Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
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:
- Internal and external stress;
- Elevated genetic and non-genetic variations (either necessary for cellular adaptation or resulting from cellular damages under stress);
- Genome-based macro-cellular evolution (genome replacement, emergent as new systems); and
- 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”
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:
- 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);
- 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
- 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 sulforaphane active 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. Normal people aren’t going to eat “4 cups BSp/per day” but we may take one capsule of a sulforaphane dietary supplement when the price is $.20 a day.
The study’s food manufacturer offers dietary products to the public without quantifying all of the active contents like sulforaphane. Good for them if they can stay in business by serving customers who can’t be bothered with scientific evidence.
These researchers shouldn’t have conducted a study using the same lack of details as the food manufacturer provided, though. They should have either tasked the manufacturer to specify the sulforaphane active content, or contracted the analysis.
Regarding timing of a sulforaphane-based broccoli sprouts diet for humans, the study also 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”
The first 2018 epigenetic clock human study was 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”
My 400th blog post curates a 2018 US/UK paper by two of the coauthors of Using an epigenetic clock to distinguish cellular aging from senescence. The authors 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.”
- The cerebellum ages more slowly than other body and brain areas
- Using an epigenetic clock with older adults
- Using an epigenetic clock with children
- The degree of epigenetic DNA methylation may be used as a proxy to measure biological age
The challenge is: 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 the personal roots of beliefs in fate/feelings of helplessness? Do beliefs in technological or divine interventions provide justifications for inactions?
https://www.nature.com/articles/s41576-018-0004-3 “DNA methylation-based biomarkers and the epigenetic clock theory of ageing” (not freely available)
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.”
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 purpose of the study:
“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?
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 utility 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:
“The fact that maintenance of telomere length by telomerase did not prevent cellular ageing defines the singular role of telomeres as that of a means by which cells restrict their proliferation to a certain number; which was the function originally ascribed to it. Cellular ageing on the other hand proceeds regardless of telomere length.”
https://www.sciencedirect.com/science/article/pii/S1535610818300084 “DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk” (not freely available)
This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.
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 the differentiation methods are further improved, iPSC-derived cell-based therapies have made their way further into clinical practice, and 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”