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

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

A third paper is a 2022 human study:

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

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

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

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

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

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

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

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

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

Nanoencapsulating Brassica bioactives with Brassica membrane vesicles

March 13, 2022March 13, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system Control group, Genetic factors

Two 2022 in vitro studies from the group that published Red cabbage effects on gut microbiota, with the first nanoencapsulating sulforaphane:

“Sulforaphane (SFN) loaded into membrane vesicles derived from broccoli plants was studied to determine anti-inflammatory potential in a human-macrophage-like in vitro cell model under both normal and inflammatory conditions.

LPS increased IL-6 levels 1.86-fold. All compounds (free SFN, unloaded broccoli membrane (BM)-vesicles, and encapsulated SFN) mediated a dose-dependent reduction in IL-6, both in basal conditions [left] and simulated inflammatory conditions [right]. Encapsulated SFN had the greatest power.

These results showed that membrane vesicles by themselves had anti-inflammatory properties. Possible routes of administration of BM-vesicles loaded with SFN are parenteral, transdermal, and oral.”

https://www.mdpi.com/1422-0067/23/4/1940/htm “Membrane Vesicles for Nanoencapsulated Sulforaphane Increased Their Anti-Inflammatory Role on an In Vitro Human Macrophage Model”

A second study nanoencapsulated Bimi®, a crossbreed between broccoli and green Chinese kale:

“The aim of this work was to increase stability of isothiocyanates (ITCs) present in extracts of Bimi® edible parts by nanoencapsulation using cauliflower-derived plasma membrane vesicles.

Bimi® has emerged as a mild-flavoured option to pungent broccoli. As a raw gourmet material, Bimi® is highly and carefully selected, with part of edible production discarded.

Indole glucosinolates (GSLs) represented 81% of total GSL content. The only aliphatic GSL detected in a quantifiable amount was glucoraphanin, accounting for 19% of total GSLs.

Comparisons between concentrations of ITCs in gastric and intestinal digestions:

A) 3,3-diindolylmethane (DIM);

Bimi® extract increased 2 times, and no differences in nanoencapsulated treatment after intestinal digestion.

Concentrations were 4- and 2-fold higher in the nanoencapsulated form than extract between gastric and intestinal digestions, respectively.

B) Indole-3-carbinol (I3C);

Bimi® extract increased 1.5 times, and nanoencapsulated treatment decreased 23% after intestinal digestion.

Concentrations were 3 times higher and 2 times higher in the nanoencapsulated form than extract between gastric and intestinal digestions, respectively.

C) SFN

Bimi® extract increased almost 10 times, and 100 times in nanoencapsulated treatment after intestinal digestion.

No differences between treatments after gastric digestion, but concentrations were 6 times higher in the nanoencapsulated form than extract after intestinal digestion.

Cauliflower-derived plasma membrane vesicles are able to enhance stability of ITCs through in vitro gastrointestinal digestion, improving their bioaccessibility and potential bioavailability.”

https://www.sciencedirect.com/science/article/pii/S0308814622006422 “Nanoencapsulation of Bimi® extracts increases its bioaccessibility after in vitro digestion and evaluation of its activity in hepatocyte metabolism”

Reversing hair greying

March 7, 2022January 29, 2025 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Stress, Telomeres DNA methylation, Genetic factors

I’ll highlight this 2021 human study’s findings regarding stress:

“We profiled hair pigmentation patterns (HPPs) along individual human hair shafts, producing quantifiable physical timescales of rapid greying transitions. White/grey hairs that naturally regain pigmentation across sex, ethnicities, ages, and body regions, quantitatively define reversibility of greying in humans.

A systematic survey of two-colored hairs on the scalp of a 35-year-old Caucasian male with auburn hair color over a 2-day period yielded five two-colored hair shafts (HSs) from the frontal and temporal scalp regions. Unexpectedly, all HSs exhibited reversal. HPP analysis further showed that all HSs underwent reversal of greying around the same time period.

A retrospective assessment of psychosocial stress levels using a time-anchored visual analog scale (participants rate and link specific life events with start and end dates) was then compared to HPPs. Reversal of greying for all hairs coincided closely with decline in stress and a 1-month period of lowest stress over the past year (0 on a scale of 0–10) following a 2-week vacation.

We were also able to examine a two-colored hair characterized by an unusual pattern of complete HS greying followed by rapid and complete reversal plucked from the scalp of a 30-year-old Asian female participant with black hair. HPP analysis of this HS showed a white segment representing approximately 2 cm.

Quantitative life stress assessment revealed a specific 2-month period associated with an objective life stressor (marital conflict and separation, concluded with relocation) where the participant rated her perceived stress as highest (9–10 out of 10) over the past year. The increase in stress corresponded in time with complete but reversible hair greying.

We document a complete switch-on/off phenomena during a single anagen cycle. Proteomic features of hair greying directly implicate multiple metabolic pathways that are both reversible in nature and sensitive to stress-related neuroendocrine factors.

This new method to quantitatively map recent life history in HPPs provides an opportunity to longitudinally examine the influence of recent life exposures on human biology. Additional prospective studies with larger sample sizes are needed to confirm robust reproducibility and generalizability of our findings.”

https://elifesciences.org/articles/67437 “Quantitative mapping of human hair greying and reversal in relation to life stress”

See Reversing hair greying, Part 2 for selected papers through 2024 that cited this study.

Vitamin K2 and hypertension

March 5, 2022 gettingwell4 2-3 stars Required further work, Epigenetics, Immune system Control group, Genetic factors

This 2021 rodent study investigated effects of Vitamin K₂ on salt-sensitive hypertension:

“Mice were supplemented with VK₂ and gut bacteria were detected by 16S rRNA. Common signaling pathway-related proteins were detected to further verify signaling pathways before validation of clinical samples.

Diets for 4 weeks were:

Normal group diet containing 0.5% NaCl;

High salt group (HS) diet containing 8% NaCl;

High salt diet plus VK₂ supplementation group (HS_VK2) diet containing 8% NaCl and additional 0.025% VK₂.

VK₂ supplementation protected blood pressure and aortic vessels in salt-induced mice:

VK₂ treated salt-sensitive hypertension by inhibiting the renin–angiotensin system.

Possible mechanisms of VK₂ for salt-sensitive hypertension.”

https://www.frontiersin.org/articles/10.3389/fnut.2021.639467/full “Network and 16S rRNA Sequencing-Combined Approach Provides Insightal Evidence of Vitamin K₂ for Salt-Sensitive Hypertension”

The form of Vitamin K₂ was MK-4 per its C₃₁H₄₀O₂ molecular formula. Data wasn’t provided to calculate a human-equivalent dose for 0.025% MK-4.

This study was part of a 2022 Gut Microbial Response to Host Metabolic Phenotypes collection which included animal studies investigating gut microbiota in contexts of β-carotene and β-sitosterol supplementation. I found this collection by it citing the 2018 rodent study GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose which was Reference 27 of Dr. Paul Clayton’s blog post Sweet Nothing.

Signaling pathways and disordered proteins

March 4, 2022March 7, 2022 gettingwell4 2-3 stars Required further work, Cortisol, Epigenetics, Glutamate, Immune system, Memory, Neurochemicals, Stress Brain neurons, Control group, Genetic factors, Neural plasticity

This 2022 review explored the title subject:

“Cell signaling imposes many demands on proteins that comprise these pathways, including abilities to form active and inactive states, and to engage in multiple protein interactions. Signaling often requires amplifying signals, regulating or tuning responses to signals, combining information sourced from multiple pathways, all while ensuring process fidelity.

Sensitivity, adaptability, and tunability are possible, in part, due to inclusion of intrinsically disordered regions in many proteins involved in cell signaling. This review highlights the critical role of intrinsically disordered proteins for signaling:

In widely diverse organisms (animals, plants, bacteria, fungi);

In every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine); and

At each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process.

Function of the glucocorticoid receptor is regulated in part by its intrinsically disordered C-terminal tail. Prior to activation, the glucocorticoid receptor resides in cytosol:

Intrinsic disorder in the glucocorticoid receptor not only enables multiple allosteric regulatory interactions to impact function, but also allows deployment of different surfaces of the protein to enable binding to many different sets of macromolecules, and regulation of these interactions via mRNA splicing and phosphorylation.

Combinations of alternative translation initiation and alternative mRNA splicing result in production of multiple glucocorticoid receptor isoforms from one gene. Various isoforms exhibit distinctive tissue distribution patterns and altered transcriptional regulatory profiles.

Greater than 90% of transcription factors either contain intrinsically disordered regions of proteins or are entirely intrinsically disordered. The many advantages conferred by disorder to cell signaling cascades means that:

Understanding signaling required definition of roles disorder plays in each pathway;

Many more examples of disordered proteins in cell signaling pathways are likely to be discovered; and

More mechanisms by which disorder functions remain to be elucidated.”

https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00821-7 “Intrinsically disordered proteins play diverse roles in cell signaling”

Cells in vivo seldom act on their own impetus. I would have liked discussion – or at least mention – of bidirectional signals between genes / cells / tissues / organs / organism / environment. This review’s topic of cell signaling pathways excluded “interactions of complex, interconnected systems spanning hierarchical levels” as explored in An environmental signaling paradigm of aging.

Vitamin K forms

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

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

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

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

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

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

This first paper cited a 2019 meta-analysis for:

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

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

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

Lumbar spine:

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

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

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

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

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

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

Femoral neck:

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

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

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

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

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

Eat broccoli sprouts for depression, Part 2

March 1, 2022January 3, 2023 gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress Antidepressants, Brain neurons, Control group, Genetic factors, Neural plasticity, Prefrontal cortex

Here are three papers that cited last year’s Part 1. First is a 2021 rodent study investigating a microRNA’s pro-depressive effects:

“Depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests.

Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury.

Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit wolfram syndrome 1 (Wfs1) transcription.

We found that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors. We didn’t investigate the role of Nrf2 in other depression models (chronic social stress model and chronic restraint stress model) and important brain regions other than hippocampus, such as prefrontal cortex and nucleus accumbens. Accordingly, other depression models and brain regions need to be designed and explored to further validate the role of Nrf2 in depression in future studies.”

https://link.springer.com/article/10.1007/s10753-021-01554-4 “Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression‑Like Behaviors” (not freely available)

This study demonstrated that activating the Nrf2 pathway inhibited brain inflammation, cognitive dysfunction, and depression. Would modulating one microRNA and one gene in vivo without Nrf2 activation achieve similar results?

A 2021 review focused on the immune system’s role in depression:

“Major depressive disorder is one of the most common psychiatric illnesses. The mean age of patients with this disorder is 30.4 years, and the prevalence is twice higher in women than in men.

Activation of inflammatory pathways in the brain is considered to be an important producer of excitotoxicity and oxidative stress inducer that contributes to neuronal damage seen in the disorder. This activation is mainly due to pro-inflammatory cytokines activating the tryptophan-kynurenine (KP) pathway in microglial cells and astrocytes.

Elevated levels of cortisol exert an inhibitory feedback mechanism on its receptors in the hippocampus and hypothalamus, stopping stimulation of these structures to restore balance. When this balance is disrupted, hypercortisolemia directly stimulates extrahepatic enzyme 2,3-indolimine dioxygenase (IDO) located in various tissues (intestine, placenta, liver, and brain) and immune system macrophages and dendritic cells.

Elevation of IDO activities causes metabolism of 99% of available tryptophan in the KP pathway, substantially reducing serotonin synthesis, and producing reactive oxygen species and nitrogen radicals. The excitotoxicity generated produces tissue lesions, and activates the inflammatory response.”

https://academic.oup.com/ijnp/article/25/1/46/6415265 “Inflammatory Process and Immune System in Major Depressive Disorder”

This review highlighted that stress via cortisol and IDO may affect the brain and other parts of the body.

A 2022 review elaborated on Part 1’s findings of MeCP2 as a BDNF inhibitor:

“Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity.

Ability to cope with stressors relies upon activation of the hypothalamic–pituitary–adrenal (HPA) axis. MeCP2 has been shown to contribute to early life stress-dependent epigenetic programming of genes that enhance HPA-axis activity.

We describe known functions of MeCP2 as an epigenetic regulator, and provide evidence for its role in modulating synaptic plasticity via transcriptional regulation of BDNF or other proteins involved in synaptogenesis and synaptic strength like reelin. We conclude that MeCP2 is a promising target for development of novel, more efficacious therapeutics for treatment of stress-related disorders such as depression.”

https://www.mdpi.com/2073-4409/11/4/748/htm “The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression”

Osprey lunch

Beneficially stressing sprouts with light

February 22, 2022August 8, 2022 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress Control group, Genetic factors

This 2021 study investigated effects of light on red cabbage sprouts and microgreens. I’ll highlight its 3-day-old sprout findings:

“Periodic ultraviolet UV-B (280–320 nm) pulses at low doses improved morphological development of red cabbage sprouts, and probably will have the same effect on other sprouts. Similarly, total phenolic content, total flavonoid content, and total antioxidant capacity presented a UV-B dose-dependence response.

Although UV-B radiation may cause damage to plant tissues, an optimum dose can promote accumulation of antioxidant and UV-protective molecules that enhance nutraceutical biosynthesis in plant foods without altering sensory quality. Such an increase in concentration of bioactive compounds is mainly due to environmental stress generated by UV-B light, which leads to changes in morphology, physiology, and molecular conformation of DNA, RNA, and proteins.

Total phenolic content of control (0, CTRL) or UV-B-treated (5, 10, and 15 kJ m⁻²) red cabbage sprouts after 10 days growth at 20 °C. Different capital letters indicate significant differences among treatments at < 0.05. Different lowercase letters indicate significant differences among time of analysis of the same treatment at p < 0.05.

Our results demonstrated that application of UV-B light during germination induces a positive effect on growth of red cabbage sprouts, as well as on secondary metabolite content related to nutritional quality. Analysed bioactive compounds (phenolics, flavonoids, and carotenoids) increased during germination, and tended to remain constant throughout a refrigerated shelf life.”

https://www.mdpi.com/2311-7524/7/12/567/htm “UV-B Radiation as Abiotic Elicitor to Enhance Phytochemicals and Development of Red Cabbage Sprouts”

I came across this study after lead author Dr. Lorena Martínez-Zamora provided an earlier study, Postharvest UV-B and UV-C radiation enhanced the biosynthesis of glucosinolates and isothiocyanates in Brassicaceae sprouts (not freely available). Its focus was also a worthwhile commercialization of cruciferous microgreens.

Nearby researchers also published studies such as Red cabbage effects on gut microbiota and Sprout bioaccessibility last year. Let’s hope a push for cruciferous sprouts and microgreens continues, although consumer acceptance is limited by products not being sweet.

I think these research efforts will succeed. Take a look at oat milk’s quick rise, for example. I had trouble getting delivery of Avena sativa seeds last month because oat milk producers bought up last year’s supplies and futures on this year’s crops.

For me, it’s been 98 weeks of spending at least 45 minutes a day growing 3-day-old broccoli, red cabbage, mustard, and oat sprouts at home. I’m satisfied with results, and won’t turn my kitchen into a laboratory to eke out extra effects with light and other elicitors.

Here’s a photo of this study’s sponsoring institution’s harbor from the latest of two visits: