Transgenerational epigenetic inheritance of thyroid hormone sensitivity

September 23, 2019October 26, 2019 gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Hypothalamus, Limbic system, Stress Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Inherited disease

My 500^th curation is a 2019 Portuguese human study of Azorean islanders:

“This study demonstrates a transgenerational epigenetic inheritance in humans produced by exposure to high TH [thyroid hormone] in fetal life, in the absence of maternal influences secondary to thyrotoxicosis. The inheritance is along the male line.

The present work took advantage of the relatively frequent occurrence of fetal exposure to high TH levels in the Azorean island of São Miguel. This is the consequence of a missense mutation in the THRB gene causing the amino-acid replacement R243Q, resulting in reduced affinity of the TH receptor beta (TRβ) for TH and thus RTHβ.

Its origin has been traced to a couple who lived at the end of the 19th century. F₀ represented the third generation and F₃ the sixth and seventh generation descendant.”

These researchers provided the first adequately evidenced human transgenerational epigenetic inheritance study! However, the lead sentence in its Abstract wasn’t correct:

“Evidence for transgenerational epigenetic inheritance in humans is still controversial, given the requirement to demonstrate persistence of the phenotype across three generations.”

Although found in this study, there is no “requirement to demonstrate persistence of the phenotype.” Observing the same phenotype in each generation is NOT required for human transgenerational epigenetic inheritance to exist!

Animal transgenerational studies have shown that epigenetic inheritance mechanisms may both express different phenotypes for each generation:

A study not cited in – but completely appropriate for – The lack of oxygen’s epigenetic effects on a fetus found heart disease effects in the F₁ generation that were different from the heart disease effects found in the F₂ and F₃ generations;

and entirely skip a phenotype in one or more generations!

Transgenerational pathological traits induced by prenatal immune activation found a F₂ and F₃ generation phenotype of impaired sociability, abnormal fear expression and behavioral despair – effects that weren’t present in the F₁ offspring;
The transgenerational impact of Roundup exposure “Found negligible impacts of glyphosate on the directly exposed F₀ generation, or F₁ generation offspring pathology. In contrast, dramatic increases in pathologies in the F₂ generation grand-offspring, and F₃ transgenerational great-grand-offspring were observed.” (a disease phenotype similarly skipped the first offspring generation);
Epigenetic transgenerational inheritance mechanisms that lead to prostate disease “There was also no increase in prostate histopathology in the directly exposed F₁ or F₂ generation.” (a prostate disease phenotype skipped the first two male offspring generations before it was observed in the F₃ male offspring); and
Epigenetic transgenerational inheritance of ovarian disease “There was no increase in ovarian disease in direct fetal exposed F₁ or germline exposed F₂ generation. The F₃ generation can have disease while the F₁ and F₂ generations do not, due to this difference in the molecular mechanisms involved.” (an ovarian disease phenotype similarly skipped the first two female offspring generations before it was observed in the F₃ female offspring).

Details of epigenetic inheritance mechanisms were provided in Another important transgenerational epigenetic inheritance study. Mechanisms from fetal exposure to the fungicide vinclozolin were compared with mechanisms from fetal DDT exposure, and summarized as:

“The fetal exposure initiates a developmental cascade of aberrant epigenetic programming, and does NOT simply induce a specific number of DMRs [DNA methylation regions] that are maintained throughout development.“

I emailed references to the studies in the first five above curations to the current study’s corresponding coauthor. They replied “What is the mechanism for the transgenerational inheritance you describe?” and my reply included a link to the sixth curation’s study.

Are there still other transgenerational epigenetically inherited effects due to fetal exposure to high thyroid hormone levels?

https://www.liebertpub.com/doi/full/10.1089/thy.2019.0080 “Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line”

Preliminary findings from a senolytics clinical trial

September 21, 2019October 17, 2020 gettingwell4 2-3 stars Required further work, Epigenetics, Stress Control group

This 2019 US human clinical trial reported preliminary results. See Reanalysis of findings from a senolytics clinical trial for ~~strikeout~~ changes.

“Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment.

Since the target of senolytics is senescent cells, these drugs do not need to be continuously present in the circulation in the same way as drugs whose mechanism of action is to occupy a receptor, modulate an enzyme, or act on a particular biochemical pathway, at least in mice. Intermittently administering D + Q effectively circumvents any potential off-target effects due to continuous receptor occupancy or modulation of an enzyme or biochemical pathway.

To test whether intermittent D + Q is effective in targeting senescent cells in humans, we administered a single 3 day course of oral D + Q and assayed senescent cell abundance 11 days after the last dose in subjects with DKD [diabetic kidney disease], the most common cause of end-stage kidney failure and which is characterized by increased senescent cell burden.

In this interim report of findings, we found the single brief course of D + Q:

Attenuated adipose tissue ~~and skin senescent~~ cell burden,

Decreased resulting adipose tissue macrophage accumulation,

Enhanced adipocyte progenitor replicative potential, and

Reduced key circulating SASP factors.”

“In adipose tissue D + Q significantly reduced raw numbers of:

p16INK4A⁺ cells by 35%;

p21CIP1⁺ cells by 17%;

SAβgal⁺ cells by 62%;

CD68⁺ macrophages by 28%; and

Crown-like structures by 86%.”

https://www.ebiomedicine.com/article/S2352-3964(19)30591-2/fulltext “Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease”

In a referenced 2019 rodent study by many of the same researchers:

“We also found that even Q alone can prevent high fat diet-induced increases in markers of senescence, renal fibrosis, decreases in renal oxygenation, and increased creatinine in mice, although Q alone did not prevent insulin resistance.”

The rodent study’s 50 mg/kg quercetin dose scaled human-equivalent dose would be (0.081 x 50 mg) = 13.3 mg/kg. This was 375% higher than a 1,000 mg/75 kg quercetin dose (clinical trial participants’ weights weren’t disclosed.)

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12950 “Targeting senescent cells alleviates obesity‐induced metabolic dysfunction”

Reversal of aging and immunosenescent trends

September 10, 2019October 17, 2020 gettingwell4 5+ stars Premium, Epigenetics, Immune system DNA methylation, Genetic factors

The title of this post is essentially the same as the 2019 human clinical trial:

“Epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment.

This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.

Analysis of CyTOF‐defined immune cell populations revealed the most robust changes to be decreases in total and CD38‐positive monocytes and resulting increases in the lymphocyte‐to‐monocyte ratio (LMR). The changes in mean monocyte populations persisted 6 months after discontinuation of treatment, and the increase in LMR remained highly significant at 18 months as well.

Example of treatment‐induced change in thymic MRI appearance. Darkening corresponds to replacement of fat with nonadipose tissue. White lines denote the thymic boundary. Volunteer 2 at 0 (a) and 9 (b) months”

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028 “Reversal of epigenetic aging and immunosenescent trends in humans”

Here’s a 2017 interview with the clinical trial lead author:

“You might also say that what also happened was to just postpone death from infectious diseases to after 60-65 years of age, which means that the same basic problem still remains.”

The popular press botched the facts as they usually do. I won’t link the UK Independent article because they couldn’t be bothered to even define epigenetic clock correctly.

A science journal article did a better job of explaining the study to readers. However, they often used hyperbole instead of trying to promote understanding.

Josh Mitteldorf’s blog post 1st Age Reversal Results—Is it HGH or Something Else? provided the most informative explanations:

“In 2015, Fahy finally had funding and regulatory approval to replicate his one-man trial in a still-tiny sample of ten men, aged 51-65. That it took so long is an indictment of everything about the way aging research is funded in this country; and not just aging – all medical research is prioritized according to projected profits rather than projected health benefits.”

Further thoughts in Reversal of aging and immunosenescent trends with sulforaphane and Part 2 of Reversal of aging and immunosenescent trends with sulforaphane.