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.

Do broccoli sprouts treat migraines?

While rereading a review in Eat broccoli sprouts today, it occurred to me that I haven’t needed to take migraine medicine during the 9 weeks I’ve been eating broccoli sprouts every day. Since 14 weeks of lockdown overlap this period, it’s also possible that I’ve avoided triggering conditions. I look at brightly-lit screens all day, but don’t have cold air blowing on my head that’s the other half of my most common triggering condition.

I started having intermittent ~monthly episodes about ten years ago. I wouldn’t take sumatriptan unless I have a half-day-long headache that doesn’t respond to acetaminophen. It stops a headache from turning into a 3-day-long migraine.

I went over to PubMed and did a “sulforaphane migraine” search, which turned up exactly 1 (!!) result. A 2016 Chinese rodent study Activation of the nuclear factor E2-related factor 2/anitioxidant response element alleviates the nitroglycerin-induced hyperalgesia in rats found:

“Activation of the Nrf2/ARE pathway inhibited the activation of TGVS [trigeminovascular system] and prevented the induction of hyperalgesia. Sulforaphane might therefore be an effective agent for hyperalgesia.”

Plausible conclusion. Nitroglycerin definitely jolts a monster headache.

Two of the eleven papers citing this study were:


There wouldn’t be any potential payoff for a company to be interested in studying a sulforaphane-migraine connection. What sponsor would be interested enough to double the number of studies in this area?

See Part 2 of Do broccoli sprouts treat migraines? for a follow up.

Part 3 of Rejuvenation therapy and sulforaphane

Part 1 focused on the study’s clinical biomarkers. Part 2 highlighted its epigenetic clocks. Now we’ll look at rejuvenation of cognitive function.

Charts for this study’s most relevant human aging applications – measured by the new human-rat relative biological age clock – were in supplementary data due to combining the study’s untreated tissue samples into clock training data. Reanalyses showed:

“Using the final version of the epigenetic clocks, we find that the treatment effects become even more significant especially for the hypothalamus.”

Human-rat relative clock percentages of rejuvenation were:

  • “Blood 70.6%
  • Liver 79.4%
  • Heart 61.6%
  • Hypothalamus 20.9%”

The Discussion section addressed hypothalamus rejuvenation:

“Why does plasma fraction treatment not reduce brain epigenetic age by the same magnitude as it does the other organs? We can only begin to address this question after having first understood what epigenetic aging entails.

As it stands, our knowledge in this area remains limited, but it is nevertheless clear that:

  1. Epigenetic aging is distinct from the process of cellular senescence and telomere attrition,
  2. Several types of tissue stem cells are epigenetically younger than non-stem cells of the same tissue,
  3. A considerable number of age-related methylation sites, including some clock CpGs, are proximal to genes whose proteins are involved in the process of development,
  4. Epigenetic clocks are associated with developmental timing, and
  5. Relate to an epigenomic maintenance system.

Collectively, these features indicate that epigenetic aging is intimately associated with the process of development and homeostatic maintenance of the body post-maturity.

  • While most organs of the body turnover during the lifetime of the host, albeit at different rates, the brain appears at best to do this at a very much slower rate.
  • While most tissues harbor stem cells that are necessary for replenishment and turnover, stem cells in adult brain have only been detected in a defined and very limited area of the subventricular zone, olfactory bulb (in rats), hippocampus and hypothalamic proliferative region.

As such, if plasma fraction treatment’s rejuvenating effect is:

  • Mediated through the process of development and
  • Involves tissue stem cells

then its effect on the epigenetic age of the brain would appear to be modest, which indeed it does.

It is to be noted however, that improving brain function does not depend on neurogenesis as much as it does on synapse formation and factors such as NMDA receptors which decline in density with age.

Assessment of plasma fraction treatment on cognitive function (learning and memory). Rats were subjected to Barnes maze test – nine consecutive days of test where the time (in seconds) required by the rats to find the escape hole (latency) was recorded and plotted. The error bars depict 2 standard errors.

Within a month of plasma fraction treatment, the rats exhibited significantly reduced latency to escape, i.e., they learned and remembered better. After the second month, the treated rats began with a slightly reduced latency period compared to the untreated old rats, and once again, they learned much faster than the latter.

By the third month, it was clear that treated rats remembered the maze much better than the untreated ones even from the first day of test as their latency period was significantly reduced and by the end of the test period their latency was similar to that of the young rats. This feature was sustained and repeated in the fourth month.”

Not sure why there’s a 62-day gap between “Second month” and “Third month.” Maybe it had something to do with “First month” starting 10 days after the first treatment and “Third month” similarly starting 13 days after the second treatment?


Regarding cognitive function, a 2019 Italian paper Polyphenol Health Effects on Cardiovascular and Neurodegenerative Disorders: A Review and Meta-Analysis analyzed pathetic results of experiments with polyphenols other than broccoli sprout compounds:

“Current treatments to halt cognitive decline are limited to counteract symptoms and have a positive impact on cognition and behavior only in a transient manner, without affecting the underlying pathology.

Although some polyphenols might improve specific markers of cardiovascular risk and cognitive status, many inconsistent data are present in literature. Therefore, definitive recommendations for the use of these compounds in the prevention of cardiovascular disease and cognitive decline are currently not applicable.”


Many of us know older people who lived well past the time of good cognitive function. We see how they’re helpless and dependent. We see how others take advantage of them as they decline past the end of their healthspan.

We can make personal plans for that day, sure. But let’s also put some urgency into applying this study’s new human-rat relative biological age clock, and make:

“A step change in aging research. Although conservation of aging mechanism could be equally deduced from the existence of multiple individual clocks for other mammals (mouse, dog), the single formula of the human-rat clock that is equally applicable to both species effectively demonstrates this fact.”

Part 2 of Rejuvenation therapy and sulforaphane

A rejuvenation therapy and sulforaphane focused on the study’s clinical biomarkers and not its biological age measurements. This Part 2 curation of the study highlights its epigenetic clocks because:

“While clinical biomarkers have obvious advantages (being indicative of organ dysfunction or disease), they are neither sufficiently mechanistic nor proximal to fundamental mechanisms of aging to serve as indicators of them. It has long been recognized that epigenetic changes are one of several primary hallmarks of aging.

DNA methylation (DNAm) epigenetic clocks capture aspects of biological age. The discrepancy between DNAm age and chronological age (term as ‘epigenetic age acceleration’) is predictive of all-cause mortality. Pathologies and conditions that are associated with epigenetic age acceleration includes, but are not limited to, cognitive and physical functioning, centenarian status, Down syndrome, HIV infection, obesity, and early menopause.

The [new] human-rat clocks apply to both species. The two human-rat pan-tissue clocks are distinct, by way of measurement parameters. One estimates absolute age (in units of years), while the other estimates relative age, which is the ratio of chronological age to maximum lifespan; with values between 0 and 1. This ratio allows alignment and biologically meaningful comparison between species with very different lifespan (rat and human), which is not afforded by mere measurement of absolute age.

Relative age estimation was made using the formula: Relative age = Age / maxLifespan where the maximum lifespan for rats and humans were set to 3.8 years and 122.5 years, respectively.”

From Supplementary Table 3, old control and old treatment subjects were males 109 weeks old, 55% of their maximum lifespan (109 / 197.6). Young control subjects were males 30 weeks old, 15% of their maximum lifespan.

The money charts for this study’s human aging applications – measured by the new human-rat relative biological age clock – were buried in Supplementary Figure 12, bar plots M through P:

“Human-rat clock measure of relative age defined as age/maximum species lifespan. Each bar-plot reports the mean value and one standard error.”

From Supplementary Table 8, the percentages of rejuvenation for the above bar plots, calculated as “(100 * (1 – Old Treated / Old Control)” were:

  • “Blood 70.6%
  • Liver 79.4%
  • Heart 61.6%
  • Hypothalamus 20.9%”

Let’s return to clinical biomarkers for comparison purposes. The current study measured pro-inflammatory cytokine IL-6 blood plasma levels at every time point, but didn’t publish numbers. Bar plots and narrative were:

“Inflammation is an important response that helps protect the body, but excess inflammation especially in terms of duration of this response can have very detrimental effects instead. This occurs when inflammation fails to subside and persists indefinitely; a condition referred to as chronic inflammation, which for reasons not well-understood, increases with age and is associated with a multitude of conditions and pathologies.

The levels of two of the most reliable and common biomarkers of chronic inflammation, interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), are found to be considerably higher in old rats, and these were very rapidly diminished, within days by plasma fraction treatment, to comparable levels with those of young rats. This was especially stark with IL-6.

In time, the levels of these inflammatory factors began to rise gradually, but they were once again very effectively reduced following the second administration of the plasma fraction on the 95th day.”

Let’s compare the above IL-6 graphic with IL-6 concentration improvements of our 2018 model clinical trial, Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects, calculated as (100 * (1 – Day _ mean / Day 0 mean):

Mean pg/ml | % improvement | Period | Broccoli sprout consumption

  • 4.594 | 0% | Day 0 | “One week before the beginning of the intervention period, subjects were asked to avoid the consumption of Brassica vegetables (broccoli, radish, cauliflower, Brussel sprouts, mustards, among others) and their derived products.”
  • 1.748 | 62.0% | Day 0 to 70 | Subjects ate 30 g raw broccoli sprouts every day, and stopped eating them after Day 70.
  • 0.896 | 80.5% | Day 0 to 90 | “After the intervention period, a follow-up recovery period for all subjects continued for another 90 days with no ingestion of broccoli sprouts.”
  • 2.170 | 52.8% | Day 0 to 160 | Subjects had not eaten broccoli sprouts after Day 70.

Results between the studies were similar in that:

  1. IL-6 levels improved during early treatments through rat Day 8 and human Day 70, respectively.
  2. IL-6 levels continued decreasing shortly after treatments for 7 days (through rat Day 15) and 20 days (through human Day 90), respectively.
  3. IL-6 levels rose after rat Day 15 and human Day 90, respectively, but were still significantly below Day 0 values at rat Day 95 and human Day 160.

The current study measured Nrf2 but didn’t publish numbers. Bar plots and narrative were:

“The reduction of these inflammation markers is consistent with the profile of the nuclear factor erythroid 2-like 2 protein (Nrf2), which plays a major role in resolving inflammation, in part by inhibiting the expression of IL-6 and TNF-α. Nrf2 also induces the expression of antioxidants that neutralizes ROS [reactive oxygen species], which is also a significant feature in inflammation.”

A PubMed search on “nrf2 sulforaphane human” didn’t turn up relevant 2020 human in vivo studies. I disregarded reviews, cancer studies, disproven hypotheses, and other compounds listed in the below graphic.

I won’t repeat the entire Nrf2 section from the Part 1 curation, just one graphic and paragraph:

It [sulforaphane] is not only a potent Nrf2 inducer but also highly bioavailable [around 80%], so that modest practical doses can produce significant clinical responses. Other Nrf2 activators [shown in the above image] not only lack potency but also lack the bioavailability to be considered as significant intracellular Nrf2 activators.”


As noted in Reviewing clinical trials of broccoli sprouts and their compounds, there are no sulforaphane clinical trials that also use epigenetic clocks. Broccoli sprouts and their compounds’ effects on human aging is an area that hasn’t drawn attention and funding.

What are the effects that broccoli sprouts and their compounds may have on human aging? With this new human-rat relative biological age clock, researchers can get reliable answers from rat studies, with human clinical trials needed only to confirm those findings!

As rejuvenation research continues, what could people do easily, cheaply, and today for our long-term selves? Don’t know about the hypothalamus, but our blood, liver, and heart biological ages may decrease as we reduce inflammation and oxidative stress by eating broccoli sprouts.

I’m at a similar percentage of species maximum lifespan as were the study’s treated subjects. It’s my choice as to what my healthspan will be.

There isn’t evidence today to definitively say that changing my inflammatory phenotype with broccoli sprouts has had / will have rejuvenation effects on biological ages of my cells, organs, and body. But if eating broccoli sprouts every day not only reduces chronic inflammation and oxidative stress as expected, but also makes me younger, I could probably learn to live with that. 🙂

Continued with Part 3 of Rejuvenation therapy and sulforaphane.

A rejuvenation therapy and sulforaphane

The founder of the epigenetic clock methodology with the coauthor of Aging as an unintended consequence released a 2020 rodent study “Reversing age: dual species measurement of epigenetic age with a single clock” at https://www.biorxiv.org/content/10.1101/2020.05.07.082917v1.full.pdf:

“We employed six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. Two of these epigenetic clocks apply to both humans and rats.

The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus.

The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs.

Plasma fraction treatment consists of two series of intravenous injections of plasma fraction. Rats were injected four times on alternate days for 8 days. A second identical series of injections were administered 95 days later. In its entirety, the experiment lasted 155 days.

Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.”

The study hasn’t been peer reviewed, so can’t be viewed yet as conclusive. Given that researchers’ single-most valuable asset is their reputations, though, will the findings have major revisions?


I was alerted to the study by Josh Mitteldorf’s blog post Age Reduction Breakthrough, who did his usual excellent curation:

“Most of the explosion in aging research (and virtually all the venture capital startups) are looking to treat aging at the cellular level. Their paradigm is that aging is an accumulation of molecular damage, and they see their job as engineering of appropriate repair mechanisms.

The truth, as Katcher [the lead lab researcher] understands it, is that, to a large extent, aging is coordinated system-wide via signal molecules in the blood. The problem is that there are thousands of constituents represented in tiny concentrations in blood plasma, but conveying messages that cells read. Which of these are responsible for aging?

The two-species clock[s] was [were] a significant innovation, a first bridge for translating results from an animal model into their probable equivalent in humans. Besides the methylation clock[s], the paper presents evidence of rejuvenation by many other measures. For example:

  • IL-6, a marker of inflammation, was restored to low youthful levels;
  • Glutathione (GSH), superoxide dismutase (SOD), and other antioxidants were restored to higher youthful levels;
  • In tests of cognitive function (Barnes maze), treated rats scored better than old rats, but not as well as young rats.;
  • Blood triglycerides were brought down to youthful levels;
  • HDL cholesterol rose to youthful levels; and
  • Blood glucose fell toward youthful levels.

These results bring together three threads that have been gaining credibility over the last decade. Mutually reinforcing, the three have a strength that none of them could offer separately.

  1. The root cause of aging is epigenetic progression = changes in gene expression over a lifetime.
  2. Methylation patterns in nuclear DNA are not merely a marker of aging, but its primary source. Thus aging can be reversed by reprogramming DNA methylation.
  3. Information about the body’s age state is transmitted system-wide via signal molecules in the blood. Locally, tissues respond to these signals and adopt a young or an old cellular phenotype as they are directed.”

Several of these aging measurements are also positively affected by sulforaphane. Using Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease as a reference:

1. “Chronic inflammation”

“Antioxidants in general and glutathione in particular can be depleted rapidly under conditions of oxidative stress, and this can signal inflammatory pathways associated with NF-κB. SFN [sulforaphane] has been shown to inhibit NF-κB in endothelial cells.

Two key inflammatory cytokines were measured at four time points in forty healthy overweight people [our model clinical trial, Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects]. The levels of both interleukin-6 (Il-6) and C-reactive protein (CRP) declined over the 70 days during which the sprouts were ingested. These biomarkers were measured again at day 90, wherein it was found that Il-6 continued to decline, whereas CRP climbed again. When the final measurement was taken at day 160, CRP, although climbing, had not returned to its baseline value. Il-6 remained significantly below the baseline level at day 160.”

OMCL2019-2716870.010

2. “Oxidative stress”

“As a mediator for amplification of the mammalian defence system against various stressors, Nrf2 [nuclear factor erythroid 2-related factor 2] sits at the interface between our prior understanding of oxidative stress and the endogenous mechanisms cells use to deal with it. Diseases known to be underpinned by oxidative stress are proving to be more responsive to amplification of cellular defences via Nrf2 activation than by administration of direct-acting antioxidant supplements.

SFN, with absolute bioavailability of around 80%, [is] capable of increasing several endogenous antioxidant compounds via the transcription factor, Nrf2.

Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain. Nrf2 was shown to prevent endothelial cells from exhibiting a proinflammatory state. Nrf2 is required for protection against glucose-induced oxidative stress and cardiomyopathy in the heart.

Well in excess of 500 genes have been identified as being activated by SFN via the Nrf2/ARE [Antioxidant Response Element] pathway, and it is likely that this underestimates the number as others are being discovered. Of the available SFN clinical trials associated with genes induced via Nrf2 activation, many demonstrate a linear dose-response. More recently, it has become apparent that SFN can behave hormetically with different effects responsive to different doses.

It [sulforaphane] is not only a potent Nrf2 inducer but also highly bioavailable so that modest practical doses can produce significant clinical responses. Other Nrf2 activators [shown in the above image] not only lack potency but also lack the bioavailability to be considered as significant intracellular Nrf2 activators.”


The study’s most relentlessly questioned, scrutinized, and criticized findings may be the two new epigenetic clocks that apply to both humans and rats. The researchers invited other researchers to validate these clocks because:

“If validated, this would be a step change in aging research. Although conservation of aging mechanism could be equally deduced from the existence of multiple individual clocks for other mammals (mouse, dog), the single formula of the human-rat clock that is equally applicable to both species effectively demonstrates this fact.”

The commonalities of this study with efforts to change my inflammatory phenotype with broccoli sprouts were summarized in the Discussion section:

“Apart from rejuvenating the vital organs of the treated rats, plasma fraction also impacted two fundamental physiological processes that underlie a great number of pathologies, namely oxidative stress and inflammation. Within a week of treatment, the markers of chronic inflammation (IL-6 and TNF-α) were significantly reduced and remained low throughout the entire experiment.

Likewise, markers of oxidative stress in brain, heart, lung and liver, which were very much higher in control old rats, were at the end of the experimental period, indistinguishable between plasma fraction-treated old rats and young ones. Concomitant with this drastic reduction in oxidative stress was the augmented levels of antioxidants (GSH, Catalase and SOD) in these tissues, indicating that modulating the levels of ROS [reactive oxygen species] to that of youthful rats is at least one way by which plasma fraction suppresses oxidative stress. It remains to be ascertained whether the rate of ROS generation is also reduced.

The levels of Nrf2, a transcription factor that impacts on oxidative stress, as well as inflammation, were raised by plasma fraction treatment of old rats to those of the young ones, indicating yet another level by which this treatment modulates these two critical processes. Collectively, these results show that plasma fraction treatment impacts not only the overt performances of organs, but also the underlying physiological processes that are pivotal for optimal organ function and health.”

Great stuff, huh? Are you ready to change your phenotype?

Continued with Part 2 of Rejuvenation therapy and sulforaphane.

We believe what we need to believe

While getting ready for bed tonight, I mused about how my younger brother had such an idealized postmortem view of our father. As he expressed six years ago in an obituary for our high school Literature teacher:

“I’ll remember my favorite teacher and how much he’s meant to my life. My father and Martin Obrentz were the two people who made me care about the things that make me the person I am today.”

Believe what you need to believe, David. But like I said five years ago in Reflections on my four-year anniversary of spine surgery:

“I don’t remember that my three siblings ever received a paddling or belting, although they were spanked. Even before he retired, 17 years before he died, the Miami-Dade County public school system stopped him and the rest of their employees from spanking, whipping, beating, and paddling children.”


It’s extremely important for a child to have a witness to their adverse childhood experiences. Otherwise, it’s crazy-making when these experiences aren’t acknowledged as truths by anyone else. Especially by those who saw but disavow what they saw.

It didn’t really drum into my conscious awareness until tonight that I had such a witness. It wasn’t my mother, of course, since she directed most of my being whipped with a belt, and beaten with a paddle that had holes in it to produce welts. She has denied and deflected my childhood experiences of her ever since then.

It wasn’t my siblings, regrettably for all of us. It wasn’t our Miami neighbors.

When I was twenty, I ran across a guy 300 miles north in Gainesville, Florida, named David Eisenberg, if I remember correctly. A couple of weeks after we met, he asked if my father was Fred Rice, Dean of Boys, West Miami Junior High School. He said he had been beaten by my father several times!

Those weren’t early childhood memories like mine. Those were experiences of a young man during grades 7-9 that he remembered more than a decade later.

I was shocked. It came at a time when I wasn’t ready to face facts about my life, though. I needed fantasies, beliefs to smother what I felt.


I don’t expect that the impacts of my childhood experiences will ever go away. After three years of Primal Therapy that ended a decade ago, at least mine don’t completely control my life anymore.

Dr. Arthur Janov put self-narratives of several patients’ experiences into his May 2016 book Beyond Belief which I partially curated in February 2017. It was partial because I couldn’t read much past Frank’s horrendous story in pages 89 – 105, “The Myth of a Happy Childhood.”

Aging as an unintended consequence

The coauthors of 2018’s The epigenetic clock theory of aging reviewed progress that’s been made todate in understanding epigenetic clock mechanisms.

1. Proven DNA methylation features of epigenetic clocks:

  1. “Methylation of cytosines is undoubtedly a binary event.
  2. The increase in epigenetic age is contributed by changes of methylation profiles in a very small percent of cells in a population.
  3. The clock ticks extremely fast in early post-natal years and much slower after puberty.
  4. Clock CpGs have specific locations in the genome.
  5. It applies to prenatal biological samples and embryonic stem cells.

While consistency with all the five attributes does not guarantee veracity of a model, inconsistency with any one will signal the unlikely validity of a hypothesis.”

2. Regarding what epigenetic clocks don’t measure:

“The effects of

  • Telomere maintenance,
  • Cellular senescence,
  • DNA damage signaling,
  • Terminal differentiation and
  • Cellular proliferation

have all been tested and found to be unrelated to epigenetic ageing.”

3. Regarding cyclical features:

Both the epigenetic and circadian clocks are present in all cells of the body, but their ticking rates are regulated. Both these clocks lose synchronicity when cells are isolated from tissues and grown in vitro.

These similarities compel one to ponder potential links between them.”

This was among the points that Linear thinking about biological age clocks missed.

4. The reviewers discussed 3 of the 5 treatment elements in Reversal of aging and immunosenescent trends:

“It is not known at this stage whether the rejuvenating effect is mediated through the regeneration of the thymus or a direct effect of the treatment modality on the body. Also, it is not known if the effect is mediated by all three compounds or one or two of them.

What we know at this stage does not allow the formation of general principles regarding the impact of hormones on epigenetic age, but their involvement in development and maintenance of the body argue that they do indeed have a very significant impact on the epigenetic clock.”

Not sure why they omitted 3000 IU vitamin D and 50 mg zinc, especially since:

“It is not known if the effect is mediated by all three [five] compounds or one or two of them.”

5. They touched on the specialty of Aging as a disease researchers with:

“Muscle stem cells isolated from mice were epigenetically much younger independently of the ages of the tissue / animal from which they were derived.

The proliferation and differentiation of muscle stem cells cease upon physical maturation. These activities are initiated in adult muscles only in response to injury.

6. The reviewers agreed with those researchers in the Conclusion:

“Epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues uninterrupted through the entire lifespan. The significance of this is profound as the question of why we age has been attributed to many different things, most commonly to ‘wear-and-tear.’

The ticking of the epigenetic clock from the embryonic state challenges this perspective and supports the notion that ageing is an unintended consequence of processes that are necessary for

  • The development of the organism and
  • Tissue homeostasis thereafter.”


https://journals.sagepub.com/doi/10.1177/1535370220918329 “Current perspectives on the cellular and molecular features of epigenetic ageing” (not freely available)

Forcing people to learn helplessness

Learned helplessness is a proven animal model. Its reliably-created phenotype is often the result of applying chronic unpredictable stress.

As we’re finding out worldwide, forcing humans to learn helplessness works in much the same way, with governments imposing what amounts to martial law. Never mind that related phenotypes and symptoms include:

  • “Social defeat
  • Social avoidance behavior
  • Irritable bowel syndrome
  • Depression
  • Anxiety
  • Anhedonia
  • Increased hypothalamic-pituitary-adrenal (HPA)-axis sensitivity
  • Visceral hypersensitivity” [1]

Helplessness is both a learned behavior and a cumulative set of experiences. Animal models demonstrate that these phenotypes usually continue on throughout the subjects’ entire lifespans.

Will the problems caused in humans by humans be treated by removing the causes? Or will the responses be approaches such as drugs to treat the symptoms?


A major difference between our current situation and the situation depicted below is that during communism, most people didn’t really trust or believe what the authorities, newspapers, television, and radio said:

Image from Prague’s Memorial to the Victims of Communism


[1] 2014 GABAB(1) receptor subunit isoforms differentially regulate stress resilience curated in If research provides evidence for the causes of stress-related disorders, why only focus on treating the symptoms?

Flatten the Panic Curve April 13-17, 2020

To better understand our internal origins of panic, here’s Dr. Arthur Janov’s interpretation of a 2013 Iowa study Fear and panic in humans with bilateral amygdala damage (not freely available):

“Justin Feinstein did a study with those who had a damaged amygdala, the hub of the emotional system. They did not have normal fear responses. But if oxygen supplies were lowered and carbon dioxide supplies were increased, mimicking suffocation (increasing acidity of the blood) there were panic attacks.

Where in the world did those attacks come from? Certainly not from the usual emotional structures.

They believe it includes the brainstem! Because the lowering of oxygen supplies and adding carbon dioxide provoked the lower structures to sense the danger and reacted appropriately.

Very much like what happens to a fetus when the mother smokes during pregnancy and produces those same effects.”


Since those of us who chronically experience panic aren’t going into therapy over this weekend, what else can we do?

1. Stop looking at the John Hopkins Panic map.

2. Search out realistic news such as: “Change in [New York state] ICU admissions is actually a negative number for the first time since we started this intense journey.”

3. Stop clicking sensational headline links.

4. Question your information, and investigate multiple views. Trust has been lost:

  • Dr. Scott Jensen, a Minnesota physician for 35 years and state senator, on the inappropriate CDC / WHO guidelines for reporting COVID-19 deaths:

    “It’s ridiculous. The determination of cause of death is a big deal. The idea that we’re going to allow people to massage and game the numbers is a real issue because we’re going to undermine trust.

    I would never put down influenza as the cause of death. Yet that’s what we’re being asked to do here.”

  • The same day, Dr. Fauci arrogantly grouped physicians in with conspiracy theorists if they didn’t conform to these bordering-on-fraudulent CDC / WHO guidelines:

    “Every time we have a crisis of any sort, there’s always this popping-up of conspiracy theories. I think the deaths that we’re seeing are coronavirus deaths, and the other deaths are not being counted as coronavirus deaths.”

    Telling people to trust him – a bureaucrat who hasn’t been in active practice for over three decades – because he had far superior medical judgment than did practicing doctors who for years continuously see patients?

  • Consider the evidence.
  • Don’t accept lies you feel uneasy about. Trust your internal BS detector.

Which herd will you choose to belong to?

https://nypost.com/video/bison-stampede-terrorizes-family-trapped-in-car/

or

An epigenetic clock review by committee

This 2019 worldwide review of epigenetic clocks was a semi-anonymous mishmash of opinions, facts, hypotheses, unwarranted extrapolations, and beliefs. The diversity of viewpoints among the 21 coauthors wasn’t evident.

1. Citations of the coauthors’ works seemed excessive, and they apologized for omissions. However:

  • Challenge 5 was titled “Single-cell analysis of aging changes and disease” and
  • Table 1 “Major biological and analytic issues with epigenetic DNA methylation clocks” had single-cell analysis as the Proposed solution to five Significant issues.

Yet studies such as High-Resolution Single-Cell DNA Methylation Measurements Reveal Epigenetically Distinct Hematopoietic Stem Cell Subpopulations were unmentioned.

2. Some coauthors semi-anonymously expressed faith that using current flawed methodologies in the future – only more thoroughly, with newer equipment, etc. – would yield better results. If the 21 coauthors were asked their viewpoints of Proposed solutions to the top three Significant issues of epigenetic clocks, what would they emphasize when quoted?

3. Techniques were praised:

“Given the precision with which DNA methylation clock age can be estimated and evolving measures of biological, phenotype-, and disease-related age (e.g., PhenoAge, GrimAge)..”

Exactly why these techniques have at times produced inexplicable results wasn’t examined, though. Two examples:

  • In Reversal of aging and immunosenescent trends, the Levine PhenoAge methodology estimated that the 51-65 year old subjects’ biological ages at the beginning of the study averaged 17.5 years less than their chronological age. Comparing that to the Horvath average biological age of 3.95 years less raised the question: exactly why did PhenoAge show such a large difference?
  • The paper mentioned the GrimAge methodology findings about “smoking-related changes.” But it didn’t explain why the GrimAge methylation findings most closely associated with smoking history also accurately predicted future disease risk with non-smokers.

Eluding explanations for these types of findings didn’t help build confidence in the methodologies.

4. A more readable approach to review by committee could have coauthors – in at least one section – answer discussion questions, as Reversing epigenetic T cell exhaustion did with 18 experts.

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1824-y “DNA methylation aging clocks: challenges and recommendations”

A review of fetal adverse events

This 2019 Australian review subject was fetal adversities:

“Adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature.

These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalizing behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalizing behaviours such as anxiety. The term ‘perinatal compromise’ serves as an umbrella term for intrauterine growth restriction, maternal immune activation, prenatal stress, early life stress, premature birth, placental dysfunction, and perinatal hypoxia.

The above conditions are associated with imbalanced excitatory-inhibitory pathways resulting from reduced GABAergic signalling. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA synthesizing enzyme Glutamate Decarboxylase 1, resulting in increased levels of glutamate is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD.

The posterior cerebellum’s role in higher executive functioning is becoming well established due to its connections with the prefrontal cortex, association cortices, and limbic system. It is now suggested that disruptions to cerebellar development, which can occur due to late gestation compromises such as preterm birth, can have a major impact on the region of the brain to which it projects.

Activation of the maternal hypothalamic-pituitary adrenal (HPA) axis and placental protection. Psychological stress is perceived by the maternal HPA axis, which stimulates cortisol release from the maternal adrenal gland.

High levels of maternal cortisol are normally prevented from reaching the fetus by the 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) enzyme, which converts cortisol to the much less active cortisone. Under conditions of high maternal stress, this protective mechanism can be overwhelmed, with the gene encoding the enzyme becoming methylated, which reduces its expression allowing cortisol to cross the placenta and reach the fetus.”


The reviewers extrapolated many animal study findings to humans, although most of their own work was with guinea pigs. The “suggest” and “may” qualifiers were used often – 22 and 37 times, respectively. More frequent use of the “appears,” “hypothesize,” “propose,” and “possible” terms was justified.

As a result, many reviewed items such as the above graphic and caption should be viewed as hypothetical for humans rather than reflecting solid evidence from quality human studies.

The reviewers focused on the prenatal (before birth) period more than the perinatal (last trimester of pregnancy to one month after birth) period. There were fewer mentions of birth and early infancy adversities.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12814 “Perinatal compromise contributes to programming of GABAergic and Glutamatergic systems leading to long-term effects on offspring behaviour” (not freely available)

Caloric restriction’s epigenetic effects

This 2019 US review subject was caloric restriction (CR) without malnutrition:

“Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Short- and long-term CRs produce significant changes in different tissues and across species, in some animal models even with sex-specific effects. Early CR onset may cause a different and even an opposite effect on physiological outcomes in animal models such as body weight.”

https://academic.oup.com/advances/article-abstract/10/3/520/5420411 “Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction” (not freely available)


1. The review didn’t present evidence to equate survival (left axis) with methylation drift (right axis) per the above graphic. Methylation drift should point in the opposite direction of survival, if anything.

2. No mention was made of the epigenetic clock method of measuring age acceleration, although it’s been available since 2013 and recent diet studies have used it. The sole citation of an age acceleration study was from 2001, which was unacceptable for a review published in 2019.

3. The review provided many cellular-level details about the subject. However, organism-level areas weren’t sufficiently evidenced:

A. Arguments for an effect usually include explanations for no effect as well as for opposite effects. The reviewers didn’t provide direct evidence for why, if caloric restriction extended lifespan, caloric overabundance produced shorter lifespans.

B. Caloric restriction evidence was presented as if only it was responsible for organism-level effects. Other mechanisms may have been involved.

An example of such a mechanism was demonstrated in a 2007 rodent study Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet which compared two 40%-calorie-restricted diets.

The calories and composition of both diets were identical. However, advanced glycation end product (AGE) levels were doubled in standard chow because heating temperatures were “sufficiently high to inadvertently cause standard mouse chow to be rich in oxidant AGEs.”

The study found that a diet with lower chow heating temperatures increased lifespan and health span irrespective of caloric restriction!

  • The low-AGE calorie-restricted diet group lived an average of 15% longer (>20 human equivalent years) than the CR group.
  • 40% of the low-AGE calorie-restricted diet group were still alive when the last CR group member died.
  • The CR group also had significantly more: 1) oxidative stress damage; 2) glucose and insulin metabolism problems; and 3) kidney, spleen, and liver injuries.

Do delusions have therapeutic value?

This 2019 UK review discussed delusions, aka false beliefs about reality:

“Delusions are characterized by their behavioral manifestations and defined as irrational beliefs that compromise good functioning. In this overview paper, we ask whether delusions can be adaptive notwithstanding their negative features.

We consider different types of delusions and different ways in which they can be considered as adaptive: psychologically (e.g., by increasing wellbeing, purpose in life, intrapsychic coherence, or good functioning) and biologically (e.g., by enhancing genetic fitness).”

https://onlinelibrary.wiley.com/doi/full/10.1002/wcs.1502 “Are clinical delusions adaptive?”


A. Although section 4’s heading was Biological Adaptiveness of Delusions, the reviewers never got around to discussing evolved roles of brain areas and beliefs (delusions). One mention of evolutionary biology was:

“Delusions are biologically adaptive if, as a response to a crisis of some sort (anomalous perception or overwhelming distress), they enhance a person’s chances of reproductive success and survival by conferring systematic biological benefits.”

B. Although section 5’s heading was Psychological Adaptiveness of Delusions, the reviewers didn’t connect feelings and survival sensations as origins of beliefs (delusions) and behaviors. They had a few examples of feelings:

“Delusions of reference and delusions of grandeur can make the person feel important and worthy of admiration.”

and occasionally sniffed a clue:

“Some delusions (especially so‐called motivated delusions) play a defensive function, representing the world as the person would like it to be.”

where “motivated delusions” were later deemed in the Conclusion section to be a:

“Response to negative emotions that could otherwise become overwhelming.”

C. Feelings weren’t extensively discussed until section 6 Delusions in OCD and MDD, which gave readers an impression that feelings were best associated with those diseases.

D. In the Introduction, sections 4, 5, and 7 How Do We Establish and Measure Adaptiveness, the reviewers discussed feeling meaning in life, but without understanding:

  1. Feelings = meaning in life, as I quoted Dr. Arthur Janov in The pain societies instill into children:

    “Without feeling, life becomes empty and sterile. It, above all, loses its meaning.

  2. Beliefs (delusions) defend against feelings.
  3. Consequentially, the stronger and / or more numerous beliefs (delusions) a person has, the less they feel meaning in life.

E. Where, when, why, and how do beliefs (delusions) arise? Where, when, why, and how does a person sense and feel, and what are the connections with beliefs (delusions)?

F. The word “sense” was used 29 times in contexts such as “make sense” and “sense of [anxiety, coherence, control, meaning, purpose, rational agency, reality, self, uncertainty]” but no framework connected biological sensing to delusions. Papers from other fields have detailed cause-and-effect explanations and predecessor-successor diagrams for every step of a process. Not this one.


Regarding any therapeutic value of someone else’s opinion of a patient’s delusions:

I’ll reuse this quotation from the Scientific evidence page of Dr. Janov’s 2011 book “Life Before Birth: The Hidden Script that Rules Our Lives” p.166:

“Primal Therapy differs from other forms of treatment in that the patient is himself a therapist of sorts. Equipped with the insights of his history, he learns how to access himself and how to feel.

The therapist does not heal him; the therapist is only the catalyst allowing the healing forces to take place. The patient has the power to heal himself.

Another way Dr. Janov wrote this was on p.58 of his 2016 book Beyond Belief as quoted in Beyond Belief: The impact of merciless beatings on beliefs:

NO ONE HAS THE ANSWER TO LIFE’S QUESTIONS BUT YOU. How you should lead your life depends on you, not outside counsel.

We do not direct patients, nor dispense wisdom upon them. We have only to put them in touch with themselves; the rest is up to them.

Everything the patient has to learn already resides inside. The patient can make herself conscious. No one else can.”

Non-emotional memories

This 2019 US review covered memory mechanisms:

“With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding.

These levels are not isolated, but linked by shared components of feedback loops.”


Despite the review’s exhaustive discussion, the reviewers never came to the point. The word cloud I made of the review’s most frequent thirty words had little to do with why memory occurs:

  • Why do some stimuli evoke a memory in response?
  • Why are almost all of the stimuli an organism receives not remembered?

Much of the discussion was baseless because it excluded emotion. Many of the citations’ memory findings relied on emotion, though.

For example, in the subsection Roles of persistent epigenetic modifications for maintaining LTF [long-term facilitation], LTP [long-term potentiation], and LTM [long-term memory]:

  • Histone acetylation is increased after fear conditioning in the hippocampus and amygdala.
  • Correspondingly, inhibition of histone deacetylase enhances fear conditioning and LTP.
  • Following fear conditioning, histone phosphorylation is also increased.
  • DNA methylation is also up-regulated in the hippocampus and amygdala after fear conditioning, and inhibition of DNA methylation blocks fear LTM.”

http://learnmem.cshlp.org/content/26/5/133.full “How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory”

Our brains are shaped by our early environments

This 2019 McGill paper reviewed human and animal studies on brain-shaping influences from the fetal period through childhood:

“In neonates, regions of the methylome that are highly variable across individuals are explained by the genotype alone in 25 percent of cases. The best explanation for 75 percent of variably methylated regions is the interaction of genotype with different in utero environments.

A meta-analysis including 45,821 individuals with attention-deficit/hyperactivity disorder and 9,207,363 controls suggests that conditions such as preeclampsia, Apgar score lower than 7 at 5 minutes, breech/transverse presentations, and prolapsed/nuchal cord – all of which involve some sort of poor oxygenation during delivery – are significantly associated with attention-deficit/hyperactivity disorder. The dopaminergic system seems to be one of the brain systems most affected by perinatal hypoxia-ischemia.

Exposure to childhood trauma activates the stress response systems and dysregulates serotonin transmission that can adversely impact brain development. Smaller cerebral, cerebellar, prefrontal cortex, and corpus callosum volumes were reported in maltreated young people as well as reduced hippocampal activity.

Environmental enrichment has a series of beneficial effects associated with neuroplasticity mechanisms, increasing hippocampal volume, and enhancing dorsal dentate gyrus-specific differences in gene expression. Environmental enrichment after prenatal stress decreases depressive-like behaviors and fear, and improves cognitive deficits.”


The reviewers presented strong evidence until the Possible Factors for Reversibility section, which ended with the assertion:

“All these positive environmental experiences mentioned in this section could counterbalance the detrimental effects of early life adversities, making individuals resilient to brain alterations and development of later psychopathology.”

The review’s penultimate sentence recognized that research is seldom done on direct treatments of causes:

“The cross-sectional nature of most epigenetic studies and the tissue specificity of the epigenetic changes are still challenges.”

Cross-sectional studies won’t provide definitive data on cause-and-effect relationships.

The question yet to be examined is: How can humans best address these early-life causes to ameliorate their lifelong effects?

https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14182 “Early environmental influences on the development of children’s brain structure and function” (not freely available)