The influence of donor age on induced pluripotent stem cell functionality

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.” “Age Is Relative-Impact of Donor Age on Induced Pluripotent Stem Cell-Derived Cell Functionality”


Sex-specific impacts of childhood trauma

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 don’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. It aims at the preconception through prenatal periods where the largest epigenetic effects on an individual are found. 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. The potential of experiential therapies to allow an individual to change their responses to these causes deserves as much investigation as do therapies that apply external “interventions.” “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.

Viruses target epigenetic processes

This 2018 Colorado review subject was general and specific ways viruses target epigenetic processes:

“We describe viral mechanisms and virus–host interactions by which DNA tumor viruses regulate host DNA methylation to evade antiviral immunity.

It is well known that most endogenous retroviruses and retrotransposons in the human genome are inactivated by DNA hypermethylation..In addition to endogenous retroviruses, the genomes of DNA viruses, such as human papillomavirus (HPV), herpes simplex virus 1 (HSV-1), adenovirus, and hepatitis B virus (HBV), are also frequently methylated and silenced in infected cells.

A recently described mechanism for viruses to epigenetically subvert host immunity is repression of immune-related gene expression by induction of DNA hypermethylation..Some host genes are not silenced simply through promoter hypermethylation or histone deacetylation alone, and therefore, viruses may have evolved mechanisms to ensure host gene downregulation through multiple epigenetic modifications.” “DNA Tumor Virus Regulation of Host DNA Methylation and Its Implications for Immune Evasion and Oncogenesis”

A second 2018 New York study focused on the Zika virus and DNA methylation:

“We studied the impact of ZIKV infection on the DNA methylation pattern across the entire genome in selected neural cell types. The virus unexpectedly alters the DNA methylome of neural progenitors, astrocytes, and differentiated neurons at genes that have been implicated in the pathogenesis of a number of brain disorders.

It remains open, however, whether the methylation changes come first or whether the viral infection dysregulates epigenetic regulatory genes prior to any epigenetic shift.” “Zika Virus Alters DNA Methylation of Neural Genes in an Organoid Model of the Developing Human Brain”

What are the chances?

This 2018 UC Davis anthropology study was on dice changes over two centuries:

“In Roman times, many dice were visibly lopsided..It did not matter what the objects were made of (metal, clay, bone, antler and ivory), or whether they were precisely symmetrical or consistent in size or shape, because, like the weather, rolls were predetermined by gods or other supernatural elements.

Dice, like many material objects, reflect a lot about people’s changing worldviews, Eerkens said. In this case, we believe it follows changing ideas about chance and fate.”

Think of a significant event in your life. Was it brought about by:

  • Fate?
  • Karma, divine intervention?
  • A prayer, belief, placebo-effect process?
  • Randomness?
  • A coin-flip, card-draw, dice-roll decision process?
  • A weighted-probability decision process?
  • Chosen behavior, thoughts, and feelings?
  • Unconscious behavior, thoughts, and feelings?
  • Culturally-guided motivations?
  • Non-arbitrary influences of other parties?

Which one or more of these factors would you now prefer to have been involved? “It’s Not How You Play the Game, but How the Dice Were Made”

Your need to feel important will run your life, and you’ll never feel satisfied

Yesterday’s team meeting at work provided one display after another of a person’s need to feel important. These eye-openers were the reason the scheduled 30-minute meeting lasted 45 minutes.

Although half of the forty or so attendees are under the age of 40, curiously, only two of them spoke during the meeting. I wasn’t among the older people who had something to say.

Not that I wasn’t tempted by the team-building exercise with its Skittles prompts:

  • Red – Tell us something you do well
  • Orange – Tell us something about your childhood
  • Purple – What could you live without?
  • Yellow – What couldn’t you live without?

Participation in the exercise was voluntary. Yes, I drew an orange Skittle.

Everyone knew there wasn’t enough time for each of us to speak and have the exercise become team-building, yet a dozen people piped up. Every one of the self-selected responses could have been prefaced with “I’m important because..”

There are many needs a person develops and tries to satisfy as substitutes for real needs that weren’t fulfilled. In this blog I’ve focused on the need to feel important.

I started with How do we assess “importance” in our lives? An example from scientists’ research choices and highlighted it on my Welcome page:

“Do you agree that an individual’s need to feel important is NOT a basic human need on the same level as nourishment, protection, and socialization? How does this need arise in our lives?”

I supported an explanation of the need to feel important with evidence and arguments on my Scientific evidence page and said:

“If the explanation is true yet someone rejected it, they at least wouldn’t have suffered from exposure to it. They’ll just remain in our world’s default mode of existence:

  1. Unaware of their own unconscious act-outs to feel important;
  2. Unaware of what’s driving such personal behavior; and
  3. Uninformed of other people’s behavioral origins as a consequence of 1 and 2.”

Other examples of substitute needs include:

What do you think? Any arguments for or against interrupting people’s default mode of existence?

Lysine acetylation is gnarly and dynamic

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).” “Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics” (not freely available) Thanks to lead author Ibraheem Ali for providing a full copy.

Epigenetic mechanisms of muscle memory

This 2018 UK human study detailed epigenetic muscle memory:

“We aimed to investigate an epigenetic memory of earlier hypertrophy in adult human skeletal muscle using a within measures design, by undertaking:

  1. Resistance exercise induced muscle growth (loading) [3 days a week for 7 weeks], followed by;
  2. Cessation of resistance exercise, to return muscle back towards baseline levels (unloading) [7 weeks], and;
  3. A subsequent later period of resistance exercise induced muscle hypertrophy (reloading) [3 days a week for 7 weeks].”

The findings were:

“Frequency of genome-wide hypomethylation is the largest after reloading induced hypertrophy where lean muscle mass is enhanced.

Hypomethylation is maintained from earlier load induced hypertrophy even during unloading where muscle mass returns back towards baseline, and is inversely associated with gene expression.

A single bout of acute resistance exercise evokes hypomethylation of genes that have enhanced gene expression in later reload induced hypertrophy.”

The study provided another example of how our bodies remember. It began with only eight male 27.6 ± 2.4 year-old subjects, though, and one of them dropped out.

See the discussion of a 2017 Netherlands human study in Are Underpowered Studies Ever Justified? with comments on studies with few subjects, such as:

“The problem occurs when people do small quantitative studies, but draw conclusions nonetheless, simply adding a disclaimer to the discussion (which they don’t put in the abstract, or the press release)..”

“Underpowered studies may only be useful to check if the experiment works out wrt understanding instructions, do the programs run, etc, but not as much for testing and estimating effects.”

“The problem with underpowered studies is that all estimates can vary erratically between samples. Combined with the desire of many researchers (and universities’ press offices) to find sensational patterns, this means that evidence from underpowered studies is ‘asymmetrically’ likely to be considered more conclusive. As in, something that seems really cool will probably be considered more conclusive than something that’s disappointing. Highly powered studies don’t afford this flexibility.” “Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy”