Gut and brain health

This 2021 human review subject was interactions of gut health and disease with brain health and disease:

“Actions of microbial metabolites are key for appropriate gut-brain communication in humans. Among these metabolites, short-chain fatty acids (SCFAs), tryptophan, and bile acid metabolites / pathways show strong preclinical evidence for involvement in various aspects of brain function and behaviour.

Dietary fibres, proteins, and fats ingested by the host contain components which are metabolized by microbiota. SCFAs are produced from fermentation of fibres, and tryptophan-kynurenine (TRP-KYN) metabolites from dietary proteins. Primary bile acids derived from liver metabolism aid in lipid digestion, but can be deconjugated and bio-transformed into secondary bile acids.

1-s2.0-S0149763421001032-gr1

One of the greatest challenges with human microbiota studies is making inferences about composition of colonic microbiota from faeces. There are known differences between faecal and caecal microbiota composition in humans along with spatial variation across the gastrointestinal tract.

It is difficult to interpret microbiome-host associations without identifying the driving influence in such an interaction. Large cohort studies may require thousands of participants on order to reach 20 % explanatory power for a certain host-trait with specific microbiota-associated metrics (Shannon diversity, relative microbial abundance). Collection of metadata is important to allow for a better comparison between studies, and to identify differentially abundant microbes arising from confounding variables.”

https://www.sciencedirect.com/science/article/pii/S0149763421001032 “Mining Microbes for Mental Health: Determining the Role of Microbial Metabolic Pathways in Human Brain Health and Disease”


Don’t understand why these researchers handcuffed themselves by only using PubMed searches. For example, two papers were cited for:

“Conjugated and unconjugated bile acids, as well as taurine or glycine alone, are potential neuroactive ligands in humans.”

Compare scientific coverage of PubMed with Scopus:

  • 2017 paper: PubMed citations 39; Scopus citations 69.
  • 2019 paper: PubMed citations 69; Scopus citations 102.

Large numbers of papers intentionally missing from PubMed probably influenced this review’s findings, such as:

  1. “There are too few fibromyalgia and migraine microbiome-related studies to make definitive conclusions. However, one fibromyalgia study found altered microbial species associated with SCFA and tryptophan metabolism, as well as changes in serum levels of SCFAs. Similarly, the sole migraine-microbiota study reported an increased abundance of the kynurenine synthesis GBM (gut-brain module).
  2. Due to heterogeneity of stroke and vascular disease conditions, it is difficult to make substantial comparisons between studies. There is convincing evidence for involvement of specific microbial genera / species and a neurovascular condition in humans. However, taxa were linked to LPS biosynthesis rather than SCFA production.
  3. Several studies suggest lasting microbial changes in response to prenatal or postnatal stress, though these do not provide evidence for involvement of SCFA, tryptophan, or bile-acid modifying bacteria. Similar to stress, there are very few studies assessing impact of post-traumatic stress disorder on microbiota.”

These researchers took on a difficult task. Their study design could have been better.


PXL_20210628_095746132

Wildlife

PXL_20210710_100826663

The amino acid ergothioneine

A trio of papers on ergothioneine starts with a 2019 human study. 3,236 people without cardiovascular disease and diabetes mellitus ages 57.4±6.0 were measured for 112 metabolites, then followed-up after 20+ years:

“We identified that higher ergothioneine was an independent marker of lower risk of cardiometabolic disease and mortality, which potentially can be induced by a specific healthy dietary intake.

overall mortality and ergothioneine

Ergothioneine exists in many dietary sources and has especially high levels in mushrooms, tempeh, and garlic. Ergothioneine has previously been associated with a higher intake of vegetables, seafood and with a lower intake of solid fats and added sugar as well as associated with healthy food patterns.”

https://heart.bmj.com/content/106/9/691 “Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease”


I came across this study by its citation in a 2021 review:

“The body has evolved to rely on highly abundant low molecular weight thiols such as glutathione to maintain redox homeostasis but also play other important roles including xenobiotic detoxification and signalling. Some of these thiols may also be derived from diet, such as the trimethyl-betaine derivative of histidine, ergothioneine (ET).

image description

ET can be found in most (if not all) tissues, with differential rates of accumulation, owing to differing expression of the transporter. High expression of the transporter, and hence high levels of ET, is observed in certain cells (e.g. blood cells, bone marrow, ocular tissues, brain) that are likely predisposed to oxidative stress, although other tissues can accumulate high levels of ET with sustained administration. This has been suggested to be an adaptive physiological response to elevate ET in the damaged tissue and thereby limit further injury.”

https://www.sciencedirect.com/science/article/pii/S2213231721000161 “Ergothioneine, recent developments”


The coauthors of this review were also coauthors of a 2018 review:

“Ergothioneine is avidly taken up from the diet by humans and other animals through a transporter, OCTN1. Ergothioneine is not rapidly metabolised, or excreted in urine, and has powerful antioxidant and cytoprotective properties.

ergothioneine in foods

Effects of dietary ET supplementation on oxidative damage in young healthy adults found a trend to a decrease in oxidative damage, as detected in plasma and urine using several established biomarkers of oxidative damage, but no major decreases. This could arguably be a useful property of ET: not interfering with important roles of ROS/RNS in healthy tissues, but coming into play when oxidative damage becomes excessive due to tissue injury, toxin exposure or disease, and ET is then accumulated.”

https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13123 “Ergothioneine – a diet-derived antioxidant with therapeutic potential”


I’m upping a half-pound of mushrooms every day to 3/4 lb. (340 g). Don’t think I could eat more garlic than the current six cloves.

PXL_20210606_095517049

I came across this subject in today’s video:

One step short of greatness

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

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

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

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

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

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

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

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


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

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

This study stopped without continuing to any F3 generations.

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

Do we ever consider our great-grandchildren?

Part 2 of Eat broccoli sprouts for DIM

Continuing Part 1 with three DIM studies, the first of which was a 2020 chemical analysis investigating:

“Anti-estrogenic, anti-androgenic, and aryl hydrocarbon receptor (AhR) agonistic activities of indole-3-carbinol (I3C) acid condensation products.

I3C is a breakdown product [isothiocyanate] of glucobrassicin. Most biological activities attributed to I3C are believed to result from its acid condensation products, as it is expected that after ingestion of cruciferous vegetables, I3C is completely converted in the stomach before it reaches the intestine.

The reaction mixture was prepared from I3C under acidic conditions. Based on the various HPLC peaks, 9 fractions were collected and tested.

DIM (3,3-diindolylmethane) displayed clear estrogenic activity, showing an additive effect when co-exposed with low concentrations of E2 [estradiol] (below EC50) [effective concentration that gives half-maximal-response of a biological pathway]. However, an anti-estrogenic activity was observed when DIM was co-exposed with higher concentrations of E2, i.e. above EC50. None of the nine fractions was able to inhibit response of E2.

I3C and DIM showed clear anti-androgenic activities when co-exposed with concentrations of T [testosterone] at EC50 or ECmax. DIM showed a relatively strong antagonistic activity, and was able to completely inhibit response of T.

All fractions displayed an AhR agonist activity. Poor activity of fraction 3 seems surprising, as it contains ICZ, which was shown to be a strong AhR agonist. This is a strong indication that ICZ is only present at a very low concentration.

Observed estrogenic and anti-androgenic effects of the reaction mixture are most likely due to DIM.

The present study is the first that demonstrates that DIM also possesses anti-estrogenic properties when co-administered with E2 concentrations above EC50. Rather than ICZ, LTr1 and several other compounds present in fractions 1 and 4 (CTr), and larger molecules present in fractions 7, 8 (LTe1) and 9 seem responsible for observed AhR activity of the reaction mixture.”

https://www.sciencedirect.com/science/article/pii/S1878535220302811 “Acid condensation products of indole-3-carbinol and their in-vitro (anti)estrogenic, (anti)androgenic and aryl hydrocarbon receptor activities”

I came across this study as a result of its citation in Brassica Bioactives Could Ameliorate the Chronic Inflammatory Condition of Endometriosis.


A second 2016 study was with humans:

“Forty-five subjects consumed vegetables, a mixture of brussels sprouts and/or cabbage, at one of seven discrete dose levels of glucobrassicin ranging from 25 to 500 μmol, once daily for 2 consecutive days.

‘Blue Dynasty’ cabbage contained 33.5 ± 4.0 μmol glucobrassicin per 100 grams food weight. ‘Jade Cross’ brussels sprouts contained 206.0 ± 12.9 μmol per 100 grams.

At 50 μmol, variability in 24-hour urinary DIM levels appears to stem from both within an individual and between individuals. At 200 and 500 μmol dose levels, most variability is coming from between individuals rather than within an individual.

Inter-individual DIM variability may reflect the relative benefit an individual derives from consuming glucobrassicin from vegetables, responsive not only to how much glucobrassicin was consumed but also to variations in I3C uptake and DIM metabolism, many of which are not characterized.

Dose curve between glucobrassicin dose (25–500 μmol) [25, 50, 100, 200, 300, 400, 500] and urinary DIM. Bars represent SD. Estimated parameters in the original scale (95% CI): Maximum DIM 421.5 pmol/mL (154.7–1,148.4), minimum DIM 5.4 pmol/mL (0.7–44.3), EC50 90.2 μmol (29.1–151.3).

We conclude that urinary DIM is a reliable biomarker of glucobrassicin exposure and I3C uptake and that feeding glucobrassicin beyond 200 μmol did not consistently lead to more urinary DIM. Our data support the notion that cancer-preventive properties that might be derived from cruciferous vegetable consumption may require neither a large quantity of vegetables nor high-dose supplements.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220883/ “Harnessing the Power of Cruciferous Vegetables: Developing a Biomarker for Brassica Vegetable Consumption Using Urinary 3,3′-Diindolylmethane”


1. Most subjects had trouble eating 500 μmol / 242.72 grams of Jade Cross brussels sprouts:

“At the 500 μmol dose level, two subjects could not finish due to the taste of the raw Brussels sprouts and were reassigned to 50 μmol dose level.

Two of the remaining five subjects at the 500 μmol dose level “Did not eat all of the assigned vegetables.” 🙂 That amount of brussels sprouts may have made two more sick because one “Missed one void during 2–6 hour collection period” and another “Missed 2 voids during the 6–12 hour collection period.”

2. From its supplementary material, there were ten subjects who ate a 200 μmol glucobrassicin dose. That’s a lot of raw cabbage (179.10 g) and brussels sprouts (67.96 g).

  • On Day 1 at the 2-6 hour point, Subject 27’s urinary DIM measured 10.21 pmol/mL and Subject 20’s measured 991.88, > 9700% higher.
  • At that 2-6 hour point on Day 2, the same subjects measured 16.15 and 687.44 pmol/mL, > 4200% higher.
  • From Table 1, their respective Mean 24-h DIM ± SE, pmol/mL measurements were 20.7 ± 4.0 and 1105 ± 45, > 5300% higher.

The 100 μmol glucobrassicin dose was 149.25 g Blue Dynasty cabbage and 24.27 g Jade Cross brussels sprouts. Could you eat that every day?

3. There’s sufficient data to make individual DIM bioavailability calculations. Don’t know why this study didn’t do that, nor did any of its 18 citing papers.


One study came close for broccoli and radish sprouts, 2017’s Bioavailability and new biomarkers of cruciferous sprouts consumption (not freely available) by researchers in the same group as Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts. They didn’t disclose and analyze individual DIM bioavailability evidence, though:

“Broccoli and radish sprouts content in GB [glucobrassicin] were ~11.4 and ~7.7 μmol/20 g F.W, respectively. After ingestion of broccoli sprouts, 49% of GB was suitably metabolised and excreted as hydrolysis metabolites, calculated as the sum of I3C and DIM (~5.57 μmol /24 h). Following radish ingestion, the percentage of GB hydrolysed and absorbed was 38% (~2.92 μmol /24 h).

These results of bioavailability contrast with the extremely low percentage (< 1%) of GB excreted as DIM after consumption of Brussels sprouts and cabbage in a previous study (Fujioka, et al., 2014). Further studies about conversion of other indole GLS [glucosinolates] to I3C and DIM are needed to know more about bioavailability of these compounds, as there is no information in literature.”


A ten-subject study in Microwave broccoli seeds to create sulforaphane found inter-individual variability of sulforaphane and its metabolites in blood plasma for the highest and lowest individuals was > 500% (2.032 / 0.359 μmol). The urinary % of dose excreted by the same subjects was > 400% higher (86.9% and 19.5%, respectively.)

These studies present an opportunity for further discovery:

  1. Which researchers will try to understand causal experiences in people’s lives that produced such effects?
  2. Which researchers will produce evidence for factors that make people responsively either alive or dead to external influences on their internal environment?
  3. Where are studies that show when an individual needs to change their responses – their phenotype – they can successfully do so?

Herding, the story of 2020

Take responsibility for your one precious life – DHEA

This 2020 meta-analysis subject was DHEA:

“Twenty-four qualified trials were included in this meta-analysis. Statistically significant increases in serum IGF-1 levels were found only in participants who were:

  1. Women; or
  2. Supplementing 50 mg/d; or
  3. Undergoing intervention for > 12 weeks; or
  4. Without an underlying comorbidity; or
  5. Over the age of 60 years.

DHEA supplementation led to an overall increase of ~16 ng/ml in serum IGF-1 levels, as well as increases of ~23 [women] and ~20 ng/ml [age > 60]. Diseased and healthy subjects ages ranged from 20 to 72 years old.”

Discussion section explanations of the above:

  1. “Women are more susceptible to biochemical and clinical shifts caused by DHEA supplementation.
  2. The majority of investigations tested DHEA at a dose of 50 mg/d.
  3. The majority of studies were performed for > 12 weeks.
  4. Participants with no comorbidities were also older in many studies.
  5. Older patients have a natural decline in the production of IGF-1 and DHEA.

Additional rigorous RCTs are warranted to better define whether and to what extent changes in IGF-1 levels caused by DHEA supplementation are relevant for health benefits.”

https://www.sciencedirect.com/science/article/abs/pii/S0531556520302977Impact of dehydroepian[d]rosterone (DHEA) supplementation on serum levels of insulin-like growth factor 1 (IGF-1): A dose-response meta-analysis of randomized controlled trials” (not freely available)


More on IGF-1 from The influence of zinc supplementation on IGF-1 levels in humans: A systematic review and meta-analysis which was cited for “Previous studies have demonstrated that IGF-1 levels can be affected by several factors.”

“IGF-1 is a growth factor synthesized in the liver, and elicits a myriad of effects on health due to its participation in the GH-IGF-1 axis, where it:

  • Is involved in tissue homeostasis;
  • Has anti-apoptotic, mitogenic, anti-inflammatory, antioxidant and metabolic actions;
  • Contributes to skeletal muscle plasticity, maintenance of muscle strength and muscle mass;
  • Neural and cardiovascular protection;
  • Development of the skeleton;
  • Possesses insulin-like effects, and
  • Is a key factor in brain, eye and lung development during fetal development.

IGF-1 plays important roles in both growth and development, and its levels vary depending on age, with peaks generally observed in the postnatal period and at puberty. IGF-1 levels influence the release of GH [growth hormone] from the hypophysis [pituitary gland] via a negative feedback loop.

A rapid decrease in IGF-1 levels is registered during the third decade of life. Levels gradually decrease between the third and the eighth decade of life.”


The Group 3 “> 12 weeks” finding was reinforced by perspectives such as:

Group 4 “with no comorbidities” was narrowly defined. All of us have degrees of diseases in progress. Consider aging effects:

  • Aging as a normal disease “Aging and its diseases are inseparable, as these diseases are manifestations of aging. Instead of healthy aging, we could use the terms pre-disease aging or decelerated aging.”
  • Aging as an unintended consequence “Epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues uninterrupted through the entire lifespan. Ageing is an unintended consequence of processes that are necessary for development of the organism and tissue homeostasis thereafter.”
  • Organismal aging and cellular senescence “If we assume that aging already starts before birth, it can be considered simply a developmental stage, required to complete the evolutionary program associated with species-intrinsic biological functions such as reproduction, survival, and selection.”
  • An environmental signaling paradigm of aging “The age-phenotype of a cell or organ depends on its environment and not its history. Organisms, organs, and their cells can be reset to different age-phenotypes depending on their environment.”

These perspectives are less important than what each of us choose to do about our own problems. Take responsibility for your one precious life.

Eat broccoli sprouts for your hair!

A trio of papers, with the first being a 2017 review exploring broccoli sprout compounds’ effects on head hair:

“Skin appendages, notably hair follicles (HFs), can be exposed to high levels of reactive oxygen species (ROS), which are generated through metabolic reactions occurring mostly in the mitochondria, peroxisomes and the endoplasmic reticulum as well as in the plasma membrane. Despite their involvement in redox stress and cellular damage, ROS also have key roles in physiological signalling processes, including but not limited to, control of stem cell quiescence / differentiation, regulation of innate and adaptive immune responses and importantly, normal HF development.

HFs are composed of a series of concentric keratinocyte layers with a central hair shaft, all of which are encapsulated by a mesenchymal connective tissue sheath. Within this structure is an area known as the ‘bulge’, housing a population of epithelial and melanocyte stem cells. The hair bulb, the lowermost portion of the HF, contains transient amplifying cells that produce the rapidly proliferating matrix keratinocytes that give rise to the various cell types of the inner root sheath and hair shaft itself.

Putative impact of NRF2 activation on protection against hair disorders:

  1. Accumulation of excess ROS within crucial HF compartments (i.e. bulb and bulge) can be induced by endogenous and exogenous stressors associated with androgenetic alopecia (AGA), alopecia areata (excessive mast cell degranulation), chemotherapy, UV exposure and even physiological processes such as melanogenesis.
  2. In the HFSCs [hair follicle stem cells] of the bulge, this can lead to reduced FOXP1 signaling, increased senescence and P21-mediated telogen retention, contributing the hair ageing.
  3. In the hair bulb, negative consequences of excessive ROS can include reduced matrix keratinocyte proliferation and Bcl-2 expression, coupled to increased p53 activity and apoptosis. This redox imbalance may also stimulate the dermal papilla-derived TGF-b1 release associated with AGA.
  4. NRF2 activation via SFN [sulforaphane] can induce the expression of numerous downstream targets, hence suggesting the potential to counteract excessive ROS and associated pathologies, for example via enhanced clearance of reactive species, detoxification, NADPH generation and GSH maintenance.
  5. In addition, NRF2 may down-regulate genes that would negatively impact on proliferation and stimulate apoptosis.
  6. Ultimately, the activation of NRF2 has the potential to protect against HF miniaturization, chemotherapy-induced apoptosis, HFSC aging and hair greying, through maintenance of normal redox homeostasis.

Whereas eumelanin (black) is involved in natural UV protection by reducing generation of free radicals, pheomelanin (red) can trigger generation of ROS. It would certainly be interesting to determine whether NRF2 activity is therefore higher in individuals with red as opposed to black hair, in order to mitigate any negative impact from higher ROS generation.

Modulation of NRF2 activity is an attractive approach for further study in the prevention of hair greying and HFSC ageing. The remarkable prospect for NRF2 activators in modulating other oxidative stress-linked disease states, strongly advocates for the development of NRF2 targeting as a novel strategy in modulating redox-associated disorders of the HF.”

https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.201700029 “Oxidative stress management in the hair follicle: Could targeting NRF2 counter age‐related hair disorders and beyond?” (not freely available)


This review was cited in a 2020 Exploring the possibility of predicting human head hair greying from DNA using whole-exome and targeted NGS data study:

“This study aimed to assess the potential of genetic data to predict hair greying in a population of nearly 1000 individuals from Poland. Most of the prediction information was brought by age alone. Genetic variants explained < 10% of hair greying variation and the impact of particular SNPs on prediction accuracy was found to be small.

Study population included 673 males (67.4%) and 325 (32.6%) females. The mean age of the participants was 30.5 ± 8.8.

Hair greying was recorded in 14.3% of individuals aged 18–30 and the prevalence of grey hair was noted to be significantly higher in young males when comparing to young females (17.8 and 9.2%, respectively). The incidence of grey hair increased to 29.5% in the group of people aged 18–40 years and was 84.2% when people aged ≥40 years were considered.

Because pleiotropy is so common, it would be impossible to predict natural phenotypes avoiding genes involved in determination of pathological phenotypes. The penetrance of individual SNP variants is usually low and they altogether can only explain a small fraction of the predisposition to the disease.

Prediction of hair greying status solely based on genetic information is currently impossible.”


A 2020 review had a pertinent evaluation scheme:

“Geroprotectors are pharmacological agents that decrease the rate of aging and extend lifespan. We proposed a set of primary and secondary selection criteria for potential geroprotectors. Primary criteria:

  1. The life extension in experiments with wild type animal models. The geroprotector should prolong the life of the model beyond the intact maximum lifespan, protecting it from one or more mechanisms of aging.
  2. Improvement of molecular, cellular, and physiological biomarkers to a younger state or slow down the progression of age-related changes in humans.
  3. Most potential geroprotectors are preventive only when applied at relatively high concentrations. The lifespan-extending dose should be several orders of magnitude less than the toxic dose.
  4. Minimal side effects at the therapeutic dosage at chronic application.
  5. The potential benefit of taking a geroprotector may come after a long period. Potential geroprotectors should initially improve some parameters of health-related quality of life: physical, mental, emotional, or social functioning of the person.”

https://www.mdpi.com/2076-3921/9/6/529/htm “Terpenoids as Potential Geroprotectors”


IMG_20200822_064852

Sleep

If you can stand the woo of two Californians trying to outwoo each other, listen to these five podcasts with a sleep scientist.

https://peterattiamd.com/matthewwalker1/

“Ambien, sedation, hypnotives, are not sleep.

Sleep is a life support system. It’s the Swiss army knife of health.

Lack of sleep is like a broken water pipe in your home that leaks down into every nook and cranny of your physiology.

Sleep research is not being transmitted to clinical practice.”


I live on the US East Coast. Hyperbole in normal conversations outside of urban centers is an exception.

It’s different on the West Coast. For example:

  • Interviewer assertions regarding heart rate variability should be compared and contrasted with Dead physiological science zombified by psychological research evidence that:

    “A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.”

  • Interviewer favorable comments for MDMA (Ecstasy) “to deal with issues of underlying trauma, anxiety, and depression.”

Day 70 results from Changing to a youthful phenotype with broccoli sprouts

Here are my Day 70 measurements* to follow up Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts, which had these findings:


Keep in mind that I’m not in the population represented by the clinical trial sample:

  1. My chronological age is above their inclusion range;
  2. My BMI is below their inclusion range; and
  3. I take supplements and meet other exclusion criteria.

I also didn’t take Day 0 measurements.

June 2019 BMI: 24.8

June 2020 BMI: 22.4

2020 IL-6: 1.0 pg / ml. See Part 2 of Rejuvenation therapy and sulforaphane for comparisons.

2020 C-reactive protein: < 1 mg / l.

IL-6 2020

2019 and 2020 No biological age measurements. Why aren’t epigenetic clocks standard and affordable?


I’ve made four lifestyle “interventions” since last summer:

  1. In July 2019 I started to reduce my consumption of advanced glycation end products after reading Dr. Vlassara’s AGE-Less Diet: How a Chemical in the Foods We Eat Promotes Disease, Obesity, and Aging and the Steps We Can Take to Stop It.
  2. In September I started non-prescription daily treatments of Vitamin D, zinc, and DHEA per clinical trial Reversal of aging and immunosenescent trends.
  3. Also in September, I started non-prescription intermittent quercetin treatments of Preliminary findings from a senolytics clinical trial.
  4. I started eating broccoli sprouts every day eleven weeks ago.

1. Broccoli sprouts oppose effects of advanced glycation end products (AGEs) provided examples of Items 1 and 4 interactions.

2. Two examples of Item 2 treatment interactions with Item 4 are in Reversal of aging and immunosenescent trends with sulforaphane:

  • “The effects of the combined treatment with BSE [broccoli sprout extract] and zinc were always greater than those of single treatments.” [Zinc and broccoli sprouts – a winning combination]
  • “Vitamin D administration decreased tumor incidence and size, and the co-administration with SFN [sulforaphane] magnified the effects. The addition of SFN decreased the activity of histone deacetylase and increased autophagy.”

3. How broccoli sprout compounds may complement three supplements I take was in a 2020 review Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer’s Disease: Targeting Mitochondria for Diagnosis and Prevention:

“The nutrients benefit mitochondria in four ways, by:

  • Ameliorating oxidative stress, for example, lipoic acid;
  • Activating phase II enzymes that improve antioxidant defenses, for example, sulforaphane;
  • Enhancing mitochondrial remodeling, for example, acetyl-l-carnitine; and
  • Protecting mitochondrial enzymes and/or stimulating mitochondrial enzyme activities, for example, enzyme cofactors, such as B vitamins and coenzyme Q10 .

In addition to using mitochondrial nutrients individually, the combined use of mitochondrial nutrients may provide a better strategy for mitochondrial protection.”

The review provided a boatload of mitochondrial multifactorial analyses for Alzheimer’s. But these analyses didn’t include effective mitochondrial treatments of ultimate aging causes. I didn’t see evidence of why, after fifteen years of treating mitochondrial effects with supplements, treating one more effect could account for my Week 9 vastly different experiences.


I nod to An environmental signaling paradigm of aging explanations. Its Section 10 reviewed IL-6, C-reactive protein, senescence, and NF-κB in terms of feedback loops, beginning with:

“It is clear that the increasing number of senescent cells depends on the post-adult developmental stage rather than chronological age. The coincidence that these processes result in particular forms of impairment in old age does not seem to be random as it is present in all mammals, and may be causative of many aspects of aging.”

A derived hypothesis: After sufficient strength and duration, broccoli sprout compounds changed my signaling environment, with appreciable effects beginning in Week 9.

I offered weak supporting evidence in Upgrade your brain’s switchboard with broccoli sprouts where a study’s insufficient one week duration of an insufficient daily 17.3 mg sulforaphane dosage still managed to change a blood antioxidant that may have changed four thalamus-brain-area metabolites. For duration and weight comparisons, I doubled my daily amount of broccoli seeds from one to two tablespoons just before Week 6 (Day 35), and from that point onward consumed a estimated 52 mg sulforaphane with microwaving 3-day-old broccoli sprouts every day.

Maybe a promised “In a submitted study, we will report that peripheral GSH levels may be correlated with cognitive functions” will provide stronger evidence? I’m not holding my breath for relevant studies because:

  • There wouldn’t be potential payoffs for companies to study any broccoli sprout compound connections with research areas such as aging, migraines, etc. Daily clinically-relevant broccoli sprout dosages can be grown for < $500 a year.
  • Sponsors would have to change paradigms, a very-low-probability event. They’d have to explain why enormous resources dedicated to current frameworks haven’t produced effective long-term treatments.

What long-term benefits could be expected if I continue eating broccoli sprouts every day?

The longest relevant clinical trial I’ve seen – referenced in Part 2 of Reversal of aging and immunosenescent trends with sulforaphane – was twelve weeks. Part 2 also provided epigenetic clock examples of changes measured after 9 months, which accelerated from there to the 12-month end-of-trial point.

Reviewing clinical trials of broccoli sprouts and their compounds pointed out:

“Biomarkers of effect need more time than biomarkers of exposure to be influenced by dietary treatment.”


A contrary argument: Perhaps people don’t require long durations to effectively change their signaling environments?

I apparently didn’t start eating an effective-for-me daily broccoli sprouts dosage until Day 35, when I changed from one to two tablespoons of broccoli seeds a day. If so, Weeks 6 through 8 may account for my substantial responses during Week 9.

  • Could eating broccoli sprouts every day for four weeks dramatically change a person’s signaling environment?
  • Do you have four weeks and $38 to find out? Two tablespoons of broccoli seeds = 21.4 g x 30 days = .642 kg or 1.42 lbs.

This is what twice-a-day one-tablespoon starting amounts of broccoli seeds look like through three days:


Maintaining the sprouting process hasn’t been a big effort compared with the benefits.

In the absence of determinative evidence, I’ll continue eating broccoli sprouts every day. Several areas of my annual physical have room for improvements. Extending my four lifestyle “interventions” a few more months may also provide hints toward inadequately researched connections.

* Results may not be extrapolatable to other people, to any specific condition, etc.

Part 2 of Reversal of aging and immunosenescent trends with sulforaphane

Reversal of aging and immunosenescent trends with sulforaphane covered only the first 13 minutes of a super informative presentation by the lead researcher of clinical trial Reversal of aging and immunosenescent trends.  Commonalities with sulforaphane research were found by PubMed searches of sulforaphane and each presentation topic, and used a 1/1/2015 publication date cutoff.

Continuing presentation topics from the 13:40 mark:

Cancer

Lymphocyte/monocyte ratio

CD38 monocytes

  • NQO1-induced activation of AMPK contributes to cancer cell death by oxygen-glucose deprivation

    “NQO1 plays a key role in AMPK-induced cancer cell death in OGD through the CD38/cADPR/RyR/Ca2+/CaMKII signaling pathway. Expression of NQO1 is elevated by hypoxia/reoxygenation or inflammatory stresses through nuclear accumulation of the NQO1 transcription factor, Nrf2 (NFE2-related factor 2). Activation of the cytoprotective Nrf2 antioxidant pathway by sulforaphane protects immature neurons and astrocytes from death caused by exposure to combined hypoxia and glucose deprivation.”

Thymus – no recent sulforaphane studies

Renal function

  • Rapid and Sustainable Detoxication of Airborne Pollutants by Broccoli Sprout Beverage: Results of a Randomized Clinical Trial in China

    “Rapid and sustained, statistically significant increases in levels of excretion of glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde were found in those receiving broccoli sprout beverage compared with placebo. Excretion of benzene-derived mercapturic acid was higher in participants who were GSTT1-positive compared to the null genotype, irrespective of study arm assignment. Measures of sulforaphane metabolites in urine indicated that bioavailability did not decline over the 12-week daily dosing period. Thus, intervention with broccoli sprouts enhances detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.”

Hair rejuvenation

Epigenetic clocks – There are no sulforaphane studies that use epigenetic clocks, although broccoli compounds have epigenetic effects on aging, as reviewed in 2019:

  • Sulforaphane – role in aging and neurodegeneration

    “SFN has been shown to modulate several cellular pathways in order to activate diverse protective responses, which might allow avoiding cancer and neurodegeneration as well as improving cellular lifespan and health span.”


Both biomarker (Lymphocyte / monocyte ratio) and epigenetic clock (GrimAge) measurements done 6 months after the clinical trial ended suggested trial subjects’ aging phenotypes had been reset:

An environmental signaling paradigm of aging explained:

Apart from being slowed down or sped up, the body clock can also be reset. Organisms, organs, and their cells can be reset to different age-phenotypes depending on their environment.

This is not so much a principle as an application of principle that the environment determines age-phenotype.

There wouldn’t be a potential payoff for a company to study any broccoli compound / aging connections. People can achieve clinically relevant, daily doses of broccoli sprouts for < $500 a year.

What sponsor would be interested enough to put sulforaphane research on the clock?

Presentation topics are continued in Uses of the lymphocytes to monocytes ratio and A review of sulforaphane and aging. This pilot trial’s follow-on clinical trial was updated in The next phase of reversing aging and immunosenescent trends.

Do genes or maternal environments shape fetal brains?

This 2019 Singapore human study used Diffusion Tensor Imaging on 5-to-17-day old infants to find:

“Our findings showed evidence for region-specific effects of genotype and GxE on individual differences in human fetal development of the hippocampus and amygdala. Gene x Environment models outcompeted models containing genotype or environment only, to best explain the majority of measures but some, especially of the amygdaloid microstructure, were best explained by genotype only.

Models including DNA methylation measured in the neonate umbilical cords outcompeted the Gene and Gene x Environment models for the majority of amygdaloid measures and minority of hippocampal measures. The fact that methylation models outcompeted gene x environment models in many instances is compatible with the idea that DNA methylation is a product of GxE.

A genome-wide association study of SNP [single nucleotide polymorphism] interactions with the prenatal environments (GxE) yielded genome wide significance for 13 gene x environment models. The majority (10) explained hippocampal measures in interaction with prenatal maternal mental health and SES [socioeconomic status]. The three genome-wide significant models predicting amygdaloid measures, explained right amygdala volume in interaction with maternal depression.

The transcription factor CUX1 was implicated in the genotypic variation interaction with prenatal maternal health to shape the amygdala. It was also a central node in the subnetworks formed by genes mapping to the CpGs in neonatal umbilical cord DNA methylation data associating with both amygdala and hippocampus structure and substructure.

Our results implicated the glucocorticoid receptor (NR3C1) in population variance of neonatal amygdala structure and microstructure.

Estrogen in the hippocampus affects learning, memory, neurogenesis, synapse density and plasticity. In the brain testosterone is commonly aromatized to estradiol and thus the estrogen receptor mediates not only the effects of estrogen, but also that of testosterone.”

https://onlinelibrary.wiley.com/doi/full/10.1111/gbb.12576 “Neonatal amygdalae and hippocampi are influenced by genotype and prenatal environment, and reflected in the neonatal DNA methylome” (not freely available)

Perinatal stress and sex differences in circadian activity

This 2019 French/Italian rodent study used the PRS model to investigate its effects on circadian activity:

“The aim of this study was to explore the influence of PRS on the circadian oscillations of gene expression in the SCN [suprachiasmatic nucleus of the hypothalamus] and on circadian locomotor behavior, in a sex-dependent manner.

Research on transcriptional rhythms has shown that more than half of all genes in the human and rodent genome follow a circadian pattern. We focused on genes belonging to four functional classes, namely the circadian clock, HPA axis stress response regulation, signaling and glucose metabolism in male and female adult PRS rats.

Our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.”

“There was a clear-cut effect of sex on the effect of PRS on the levels of activity:

  • During the period of lower activity (light phase), both CONT and PRS females were more active than males. During the light phase, PRS increased activity in males, which reached levels of CONT females.
  • More interestingly, during the period of activity (dark phase), male PRS rats were more active than male CONT rats. In contrast, female PRS rats were less active than CONT females.
  • During the dark phase, CONT female rats were less active than CONT male rats.

The study presented evidence for sex differences in circadian activity of first generation offspring that was caused by stress experienced by the pregnant mother:

“Exposure to gestational stress and altered maternal behavior programs a life-long disruption in the reactive adaptation such as:

  •  A hyperactive response to stress and
  • A defective feedback of the hypothalamus-pituitary-adrenal (HPA) axis together with
  • Long-lasting modifications in stress/anti-stress gene expression balance in the hippocampus.”

It would advance science if these researchers carried out experiments to two more generations to investigate possible transgenerational epigenetic inheritance of effects caused by PRS. What intergenerational and transgenerational effects would they possibly find by taking a few more months and extending research efforts to F2 and F3 generations? Wouldn’t these findings likely help humans?


One aspect of the study was troubling. One of the marginally-involved coauthors was funded by the person described in How one person’s paradigms regarding stress and epigenetics impedes relevant research. Although no part of the current study was sponsored by that person, there were three gratuitous citations of their work.

All three citations were reviews. Unlike study researchers, reviewers aren’t bound to demonstrate evidence from tested hypotheses. Reviewers are free to:

  • Express their beliefs as facts;
  • Over/under emphasize study limitations; and
  • Disregard and misrepresent evidence as they see fit.

Fair or not, comparisons of reviews with Cochrane meta-analyses of the same subjects consistently show the extent of reviewers’ biases. Reviewers also aren’t obligated to make post-publication corrections for their errors and distortions.

As such, reviews can’t be cited for reliable evidence. Higher-quality studies that were more relevant and recent than a 1993 review could have elucidated points.

Sucking up to the boss and endorsing their paradigm was predictable. Since that coauthor couldn’t constrain themself to funder citations only in funder studies, it was the other coauthors’ responsibilities to edit out unnecessary citations.

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00089/full “Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle”

The transgenerational impact of Roundup exposure

This 2019 Washington rodent study from Dr. Michael Skinner’s lab found adverse effects in the grand-offspring and great-grand-offspring following their ancestor’s exposure during pregnancy to the world’s most commonly used herbicide:

“Using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed.

The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities:

  1. Prostate disease in approximately 30% of F3 generation glyphosate lineage males, a three-fold increase in disease rate over controls.
  2. A transgenerational (F3 generation) obese phenotype was observed in approximately 40% of the glyphosate lineage females and 42% of the glyphosate lineage males.
  3. An increased incidence of kidney disease observed in the F3 generation glyphosate lineage females affecting nearly 40% of females.
  4. A significant increase in ovarian disease observed in the F2 [48% vs. 21% for controls] and F3 [36% vs. 15% for controls] generation glyphosate lineage females.
  5. During the gestation of F2 generation mothers with the F3 generation fetuses, dramatic parturition abnormalities were observed in the glyphosate lineage. The frequency of unsuccessful parturition was 35%. To further investigate the parturition abnormalities an outcross of F3 generation glyphosate lineage males with a wildtype female was performed. There were parturition abnormalities observed with a frequency of 30%.

Classic and current toxicology studies only involve direct exposure of the individual, while impacts on future generations are not assessed. The ability of glyphosate and other environmental toxicants to impact our future generations needs to be considered, and is potentially as important as the direct exposure toxicology done today for risk assessment.”


Why isn’t coverage of this study the top story of the world’s news organizations? Is what’s reported more important than reliable evidence of generational consequences to environmental experiences?

Current toxicology practices are a scientific disgrace:

  • What are the hypotheses of practices that only test effects on somatic cells, that don’t look for generational effects of germ cell modifications?
  • Are they selected for their relative convenience instead of chosen for their efficacy?

Why don’t sponsors fund and researchers perform human studies of transgenerational epigenetic inheritance? For example, from Burying human transgenerational epigenetic evidence:

“From the late 1930s through the early 1970s, DES was given to nearly two million pregnant women in the US alone.

Fourth [F3] generation effects of prenatal exposures in humans have not been reported.

Zero studies of probably more than 10,000,000 F3 great-grandchildren of DES-exposed women just here in the US!

There will be abundant human evidence to discover if sponsors and researchers will take their fields seriously.

https://www.nature.com/articles/s41598-019-42860-0.pdf “Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology”

A therapy to reverse cognitive decline

This 2018 human study presented the results of 100 patients’ personalized therapies for cognitive decline:

“The first examples of reversal of cognitive decline in Alzheimer’s disease and the pre-Alzheimer’s disease conditions MCI (Mild Cognitive Impairment) and SCI (Subjective Cognitive Impairment) have recently been published..showing sustained subjective and objective improvement in cognition, using a comprehensive, precision medicine approach that involves determining the potential contributors to the cognitive decline (e.g., activation of the innate immune system by pathogens or intestinal permeability, reduction in trophic or hormonal support, specific toxin exposure, or other contributors), using a computer-based algorithm to determine subtype and then addressing each contributor using a personalized, targeted, multi-factorial approach dubbed ReCODE for reversal of cognitive decline.

An obvious criticism of the initial studies is the small number of patients reported. Therefore, we report here 100 patients, treated by several different physicians, with documented improvement in cognition, in some cases with documentation of improvement in electrophysiology or imaging, as well.”

https://www.omicsonline.org/open-access/reversal-of-cognitive-decline-100-patients-2161-0460-1000450-105387.html “Reversal of Cognitive Decline: 100 Patients”


The lead author commented on Josh Mitteldorf’s informative post A cure for Alzheimer’s? Yes, a cure for Alzheimer’s!:

  1. “We have a paper in press, due to appear 10.22.18 (open access, JADP, I’ll send a copy as soon as available), showing 100 patients with documented improvement – some with MRI volumetrics improved, others with quantitative EEG improvements, others with evoked response improvements, and all with quantitative cognitive assessment improvement. Some are very striking – 12 point improvements in MoCA [Montreal Cognitive Assessment], for example – others less so, but all also have subjective improvement. Hopefully this will address some of the criticisms that we haven’t documented improvement in enough people.
  2. We were just turned down again for a randomized, controlled clinical trial, so on the one hand, we are told repeatedly that no one will believe that this approach works until we publish a randomized, controlled study, and on the other hand, we’ve been turned down (first in 2011/12, and now in 2018), with the complaint that we are trying to address more than one variable in the trial (as if AD is a single-variable disease!). Something of a catch-22. We are now resubmitting (unfortunately, the IRBs are not populated by functional medicine physicians, so they are used to seeing old-fashioned drug studies), and we’ll see what happens.
  3. I’ve been extending the studies to other neurodegenerative diseases, and it has been impressive how much of a programmatic response there seems to be in these ‘diseases.’
  4. I agree with you that there are many features in common with aging itself.
  5. You made a good point that APP [amyloid precursor protein] is a dependence receptor, and in fact it functions as an integrating dependence receptor, responding to numerous inputs (Kurakin and Bredesen, 2015).
  6. In the book and the publications, we don’t claim it is a “cure” since we don’t have pathological evidence that the disease process is gone. What we claim is ‘reversal of cognitive decline’ since that is what we document.
  7. As I mentioned in the book, AD is turning out to be a protective response to multiple insults, and this fits well with the finding that Abeta has an antimicrobial effect (Moir and Tanzi’s work). It is a network-downsizing, protective response, which is quite effective – some people live with the ongoing degenerative process for decades.
  8. We have seen several cases now in which a clinical trial of an anti-amyloid antibody made the person much worse in a time-dependent manner (each time there was an injection, the person would get much worse for 5-10 days, then begin to improve back toward where he/she was, but over time, marked decline occurred), and this makes sense for the idea that the amyloid is actually protecting against pathogens or toxins or some other insult.
  9. It is important to note that we’ve never claimed that all people get better – this is not what we’ve seen. People very late in the process, or who don’t follow the protocol, or who don’t address the various insults, do not improve. It is also turning out to be practitioner dependent – some are getting the vast majority of people to improve, others very few, so this is more like surgery than old-fashioned prescriptive medicine – you have to do a somewhat complicated therapeutic algorithm and get it right for best results.
  10. I’m very interested in what is needed to take the next step in people who have shown improvement but who started late in the course. For example, we have people now who have increased MoCA from 0 to 9 (or 0 to 3, etc.), with marked subjective improvement but plateauing at less than normal. These people had extensive synaptic and cellular loss prior to the program. So what do we need to raise the plateau? Stem cells? Intranasal trophic support? Something else?
  11. I haven’t yet seen a mono-etiologic theory of AD or a mono-therapeutic approach that has repeatedly positive results, so although I understand that there are many theories and treatments, there doesn’t seem to be one etiology to the disease, nor does there seem to be one simple treatment that works for most. It is much more like a network failure.”

At a specific level:

  • “There doesn’t seem to be one etiology to the disease,
  • Nor does there seem to be one simple treatment that works for most.
  • We don’t have pathological evidence that the disease process is gone.”

For general concepts, however:

  • “AD is turning out to be a protective response to multiple insults.
  • It is a network-downsizing, protective response, which is quite effective.
  • The amyloid is actually protecting against pathogens or toxins or some other insult.”

For a framework of an AD cure to be valid, each source of each insult that evoked each “protective response” should be traced.

Longitudinal studies would be preferred inside this framework. These study designs would investigate evidence of each insult’s potential modifying effect on each “protective response” that could affect the cumulative disease trajectory of each individual.

In many cases, existing study designs would be adequate if they extended their periods to the end of the subjects’ natural lifetimes. One AD-relevant example would be extending the prenatally-restraint-stressed model used in:

The framework would also encourage extending studies to at least three generations to investigate evidence for transgenerational effects, as were found in:

Epigenetic transgenerational inheritance mechanisms that lead to prostate disease

This 2019 Washington State University rodent study found:

“Ancestral exposure to toxicant vinclozolin induces an epigenetic transgenerational increase in susceptibility to prostate pathology in F3 [male great-grandchildren] generation rats. These results are in agreement with previous studies which found a transgenerational increase in rates of prostatic:

  • Epithelial atrophy;
  • Cystic hyperplasia; and
  • Prostatitis

in transgenerational F3 and F4 [male great-great-grandchildren] generations after exposure of F0 [great-great-grandmother] generation pregnant rats to vinclozolin. These effects were accompanied by transgenerational changes in mRNA expression in F3 generation ventral prostate epithelial cells.

A number of previous transgenerational studies have shown no ventral prostate histopathology or disease detected. Therefore, observations suggest ancestral exposure specificity in the ability to induce transgenerational inheritance of prostate disease.

There was also no increase in prostate histopathology in directly exposed F1 [male children] or F2 [male grandchildren] generation vinclozolin lineage rats compared to controls.

prostate pathology

The mechanism by which epigenetic transgenerational inheritance affects prostate epithelium involves control of gene expression by DNA methylation and lncRNAs. It will be necessary to determine exact gene targets of these epigenetic modifications to determine further mechanisms.

Future studies need to investigate if similar mechanisms are at work in human males who have adult-onset BPH or prostate cancer. Ancestral exposures to toxicants and epigenetic transgenerational inheritance may contribute to development of prostate disease in men today.”


This study’s above bolded sentence added to evidence that epigenetic effects may skip generations. A study by the same group, Epigenetic transgenerational inheritance of ovarian disease, found in females:

There was no increase in ovarian disease in direct fetal exposed F1 or germline exposed F2 generation vinclozolin or DDT lineage rats compared to controls.

A disturbance in the paradigm of child abuse referenced other studies that found generation-skipping effects.

Researchers are closer to discovering evidence for precise mechanisms of epigenetic transgenerational inheritance. It’s well past time that other researchers performing studies like Burying human transgenerational epigenetic evidence:

  • Turn things around;
  • Take their work seriously; and
  • Truly investigate human evidence for epigenetic transgenerational inheritance.

What are more important research and funding priorities than such human studies?

https://www.nature.com/articles/s41598-019-38741-1 “Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Prostate Pathology and Stromal-Epithelial Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Prostate Disease”

Epigenetic causes of sexual orientation and handedness?

This 2018 Austrian human study subject was various associations of prenatal testosterone levels to fetal development:

“The available evidence suggests, albeit not conclusively, that prenatal testosterone levels may be one cause for the association of sexual orientation with handedness. Associations among women were consistent with predictions of the Geschwind–Galaburda theory (GGT), whereas those among men were consistent with predictions of the callosal hypothesis. However, research on the associations between sexual orientation and handedness appears to be compromised by various methodological and interpretational problems which need to be overcome to arrive at a clearer picture.

The GGT posits that high prenatal testosterone levels cause a delay in the fetal development of the left cerebral hemisphere which results in a right-hemisphere dominance and hence in a tendency for left-handedness. According to the GGT, high prenatal testosterone levels entail not only a masculinization of the female fetus, but also a feminization of the male fetus (contrary to neurohormonal theory). Overall, the male fetus is subjected to higher levels of intrauterine testosterone than the female fetus. The GGT is thus consistent with the higher prevalence of left-handedness among men than among women.

The callosal hypothesis applies to men only and assumes, in line with neurohormonal theory, that low prenatal testosterone levels are associated with later homosexuality. According to the CH, high prenatal testosterone enhances processes of cerebral lateralization through mechanisms of axonal pruning, thereby resulting in stronger left-hemisphere dominance and a smaller corpus callosum. Consistent with this, women have a larger corpus callosum than men.”


The study’s Limitations section included the following:

  1. “Limitations of the current study pertain to the self-report nature of our data. Behavioral data may provide differing results from those obtained here.
  2. Assessment of sexual orientation relied on a single-item measure. Utilization of rating scales (e.g., the Kinsey Sexual Orientation Scale) or of multi-item scales, and assessing different components of sexual orientation, would have allowed for a more fine-grained analysis and for a cross-validation of sexual orientation ratings with sexual attraction.
  3. Albeit both our samples were large, the proportions of bisexual and homosexual individuals were, expectedly, only small, as were effects of lateral preferences. Thus, in analysis we could not differentiate bisexual from homosexual individuals. Bisexual and homosexual individuals may differ with regard to the distribution of lateral preferences.
  4. Some effect tests in this study have been underpowered. Independent replications with even larger samples are still needed.”

The largest unstated limitation was no fetal measurements. When a fetus’ epigenetic responses and adaptations aren’t considered, not only can the two competing hypotheses not be adequately compared, but causes for the studied phenotypic programming and other later-life effects will also be missed.

https://link.springer.com/article/10.1007/s10508-018-1346-9 “Associations of Bisexuality and Homosexuality with Handedness and Footedness: A Latent Variable Analysis Approach”