Week 10 of Changing to a youthful phenotype with broccoli sprouts

To follow up Week 9 of Changing to a youthful phenotype with broccoli sprouts:

1. I increased three of eight upper body exercises by 50% through adding another set. I did it because I didn’t feel muscle exhaustion after two sets like I’d previously felt. 🙂

Cognitively, see A claim of improved cognitive function and its follow on Upgrade your brain’s switchboard with broccoli sprouts.

2. It’s been inspirational at times, and at other times, dull, duller, dullest, to do what’s necessary and keep on track. But the efforts paid off when Week 9 was unlike any previous week!

I expressed appreciation in Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts because scientific evidence provides great bases for intentional behavior. It’s still up to me to voluntarily carry out my part. And why wouldn’t I act when my healthspan and lifespan are the consequences? Except…

What if I’d been:

  • Tired of the hassle, or bored with self-imposed discipline, or lazy, and quit?
  • Projecting personal problems onto others, such that improving my present and future became less important than act-outs?
  • Distracted by, or believed propaganda, or participated in Madness of Crowds behavioral contagion, and missed day after day of required actions?

I may not have ever experienced Week 9’s intermediate-term benefits!

If I keep going past ten weeks, what long-term benefits could be expected?

Our model clinical trial didn’t say how researchers decided on a ten-week period for subjects to consume broccoli sprouts every day. I asked a study coauthor about trial duration, but no answer yet.

A few of the same coauthors answered generally in Reviewing clinical trials of broccoli sprouts and their compounds:

Biomarkers of effect are early stage end-points, for instance the modulation of phase 2 enzymes by glucosinolates. They need more time than biomarkers of exposure to be influenced by the dietary treatment.

Hence, length or duration of the study must be defined according to the biomarker measured to be modified, that is, to define perfectly the time of exposure to observe changes in relevant parameters. Gene expression is one important target for glucosinolates, and it requires a sufficient period of exposure to (de)activate signaling pathways involved.

It is crucial to find appropriate biomarkers of effect that are linked to later disease outcomes, and more investigation is needed in this sense. Post-study follow-up can be of great value in assessing the persistence of certain effects, or in discovering those that appear more long-term.

3. I’ll go into a clinic on Sunday for Day 70 truth tests. Here they are: Day 70 results from Changing to a youthful phenotype with broccoli sprouts!

Our model clinical trial for Changing to a youthful phenotype with broccoli sprouts

The further I get into a daily regimen of eating broccoli sprouts for ten weeks, the more I appreciate “Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects.”

“This study represents an advance in intervention studies as the broccoli sprouts were included in a daily dietary pattern in quantities that reflect a real consumption. The hypothesis of our research is that broccoli sprouts are able to reduce the inflammatory status in overweight subjects due to their content in phytochemicals, mainly glucosinolates.

Total concentration of aliphatic glucosinolates was 80.50 mg/30 gf.w. This concentration was two-fold higher than indolic glucosinolates. Volunteers consumed an average of 51 mg (117 μmol) and 20 mg (42 μmol) of glucoraphanin and neoglucobrassicin, respectively, on a daily basis, during the 70 days of the dietary intervention. Considering an amount of GRA [glucoraphanin] of 117 μmol by serving, a 4% on average was metabolized through mercapturic acid pathway.

No significant changes were observed in weight and BMI. By contrast, body fat mass slightly decreased significantly after 70 days of broccoli [sprout] consumption and returned to basal levels at day 90, a state that was maintained until day 160.

The decrease in IL-6 levels was significantly related to the increase in 24 h urine SFN [sulforaphane] levels. In case of C-reactive protein, the decrease was significantly related to the increases in 24 h urine SFN-NAC [SFN-N-acetylcysteine] and SFN-CYS [SFN-cysteine].

The possible synergistic interaction of both SFN and 3,30-DIM and the isothiocyanates erucin and sulforaphane are interconvertible, so that the anti-inflammatory effects observed with broccoli sprouts intake are likely due to the combined effects of all the hydrolysis products of glucosinolates.

https://www.sciencedirect.com/science/article/abs/pii/S0261561418301183 (Not freely available, better format) and https://researchonline.lshtm.ac.uk/id/eprint/4647168/ (freely available)


Modifications I’ve made to the clinical trial’s protocols include:

  1. I start new broccoli sprout batches twice a day with one tablespoon of seeds per A pair of broccoli sprout studies.
  2. I eat 131 grams daily as calculated in Estimating daily consumption of broccoli sprout compounds.
  3. Per 3-day-old broccoli sprouts have the optimal yields, I consume broccoli sprouts when they’re 3 days old. The clinical trial subjects ate broccoli sprouts that were at least a week old.
  4. I immerse 3-day-old broccoli sprouts in 100 ml distilled water, then microwave them on 1000W full power for 35 seconds to achieve up to but not exceeding 60°C (140°F) per Microwave broccoli to increase sulforaphane levels.
  5. Per Enhancing sulforaphane content, after microwaving I transfer broccoli sprouts to a strainer, and allow further myrosinase hydrolization of glucoraphanin and other glucosinolates into sulforaphane and other healthy compounds.

I use the above studies as guides to create broccoli sprout hydrolysis compounds just before eating them. I don’t depend on my metabolism to create sulforaphane, indole-3-carbinol, erucin, and other hydrolysis compounds as did the clinical trial. But then again, those subjects ate super sprouts:

“We used the elicitor methyl jasmonate (MeJA) by priming the seeds as well as by spraying daily over the cotyledons from day 4-7 of germination. We observed that MeJA at concentrations of 250 μmol act as stressor in the plant and enhances the biosynthesis of the phytochemicals glucosinolates.

Compared to control plants without MeJA treatment, the content of compounds as the aliphatic glucosinolate glucoraphanin was enhanced up to a 70% and similar increases were observed with glucoiberin or glucobrassicin. In this way, we improved the content of these health-promoting compounds.”


I’ve referenced our model clinical trial in 15 previous blog posts. They are, in date descending order:

  1. A pair of broccoli sprout studies
  2. Reversal of aging and immunosenescent trends with sulforaphane
  3. A hair color anecdote
  4. Week 7 of Changing to a youthful phenotype with broccoli sprouts
  5. Part 2 of Rejuvenation therapy and sulforaphane
  6. A rejuvenation therapy and sulforaphane
  7. Week 6 of Changing an inflammatory phenotype with broccoli sprouts
  8. Week 3 of Changing an inflammatory phenotype with broccoli sprouts
  9. Broccoli sprouts oppose effects of advanced glycation end products (AGEs)
  10. Reviewing clinical trials of broccoli sprouts and their compounds
  11. Understanding a clinical trial’s broccoli sprout amount
  12. Week 2 of Changing an inflammatory phenotype with broccoli sprouts
  13. Changing an inflammatory phenotype with broccoli sprouts
  14. Growing a broccoli sprouts Victory Garden
  15. How much sulforaphane is suitable for healthy people?

Week 9 of Changing to a youthful phenotype with broccoli sprouts

To follow up Week 8 of Changing to a youthful phenotype with broccoli sprouts:

1. This week has really been different.

A. Physically, on Friday Eve I worked out per my usual upper-body-workout-every four-days routine. I felt strong, and on one exercise I increased the weight by 33%. No problem doing the same number of reps and sets! Keeping good form was challenging.

Per Week 7, I eight-count each concentric rep slowly, then perform each eccentric rep to the same count, with a goal to reach muscle exhaustion during each set. Then pause and do another set.

What changed? Could I have done all this before?

No. I’d tried, making baby steps with increasing weight and keeping good form. But now I can, and I’ll do it again, along with other physical challenges.

B. Seven of this week’s blog posts may be evidence of improved cognitive function. Awakening was how it felt.

Is A claim of improved cognitive function sufficient evidence?

C. This 35th blog post for May comes after 30 posts in April. It wasn’t my goal to do one a day. It’s my goal to Surface Your Real Self. Did a few of them help?

I hope to do other things with my life in June. But the fact remains that humans are herd animals. We “think in herds, go mad in herds, while they [we] only recover their [our] senses slowly, one by one.” We’ll stay in the Madness of Crowds phase until enough people refuse to be propagandized.

2. As a result of reading A pair of broccoli sprout studies, I changed practices to start batches with one tablespoon of broccoli seeds twice a day so I could consume broccoli sprouts twice daily. Right now it’s a PITA task that requires optimization.

The two studies’ findings were:

  1. Broccoli sprouts are better than supplements.
  2. Eating sprouts twice a day is better than eating them once a day.
  3. When in doubt, refer back to Item 1.

3. I reordered broccoli seeds and will receive them next week. In the meantime, I introduced yet another unknown by consuming sprouts that came from a different vendor:

These seeds are smaller. Hundreds of seeds and seed coats annoyingly pass through my strainer, which didn’t happen with larger seeds. 3-day-old sprout sizes are smaller, and they smell and taste different.

This vendor put “seed” four times on their label. The other vendor didn’t bother to put “seed” even once on their broccoli seed package label.

Like other vendors, they prefer buzzword marketing with “microgreen” and “sprouting” rather than provide useful consumer information such as number of seeds and broccoli variety characteristics. Will people buy “Broccoli Sprouting Seeds” but won’t buy Broccoli Seeds? Do people say “Cool beans!” anymore?

My reorder states there are ~720,000 broccoli seeds in that 5 lb. package. I’ll update with its volume after it arrives.

See Week 10 of Changing to a youthful phenotype with broccoli sprouts for follow ups.

Uses of the lymphocytes to monocytes ratio

To follow up a presentation topic of Part 2 of Reversal of aging and immunosenescent trends with sulforaphane, here are a few papers no earlier than 2015 that address the ratio of lymphocytes to monocytes (LMR), or its reciprocal MLR. Because inquiring minds want to know. 🙂

  1. Monocyte heterogeneity and functions in cancer

    “The ratio of lymphocytes to monocytes has emerged as a prognostic factor, including for B cell lymphoma, colorectal cancer, lung cancer, and ovarian cancer. For example, in patients with stage III colon cancer, a higher lymphocyte to monocyte ratio was associated with increased time to recurrence and overall survival.”

  2. Distinct Transcriptional and Anti-Mycobacterial Profiles of Peripheral Blood Monocytes Dependent on the Ratio of Monocytes: Lymphocytes

    “Our observation of monocyte functional and transcriptional differences dependent on the ML ratio (but on neither constituent alone) suggests that qualitative differences in monocytes are better reflected by the ML ratio than by monocyte counts alone, potentially explaining epidemiologic associations of the ratio. The ML ratio was associated with mycobacterial growth in vitro (β = 2.23, SE 0.91, p = 0.02). The significant enrichment of interferon signalling we found supports a common role for type I and II interferons in altering the ML ratio and monocyte function sufficiently to explain altered disease course, consistent with the central role of interferons in mycobacterial and inflammatory diseases. In humans, myeloid-biased HSC accumulate with age and explain the relative increase in myeloid cells in blood with age. Therefore changes in ML ratio in blood are likely a marker of changes in the frequency of lineage-biased HSC.”

  3. Monocyte–lymphocyte ratio is a valuable predictor for diabetic nephropathy in patients with type 2 diabetes

    “T2D patients without diabetic-related complications had higher MLR than control patients. MLR was significantly higher in DN patients than in T2D patients without diabetic-related complications.”

  4. Monocyte lymphocyte ratio predicts the new-onset of chronic kidney disease: A cohort study

    “Increased baseline MLR is strongly associated with the risk of new-onset CKD in people with normal or near-normal kidney function at baseline. Inflammatory markers such as interleukin are difficult to be measured by primary medical care. Therefore, search for simpler inflammatory markers to predict the risk of CKD. MLR represent[s] the state of balance between inflammatory activators and inflammatory regulators. The higher the ratio, the greater the imbalance, the more severe the inflammatory response and the stronger the immune suppression. In addition to increasing the risk of new-onset CKD, our study found MLR was positively related to inflammatory factors, such as leukocytes, neutrophils, NLR, PLR and platelet distribution width. In addition, MLR was positively correlated with age, blood pressure and BMI. However, there was no significant correlation between MLR and fasting plasma glucose in non-diabetic participants. A total of 11280 participants (6592 male and 4688 female) were enrolled in this longitudinal study.”


A LMR of 5 and a MLR of 0.2 are easy-to-measure heuristics, adequate for screening people. These ratios can be used along with many other measurements as starting points to investigate underlying causes.

Item 1 described how LMR also has prognostic value for cancers. The other studies used MLR as a biomarker for the future course of inflammatory diseases per:

“The higher the ratio, the greater the imbalance, the more severe the inflammatory response and the stronger the immune suppression.”


I’d seen the below presentation graphic several times since September 2019. My reaction was “Oh, that’s interesting” each time.

On Friday I understood it: This was what resetting your internal environment looked like.

Did my paradigm change? Yes, among other things, and all of that allowed me to see.

An environmental signaling paradigm of aging provided evidence up through 2015 for its hypothesis and framework. Its treatments’ capabilities to:

“Reset to different age-phenotypes

will be tested as the 2020 study underlying A rejuvenation therapy and sulforaphane is tested.

Caution is warranted before getting carried away with ratio analyses of a 9-subject pilot study. Are hormone ratios useful in explaining health? Behavior? Neurobiology? Anything? recommended:

“Analysis of the individual variables offers more information and a more accurate picture of the underlying relationships.

Ratios should either be analyzed with non-parametric techniques, or be log-transformed before parametric statistical methods are applied.”

There was monocyte but not lymphocyte data in the clinical trial’s supplementary material.

A review of sulforaphane and aging

This 2019 Mexican review stated:

“We describe some of the molecular and physical characteristics of SFN, its mechanisms of action, and the effects that SFN treatment induces in order to discuss its relevance as a ‘miraculous’ drug to prevent 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.

NF-κB is in charge of inflammatory response regulation. Under basal conditions, NF-κB is sequestrated into the cytosol by IκB, but when pro-inflammatory ligands bind to its receptors, the IKK protein family phosphorylates IκB to degrade it via proteasome, so NF-κB is able to translocate into the nucleus and transcript several inflammatory mediators. Sulforaphane is capable to inhibit IκB phosphorylation and NF-κB nuclear translocation.

SFN upregulated Nrf2 expression by reducing DNA demethylation levels of the Nrf2 promoter. In another model using the triple-transgenic mouse model of Alzheimer’s disease (3 × Tg-AD), the use of SFN regulates the expression of the Brain-derived neurotrophic factor (BDNF) via HDAC inhibition, thus increasing H3 and H4 acetylation on the BDNF promoter. Enhancing BDNF expression as an effect of SFN treatment increased the neuronal content of several synaptic molecules like MAP 2, synaptophysin, and PSD-95 in primary cortical neurons of 3 × Tg-AD.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885086/ “Sulforaphane – role in aging and neurodegeneration”


I came across this review while searching PubMed for sulforaphane commonalities with presentation topics in Part 2 of Reversal of aging and immunosenescent trends with sulforaphane. The review outlined some aging aspects and presented relevant sulforaphane studies. Others such as eye and muscle decline weren’t addressed.

Since sulforaphane’s “a ‘miraculous’ drug” in the Abstract, I expected but didn’t see corresponding excitement in the review body. Just phrases like “it is known” and non-specific “more research is needed.”

Other papers published after this review were found by a PubMed “sulforaphane signal aging” search:


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 the AMPK-induced cancer cell death in OGD through the CD38/cADPR/RyR/Ca2+/CaMKII signaling pathway. The 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 the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%), but not crotonaldehyde were found in those receiving broccoli sprout beverage compared with placebo. Excretion of the 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 the 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.

A pair of broccoli sprout studies

This 2015 Oregon human study found:

  • “Plasma and urinary levels of total SFN [sulforaphane] metabolites were ~3–5 times higher in sprout consumers compared to BSE [broccoli sprout extract] consumers.
  • In sprout consumers, plasma concentrations were 2.4-fold higher after consuming the second dose than after the first dose.
  • Calculated SFN bioavailability from broccoli sprouts exceeded 100%.

a Following consumption of a single 200-µmol SFN dose. b Cumulative excretion of SFN metabolites from baseline collection through the 48-hr study period. c Bioavailability F calculated based on total micromoles excreted in urine. Cmax, maximum concentration observed; AUC, area under the curve; h, hour; L, liter; t1/2, half-life; Tmax, time at Cmax. Values represent mean ± SD, n = 10.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394840/ “Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract”


Another way to state findings:

  1. Broccoli sprouts are better than supplements.
  2. Eating sprouts twice a day is better than eating them once a day.

No explanation was given for sprout weight variability, although one was needed, because 127.6 g / 2 = 63.8 g, not 46.8 g:

“In the divided-dose phase (two weeks later), subjects (fasting) consumed half the original dose (100 μmol SFN equivalents) at 8 AM from sprouts or the BSE and the other half (not fasting) 12 h later.”

A “SFN potential” process demonstrated sulforaphane amount equivalencies, but didn’t explain non-intuitive sprout weight measurements. Was it too difficult to control sprout variability? The difficulties were instead pushed onto other researchers trying to replicate the study, and consumers looking for practical guidance.

Regardless, I adjusted my practices to twice daily start a new broccoli sprout batch with one tablespoon of seeds rather than once a day with two tablespoons. I eat them with breakfast and dinner.

I microwave 3-day-old sprouts immersed in 100 ml distilled water on full 1000W power for 35 seconds to achieve 58°C. I immediately put them into a strainer to allow further myrosinase hydrolization of glucoraphanin and other glucosinolates into sulforaphane and other healthy compounds.


I’d overlooked the above study until I saw it referenced in its successor 2018 human study Untargeted metabolomic screen reveals changes in human plasma metabolite profiles following consumption of fresh broccoli sprouts and cited it in Reversal of aging and immunosenescent trends with sulforaphane for its DHEA findings. The clinical trial treatments included:

“Both dehydroepiandrosterone (DHEA) and metformin in an attempt to limit the “diabetogenic” effect of GH [growth hormone]. DHEA has many effects, in both men and women, that oppose deleterious effects of normal aging.”

A PubMed search on DHEA found Impact of Dehydroepianrosterone (DHEA) Supplementation on Serum Levels of Insulin-Like Growth Factor 1 (IGF-1): A Dose-Response Meta-Analysis of Randomized Controlled Trials which confirmed the clinical trial’s DHEA dose would increase IGF-1.

This study observed a significant decrease in DHEA after eating broccoli sprouts, but didn’t provide a plausible explanation for this finding, or cite relevant studies. Ten other significant decreases were related to antioxidants and fatty acids.

It isn’t clear that I needed to take DHEA anyway, since the clinical trial’s purpose for DHEA treatment was to oppose effects of growth hormone, which I’m not taking. But I’m getting good results, so I’ll just keep doing what I’ve been doing for a limited time.

The study said:

“While this study focuses largely on the potential effects of SFN, broccoli sprouts contain many other bioactive components that could be responsible for our observations as well as additional health benefits.”

Our model clinical trial Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects said much the same:

“The anti-inflammatory effects observed with broccoli sprouts intake are likely due to the combined effects of all the hydrolysis products of glucosinolates.”

The 3-day-old broccoli sprouts have the optimal yields study said:

Although germination reduces SF [sulforaphane] yield to some extent, it is beneficial to the formation and accumulation of total phenol and flavonoids, ensuring the health properties of sprouts.”

Combining the pair of Oregon studies’ findings:

  1. Broccoli sprouts are better than supplements.
  2. Eating sprouts twice a day is better than eating them once a day.
  3. When in doubt, refer back to Item 1.

 

Reversal of aging and immunosenescent trends with sulforaphane

Sulforaphane research findings have commonalities with a super informative presentation by the lead researcher of clinical trial Reversal of aging and immunosenescent trends. I did a PubMed search of sulforaphane and each presentation topic, and used a 1/1/2015 publication date cutoff.

Presentation topics through the first 13 minutes were:

Thymus – no recent sulforaphane studies

Treatments

PSA

C-reactive protein and IL-6

Bone marrow fat – no recent studies

T cells

PD-1 / PD-L1

Treatment cost

I estimate the annual cost of the non-prescription treatments of the clinical trial to be $100. The estimated annual cost of eating broccoli sprouts every day is < $500 for the broccoli seeds.

broccoli seed label

The above image isn’t an endorsement although it’s what I’ve used. It’s buzzword marketing to put “sprouts” and “sulforaphane” but not “seeds” on the label of a broccoli seeds package. For another thing, broccoli sprouts don’t “abound with phytochemical sulforaphane.”

Repeating a point from Estimating daily consumption of broccoli sprout compounds, broccoli seeds and sprouts contain little or no sulforaphane. They have glucoraphanin and myrosinase enzyme which are structurally separated. Disturbing their cells mixes the two, and the enzyme hydrolyzes glucoraphanin and other glucosinolates into sulforaphane and other healthy compounds.

Continue presentation topic commonalities with sulforaphane research at A pair of broccoli sprout studies and Part 2 of Reversal of aging and immunosenescent trends with sulforaphane.

Reevaluate findings in another paradigm

It’s challenging for people to change their framework when their paychecks or mental state or reputations depend on it not changing.

I’ll use The hypothalamus and aging as an example. The review was alright for partial fact-finding up through 2018. The review’s facts were limited, however, to what fit into the reviewers’ paradigm.

The 2015 An environmental signaling paradigm of aging provided examples of findings that weren’t considered in the review. It also presented a framework that better incorporated what was known at the time.


Here’s how they viewed the same 2013 study, Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH (not freely available).

Paradigm: “The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body.”

Study assessment:

“The age-associated inflammation increase is mediated by IκB kinase-β (IKK-β) and nuclear factor κB (NF-κB) in the microglia and, subsequently, nearby neurons through the microglia–neuron interaction in the mediobasal hypothalamus. Apparently, blocking the hypothalamic or brain IKK-β or NF-κB activation causes delayed aging phenotype and improved lifespan.

Aging correlates with a decline in the hypothalamic GnRH expression in mice and, mechanistically, activated IKK-β and NF-κB significantly down regulates the GnRH transcription. Notably, GnRH therapy through either hypothalamic third ventricularor subcutaneous injection leads to a significant recovery of neurogenesis in the hypothalamus and hippocampus and a noticeable improvement of age-related phenotype in the skin thickness, bone density, and muscle strength when applied in middle-aged mice.”

Paradigm: Environmental signaling model of aging

Study assessment:

“A link between inflammation and aging is the finding that inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that reduces production of gonadotropin-releasing hormone (GnRH) by neurons. GnRH decline contributes to aging-related changes such as bone fragility, muscle weakness, skin atrophy, and reduced neurogenesis. Consistent with this, GnRH treatment prevents aging-impaired neurogenesis and decelerates aging in mice.

Zhang et al. report that there is an age-associated activation of NF-κB and IKK-β. Loss of sirtuins may contribute both to inflammation and other aspects of aging, but this explanation, also given by Zhang et al. merely moves the question to why there a loss of sirtuins.

The case is particularly interesting when we realize that the aging phenotype can only be maintained by the continuous activation of NF-κB – a product of which is the production of TNF-α. Reciprocally when TNF-α is secreted into the inter-cellular milieu, it causes the activation of NF-κB. In their study, Zhang et al. noted that the activation of NF-κB began in the microglia (the immune system component cells found in the brain), which secreted TNF-α, resulting in a positive feedback loop that eventually encompassed the entire central hypothalamus.

The net result of this is a diminution in the production of gonadotropin-releasing factor which accounted for a shorter lifespan because provision of GnRH eliminated that effect, while either preventing NF-κB activation (or that of the IKK-β upstream activator) or by providing gonadotropin-releasing factor directly into the brain, or peripherally, extended lifespan by about 20%.

In spite of the claim of Zhang et al. that the hypothalamus is the regulator of lifespan in mice, their experiments show that only some aspects of lifespan are controlled by the hypothalamus, as preventing NF-κB activation in this organ did not stop aging and death. Similar increased NF-κB activation with age has been seen in other tissues as well and said to account for dysfunction in aging adrenal glands. It was demonstrated that increased aging occurred as a result of lack of gonadotropin-releasing hormone and that increased lifespan resulted from its provision during aging.

In this manner:

  1. The aging of hypothalamic microglia leads to
  2. The aging of the hypothalamus, which leads to
  3. Aging elsewhere in the body.

So here we have a multi-level interaction:

  1. The activation of NF-κB leads to
  2. Cellular aging, leading to
  3. A diminished production of GnRH, which then
  4. Acts (through the cells with a receptor for it, or indirectly as a result of changes to GnRH-receptor-possessing cells) to decrease lifespan.

So the age state of hypothalamic cells, at least with respect to NF-κB activation, is communicated to other cells via the reduced output of GnRH.”


Not using the same frameworks, are they?

In 2015, the researcher told the world what could be done to dramatically change the entire research area. He and other researchers did so recently as curated in Part 3 of Rejuvenation therapy and sulforaphane which addressed hypothalamus rejuvenation.

A hair color anecdote

Will you excuse a poorly-evidenced observation that’s a positive development I left out of Week 8 of Changing to a youthful phenotype with broccoli sprouts?

I got a haircut last weekend after waiting for Governor Klan Robes Blackface to not arrest barbershop and hair salon owners for the crime of earning a living. A thirty-something tattooed barber wearing a face mask and face shield said my last haircut had been on February 1, 2020, so it had been 14 weeks. She used a #4 clipper to cut everything to about 1/2 inch.

I’d eaten broccoli sprouts every day for 7 weeks at that point. Post-haircut visible hair was all from that period, probably since Week 3, which was also when broccoli sprouts’ effects on inflammation became noticeable.

One evening as I brushed my teeth, I noticed overall hair appearance was mainly dark brown again, an unexpected phenomenon. Maybe white hair will show up as it gets longer?

Feedback on hair color from a back-of-the-head picture was mixed, ranging from “Yes. Definitely!” to Unsupported non-evidence since before and after pictures weren’t taken under the same lighting conditions. Even if validated, other factors could be in play, such as working from home without the stress of going into work.


While eating my usual steel cut oats for breakfast this morning, I remembered a super informative presentation by the lead researcher of clinical trial Reversal of aging and immunosenescent trends. I rewatched it, pausing after two minutes to reabsorb when he said:

“There’s a collapse that takes place somewhere between the ages of sixty to eighty in which you lose 98% of your ability to recognize foreign antigens.”

You will have forgotten why I drew your attention to this super interesting presentation by the 21:25 mark. But pause for the “Hair Rejuvenation?” slide with before and after photos:

“A couple of guys came to us and said they seemed to notice that their hair was growing in darker again. It’s an anecdote. It didn’t apply to most of the guys. But it’s a sign that maybe something interesting is going on.”

That’s followed by epigenetic clock findings using four different clocks. Note that no significant effects on biological age were found until the trial’s 9-month point, and those weren’t as strong as improvements by 12 months.

Improvements accelerated between 9 and 12 months, and at 12 months, subjects had increased their life expectancies by 2 years. The GrimAge clock showed the subjects’ predicted lifespan and health span was unchanged 6 months after the trial ended.


I started and have continued four lifestyle “interventions” since last summer:

  1. In July I dramatically reduced 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 this trial’s non-prescription daily treatments of Vitamin D, zinc, and DHEA.
  3. Also in September, I started non-prescription intermittent quercetin treatments of Preliminary findings from a senolytics clinical trial.
  4. Eight weeks ago I started eating broccoli sprouts every day per clinical trial Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects.

In a month or so I should be able to say whether or not my hair really is growing in darker. One way to find out which “intervention” had the largest effect may be to stop one or more of them. That might happen anyway because:

  1. Consistently eating AGE-less food is boring.
  2. I’m leery of taking more than RDAs.
  3. Ehh.
  4. I still sadly hope against reality that we’re past the Madness of Crowds phase and can accelerate the “recover their senses slowly, one by one” phase. It would be harder to take care of my broccoli sprout farm if I have to go into work every day.

Or maybe An environmental signaling paradigm of aging is correct, and at a certain point, clocks are reset and none of these “interventions” will be needed? What do you think?