2-3 stars Required further work

Research needing further work

Do epigenetic clocks measure causes or effects?

gettingwell4 2-3 stars Required further work, Epigenetics , ,

Starting the sixth year of this blog with a 2020 article authored by the founder of the PhenoAge epigenetic clock methodology:

“The Ge[r]oscience paradigm suggests that targeting the aging process could delay or prevent the risk of multiple major age-related diseases. We need clinically valid measures of the underlying biological process and/or classification criteria for what it means to be biologically, rather than chronologically, “aged”.

The majority of aging biomarkers, including the first-generation epigenetic clocks, are developed using cross-sectional data, in which the researchers take a variable that proxies aging (e.g. chronological age) and apply supervised machine learning, or deep learning, approaches to predict that variable using tens to hundreds of thousands of input variables. The problem with this approach is that it doesn’t account for mortality selection. This biases the algorithm to select markers that are not causal, but instead correlative with aging.

When considering individuals of the same chronological age, do those with higher epigenetic age look phenotypically older on average (e.g. have higher mortality rates, greater disease burden, and worse physical and cognitive functioning)? FEV1 [forced expiratory volume in one second] declined at a faster rate for individuals with higher baseline GrimAge and/or PhenoAge. A similar finding was observed for the decline in grip strength as a function of GrimAge; however, the rate of change for any of the epigenetic clocks was not associated with rate of change in any performance measure.

Loci that show consistent trends with chronological age, even at higher ages, are likely not causal. By using a cross-sectional study design for biomarker development there was a propensity away from selecting causal loci, to the point where fewer causal loci were selected than if loci had been chosen at random.

The power of these measures as diagnostic and prognostic may stem from the use of longitudinal data in training them. Rather than continuing to train chronological age predictors using diverse data, it may be more advantageous to retrain some of the existing measures by predicting longitudinal outcomes.”

https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/glaa021/5717592 “Assessment of Epigenetic Clocks as Biomarkers of Aging in Basic and Population Research” (not freely available)

A cited 2019 study modeled corrections to “account for mortality selection.” It modified datasets “by incorporating correlates of mortality identified from longitudinal studies, allowing cross-sectional studies to effectively identify the causal factors of aging.”

https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/glz174/5540066 “Biomarkers for Aging Identified in Cross-sectional Studies Tend to Be Non-causative” (not freely available)

The article didn’t present a complete case to determine whether an individual’s epigenetic clock measurements over time may show causes of biological aging.

Other viewpoints include:

1. A blood plasma aging clock presented evidence with its 46-protein conserved aging signature that some causes of biological aging are under genetic control. If the principle of this finding applies to CpG DNA methylation, the statement:

Loci that show consistent trends with chronological age, even at higher ages, are likely not causal.

may not hold. Such epigenetic changes could be among both the causes of senescence and the effects of evolution’s selection mechanisms.

2. An epigenetic clock review by committee, particularly in:

  • Challenge 3 “Integration of epigenetics into large and diverse longitudinal population studies”;
  • Challenge 5 “Single-cell analysis of aging changes and disease”; and
  • Table 1 “Major biological and analytic issues with epigenetic DNA methylation clocks” with single-cell analysis as the solution to five Significant issues.

Clearing out the 2019 queue of interesting papers

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Oxytocin, Serotonin, Stress , , , , , , , ,

I’m clearing out the below queue of 27 studies and reviews I’ve partially read this year but haven’t taken the time to curate. I have a pesky full-time job that demands my presence elsewhere during the day. :-\

Should I add any of these back in? Let’s be ready for the next decade!

Early life

https://link.springer.com/article/10.1007/s12035-018-1328-x “Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid” (not freely available)

https://www.sciencedirect.com/science/article/pii/S0166432818309392 “Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex” (not freely available)

https://www.nature.com/articles/s41380-018-0265-4 “Intergenerational transmission of depression: clinical observations and molecular mechanisms” (not freely available)

mother

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454089/ “Epigenomics and Transcriptomics in the Prediction and Diagnosis of Childhood Asthma: Are We There Yet?”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628997/ “Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770436/ “Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study”

https://www.sciencedirect.com/science/article/pii/S0889159119306440 “Environmental influences on placental programming and offspring outcomes following maternal immune activation”

https://academic.oup.com/mutage/article-abstract/34/4/315/5581970 “5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns” (not freely available)

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP278270 “Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13751 “Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811979/ “Genome-wide DNA methylation data from adult brain following prenatal immune activation and dietary intervention”

https://link.springer.com/article/10.1007/s00702-019-02048-2 “miRNAs in depression vulnerability and resilience: novel targets for preventive strategies”

Later life

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543991/ “Effect of Flywheel Resistance Training on Balance Performance in Older Adults. A Randomized Controlled Trial”

https://www.mdpi.com/2411-5142/4/3/61/htm “Eccentric Overload Flywheel Training in Older Adults”

https://www.nature.com/articles/s41577-019-0151-6 “Epigenetic regulation of the innate immune response to infection” (not freely available)

https://link.springer.com/chapter/10.1007/978-981-13-6123-4_1 “Hair Cell Regeneration” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422915/ “Histone Modifications as an Intersection Between Diet and Longevity”

https://www.sciencedirect.com/science/article/abs/pii/S0306453019300733 “Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0047637419300338 “Frailty biomarkers in humans and rodents: Current approaches and future advances” (not freely available)

https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12901 “Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627480/ “In Search of Panacea—Review of Recent Studies Concerning Nature-Derived Anticancer Agents”

https://www.sciencedirect.com/science/article/abs/pii/S0028390819303363 “Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus” (not freely available)

https://www.futuremedicine.com/doi/10.2217/epi-2019-0102 “Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834159/ “The Beige Adipocyte as a Therapy for Metabolic Diseases”

https://www.sciencedirect.com/science/article/abs/pii/S8756328219304077 “Bone adaptation: safety factors and load predictability in shaping skeletal form” (not freely available)

https://www.nature.com/articles/s41380-019-0549-3 “Successful treatment of post-traumatic stress disorder reverses DNA methylation marks” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0166223619301821 “Editing the Epigenome to Tackle Brain Disorders” (not freely available)

An epigenetic clock review by committee

gettingwell4 2-3 stars Required further work, Beliefs, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Memory, Stress, Telomeres , , , , ,

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

1. Citations of 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 all 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, 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 Horvath average biological age of 3.95 years less raised the question: exactly why did PhenoAge show such a large difference?
  • The paper mentioned GrimAge methodology findings about “smoking-related changes.” But it didn’t explain why 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 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

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Brain development, Cerebellum, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress , , , , , , ,

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)

Organismal aging and cellular senescence

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Hypothalamus, Immune system, Limbic system, Memory, Stress, Telomeres , , , , ,

I’ll curate this 2019 German review through its figures:

“With the discovery of beneficial aspects of cellular senescence and evidence of senescence being not limited to replicative cellular states, a redefinition of our comprehension of aging and senescence appears scientifically overdue.

Figure 1. Current determinants and relevant open questions, marking the processes of aging and senescence as discussed in the text. Aspects represented in green are considered as broadly accepted or scientifically consolidated. Novel aspects that are yet unproven, or are under debate, are highlighted in red.

SASP = senescence-associated secretory phenotype. AASP = putative aging-associated secretory phenotype as suggested in the text.

Figure 2. Theories on the causality and purpose of aging. Graphically summarized are four contrasting concepts crystallized from current evidence addressing the inductive driving force of aging. Apart from a stochastic deleteriome, there are arguments for a pseudo-programmed, programmed or at least partially programmed nature of aging.

Figure 3. Comparative representation of the aging and senescence processes highlighting different levels of interaction and putative sites of interventions.

(1) As discussed in the text, causative mechanisms of aging are still not well understood, however, multiple factors including genetic, epigenetic and stress-related effects seem to have an orchestrated role in the progression of aging. Senescence on the other hand, is seen as a programmed response to different kinds of stressors, which proceed in defined stages. Whether, in analogy, aging also follows a defined program or sequential stages is not known.

(2) Senescence involves autocrine and paracrine factors, which are responsible for a ‘seno-infection’ or bystander effect in neighboring cells. There is currently no direct evidence for a similar factor composition propagating the aging process via a kind of ‘gero-infection’.

(3) Accumulation of senescent cells has been described as a hallmark of aging; however, whether they are a causative factor or a consequence of tissue and organismal aging is still unknown. As discussed in the text, it appears possible that aging and senescence mutually influence each other through positive feedback at this level, leading to accelerated tissue damage and aging.

(4,5) Clearance of senescent or aging cells might constitute putative targets for interventional approaches aimed to reduce or reverse the impact of aging and improve cell and tissue homeostasis by inducing a ‘rejuvenation’ process.

Figure 4. Pathological and beneficial functions of aging and senescence, according to current knowledge. In red are represented pathological consequences and in green beneficial functions of aging and senescence.

The impact of aging has mainly been described at the organismal level, since a complete cellular functional profile has not yet been established. Accordingly, whether beneficial consequences of the aging process exist at the cellular level is unclear.”

The assertion of Figure 3 (2) that:

“There is currently no direct evidence for a similar factor composition propagating the aging process via a kind of ‘gero-infection.”

was shown to be false in Reevaluate findings in another paradigm:

“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. A 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 reduced output of GnRH.”

The reviewers’ position on Figure 2 was:

“In our view, recent evidence that

  • Senescence is based on an unterminated developmental growth program and the finding that
  • The concept of post-mitotic senescence requires the activation of expansion, or ‘growth’ factors as a second hit,

favor the assumption that aging underlies a grating of genetic determination similarly to what is summarized above under the pseudo-programmed causative approach.”

Their position on Figure 4’s beneficial effects of aging began with the sentence:

“If we assume that aging already starts before birth, it can be considered simply a developmental stage, required to complete the evolutionary program associated with species-intrinsic biological functions such as reproduction, survival, and selection.”

Cited studies included:

https://www.mdpi.com/2073-4409/8/11/1446 “Dissecting Aging and Senescence-Current Concepts and Open Lessons”

May you be the hero who solves your own problems

gettingwell4 2-3 stars Required further work, Primal Therapy , ,

This 2019 Germany/US review subject was the failure of psychotherapy and pharmacotherapy:

“Each mental disorder raises its own host of issues. However, recent evidence across multiple meta-analyses on key mental disorders provides an overarching picture of limited benefits for both psychotherapy and pharmacotherapy.

Some differences for specific disorders are not strong enough to weaken the overall impression that a dead end has been reached in the treatment of mental disorders. For this reason, a paradigm shift seems to be required.”

Investigate the above linked Primal Therapy category to figure out what you could do for yourself. Follow the below review link for reasons to avoid treatments that waste your one precious life.

https://www.cambridge.org/core/journals/psychological-medicine/article/toward-a-paradigm-shift-in-treatment-and-research-of-mental-disorders/FDE68FF26E946276A334FA90ACE28D9F/core-reader “Toward a paradigm shift in treatment and research of mental disorders”

Transgenerational epigenetic inheritance of thyroid hormone sensitivity

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Hypothalamus, Limbic system, Stress , , , , ,

My 500th 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:

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

gettingwell4 2-3 stars Required further work, Epigenetics, Stress

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.”

gr2_lrg.jpg

“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”

Effects of advanced glycation end products on quality of life and lifespan

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Stress ,

This 2018 Chinese review concerned advanced glycation end products (AGE) mobility interventions:

“Only a limited number of studies have focused on measuring the effects of low AGEs levels or AGEs inhibitors on mobility, although many observational human studies and in vitro studies have reported the correlation of AGEs with and the contribution of AGEs to mobility, particular in diseases such as:

  • osteoporosis,
  • cartilage degradation,
  • osteoarthritis and
  • sarcopenia.

There is insufficient information from previous animal and human studies for use as a reference to determine the intervention period. Although serum AGEs levels can be easily affected by a lower AGEs diet or AGEs inhibitors, it may take longer to see the changes in certain organs or tissues, as a result of a reduction in AGEs accumulation.”

“Effect of AGEs on apoptosis signalling. AP-1, activator protein 1; ERK, extracellular signal-regulated protein kinases; IGF-I, insulin-like growth factor I; IL-6, interleukin-6; JAK, Janus kinase; JNK, c-Jun N-terminal kinases; MEK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; p38 MAPK, p38 mitogen-activated protein kinase; RAGE, receptor for AGEs; STAT3, signal transducers and activators of transcription 3; TGF-β, transforming growth factor-β”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180645/ “Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies”

Citations aren’t validations of the reference’s quality and strength of evidence. This review would have benefited from not citing reviews that contained misrepresentations, such as one mentioned in Wikipedia is a poor source of information on advanced glycation end products (AGEs).

I came across this review as a result of it citing the excellent 2008 rodent study Oral Glycotoxins Determine the Effects of Calorie Restriction on Oxidant Stress, Age-Related Diseases, and Lifespan which found:

“Higher levels of oxidant AGEs in offspring of Reg-F0 dams may be attributable to placental transmission from mothers with high AGE levels. These high intrauterine AGE levels may predispose the offspring to the development of chronic inflammation and diseases in adulthood, such as insulin resistance and diabetes.

Increasing the intake of AGEs in the diet erases the benefits of CR [calorie restriction]. OS [oxidant stress] can be reduced, and healthspan increased, in mice fed a diet that is restricted in the content of AGEs.

The beneficial effects of a CR diet may be partly related to reduced oxidant intake rather than decreased energy intake.”

A drug that countered effects of a traumatizing mother

gettingwell4 2-3 stars Required further work, Acetylcholine, Amygdala, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Oxytocin, Stress, Telomeres , , , , , , , , , , ,

This 2019 US rodent study concerned transmitting poor maternal care to the next generation:

“The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. Infant experiences with a caregiver have lifelong behavioral consequences.

Maternal behavior is a complex behavior requiring the recruitment of multiple brain regions including the nucleus accumbens, bed nucleus of the stria terminalis, ventral tegmental area, prefrontal cortex, amygdala, and medial preoptic area. Dysregulation within this circuitry can lead to altered or impaired maternal responsiveness.

We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring.

  1. We replicate that dams with a history of maltreatment mistreat their own offspring.
  2. We show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring.
  3. We show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care.
  4. We show altered methylation and gene expression in maltreated dams normalized by zebularine.

These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.

Maternal behavior is an intergenerational behavior. It is important to establish the neurobiological underpinnings of aberrant maternal behavior and explore treatments that can improve maternal behavior to prevent the perpetuation of poor maternal care across generations.”

The study authors demonstrated intergenerational epigenetic effects, and missed an opportunity to also investigate transgenerational epigenetically inherited effects. They cited reference 60 for the first part of the above quotation, but the cited reviewer misused the transgenerational term by applying it to grand-offspring instead of the great-grand-offspring.

There were resources available to replicate the study authors’ previous findings, which didn’t show anything new. Why not use such resources to uncover evidence even more applicable to humans by extending experiments to great-grand-offspring that would have no potential germline exposure to the initial damaging cause?

Could a study design similar to A limited study of parental transmission of anxiety/stress-reactive traits have been integrated? That study’s thorough removal of parental behavior would be an outstanding methodology to confirm by falsifiability whether parental behavior is both an intergenerational and a transgenerational epigenetic inheritance mechanism.

Rodent great-grand-offspring can be studied in < 9 months. It takes > 50 years for human studies to reach the great-grand-offspring transgenerational generation.

  • Why not attempt to “prevent the perpetuation of poor maternal care across generations?”
  • Isn’t it a plausible hypothesis that humans “with a history of maltreatment mistreat their own offspring?”
  • Isn’t it worth the extra effort to extend animal research to investigate this unfortunate chain?

https://www.nature.com/articles/s41598-019-46539-4 “Pharmacological manipulation of DNA methylation normalizes maternal behavior, DNA methylation, and gene expression in dams with a history of maltreatment”

Linking adult neurogenesis to Alzheimer’s disease

gettingwell4 2-3 stars Required further work, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Stress , , , , , ,

This 2019 Spanish human study compared DNA methylation, chromatin and histone modifications in the hippocampus of deceased Alzheimer’s disease patients with controls:

“A significant percentage of the differentially methylated genes were related to neural development and neurogenesis. It was astounding that other biological, cellular, and molecular processes generally associated with neurodegeneration such as apoptosis, autophagy, inflammation, oxidative stress, and mitochondrial or lysosomal dysfunction were not overrepresented.

The results of the present study point to neurogenesis-related genes as targets of epigenetic changes in the hippocampus affected by AD. These methylation changes might be built throughout life due to external and internal cues and would represent an example of epigenetic interaction between environmental and genetic factors in developing AD.

As an alternative explanation, these epigenetic marks might also represent the trace of DNA methylation alterations induced during early developmental stages of the hippocampus, which would remain as a fingerprint in the larger proportion of hippocampal neurons that are not exchanged. This second hypothesis would link AD to early life stages, in concordance with recent studies that revealed abnormal p-tau deposits (pre-tangles) in brains of young individuals under 30, suggesting AD pathology would start earlier in life than it was previously thought. The influence of the genetic risk for AD has also been postulated to begin in early life, and other AD risk factors may be influenced by in utero environment.”

The study cited references to adult neurogenesis:

“Though strongly related to brain development, neurogenesis is also maintained in the adult human brain, mainly in two distinct areas, i.e., the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. There is substantial neurogenesis throughout life in the human hippocampus as it is estimated that up to one third of human hippocampal neurons are subject to constant turnover.

Adult neurogenesis is linked to hippocampal-dependent learning and memory tasks and is reduced during aging. Recent evidence suggests that adult neurogenesis is altered in the neurodegenerative process of AD, but it is still controversial with some authors reporting increased neurogenesis, whereas others show reduced neurogenesis. In the human hippocampus, a sharp drop in adult neurogenesis has been observed in subjects with AD.”

One of the study’s limitations was its control group:

“There was a significant difference in age between controls [12, ages 50.7 ± 21.5] and AD patients [26, ages 81.2 ± 12.1], being the latter group older than the former group. Although we adjusted for age in the statistical differential methylation analysis, the accuracy of this correction may be limited as there is little overlap in the age ranges of both groups.”

https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-019-0672-7 “DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis”

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.”

Statistical inferences vs. biological realities

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory, Stress, Telomeres , ,

A 2019 UCLA study introduced a derivative of the epigenetic clock named GrimAge:

“DNAm GrimAge, a linear combination of chronological age, sex, and DNAm-based surrogate biomarkers for seven plasma proteins and smoking pack-years, outperforms all other DNAm-based biomarkers, on a variety of health-related metrics.

An age-adjusted version of DNAm GrimAge, which can be regarded as a new measure of epigenetic age acceleration (AgeAccelGrim), is associated with a host of age-related conditions, lifestyle factors, and clinical biomarkers. Using large scale validation data from three ethnic groups, we demonstrate that AgeAccelGrim stands out among pre-existing epigenetic clocks in terms of its predictive ability for time-to-death, time-to-coronary heart disease, time-to-cancer, its association with computed tomography data for fatty liver/excess fat, and early age at menopause.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366976/ “DNA methylation GrimAge strongly predicts lifespan and healthspan”

A miserable attempt at reporting the study’s findings included angles of superstition, fear-of-the-future, and suspicion-by-spurious-association:

“The research has already captured the attention of the life insurance industry. After all, a solid death date could mean real savings when it comes to pricing policies.

The hope is that if and when legitimate anti-aging drugs are developed, GrimAge could be used to test their effectiveness. In a world with functional anti-aging drugs, “doctors could test [your GrimAge number] and say, ‘You know what, you’re aging too quickly. Take this,'” Horvath said.”

https://onezero.medium.com/a-new-test-predicts-when-youll-die-give-or-take-a-few-years-2d08147c8ea6 “A New Test Predicts When You’ll Die (Give or Take a Few Years)”

A detailed blog post from Josh Mitteldorf provided scientific coverage of the study:

“Methylation sites associated with smoking history predicted how long the person would live more accurately than the smoking history itself. Even stranger, the methylation marks most closely associated with smoking were found to be a powerful indication of future health even when the sample was confined to non-smokers.

The DNAm GrimAge clock was developed in two stages, a correlation of a correlation. Curiously, the indirect computation yields the better result.

Horvath’s finding that secondary methylation indicators are more accurate than the underlying primary indicator from which they were derived is provocative, and calls out for a new understanding.”

https://joshmitteldorf.scienceblog.com/2019/03/05/dnam-grimage-the-newest-methylation-clock “DNAm GrimAge—the Newest Methylation Clock”

When there are logical disconnects in findings like the above, it’s time to examine underlying premises. As noted in Group statistics don’t necessarily describe an individual, an assumption required by statistical analyses is that each measured item in the sample is interchangeable with the next.

This presumption is often false, producing individually inapplicable results. For example, Immune memory vs. immune adaptation included this description of the adaptive immune system:

“To be effective, highly specific immune response requires huge diversity of receptors and antibodies, which is achieved by somatic rearrangement of gene segments. Recombination results in millions of TCR [T cell receptor] and antibody variants able to recognize and neutralize millions of various antigens.”

Standard statistics of millions of T cell receptor and antibody variants won’t represent their individually unique properties. But individual differences are both their purpose and benefit to us.

The GrimAge study’s overreach was most apparent in stratifying educational attainment to develop correlations. As mentioned in Does a societal mandate cause DNA methylation? such statistics are poor evidence of each individual’s biological realities.

Neither derivatives of group statistics, nor correlations of correlations, seem to be the techniques needed to understand biological causes of effects. Another commentary on the GrimAge study mentioned but glossed over this point:

“It remains a mystery why exactly the epigenetic clocks work, and whether age-related changes in DNA methylation contribute to the cause of aging or are a result of it.”

Immune memory vs. immune adaptation

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory ,

This 2019 Dutch/German/Romanian perspective aimed for a better understanding of immune systems:

“Based on molecular, immunological, and evolutionary arguments, we propose that innate immune memory is a primitive form of immune memory present in all living organisms, while adaptive immune memory is an advanced form of immune memory representing an evolutionary innovation in vertebrates.

Innate immune responses have the capacity to be trained, and thereby exert a new type of immunological memory upon reinfection. The central feature of trained innate immune cells is their ability to mount a qualitatively and quantitatively different transcriptional response when challenged with microbes or danger signals. Evidence supports convergence of multiple regulatory layers for mediating innate immune memory, including changes in chromatin organization, DNA methylation, and probably non-coding RNAs such as microRNAs and/or long non-coding RNAs.

Two properties of adaptive immune response are mediated by two fundamentally different types of mechanisms:

  1. Higher magnitude and speed of the response is mediated by epigenetic programming.
  2. Specificity of the response is insured by gene recombination of TCR [T cell receptor] and BCR [B cell receptor] and clonal expansion of specific cell subpopulations upon antigen recognition.

To be effective, highly specific immune response requires huge diversity of receptors and antibodies, which is achieved by somatic rearrangement of gene segments. Recombination results in millions of TCR and antibody variants able to recognize and neutralize millions of various antigens.“

This paper included speculations such as “Evidence supports..probably non-coding RNAs” quoted above, and the penultimate sentence:

“One can envision that vaccines that are capable of inducing both forms of immune memory at the same time would be more effective.”

100% factual evidence is preferred. Overall information can only be as accurate as the least accurate information.

This review highlighted a goal for humans to have both a functional innate immune system and a functional adaptive immune system. The lead author coauthored A dietary supplement that trains the innate immune system and a study referenced in Eat your oats.

https://www.sciencedirect.com/science/article/pii/S1931312818306334 “Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host’s Response to Pathogens” (not freely available)

Our brains are shaped by our early environments

gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Lower brain, Memory, Neurochemicals, Oxytocin, Primal Therapy, Serotonin, Stress , , , , , , , , , , ,

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)