Reputations

Epigenetic clocks so far in 2021

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2021’s busiest researcher took time out this month to update progress on epigenetic clocks:

Hallmarks of aging aren’t all associated with epigenetic aging.

epigenetic aging vs. hallmarks of aging

Interventions that increase cellular lifespan aren’t all associated with epigenetic aging.

epigenetic aging vs. cellular lifespan

Many of his authored or coauthored 2021 papers developed human / mammalian species relative-age epigenetic clocks.

epigenetic clock mammalian maximum lifespan

Relative-age epigenetic clocks better predict human results from animal testing.

pan-mammalian epigenetic clock

Previously curated papers that were mentioned or relevant included:

Reverberations, harmonics, history

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Catching up with Martin Armstrong from 2012:

“Corruption within the Roman Republic was certainly at its peak during the first century BC. There was a brewing debt crisis in Rome and the oligarchy was determined to keep power at any cost. Corruption was so widespread that interest rates doubled from 4% to 8% for the elections of 54 BC because there was so much bribery going on to gain votes.

Caesar was clearly a Popularis, a man of the people who stood against the corruption of the Republic. Like today, we have no real voting control over the fate of the nation. Those who are in charge of the political machine control the real political state.

Caesar knew who his enemies truly were. He clung to his belief that if the majority of the Senate were free of the Oligarchy of Cato and Cicero, they would surely see the light. To persuade them, Caesar wrote his seven books on his truly remarkable conquest of Gaul.

Cato and his Oligarchy were so intensely anti-Caesar that they were willing to do anything to anybody. But this was a moment in time where the corruption had simply gone too far.

By September 29th, 51 BC, Caesar ran out of civilized options. Crossing the Rubicon became the only option.

Janus was the symbol of a cyclical change, the departing of one era and the birth of another. His shrine consisted of two doorways that traditionally were left open in time of war and kept closed when Rome was at peace. Leaving the doors open in time of war symbolized the new era that was possible.

Property values were collapsing. Debts were excessive. Those who held mortgages refused to accept just the property back.

Caesar dealt with this major extraordinary situation in a truly astonishing manner, realizing that assets and money are in a union of opposing forces, yet bound together. Value of property is not a constant relationship for money itself is not like a ruler.

Money is more akin to a rubber band even when it may be gold or silver. Money is like everything else – subject to the whims of supply and demand.

The economy is a dynamic relationship between everything with no real constant. We are at a tremendous disadvantage because we have grown up thinking in a flat linear world that does not exist. We limit ourselves by thinking in money,

Caesar explained that he had to borrow to fund the war and it was unethical for him to cancel all debts since he himself would benefit. Generals come and go, but true economic reformers of the state to save the nation are rare indeed. Caesar paid for his economic reform with his life.

There can be no greater example of political corruption that required desperate reform than the calendar. Caesar replaced the typical lunar year and introduced his new calendar based on 365¼ solar days on January 1st, 45 BC.

Sulla [138 – 78 BC] was a highly original, gifted and skillful general, never losing a battle. His rival described Sulla as having the cunning of a fox and the courage of a lion – but that it was the former attribute that was by far the most dangerous. This mixture was later referred to by Machiavelli in his description of the ideal characteristics of a ruler.

Sulla was more interested in retaining institutes of government while eliminating people occupying them whereas Caesar was far more compelled to act to restore institutions and to spare people, even his more threatening enemies. These are not actions of a man interested in personal power, but a man interested in saving his country.

You live in an oligarchy no different today than what Caesar faced back then. One maxim always holds true; Absolute power, corrupts absolutely!”

It appears that only Julius Caeser ever understood

100-44 BC

A normal distribution

Week 34 of Changing to a youthful phenotype with broccoli sprouts

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1. Thank you to readers of this blog who find the 650+ curations and other posts worth their time. I reread blog posts after you read them, and sometimes improve them for our mutual benefit.

One such post this week was Broccoli sprout compounds include sinapic acid derivatives. Although it was already fairly detailed, it received a half-dozen improvements.

  • Those researchers measured composition changes of 31 compounds (18 sinapic acid derivatives, 8 glucosinolates, and 5 flavonoids) identified in seed-2-4-6-day germination stages of one cultivar. They provided convertible dry weight and fresh weight measurements in mg / g.
  • It complemented the 3-day-old broccoli sprouts have the optimal yields study comparisons of six cultivated varieties’ seed-3-5-7-day germination stage weights and measurements with their origins using a milligram-per-gram-of-seeds scale:

    “To be comparable, the content of these bioactive compounds from 100 fresh sprouts was divided by the weight (g) of 100 seeds, and then this value was compared with their content from one gram seeds.”

  • The sinapic acid study discussed another study for:

    “In a study, diminishing amounts of total phenolic acids in sprouts of three broccoli cultivars was observed only between 3rd and 7th day of germination under photoperiod conditions and only when expressed on fresh weight basis. After recalculating results to dry weight, amounts were increasing during the whole 14-day observation period.”

All studies were scientifically informative. Still, results depended on researchers’ operative paradigms, and human behavior such as unconscious act-outs of unsatisfied needs to feel important.

2. Speaking of which, I viewed a 1:48 video with broccoli sprout experts who disparaged microwaving around the 1:10 mark. I’m not an expert, but I’ve eaten a clinically-relevant dose of microwaved broccoli sprouts every day for 34 weeks now.

Here are a few studies of microwaving’s effects on phenolic, glucosinolate, and flavonoid broccoli compounds. Just for those who value evidence more than opinion.

  • Microwaving broccoli sprouts may not affect phenolic levels found four of five test cases didn’t significantly diminish total phenolic fresh weight contents of whole broccoli. They blended 100 grams broccoli in 200 ml water, halved the purée, then microwaved half on 700W power for 30 seconds. No disclosure of what temperature was achieved, but it was probably < 60°C (140°F). Microwaving significantly increased the glucosinolate hydrolysis product indole-3-carbinol:

    “I3C in broccoli was increased by 3.1, 9.1 and 1.9 folds respectively using blenders 1, 2 and 5 with microwaving.”

  • Microwave broccoli to increase flavonoid levels study design was “Broccoli florets (150 g) were put in a microwave safe bowl with a 1 tablespoon [15 ml] of water” and a 1200W microwave on full power for one minute. Although this may have produced temperatures > 60°C, flavonoid fresh weight contents increased > 30%:

    “Microwaving may increase extractability and/or release from binding to other compounds as a result of matrix softening.“

  • Microwave broccoli to increase sulforaphane levels demonstrated significant differences for 475W (LL) and 950W (HL) power settings in glucoraphanin and sulforaphane dry weight amounts when broccoli florets were microwaved to the same temperatures. Compare white bar sulforaphane amounts for LL60 and HL60 (both 60°C), annotated as E and F:

    “Microwave treatment causes a sudden collapse of cell structure due to the increase in osmotic pressure difference over vacuole membrane. Microwave irradiation might help to release more conjugated forms of glucosinolates and then get hydrolyzed by released myrosinase.“

  • Enhancing sulforaphane content confirmed the above 60°C finding with broccoli florets:

    “The best treatment temperature for maximizing sulforaphane yield was 60 °C. The slightly higher sulforaphane yield than would be predicted from the level of glucoraphanin in raw broccoli requires further investigation. Sulforaphane yield of broccoli after 5 min thermal treatment at 65 °C was even lower than the value obtained for raw broccoli.“

3. I see socialistic animal behavior often during beach walks. If one seagull pecks a food morsel, a half-dozen others immediately position themselves to take it. It’s a race to the bottom of existence.

Too bad we humans don’t learn pertinent lessons from others’ experiences, much less our own. Today’s US Thanksgiving provides one example.

Richard Ebeling presented the factual Thanksgiving story a while back. Have you read about collectivism that arrived with the Mayflower in 1620? Do you think we’ve learned what we needed to learn about communism from four centuries ago through today?

4. Seagulls are also inspirational in their flock behavior of joie de vivre predawn flying.

Reevaluate findings in another paradigm

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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. This review was alright for partial fact-finding up through 2018. Its 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 this 2018 review. It also presented a framework that better incorporated what was known in 2015.

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:

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

Aging correlates with a decline in hypothalamic gonadotropin-releasing hormone (GnRH) expression in mice. Mechanistically, activated IKK-β and NF-κB significantly down-regulates GnRH transcription. GnRH therapy through either hypothalamic third ventricularor or subcutaneous injection leads to a significant recovery of neurogenesis in the hypothalamus and hippocampus, and a noticeable improvement of age-related phenotype in 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 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 is a loss of sirtuins.

The case is particularly interesting when we realize that the aging phenotype can only be maintained by continuous activation of NF-κB – a product of which is production of TNF-α.

Reciprocally, when TNF-α is secreted into the inter-cellular milieu, it causes activation of NF-κB. In their study, Zhang et al. noted that activation of NF-κB began in 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 production of gonadotropin-releasing factor which accounted for a shorter lifespan. 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, extending 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. Aging of hypothalamic microglia leads to
  2. Aging of the hypothalamus, which leads to
  3. Aging elsewhere in the body.

So here we have a multi-level interaction:

  1. Activation of NF-κB leads to
  2. Cellular aging, leading to
  3. Diminished production of GnRH, which then
  4. Acts (through 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, this researcher told the world what could be done to dramatically change the entire aging research area. He and other researchers did so recently as curated in Part 3 of Rejuvenation therapy and sulforaphane which addressed hypothalamus rejuvenation.

Part 3 of Rejuvenation therapy and sulforaphane

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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 study untreated tissue samples into clock training data. Reanalyses showed:

“Using the final version of the epigenetic clocks, we find that 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 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 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 rats to find the escape hole (latency) was recorded and plotted. Error bars depict 2 standard errors.

Within a month of plasma fraction treatment, rats exhibited significantly reduced latency to escape, i.e., they learned and remembered better. After the second month, treated rats began with a slightly reduced latency period compared to 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 untreated ones even from the first day of test as their latency period was significantly reduced. By the end of the test period, their latency was similar to that of 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?

Many of us know older people who lived well past their time of good cognitive function:

  • We see how they’re helpless and dependent; and
  • We see how others take advantage of them in their morbidity phase, where healthspan stops increasing but lifespan continues.

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

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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 effects may broccoli sprout compounds 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

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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.

Flatten the Panic Curve April 13-17, 2020

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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

Restrict information in the name of science?

gettingwell4 < 0 Detracted from science, Beliefs, Cerebrum

A Stanford researcher was annoyed that we live in the 21st century, and advocated we return to previous centuries’ information-flow check valves of wise old men. No doubt the publishers of and subscribers to the Journal of the American Medical Association applauded the same old tired prescription.

Ten instances of the word “should” in the final two paragraphs provided ample evidence of the paper’s intent. Mirroring the current political climate – projecting – accusations made of others were items the accusers were guilty of themselves, such as:

“When these scientists act as investigators in the hundreds of observational studies that they publish, or as editors and peer reviewers in evaluating submissions from others, would they tolerate publishing analyses and funding proposals that might contradict their belief system?”

https://jamanetwork.com/journals/jama/fullarticle/2753533 “Neglecting Major Health Problems and Broadcasting Minor, Uncertain Issues in Lifestyle Science”

One of the paper’s references included an informative graphic:

“A histogram of the total number of rumor cascades in our data across the seven most frequent topical categories.”

https://science.sciencemag.org/content/359/6380/1146 “The spread of true and false news online”

I’ll borrow from the curation of another Stanford paper Online dating cuts out the middlemen in conclusion:

“Are there examples where it wouldn’t potentially improve a person’s life to choose their information sources? Friends, family, and other social groups – and religious, educational, and other institutions – have had their middlemen/guarantor time, and have been found lacking.

Make your own choices for your one precious life.”

Online dating cuts out the middlemen

gettingwell4 4-5 stars Advanced knowledge ,

This information is from a 2019 prepublication Stanford study:

“We present new data from a nationally representative 2017 survey showing that meeting online has continued to grow for heterosexual couples, and meeting through friends has continued its sharp decline. As a result of the continued rise of meeting online and the decline of meeting through friends, online has become the most popular way heterosexual couples in the U.S.

Meeting through friends and family provided guarantees that any potential partner had been personally vetted and vouched for by trusted alters. We would expect any rise in Internet dating to reinforce rather than to displace the traditional roles of friends and family as introducers and intermediaries. [Hypothesis 2]

Results reflect support of Hypothesis 1, as the percentage of heterosexual couples meeting online has surged in the post‐2009 smart phone era. Because the results show that meeting online has displaced meeting through friends and meeting through family, we find evidence to reject Hypothesis 2, which led us to expect that online dating would reinforce existing face‐to‐face social networks.

Figure 1’s apparent post‐2010 rise in meeting through bars and restaurants for heterosexual couples is due entirely to couples who met online and subsequently had a first in‐person meeting at a bar or restaurant or other establishment where people gather and socialize. If we exclude the couples who first met online from the bar/restaurant category, the bar/restaurant category was significantly declining after 1995 as a venue for heterosexual couples to meet.”

Are there examples where it wouldn’t potentially improve a person’s life to choose their information sources? Friends, family, and other social groups – and religious, educational, and other institutions – have had their middlemen / guarantor time, and have been found lacking.

Make your own choices for your one precious life. Similar themes are explored in:

https://web.stanford.edu/~mrosenfe/Rosenfeld_et_al_Disintermediating_Friends.pdf “Disintermediating your friends”

Why do we believe obvious lies?

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum

Here are two accounts of this weekend’s news from real journalists, neither of whom are fans of the current US president.

Matt Taibbi of Rolling Stone
https://taibbi.substack.com/p/russiagate-is-wmd-times-a-million
“It’s official: Russiagate is this generation’s WMD”

He cited intentional misreporting (lying) multiple times from the New York Times, Washington Post, CNN, Wall Street Journal, MSNBC, Mother Jones; and from NBC, ABC, McClatchy, New Yorker, New York Magazine, Bloomberg, BuzzFeed, Slate, Yahoo, Fortune, Guardian; and from numerous US congressmen and senators. Most of these false stories have still not yet been corrected or retracted.

  • “Recapping: the reporter who introduced Steele to the world (his September 23, 2016 story was the first to reference him as a source), who wrote a book that even he concedes was seen as “validating” the pee tape story, suddenly backtracks and says the whole thing may have been based on a Las Vegas strip act, but it doesn’t matter because Stormy Daniels, etc.
  • When explosive #Russiagate headlines go sideways, the original outlets simply ignore the new development, leaving the “retraction” process to conservative outlets that don’t reach the original audiences.
  • The Russiagate era has so degraded journalism that even once “reputable” outlets are now only about as right as politicians, which is to say barely ever, and then only by accident.
  • Authorities have been lying their faces off to reporters since before electricity! It doesn’t take much investigation to realize the main institutional sources in the Russiagate mess – the security services, mainly – have extensive records of deceiving the media.
  • As noted before, from World War I-era tales of striking union workers being German agents to the “missile gap” that wasn’t (the “gap” was leaked to the press before the Soviets had even one operational ICBM) to the Gulf of Tonkin mess to all the smears of people like Martin Luther King, it’s a wonder newspapers listen to whispers from government sources at all.”

Glenn Greenwald of The Intercept
https://twitter.com/ggreenwald

  1. “Can’t the people who got rich exploiting liberal #Resistance fears by feeding them false conspiracies at least content themselves to their bulging bank accounts from the scam they pulled off & have one day of silence where they don’t try to pretend that they were right all along?
  2. If you’re just going to let stuff like this go – unexamined, unacknowledged, and unaccounted for – don’t expect anyone to be remotely sympathetic to the fact that public trust in big media is nonexistent and politicians benefit by making journalists their enemies.
  3. And just for future reference: documenting the falsehoods, baseless conspiracies, and deceitful narratives being peddled without dissent by the major corporate media isn’t “blogging” or “media criticism.” It’s journalism. It’s reporting. And it’s vital.
  4. Nothing kills journalism worse than cowardly group-think, and it’s worse than ever since they’re congregated in the same places in Brooklyn and the West Coast and petrified of saying anything that makes them unpopular among their peers.
  5. Check every MSNBC personality, CNN law “expert,” liberal-centrist outlets and #Resistance scam artist and see if you see even an iota of self-reflection, humility or admission of massive error.
  6. I wrote this with @GGreenwald in November 2016, warning Russiagate was being used to attack, smear, and censor alternative media. Those blacklisted alternative media ended up being correct about Russiagate – while the corporate media spread actual fake news.
  7. There should be major accountability in the US media and in the intelligence community they united with to drown US political discourse for 2 years straight in unhinged conspiratorial trash, distracting from real issues. That’s what should happen as a first step. But it won’t.”

Hidden hypotheses of epigenetic studies

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Stress , , , ,

This 2018 UK review discussed three pre-existing conditions of epigenetic genome-wide association studies:

“Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting ‘hypothesis-free’ examinations in relation to adversity and/or mental health problems. Results of EWAS are in fact conditional on several a priori hypotheses:

  1. EWAS coverage is sufficient for complex psychiatric problems;
  2. Peripheral tissue is meaningful for mental health problems; and
  3. The assumption that biology can be informative to the phenotype.

1. CpG sites were chosen as potentially biologically informative based on consultation with a consortium of DNA methylation experts. Selection was, in part, based on data from a number of phenotypes (some medical in nature such as cancer), and thus is not specifically targeted to brain-based, stress-related complex mental health phenotypes.

2. The assumption is often that distinct peripheral tissues are interchangeable and equally suited for biomarker detection, when in fact it is highly probable that peripheral tissues themselves correspond differently to environmental adversity and/or disease state.

3. Analyses result in general statements such as ‘neurodevelopment’ or the ‘immune system’ being involved in the aetiology of a given phenotype. Whether these broad categories play indeed a substantial role in the aetiology of the mental health problem is often hard to determine given the post hoc nature of the interpretation.”

The reviewers mentioned in item #2 the statistical flaw of assuming that measured entities are interchangeable with one another. They didn’t mention that the problem also affected item #1 methodologies of averaging CpG methylation measurements in fixed genomic bins or over defined genomic regions, as discussed in:

The reviewers offered suggestions for reducing the impacts of these three hypotheses. But will doing more of the same, only better, advance science?

Was it too much to ask of researchers whose paychecks and reputations depended on a framework’s paradigm – such as the “biomarker” mentioned a dozen and a half times – to admit the uselessness of gathering data when the framework in which the data operated wasn’t viable? They already knew or should have known this.

Changing an individual’s future behavior even before they’re born provided one example of what the GWAS/EWAS framework missed:

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

DNA methylation and childhood adversity concluded that:

“Blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”

The truth about complex traits and GWAS added another example of how this framework and many of its paradigms haven’t produced effective explanations of “the aetiology of the mental health problem”

“The most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.”

Researchers need to reevaluate their framework if they want to make a difference in their fields. Recasting GWAS as EWAS won’t make it more effective.

https://www.sciencedirect.com/science/article/pii/S2352250X18300940 “Hidden hypotheses in ‘hypothesis-free’ genome-wide epigenetic associations”

The Not-Invented-Here syndrome

gettingwell4 0-1 star Wasted resources, Brain development, Epigenetics, Memory, Stress ,

I have high expectations of natural science researchers. I assume that their studies will improve over time, and develop methods and experiments that produce reliable evidence to inform us of human conditions.

My confidence is often unrealistic. Scientists are people, after all, and have the same foibles as the rest of us.

I anticipate that researchers will keep abreast of others’ work around the world. If other groups in their research areas are developing better methods and exploring hypotheses that discover better applications for humans, why not adopt them in the interest of advancing science?

That’s not what happened with this 2018 UK rodent study. The rat model some of the coauthors have built their reputations on depends on disturbing rat pregnancies by administering glucocorticoids. But both the rat model and a guinea pig model in Do you have your family’s detailed medical histories? demonstrated that physicians who disturb their pregnant human patients in this way may be acting irresponsibly toward their patients’ fetuses and their future generations.

This study didn’t find mechanisms that explained transgenerational epigenetic birth weight effects through the F2 grandchild generation:

“Although the phenotype is transmitted to a second generation, we are unable to detect specific changes in DNA methylation, common histone modifications or small RNA [including microRNA] profiles in sperm.

The inheritance mechanism for the paternally derived glucocorticoid-reprogrammed phenotype may not be linked with the specific germline DNA, sRNA and chromatin modifications that we have profiled here.”


The linked guinea pig model was developed specifically to inform physicians of the consequences through the F3 great-grandchild generation of disturbing human pregnancies with glucocorticoids:

“Antenatal exposure to multiple courses of sGC [synthetic glucocorticoid] has been associated with hyperactivity, impaired attention, and neurodevelopmental impairment in young children and animals. It is imperative that the long-term effects of antenatal exposure to multiple courses of sGC continue to be investigated since the use of a ‘rescue’ (i.e. a second) course of sGC has recently re-introduced the practice of multiple course administration.”

If a study’s purpose is to investigate potential mechanisms of epigenetic inheritance, why not adopt a model that better characterizes common human conditions, regardless of which research group initially developed it?

The prenatal stress model used in The lifelong impact of maternal postpartum behavior is one model that’s more representative of human experiences. Those researchers pointed out in Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies:

“Corticosterone-treated mice and rats exposed to chronic stress are models that do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period.”

Animal models that chemically redirect fetal development also “do not recapitulate the early programming of stress-related disorders.”

Other than research that’s done to warn against disrupted development, how can animal studies like the current study help humans when their models don’t replicate common human conditions? This failure to use more relevant models has follow-on effects such as human intergenerational and transgenerational epigenetic inheritance being denigrated due to insufficient evidence.

Of course there’s insufficient human evidence! Researchers developed and sponsors funded animal study designs that ensured there wouldn’t be wide applicability to humans!! Few derivative human studies have been developed and funded as a result.

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1422-4 “Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations”

A review that inadvertently showed how memory paradigms prevented relevant research

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2016 Swiss review of enduring memories demonstrated what happens when scientists’ reputations and paychecks interfered with them recognizing new research and evidence in their area but outside their paradigm: “A framework containing the basic assumptions, ways of thinking, and methodology that are commonly accepted by members of a scientific community.”

A. Most of the cited references were from decades ago that established these paradigms of enduring memories. Fine, but the research these paradigms excluded was also significant.

B. All of the newer references were continuations of established paradigms. For example, a 2014 study led by one of the reviewers found:

“Successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones.

Recalling remote memories fails to induce histone acetylation-mediated plasticity.”

The researchers elected to pursue a workaround of the memory reconsolidation paradigm when the need for a new paradigm of enduring memories directly confronted them!

C. None of the reviewers’ calls for further investigations challenged existing paradigms. For example, when the reviewers suggested research into epigenetic regulation of enduring memories, they somehow found it best to return to 1984, a time when dedicated epigenetics research had barely begun:

“Whether memories might indeed be ‘coded in particular stretches of chromosomal DNA’ as originally proposed by Crick [in 1984] and if so what the enzymatic machinery behind such changes might be remain unclear. In this regard, cell population-specific studies are highly warranted.”

Two examples of relevant research the review failed to consider:

1. A study that provided evidence for basic principles of Primal Therapy went outside existing paradigms to research state-dependent memories:

“If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again.

It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories.”

What impressed me about that study was the obvious nature of its straightforward experimental methods. Why hadn’t other researchers used the same methods decades ago? Doing so could have resulted in dozens of informative follow-on study variations by now, which is my point in Item A. above.

2. A relevant but ignored 2015 French study What can cause memories that are accessible only when returning to the original brain state? which supported state-dependent memories:

“Posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval.”

The review also showed the extent to which historical memory paradigms depend on the subjects’ emotional memories. When it comes to human studies, though, designs almost always avoid studying emotional memories.

It’s clearly past time to Advance science by including emotion in research.

http://www.hindawi.com/journals/np/2016/3425908/ “Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories”

Confusion may be misinterpreted as altruism and prosocial behavior

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This 2015 Oxford human study of altruism found:

“Division of people into distinct social types relies on the assumption that an individual’s decisions in public-goods games can be used to accurately measure their social preferences. Specifically, that greater contributions to the cooperative project in the game reflect a greater valuing of the welfare of others, termed “prosociality.”

Individuals behave in the same way, irrespective of whether they are playing computers or humans, even when controlling for beliefs. Therefore, the previously observed differences in human behavior do not need to be explained by variation in the extent to which individuals care about fairness or the welfare of others.

Conditional cooperators, who approximately match the contributions of their groupmates, misunderstand the game. Answering the standard control questions correctly does not guarantee understanding.

We find no evidence that there is a subpopulation of players that understand the game and have prosocial motives toward human players.

These results cast doubt on certain experimental methods and demonstrate that a common assumption in behavioral economics experiments, that choices reveal motivations, will not necessarily hold.

When attempting to measure social behaviors, it is not sufficient to merely record decisions with behavioral consequences and then infer social preferences. One also needs to manipulate these consequences to test whether this affects the behavior.”

The researchers are evolutionary biologists who had made similar points in previous studies. They addressed possible confounders in the study and supporting information, and provided complete details in the appendix. For example, regarding reciprocity:

“Communication was forbidden, and we provided no feedback on earnings or the behavior of groupmates. This design prevents signaling, reciprocity, and learning and therefore minimizes any order effects.

It might also be argued that people playing with computers cannot help behaving as if they were playing with humans. Such ingraining of behavior would suggest a major problem for the way in which economic games have been used to measure social preferences. In particular, behavior would reflect everyday expectations from the real world, such as reputation concerns or the possibility of reciprocity, rather than the setup of the game and the true consequences of choices.”

Some of the news coverage missed the lead point of how:

“Economic experiments are often used to study if humans altruistically value the welfare of others.

These results cast doubt on certain experimental methods and demonstrate that a common assumption in behavioral economics experiments, that choices reveal motivations, will not necessarily hold.”

Here are several expressions of beliefs in one news coverage article where the author attempted to flip the discussion to cast doubt on the study. It was along the lines of “There’s something wrong with this study (that I haven’t thoroughly read) because [insert aspersion about sample size, etc.]” What motivates such reflexive behavior?

This study should inform social behavior studies that draw conclusions from flawed experimental designs. For example, both:

based their findings on a video game of popping balloons. Neither study properly interpreted their subjects’ decisions per the current study’s recommendation:

“When attempting to measure social behaviors, it is not sufficient to merely record decisions with behavioral consequences and then infer social preferences. One also needs to manipulate these consequences to test whether this affects the behavior.”

http://www.pnas.org/content/113/5/1291.full “Conditional cooperation and confusion in public-goods experiments”

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