Telomeres

Reversing epigenetic changes with CRISPR/Cas9

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Limbic system, Stress, Telomeres , , , , ,

This 2018 Chinese review highlighted areas in which CRISPR/Cas9 technology has, is, and could be applied to rewrite epigenetic changes:

“CRISPR/Cas9-mediated epigenome editing holds a great promise for epigenetic studies and therapeutics.

It could be used to selectively modify epigenetic marks at a given locus to explore mechanisms of how targeted epigenetic alterations would affect transcription regulation and cause subsequent phenotype changes. For example, inducing histone methylation or acetylation at the Fosb locus in the mice brain reward region, nucleus accumbens, could affect relevant transcription network and thus control behavioral responses evoked by drug and stress.

Epigenome editing has the potential for epigenetic treatment, especially for the disorders with abnormal gene imprinting or epigenetic marks. Targeted epigenetic silencing or reactivation of the mutant allele could be a potential therapeutic approach for diseases such as Rett syndrome and Huntington’s disease.

Noncoding RNA plays important roles in gene imprinting and chromatin remodeling. CRISPR/Cas9 has been shown to be potential for manipulating noncoding RNA expression, including microRNA, long noncoding RNA, and miRNA families and clusters.

In vivo overexpression of the Yamanaka factors have proven to be able to fully or partially help somatic cells to regain pluripotency in situ. These rejuvenated cells would subsequently differentiate again to replace the lost cell types.”

The last paragraph was described in The epigenetic clock theory of aging as a promising technique:

“To date, the most effective in vitro intervention against epigenetic ageing is achieved through expression of Yamanaka factors, which convert somatic cells into pluripotent stem cells, thereby completely resetting the epigenetic clock.”

The reviewers cited three references for in vivo studies of this technique. Overall, I didn’t see that any of the review’s references were in vivo human studies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079388/ “Novel Epigenetic Techniques Provided by the CRISPR/Cas9 System”

The epigenetic clock now includes skin

gettingwell4 5+ stars Premium, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Telomeres , , , , , ,

The originator of the 2013 epigenetic clock improved its coverage with this 2018 UCLA human study:

“We present a new DNA methylation-based biomarker (based on 391 CpGs) that was developed to accurately measure the age of human fibroblasts, keratinocytes, buccal cells, endothelial cells, skin and blood samples. We also observe strong age correlations in sorted neurons, glia, brain, liver, and bone samples.

The skin & blood clock outperforms widely used existing biomarkers when it comes to accurately measuring the age of an individual based on DNA extracted from skin, dermis, epidermis, blood, saliva, buccal swabs, and endothelial cells. Thus, the biomarker can also be used for forensic and biomedical applications involving human specimens.

The biomarker applies to the entire age span starting from newborns, e.g. DNAm of cord blood samples correlates with gestational week.

Furthermore, the skin & blood clock confirms the effect of lifestyle and demographic variables on epigenetic aging. Essentially it highlights a significant trend of accelerated epigenetic aging with sub-clinical indicators of poor health.

Conversely, reduced aging rate is correlated with known health-improving features such as physical exercise, fish consumption, high carotenoid levels. As with the other age predictors, the skin & blood clock is also able to predict time to death.

Collectively, these features show that while the skin & blood clock is clearly superior in its performance on skin cells, it crucially retained all the other features that are common to other existing age estimators.”

http://www.aging-us.com/article/101508/text “Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies”

An introduction to the study highlighted several items:

“Although the skin-blood clock was derived from significantly less samples (~900) than Horvath’s clock (~8000 samples), it was found to more accurately predict chronological age, not only across fibroblasts and skin, but also across blood, buccal and saliva tissue. A potential factor driving this improved accuracy in blood could be related to the approximate 18-fold increase in genomic coverage afforded by using Illumina 450k/850k beadarrays.

It serves as a roadmap for future clock studies, pointing towards the importance of constructing tissue or cell-type specific epigenetic clocks, to more accurately measure biological aging in the given tissue/cell-type, and therefore with the potential to be more informative of disease-risk or the success of disease interventions in the tissue or cell-type of interest.”

http://www.aging-us.com/article/101533/text “Epigenetic clocks galore: a new improved clock predicts age-acceleration in Hutchinson Gilford Progeria Syndrome patients”

Hijacking the epigenetic clock paradigm

gettingwell4 < 0 Detracted from science, Epigenetics, Telomeres

This 2018 German human study’s last sentence was:

“Additionally we found an association between DNAm [DNA methylation] age acceleration and rLTL [relative leukocyte telomere length], suggesting that this epigenetic clock, at least partially and possibly better than other epigenetic clocks, reflects biological age.”

Statements in the study that contradicted, qualified, and limited the concluding sentence included:

“The epigenetic clock seems to be mostly independent from the mitotic clock as measured by the rLTL.

It could be possible that associations are confounded due to short age ranges or non-continuous age distribution, as displayed in the BASE-II cohort (no participants between the age of 38 and 59 years). [see the below graphic]

The BASE-II is a convenience sample and participants have been shown to be positively selected with respect to education, health and cognition.

Samples in which DNAm age and chronological age differed more than three standard deviations from the mean were excluded (N=19).

While the original publication employed eight CpG sites for DNAm age estimation, we found that one of these sites did not significantly improve chronological age prediction in BASE-II. Thus, we reduced the number of sites considered to seven in the present study and adapted the algorithm to calculate DNAm age.

  • Horvath described a subset of 353 methylation sites predicting an individual’s chronological age with high accuracy..
  • Even though the available methods using more CpG sites to estimate DNAm age predict chronological age with higher accuracy..
  • It is not clear how much of the deviation between chronological age and DNAm age reflects measurement error/low number of methylation sites and which proportion can be attributed to biological age.

Due to the statistical method employed, we encountered a systematic deviation of DNAm age in our dataset.”

Findings that aren’t warranted by the data is an all-too-common problem with published research. This study illustrated how researcher hypothesis-seeking behavior – that disregarded what they knew or should have known – can combine with a statistics package to produce almost any finding.

It reminded me of A skin study that could have benefited from preregistration that made a similar methodological blunder:

The barbell shape of the subjects’ age distribution wouldn’t make sense if the researchers knew they were going to later use the epigenetic clock method.

The researchers did so, although the method’s instructive study noted:

“The standard deviation of age has a strong relationship with age correlation”

and provided further details in “The age correlation in a data set is determined by the standard deviation of age” section.

Didn’t the researchers, their organizations, and their sponsors realize that this study’s problematic design and performance could misdirect readers away from the valid epigenetic clock evidence they referenced? What purposes did it serve for them to publish this study?

https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/gly184/5076188 “Epigenetic clock and relative telomere length represent largely different aspects of aging in the Berlin Aging Study II (BASE-II)” (not freely available)

Epigenetic effects of breast cancer treatments

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

This 2018 UC San Diego review subject was the interplay between breast cancer treatments and their effects on aging:

“Although current breast cancer treatments are largely successful in producing cancer remission and extending lifespan, there is concern that these treatments may have long lasting detrimental effects on cancer survivors, in part, through their impact on non-tumor cells. It is unclear whether breast cancer and/or its treatments are associated with an accelerated aging phenotype.

In this review, we have highlighted five of nine previously described cellular hallmarks of aging that have been described in the context of cytotoxic breast cancer treatments:

  1. Telomere attrition;
  2. Mitochondrial dysfunction;
  3. Genomic instability;
  4. Epigenetic alterations; and
  5. Cellular senescence.”

The review was full of caveats weakening the above graphic’s associations:

  1. “Telomere attrition – Blood TL [telomere length] was not associated with chemotherapy in three out of four studies;
  2. Mitochondrial dysfunction – How cancer therapies affect cellular energetics as they relate to rate of aging is unclear;
  3. Genomic instability – Potentially contributing to accelerated aging;
  4. Epigenetic alterations – Although some of the key regulators of these processes have begun to be identified, including DNA and histone methylases and demethylases, histone acetylases and de-acetylases and chromatin remodelers, how they regulate the changes in aging through alteration of global transcriptional programs, remains to be elucidated; and
  5. Cellular senescence – Dysregulated pathways can be targeted by cytotoxic chemotherapies, resulting in preferential cell death of tumor cells, but how these treatments also affect normal cells with intact pathways is unclear.”

To their credit, these reviewers at least presented some of the contrary evidence, and didn’t continue on with a directed narrative as other reviewers are prone to do.

https://www.sciencedirect.com/science/article/pii/S1879406818301176 “Breast cancer treatment and its effects on aging” (not freely available)

The originator of the epigenetic clock methodology was a coauthor of the review. Only one of his works was cited in the Epigenetic alterations subsection:

https://link.springer.com/article/10.1007%2Fs10549-017-4218-4 “DNA methylation age is elevated in breast tissue of healthy women”

This freely-available 2017 study quoted below highlighted that epigenetic clock measurements as originally designed were tissue-specific:

“To our knowledge, this is the first study to demonstrate that breast tissue epigenetic age exceeds that of blood tissue in healthy female donors. In addition to validating our earlier finding of age elevation in breast tissue, we further demonstrate that the magnitude of the difference between epigenetic age of breast and blood is highest in the youngest women in our study (age 20–30 years) and gradually diminishes with advancing age. As women approach the age of the menopausal transition, we found that the epigenetic of age of blood approaches that of the breast.”

Additional caution was justified in both interpreting age measurements and extending them into “cellular hallmarks” when the tissue contained varying cell types:

“Our studies were performed on whole breast tissue. Diverse types of cells make up whole breast tissue, with the majority of cells being adipocytes. Other types of cells include epithelial cells, cuboidal cells, myoepithelial cells, fibroblasts, inflammatory cells, vascular endothelial cells, preadipocytes, and adipose tissue macrophages.

This raises the possibility that the magnitude of the effects we observe, of breast tissue DNAm age being greater than other tissues, might be an underestimation, since it is possible that not all of the cells of the heterogenous sample have experienced this effect. Since it is difficult to extract DNA from adipose tissue, we suspect that the majority of DNA extracted from our whole breast tissues was from epithelial and myoepithelial cells.”

Starving awakens ancient parasite DNA within us

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Stress, Telomeres , ,

This 2018 Italian human cell study conducted a series of experiments on the effects of nutrient deprivation:

“Reduced food intake, and in particular protein or amino acid (AA) restriction, extends lifespan and healthspan.

We have previously shown that, in mammalian cells, deprivation of essential AAs (methionine/cysteine or tyrosine) leads to the transcriptional reactivation of integrated silenced transgenes by a process involving epigenetic chromatic remodeling and histone acetylation.

Here we show that the deprivation of methionine/cysteine also leads to the transcriptional upregulation of endogenous retroviruses [ERVs], suggesting that essential AA starvation affects the expression not only of exogenous non-native DNA sequences, but also of endogenous anciently-integrated and silenced parasitic elements of the genome.

ERVs, comprising 8% of the human genome, represent the remnants of past infections of germ cells by exogenous retroviruses, and are mostly unable to retrotranspose in the human genome. However, they can reactivate during physiological development, or in pathological conditions like cancer, and regulate the expression of nearby genes by their LTR elements, leading to general transcriptional reprogramming.

Dissection of the underlying mechanism ruled out a role for the main AA-deficiency sensor GCN2 and pointed to the ribosome as the possible master controller.”

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200783 “Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences”

The study found that reality is sometimes stranger than what fiction writers dream up. 🙂

The authors cited a 2016 Danish review I hadn’t previously curated:

https://www.nature.com/articles/nrendo.2016.87 “The role of diet and exercise in the transgenerational epigenetic landscape of T2DM” (not freely available)

Contrary to what’s implied by its title, though, and as I noted in How to hijack science: Ignore its intent and focus on the 0.0001%, those reviewers didn’t cite any human studies that adequately demonstrated transgenerational epigenetic inheritance causes and effects. They admitted:

“Direct evidence that epigenetic factors drive the inheritance of T2DM [type 2 diabetes mellitus] in humans is lacking.”

The Danish reviewers then continued on as if proof of human transgenerational epigenetic inheritance was a foregone conclusion! It didn’t serve any valid scientific purpose to assume such evidence into existence.

A mid-year selection of epigenetic topics

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Anterior cingulate cortex, Beliefs, Brain development, Brainstem, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Telomeres, Testosterone, Vasopressin , , , , , , , , , , , , , , , , , ,

Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:

The pain societies instill into children

DNA methylation and childhood adversity

Epigenetic mechanisms of muscle memory

Sex-specific impacts of childhood trauma

Sleep and adult brain neurogenesis

This dietary supplement is better for depression symptoms than placebo

The epigenetic clock theory of aging

A flying human tethered to a monkey

Immune memory in the brain

The lack of oxygen’s epigenetic effects on a fetus

An evolutionary view of stress and cancer

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

This 2018 Michigan review subject was cancer evolution:

“Based on the fact that cancer typically represents a complex adaptive system, where there is no linear relationship between lower-level agents (such as each individual gene mutation) and emergent properties (such as cancer phenotypes), we call for a new strategy based on the evolutionary mechanism of aneuploidy [abnormal number of chromosomes] in cancer, rather than continuous analysis of various individual molecular mechanisms.

Cancer evolution can be understood by the dynamic interaction among four key components:

  1. Internal and external stress;
  2. Elevated genetic and non-genetic variations (either necessary for cellular adaptation or resulting from cellular damages under stress);
  3. Genome-based macro-cellular evolution (genome replacement, emergent as new systems); and
  4. Multiple levels of system constraint which prevent/slow down cancer evolution (from tissue/organ organization to the immune system interaction).

Since the sources of stress are unlimited and unavoidable (as they are required by all living systems), there are large numbers of gene mutations / epigenetic events / chromosomal aberrations, such as aneuploidy, that can be linked to stress-mediated genomic variants. Furthermore, as environmental constraints are constantly changing, even identical instances of aneuploidy will have completely different outcomes in the context of cancer evolution, as the results of each independent run of evolution will most likely differ.

Most current research efforts are focusing on molecular profiles based on an average population, and outliers are eliminated or ignored, either by the methods used or statistical tools. The traditional view of biological research is to identify patterns from “noise,” without the realization that the so-called “noise” in fact is heterogeneity, which represents a key feature of cancer evolution by functioning as the evolutionary potential.

Understanding the molecular mechanism (both cause and effect) of aneuploidy is far from enough. A better strategy is to monitor the evolutionary process by measuring evolutionary potential. For example, the overall degree of CIN [chromosome instability] is more predictive than individual gene mutation profile.”

Although I read many abstracts of cancer research papers every week, I usually don’t curate them. I curated this paper because the reviewers emphasized several themes of this blog, including:

  • Further examples of how stress may shape one’s life.
  • How researchers miss information when they ignore or process away variation:

    “Studies have demonstrated the importance of outliers in cancer evolution, as cancer is an evolutionary game of outliers. While this phenomenon can provide a potential advantage for cellular adaptation, it can also, paradoxically, generate non-specific system stress, which can further produce more genetic and non-genetic variants which favor the disease condition.”

Epigenetics researchers may benefit from evolutionary viewpoints that incorporate the interactions of stress and “genetic and non-genetic variants.”

Since epigenetic changes require inheritance in order to persist, it would be a step forward to see researchers start “measuring evolutionary potential” of these inheritance processes.

https://molecularcytogenetics.biomedcentral.com/articles/10.1186/s13039-018-0376-2 “Understanding aneuploidy in cancer through the lens of system inheritance, fuzzy inheritance and emergence of new genome systems”

in utero prevention of breast cancer by a broccoli sprouts diet

gettingwell4 0-1 star Wasted resources, Brain development, Epigenetics, Telomeres , , , , ,

This 2018 Alabama rodent study investigated the epigenetic effects on developing breast cancer of timing a sulforaphane-based broccoli sprouts diet. Timing of the diet was as follows:

  1. Conception through weaning (postnatal day 28), named the Prenatal/maternal BSp (broccoli sprouts) treatment (what the mothers ate starting when they were adults at 12 weeks until their pups were weaned; the pups were never on a broccoli sprouts diet);
  2. Postnatal day 28 through the termination of the experiment, named the Postnatal early-life BSp treatment (what the offspring ate starting at 4 weeks; the mothers were never on a broccoli sprouts diet); and
  3. Postnatal day 56 through the termination of the experiment, named the Postnatal adult BSp treatment (what the offspring ate starting when they were adults at 8 weeks; the mothers were never on a broccoli sprouts diet).

“The experiment was terminated when the mean tumor diameter in the control mice exceeded 1.0 cm.

Our study indicates a prenatal/maternal BSp dietary treatment exhibited maximal preventive effects in inhibiting breast cancer development compared to postnatal early-life and adult BSp treatments in two transgenic mouse models that can develop breast cancer.

Postnatal early-life BSp treatment starting prior to puberty onset showed protective effects in prevention of breast cancer but was not as effective as the prenatal/maternal BSp treatment. However, adulthood-administered BSp diet did not reduce mammary tumorigenesis.

The prenatal/maternal BSp diet may:

  • Primarily influence histone modification processes rather than DNA methylation processes that may contribute to its early breast cancer prevention effects;
  • Exert its transplacental breast cancer chemoprevention effects through enhanced histone acetylation activator markers due to reduced HDAC1 expression and enzymatic activity.

This may be also due to the importance of a dietary intervention window that occurs during a critical oncogenic transition period, which is in early life for these two tested transgenic mouse models. Determination of a critical oncogenic transition period could be complicated in humans, which may partially explain the controversial findings of the adult BSp treatment on breast cancer development in the tested mouse models as compared the previous studies. Thus long-term consumption of BSp diet is recommended to prevent cancers in humans.”

“The dietary concentration for BSp used in the mouse studies was 26% BSp in formulated diet, which is equivalent to 266 g (~4 cups) BSp/per day for human consumption. Therefore, the concentration of BSp in this diet is physiological available and represents a practical consumption level in the human diet.

Prior to the experiment, we tested the potential influences of this prenatal/maternal BSp regimen on maternal and offspring health as well as mammary gland development in the offspring. Our results showed there was no negative effect of this dietary regimen on the above mentioned factors (data not shown) suggesting this diet is safe to use during pregnancy.”

I downgraded the study’s rating because I didn’t see where the above-labelled “Broccoli Sprout Seeds” content of the diet was defined. It’s one thing to state:

“SFN as the most abundant and bioactive compound in the BSp diet has been identified as a potent HDAC inhibitor that preferably influences histone acetylation processes.”

and describe how sulforaphane may do this and may do that, and include it in the study’s title. It’s another thing to quantify an animal study into findings that can help humans.

The study’s food manufacturer offers dietary products to the public without quantifying all of the contents. Good for them if they can stay in business by serving customers who can’t be bothered with scientific evidence.

What’s the difference between the above-labelled “Broccoli Sprout Seeds” and broccoli seeds? Where was the evidence that “Broccoli Sprout Seeds” and SPROUTED “Broccoli Sprout Seeds” were equivalent to the point of claiming:

“Equivalent to 266 g (~4 cups) BSp/per day for human consumption. Therefore, the concentration of BSp in this diet is physiological available and represents a practical consumption level in the human diet.”

To help humans, this animal study had to have more details than the food manufacturer provided. The researchers should have either tasked the manufacturer to specify the “Broccoli Sprout Seeds” content, or contracted out the analysis if they weren’t going to do it themselves.

Regarding timing of a broccoli sprouts diet for humans, the study didn’t provide evidence for recommending:

“Thus long-term consumption of BSp diet is recommended to prevent cancers in humans.”

http://cancerpreventionresearch.aacrjournals.org/content/early/2018/05/15/1940-6207.CAPR-17-0423.full-text.pdf “Temporal efficacy of a sulforaphane-based broccoli sprout diet in prevention of breast cancer through modulation of epigenetic mechanisms”

A trio of epigenetic clock studies

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Stress, Telomeres , , , ,

We’ll start with a 2018 epigenetic clock human study from Finland:

“We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems.

Maternal history of depression diagnosed before pregnancy and greater antenatal depressive symptoms were associated with child’s lower epigenetic GA. Child’s lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys.”

Listening to a podcast by one of the coauthors, although the researchers’ stated intent was to determine the etiology of the findings, I didn’t hear any efforts to study the parents in sufficient detail to be able to detect possible intergenerational and transgenerational epigenetic inheritance causes and effects. There were the usual “associated with” and “it could be this, it could be that” hedges, which were also indicators of the limited methods employed toward the study’s limited design.

Why was an opportunity missed to advance human research in this area? Are researchers satisfied with non-causal individual differences non-explanations instead of making efforts in areas that may produce etiological findings?

https://www.jaacap.org/article/S0890-8567(18)30107-2/pdf “The Epigenetic Clock at Birth: Associations With Maternal Antenatal Depression and Child Psychiatric Problems” (not freely available)

The second 2018 epigenetic clock human study was from Alabama:

“We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations.

Both DNA methylation age estimates were highly correlated with chronological age. We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated.

The Horvath age acceleration measure exhibited marginal associations with increased postprandial [after eating a meal] HDL [high-density lipoprotein], increased postprandial total cholesterol, and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL and positively associated with postprandial TG [triglyceride], interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNFα).

Overall, the observed effect sizes were small.“


https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-018-0481-4 “Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study”

The third 2018 epigenetic clock human study was a meta-analysis of cohorts from the UK, Italy, Sweden, and Scotland:

“The trajectories of Δage showed a declining trend in almost all of the cohorts with adult sample collections. This indicates that epigenetic age increases at a slower rate than chronological age, especially in the oldest population.

Some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like underlying training population for the respective clocks may also have influenced this trend. It may also be possible that there is a ceiling effect for Δage whereby epigenetic clock estimates plateau.”

https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/gly060/4944478 “Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data”

The epigenetic clock theory of aging

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Brain development, Cerebellum, Cerebrum, Epigenetics, Lower brain, Memory, Stress, Telomeres , , , , , , ,

My 400th curation is a 2018 US/UK paper by coauthors of Using an epigenetic clock to distinguish cellular aging from senescence. They reviewed the current state of epigenetic clock research, and proposed a new theory of aging:

“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes, the molecular footprints of which give rise to DNAm [DNA methylation] age estimators.

It is best to interpret epigenetic age estimates as a higher-order property of a large number of CpGs much in the same way that the temperature of a gas is a higher-order property that reflects the average kinetic energy of the underlying molecules. This interpretation does not imply that DNAm age simply measures entropy across the entire genome.

To date, the most effective in vitro intervention against epigenetic ageing is achieved through expression of Yamanaka factors, which convert somatic cells into pluripotent stem cells, thereby completely resetting the epigenetic clock. In vivo, haematopoietic stem cell therapy resets the epigenetic age of blood of the recipient to that of the donor.

Future epidemiological studies should consider other sources of DNA (for example, buccal cells), because more powerful estimates of organismal age can be obtained by evaluating multiple tissues. Other types of epigenetic modifications such as adenine methylation or histone modifications may lend themselves for developing epigenetic age estimators.”


https://www.nature.com/articles/s41576-018-0004-3 “DNA methylation-based biomarkers and the epigenetic clock theory of ageing” (not freely available)

I curated four other papers cited in this review:

Do you want your quality of life to be under or over this curve?

What are you doing to reverse epigenetic processes and realize what you want?

  • Do you have ideas and/or behaviors that interfere with taking constructive actions to change your phenotype?
  • If you aren’t doing anything, are you honest with yourself about feelings of helplessness?
  • Do your beliefs in fate, or in technology, or in divine interventions justify inactions?

Cell senescence and DNA methylation

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

This 2018 Baltimore cell study found:

“Based on similarities in overall methylation patterns in replicative senescence and cancers, it is hypothesized that tumor-promoting DNA methylation in cancers derives from cells escaping senescence.

We show that the tumor-associated methylation changes evolve independently of senescence and are pro-survival events with functional implications contrasting that in senescence.

In our analyses, although overall global gains and losses in DNA methylation are similar, at individual genomic regions the methylation patterns are very different for senescence versus transformation.”

https://www.sciencedirect.com/science/article/pii/S1535610818300084 “DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk” (not freely available)

I hesitated to use the study’s main graphic:
because the “Stochastic” labeling of the upper branch didn’t represent the vector’s meaning. The In Brief and the Summary sections contributed to the misrepresentation by stating:

“transformation-associated methylation changes arise stochastically.”

which wasn’t the study’s main finding:

“Our data outlined in the above sections strongly suggest against this senescence bypass hypothesis.”

Although the experimental design and methods evoked randomness:

“Immortalization on the path to malignant transformation involves stochastic epigenetic patterns from which cells contributing to transformation may evolve.”

the graphic’s upper branch vector represented the cells’ evolutionary responses. The Significance section best characterized what the study found:

“Tumor-associated methylation changes evolve independently of senescence and are pro-survival events.”

Would anyone at John Hopkins argue, as the graphic’s upper branch labeling suggested, that cellular aging is a predominantly random process? NO!

1. Epigenetics research and evolution promoted understanding the graphic’s upper branch vector:

“Evolution is an ongoing set of iterative interactions between organisms and the environment. Directionality is introduced by the agency of organisms themselves.”

2. The current study provided another data point about the uselessness of convenient but non-etiologic, inconsequential measurements of global methylation:

“Although overall global gains and losses in DNA methylation are similar, at individual genomic regions the methylation patterns are very different.”

3. The current study was congruent with the below finding of Using an epigenetic clock to distinguish cellular aging from senescence regarding the differentiation of cellular aging from senescence:

“Cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

The influence of donor age on induced pluripotent stem cell functionality

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Telomeres ,

This 2018 German review subject was the influence of donor age on induced pluripotent stem cell functionality:

“Induced pluripotent stem cells (iPSCs) avoid many of the restrictions that hamper the application of human embryonic stem cells. Also, the donor’s clinical phenotype is often known when working with iPSCs.

Typical signs of cellular ageing are reverted in the process of iPSC reprogramming, and iPSCs from older donors do not show diminished differentiation potential nor do iPSC-derived cells from older donors suffer early senescence or show functional impairments when compared with those from younger donors.”

The reviewers discussed limitations in the current research:

  • “Mutations in nuclear and mitochondrial DNA acquired over the donor’s lifespan and during the reprogramming process might persist.
  • It is not yet known how strongly the variable genetic background of individual donors affects the reprogramming process and the quality of resulting iPSCs.
  • A low number of donors and cell lines is a general problem in almost all research articles on the topic of iPSCs. This combined with the lack of a standardised protocol for optimal iPSC derivation, culture and quality control makes any comparison between different publications very difficult if not impossible. Especially, since it has been shown that many factors influence the quality of iPSCs and iPSC-derived cells, such as time and cell type used for reprogramming, time in culture, or reprogramming modality.
  • A problem lies in the retention of tissue-specific epigenetic alterations which in part could be caused by incomplete reprogramming and might be improved by vigorous quality testing and careful selection of iPSC colonies during reprogramming and passaging.
  • The question regarding tumourigenicity will most likely only be answered satisfactorily once 1) the differentiation methods are further improved, 2) iPSC-derived cell-based therapies have made their way further into clinical practice, and 3) patients receiving treatments have been observed for multiple years.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790033/pdf/fcvm-05-00004.pdf “Age Is Relative-Impact of Donor Age on Induced Pluripotent Stem Cell-Derived Cell Functionality”

Sex-specific impacts of childhood trauma

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Anterior cingulate cortex, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres, Testosterone , , , , ,

This 2018 Canadian paper reviewed evidence for potential sex-specific differences in the lasting impacts of childhood trauma:

“This paper will provide a contextualized summary of neuroendocrine, neuroimaging, and behavioral epigenetic studies on biological sex differences contributing to internalizing psychopathology, specifically posttraumatic stress disorder and depression, among adults with a history of childhood abuse.

Given the breadth of this review, we limit our definition [of] trauma to intentional and interpersonal experiences (i.e., childhood abuse and neglect) in childhood. Psychopathological outcomes within this review will be limited to commonly explored internalizing disorders, specifically PTSD and depression.

Despite the inconsistent and limited findings in this review, a critical future consideration will be whether the biological effects of early life stress can be reversed in the face of evidence-based behavioral interventions, and furthermore, whether these changes may relate to potentially concurrent reductions in susceptibility to negative mental health outcomes.”

It was refreshing to read a paper where the reviewers often interrupted the reader’s train of thought to interject contradictory evidence, and display the scientific method. For example, immediately after citing a trio of well-respected studies that found:

“Psychobiological research on relationships linking impaired HPA axis functioning and adult internalizing disorders are suggestive of lower basal and afternoon levels of plasma cortisol in PTSD phenotype.”

the reviewers stated:

“However, a recent meta-analysis suggests no association between basal cortisol with PTSD.”

and effectively ended the cortisol discussion with:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

The reviewers also provided good summaries of aspects of the reviewed subject. For example, the “Serotonergic system genetic research, childhood trauma and risk of psychopathology” subsection ended with:

“Going forward, studies must explore the longitudinal effects of early trauma on methylation as well as comparisons of multiple loci methylation patterns and interactions to determine the greatest factors contributing to health outcomes. Only then, can we start to consider the role of sex in moderating risk.”

I didn’t agree with the cause-ignoring approach of the behavior therapy mentioned in the review. Does it make sense to approach one category of symptoms:

“the biological effects of early life stress”

by treating another category of symptoms?

“can be reversed in the face of evidence-based behavioral interventions.”

But addressing symptoms instead of the sometimes-common causes that generate both biological and behavioral effects continues to be the direction.

After receiving short-term symptom relief, wouldn’t people prefer treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

I was encouraged by the intergenerational and transgenerational focus of one of the reviewer’s research:

“Dr. Gonzalez’s current research focus is to understand the mechanisms by which early experiences are transmitted across generations and how preventive interventions may affect this transmission.”

This line of hypotheses requires detailed histories, and should uncover causes for many effects that researchers may otherwise shrug off as unexplainable individual differences. Its aims include the preconception through prenatal periods when both the largest and the largest number of epigenetic changes occur, and is when our susceptibility and sensitivity to our environment is greatest. There are fewer opportunities for effective “preventive interventions” in later life compared with these early periods.

Unlike lab rats, women and men can reach some degree of honesty about our early lives’ experiential causes of ongoing adverse effects. Experiential therapies that allow humans to potentially change their responses to these causes deserve more investigation than do therapies that apply external “interventions.”

https://www.sciencedirect.com/science/article/pii/S0272735817302647 “Biological alterations affecting risk of adult psychopathology following childhood trauma: A review of sex differences” (not freely available) Thanks to lead author Dr. Ashwini Tiwari for providing a copy.

Lysine acetylation is gnarly and dynamic

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Stress, Telomeres , ,

This 2018 UC San Francisco cell review provided details of lysine acetylation:

“Lysine acetylation has moved from being a specialized mark on histones to a critical modification controlling cell fate, proliferation, and metabolism.

During the lifetime of a protein there are many points at which an acetyl group may be added to influence function. The dynamic interplay between the writers, erasers, and readers of acetylation regulates critical epigenomic and metabolic processes, in addition to other major cellular functions.

Acetylation sites are well conserved, in contrast to methylation, where species-specific differences exist.”

The review included a section on mitochondrial protein acetylation:

“Mitochondria have emerged as organelles in which acetylation is more prominent than phosphorylation and plays a key role in integrating metabolic cues with the bioenergetic equilibrium of the cell.

Increased mitochondrial protein acetylation is associated with physiological conditions that result in higher levels of acetyl-CoA (e.g., fasting, calorie restriction, high-fat diet, and ethanol intoxication).”

https://pubs.acs.org/doi/full/10.1021/acs.chemrev.7b00181 “Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics” (not freely available) Thanks to lead author Ibraheem Ali for providing a full copy.

A review of human pluripotent stem cell research

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Telomeres , , ,

Starting the fourth year of this blog with a 2018 Belgian review of human pluripotent stem cells (hPSCs):

“hPSCs are now starting to live up to the great expectations they created after their first derivation nearly twenty years ago. The first results of clinical trials to treat macular degeneration are being published, and an increasing number of clinical or preclinical trials are being started for conditions such as spinal cord injury, diabetes, and heart disease.

This imminent transition of pluripotent stem cells to the clinic has resulted in researchers and clinicians becoming acutely aware of the problems related to the genetic and epigenetic diversity of these cells, included acquired mutations.”

The review included a section on mitochondrial processes that impact the differentiation capacity of pluripotent stem cells, summarized by:

“From this overview, we also observe a more ample contribution of mtDNA in cell fate determination than is represented in many studies tackling the topic.

The transition from aerobic glycolysis to aerobic phosphorylation plays a vital role in cells’ ability to correctly proceed through differentiation, though the mtDNA is rarely evaluated.”

https://academic.oup.com/humupd/advance-article-abstract/doi/10.1093/humupd/dmx042/4825062?redirectedFrom=fulltext “Genetic and epigenetic factors which modulate differentiation propensity in human pluripotent stem cells” (not freely available) Thanks to lead author Alexander Keller for providing a copy.