Telomeres

Transgenerational effects of early environmental insults on aging and disease

gettingwell4 0-1 star Wasted resources, Brain development, Brain hemispheres, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress, Telomeres, Testosterone , , , , , , ,

The first paper of Transgenerational epigenetic inheritance week was a 2017 Canadian/Netherlands review that’s organized as follows:

“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”

A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to F2 grandchildren in the paternal lineage, or to F3 great-grandchildren in the maternal lineage.

The reviewers noted that mechanisms of transgenerational programming are complex and multivariate.  Severity, timing, and type of exposure; lineage of transmission; germ cell exposure; and gender of an organism were the main factors that may determine consequences. Mechanisms reviewed were:

  1. Parental exposure to an adverse environment;
  2. Altered maternal behavior and care of offspring; and
  3. Experience-dependent modifications of the epigenome.

There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most studies were of animals, but a few were human, such as those done on effects of extended power outages during a Quebec ice storm of January 1998.

One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers. But researchers could probably find enough instances to develop studies of the effectiveness of such placements in reversing a transgenerational phenotype.

The review didn’t have suggestions for reversing human transgenerational phenotypes, just “potential interventions to reverse negative effects of transgenerational programming.” Interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced impacts of transgenerational epigenetic effects.

Tricky wording of “reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review was insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

When reversals of human phenotypes aren’t researched, problems may compound by being transmitted to the next generations.

http://www.sciencedirect.com/science/article/pii/S014976341630714X “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)

The cerebellum ages more slowly than other body and brain areas

gettingwell4 4-5 stars Advanced knowledge, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Limbic system, Lower brain, Telomeres , , ,

This 2015 UCLA human study used the epigenetic clock methodology to find:

“All brain regions have similar DNAm ages in subjects younger than 80, but brain region becomes an increasingly significant determinant of age acceleration in older subjects. The cerebellum has a lower epigenetic age than other brain regions in older subjects.

To study age acceleration effects in non-brain tissues as well, we profiled a total of 30 tissues of a 112 year old woman. The cerebellum exhibited the lowest (negative) age acceleration effect compared to the remaining 29 other regions. In contrast, bone, bone marrow, and blood exhibit relatively older DNAm ages.”

Limitations included:

  • “While the epigenetic age of blood has been shown to relate to biological age, the same cannot yet be said about brain tissue.
  • Cellular heterogeneity may confound these results since the cerebellum involves distinct cell types.
  • This cross-sectional analysis does not lend itself for dissecting cause and effect relationships.”

The study didn’t determine why the cerebellum was relatively younger. Some hypotheses were:

  • “Our findings suggest that cerebellar DNA is epigenetically more stable and requires less ‘maintenance work.’
  • The cerebellum has a lower metabolic rate than cortex.
  • It has far fewer mitochondrial DNA (mtDNA) deletions than cortex especially in older subjects, and it accumulates less oxidative damage to both mtDNA and nuclear DNA than does cortex.”

http://impactaging.com/papers/v7/n5/full/100742.html “The cerebellum ages slowly according to the epigenetic clock”

The current paradigm of child abuse limits pre-childhood causal research

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Brain development, Brainstem, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Neurochemicals, Oxytocin, Serotonin, Stress, Telomeres, Testosterone, Thalamus, Vasopressin , , , , ,

As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments for causes of your symptoms?

Such information wasn’t available in this 2016 Miami review of the effects of child abuse. The review laid out the current paradigm mentioned in Grokking an Adverse Childhood Experiences (ACE) score, one that limits research into pre-childhood causes for later-life symptoms.

The review’s goal was to describe:

“How numerous clinical and basic studies have contributed to establish the now widely accepted idea that adverse early life experiences can elicit profound effects on the development and function of the nervous system.”

The hidden assumptions of almost all of the cited references were that these distant causes could no longer be addressed. Aren’t such assumptions testable today?

As an example, the Discussion section posed the top nine “most pressing unanswered questions related to the neurobiological effects of early life trauma.” In line with the current paradigm, the reviewer assigned “Are the biological consequences of ELS [early life stress] reversible?” into the sixth position.

If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of damage would also reverse damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

The review also demonstrated how the current paradigm of child abuse misrepresented items like telomere length and oxytocin. Researchers on the bandwagon tend to forget about the principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

That single experiment for telomere length arrived in 2016 with Using an epigenetic clock to distinguish cellular aging from senescence. The review’s seven citations for telomere length that all had findings “associated with” or “linked to” child abuse should now be viewed in a different light.

The same light shone on oxytocin with Testing the null hypothesis of oxytocin’s effects in humans and Oxytocin research null findings come out of the file drawer. See their references, and decide for yourself whether or not:

“Claimed research findings may often be simply accurate measures of the prevailing bias.”

http://www.cell.com/neuron/fulltext/S0896-6273%2816%2900020-9 “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

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Using an epigenetic clock with older adults

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

This 2016 German human study found:

“Epigenetic age acceleration is correlated with clinically relevant aging-related phenotypes through pathways unrelated to cellular senescence as assessed by telomere length.

The current work employed the frailty index, a multi-dimensional approach that combines [34] parameters of multiple physiological systems and functional capacities. The present findings were based on [1,820] study participants aged 50 to 75 years.

Innovative approaches like Mendelian randomization will be needed to elucidate whether epigenetic age acceleration indeed plays a causal role for the development of clinical phenotypes.”

The study had an informative “Age acceleration and telomere length are not correlated” section with references. It was another step toward establishing the Horvath epigenetic clock for widespread usage.

http://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0186-5 “Frailty is associated with the epigenetic clock but not with telomere length in a German cohort”

The link between scientific value and content is broken at PNAS.org

gettingwell4 < 0 Detracted from science, Neurochemicals, Oxytocin, Telomeres

Should we expect content posted on the Proceedings of the National Academy of Sciences of the United States of America to have scientific value?

This 2016 Singapore study was a “PNAS Direct Submission” that claimed:

“This paper makes a singular contribution to understanding the association between biological aging indexed by leukocyte telomeres length (LTL) and delay discounting measured in an incentivized behavioral economic task.

LTL is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient.”

1. Whether measured at the level of a human or of a blood cell, in 2016 there wasn’t incontrovertible evidence to support:

  • “Biological aging indexed by leukocyte telomeres length
  • LTL is an emerging marker of aging at the cellular level”

Using an epigenetic clock to distinguish cellular aging from senescence found:

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

If that study was too recent, the researchers and reviewer knew or should have known of studies such as this 2009 study that found the correlation between a person’s chronological age and blood cell telomere length was r = −0.51 in women and r = −0.55 in men.

2. A study of biological aging in young adults with limited findings was cited for evidence that “the seeds of biological aging are widely thought to be planted early in life.” That study didn’t elucidate the point, however, as it didn’t fully link its measurements of 38-year-old subjects with measurements taken during the subjects’ early lives.

F2.large

3. Problematic research with telomere length was cited for evidence that “other factors, such as the early family environment, lifestyle, and stress, also have considerable impact on cellular aging.” The researchers had to be willing to overlook that study’s multiple questionable practices in order to cite it as evidence for anything.

4. Deliberately overlooking abundant disconfirming evidence, the current study used a one-to-one correspondence of telomere length and cellular aging.

The researchers went on to speciously model a relationship between telomere length and the behavioral trait “poor decision making that often entails being overly impatient.” That overreach was further stretched to the breaking point:

“We then asked if genes possibly modulate the effect of impatient behavior on LTL.

The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor β gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females.”

The “significantly mitigate” finding was “fun with numbers” that produced false effects rather than solid evidence. Consider that:

  1. The study’s model disregarded the probability that “Cellular ageing is independent of telomere length.”
  2. The researchers provided no mechanisms that plausibly linked performance “in an incentivized behavioral economic task” with telomere length.
  3. The researchers didn’t demonstrate any causal mechanisms whereby two gene variants plausibly affected the task performance’s purported effect on telomere length.

What’s the real reason this poor-quality paper’s reviewer forwarded it to PNAS.org?

http://www.pnas.org/content/113/10/2780.full “Delay discounting, genetic sensitivity, and leukocyte telomere length”

Using an epigenetic clock to distinguish cellular aging from senescence

gettingwell4 5+ stars Premium, Epigenetics, Telomeres

The 2016 UK/UCLA human study found:

“Induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway, highlighting the independence of senescence from cellular ageing.

We used primary endothelial cells (ECs) that were derived from the human coronary artery of a 19 year old male.

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.

Collectively, our results reveal that cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

The following was the closest the study came to a Limitations statement:

“Although the characteristics of cellular ageing are still not well known, the remarkable precision with which the epigenetic clock can measure it and correlate it to biological ageing remove any doubt of its existence, distinctiveness and importance. This inevitably raises the question of what is the nature of this cellular ageing, and what are its eventual physical consequences.

Admittedly, the observations above do not purport to provide the answer, but they have however, cleared the path to its discovery by unshackling cellular ageing from senescence, telomeres and DNA damage response, hence inviting fresh perspectives into its possible mechanism.”

The epigenetic clock method was the same used by:

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7383&path[]=21162 “Epigenetic clock analyses of cellular senescence and ageing”

Use it or lose it: the interplay of new brain cells, age, and activity

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres, Testosterone , , , ,

This 2015 German review was of aging and activity in the context of adult neurogenesis:

“Adult neurogenesis might be of profound functional significance because it occurs at a strategic bottleneck location in the hippocampus.

Age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis, because adult neurogenesis is neuronal development under the conditions of the adult brain.

The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes (e.g., in cell or synapse numbers), but emerge on a systems level and above when an organism ages. With respect to adult neurogenesis, only one multilevel experiment including morphology and behavior has been conducted, and, even in that study, only three time points were investigated.

In old age, adult neurogenesis occurs at only a small fraction of the level in early adulthood. The decline does not seem to be ‘regulated’ but rather the by-product of many age-related changes of other sorts.

From a behavioral level down to a synaptic level, activity increases adult neurogenesis. This regulation does not seem to occur in an all-or-nothing fashion but rather influences different stages of neuronal development differently. Both cell proliferation and survival are influenced by or even depend on activity.

The effects of exercise and environmental enrichment are additive, which indicates that increasing the potential for neurogenesis is sufficient to increase the actual use of the recruitable cells in the case of cognitive stimulation. Physical activity would not by itself provide specific hippocampus-relevant stimuli that induce net neurogenesis but be associated with a greater chance to encounter specific relevant stimuli.

Adult hippocampal neurogenesis might contribute to a structural or neural reserve that if appropriately trained early in life might provide a compensatory buffer of brain plasticity in the face of increasing neurodegeneration or nonpathological age-related functional losses. There is still only limited information on the activity-dependent parameters that help to prevent the age-dependent decrease in adult neurogenesis and maintain cellular plasticity.

The big question is what the functional contribution of so few new neurons over so long periods can be. Any comprehensive concept has to bring together the acute functional contributions of newly generated, highly plastic neurons and the more-or-less lasting changes they introduce to the network.”

I’ve quoted quite a lot, but there are more details that await your reading. A few items from the study referenced in the first paragraph above:

“The hippocampus represents a bottleneck in processing..adult hippocampal neurogenesis occurs at exactly the narrowest spot.

We have derived the theory that the function of adult hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty..a mechanism for preparing the hippocampus for processing greater levels of complexity.”

The role of the hippocampus in emotion was ignored as it so often is. The way to address many of the gaps mentioned by the author may be to Advance science by including emotion in research.

For example, from the author’s The mystery of humans’ evolved capability for adults to grow new brain cells:

“Adult neurogenesis is already effective early in life, actually very well before true adulthood, and is at very high levels when sexual maturity has been reached. Behavioral advantages associated with adult neurogenesis must be relevant during the reproductive period.”

When human studies are designed to research how “behavioral advantages associated with adult neurogenesis must be relevant” what purpose does it serve to exclude emotional content?

http://cshperspectives.cshlp.org/content/7/11/a018929.full “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”

Telomerase activity outside of telomere maintenance

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

This 2016 Singapore review was on the role of telomerase in cancers. From its background section:

“Telomeres are conserved, repetitive sequences located at the ends of eukaryotic chromosomes which protect the integrity of genomic DNA. DNA polymerase is unable to replicate the 5′ [carbon number] ends of chromosomes, hence, cells require a RNA dependent DNA polymerase called telomerase to synthesize DNA on the lagging strand. Telomerase activity is tightly regulated and seen mainly in germ cells, stem cells and some immune cell types which have high proliferative needs.

In contrast, somatic cells do not display detectable telomerase activity. As a result, the chromosomes of normal somatic cells shorten 50–200 bp [base pair] each replication at the telomeres due to the problem of end replication. Thus, somatic cells are eventually burdened with DNA damage, replication crisis, cellular senescence or apoptosis and can divide only limited number of times, whereas cells that have active telomerase possess unlimited proliferative potential.”

The main section of the review described the details of how:

“Reactivation of telomerase has been considered as a strategy for telomere maintenance and is a major hallmark of cancer. Although the major function of telomerase is thought to be telomere elongation, accumulating evidence has suggested that it can modulate expression of various genes which affect cancer progression and tumorigenesis.”

http://link.springer.com/article/10.1007/s00018-016-2146-9/fulltext.html “Reactivation of telomerase in cancer”

Epigenetic effects of cow’s milk

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

This 2015 German paper with 342 references described:

“Increasing evidence that milk is not “just food” but represents a sophisticated signaling system of mammals.

This paper highlights the potential role of milk as an epigenetic modifier of the human genome paying special attention to cow milk-mediated overactivation of FTO [a gene associated with fat mass and obesity] and its impact on the transcriptome of the human milk consumer.”

The author declared “no competing interests” and “There are no sources of funding.” He presumably wasn’t pressured into writing this paper.

The paper wasn’t agenda-free, however. The main thesis was:

“Persistent milk-mediated epigenetic FTO signaling may explain the epidemic of age-related diseases of civilization.”

There were separate sections on how milk may promote:

  • Breast cancer
  • Prostate cancer
  • Obesity
  • Metabolic syndrome
  • Coronary heart disease
  • Early menarche
  • Type 2 diabetes
  • Neurodegenerative diseases

I don’t eat or drink dairy products because I’m lactose-intolerant. I coincidentally don’t have any of the diseases mentioned in the paper.

My life experiences haven’t led me to share the author’s sense of alarm, or to attribute other people’s problems to their consumption of milk products. However, more than a few problems I’ve had are things I’ve done to myself through actions or inaction that may have turned out differently if I had better information.

So I curated this article in case we’re insufficiently informed about the harmful epigenetic effects of milk. What do you think?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687119/ “Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases”

A review of genetic and epigenetic approaches to autism

gettingwell4 0-1 star Wasted resources, Beliefs, Brain development, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Neurochemicals, Serotonin, Stress, Telomeres, Thalamus , , , , , , , ,

This 2015 Chicago review noted:

“Recent developments in the research of ASD [autistic spectrum disorder] with a focus on epigenetic pathways as a complement to current genetic screening.

Not all children with a predisposing genotype develop ASD. This suggests that additional environmental factors likely interact with the genome in producing ASD.

Increased risk of ASD is associated with mutations in genes that overlap with chromatin remodeling proteins, transcriptional regulators and synapse-associated proteins. Interestingly, these genes are also targets of environmentally induced changes in gene expression.”

Evidence was discussed for both broad and specific epigenetic ASD causes originating in the prenatal environment:

  • Maternal stress:

    “Prenatal stress exerts a profound epigenetic influence on GABAergic interneurons by altering the levels of proteins such as DNMT1 and Tet1 and decreasing the expression of various targets such as BDNF.

    Ultimately, this results in reducing the numbers of fully functional GABAergic neurons postnatally and a concomitant increased susceptibility toward hyperexcitability. The delayed migration of GABAergic interneuron progenitors results in reduced gene expression postnatally which is likely the consequence of increased amounts of DNA methylation.

    The net effect of stress during early development is to disrupt the balance of excitatory/inhibitory neuronal firing due to the loss of function associated with disrupted neuronal migration and maturation.”

  • Prenatal nutrition:

    “Exposure to a wide range of environmental toxins that impact neurodevelopment also result in global DNA hypomethylation. This model was extended to connect pathways between dietary nutrition and environmental exposures in the context of DNA hypomethylation. More recently, this hypothesis was expanded to show how dietary nutrients, environmental toxins, genome instability and neuroinflammation interact to produce changes to the DNA methylome.”

  • Maternal infections:

    “Inflammation, autoimmunity and maternal immune activation have long been suspected in the context of aberrant neurodevelopment and ASD risk.”

  • Exposure to pollutants, medications, alcohol

This was a current review with many 2015 and 2014 references. However, one word in the reviewers’ vernacular that’s leftover from previous centuries was “idiopathic,” as in:

“Idiopathic (nonsyndromic) ASD, for which an underlying cause has not been identified, represent the majority of cases.”

It wasn’t sufficiently explanatory to use categorization terminology from thousands of years ago.

Science has progressed enough with measured evidence from the referenced studies that the reviewers could have discarded the “idiopathic” category and expressed probabilistic understanding of causes. They could have generalized conditional origins of a disease, and not reverted to “an underlying cause has not been identified.”

Another word the reviewers used was “pharmacotherapeutic,” as in:

“The goal for the foreseeable future is to provide a better understanding of how specific genes function to disrupt specific biological pathways and whether these pathways are amenable to pharmacotherapeutic interventions.”

Taking “idiopathic” and “pharmacotherapeutic” together – causes for the disease weren’t specifically identified, but the goal of research should be to find specific drug treatments?

Of course reviewers from the Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago are biased to believe that “the design of better pharmacotherapeutic treatments” will fulfill peoples’ needs.

Are their beliefs supported by evidence? Without using drugs, are humans largely incapable of therapeutic actions such as:

  • Preventing epigenetic diseases from beginning in the prenatal environment?
  • Treating epigenetic causes for and alleviating symptoms of their own disease?

http://www.futuremedicine.com/doi/full/10.2217/epi.15.92 “Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder”

Telomere dynamics, stress, and aging across generations

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress, Telomeres , , ,

This 2015 Pennsylvania/North Dakota animal and human review noted:

“The mechanisms linking stress exposure to disease progression and ageing either within individuals or across generations are still unclear, but recent work suggests that telomere dynamics (length and loss rate) may play an important role.

Parental stress may directly influence the parental germline telomeres pre-fertilization, affecting the telomere length inherited by offspring. Alternatively, parental stress may affect telomere dynamics indirectly either pre- or post-natally. The physiological mechanisms by which stress elicits changes in telomere length are also diverse.

We need more information about how these effects vary between developmental stages, among individuals, and within tissues of individuals..to mitigate the effects of early life adversity on human health.”

I was disappointed that the reviewers chose Problematic research with telomere length as a reference. Then again, maybe their statement:

“how these traits are related to one another clearly deserves more study”

is a polite way of saying that study’s methodology was flawed?

Regarding evolutionary biology:

“While most evidence suggests that the effect of parental stress exposure on offspring telomeres is negative, it is important to remember that this is just one trait that can contribute to parental and offspring fitness.

Investment in traits that increase fitness is expected to be favoured, even if they come at a cost to traits associated with longevity, such as telomere length.”

A similar point was made in a reference of A study of DNA methylation and age that:

“Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”

 

http://rsbl.royalsocietypublishing.org/content/11/11/20150396 “Telomere dynamics may link stress exposure and ageing across generations”

Using epigenetic DNA methylation markers to estimate biological age

gettingwell4 < 0 Detracted from science, Epigenetics, Stress, Telomeres

I curated this 2015 Georgia human study only for its use of two methods of estimating biological age. The researchers misguidedly used these techniques to help paint a scientific patina on an agenda.

One of the methods was originated by a coauthor of The degree of epigenetic DNA methylation may be used as a proxy to measure biological age study. He compared his epigenetic clock technique with the other technique here:

  • His technique used the same 353 DNA regions (CpGs, cytosine and guanine separated by only one phosphate link) across different tissues to compare tissue/organ ages;

  • “The DNA methylation levels of 193 of these markers increase with age but the remaining 160 markers show the opposite behavior.”

  • His technique had a Pearson correlation coefficient of r=0.96 with chronological age in this 2013 study;
  • The other technique:

    “Works poorly for blood samples from subjects who are younger than 20.”

That such methods were available calls into question why the researchers of A study of biological aging in young adults with limited findings didn’t avail themselves of these techniques. They used techniques that were less informative such as telomere length. As an example of how that study’s methods were known to be limited, this 2009 study found that the correlation between chronological age and telomere length was r = −0.51 in women and r = −0.55 in men.

http://www.pnas.org/content/112/33/10325.full “Self-control forecasts better psychosocial outcomes but faster epigenetic aging in low-SES youth”

A study of biological aging in young adults with limited findings

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

This 2015 New Zealand human study used the same subjects of the More from the researchers that found people have the same personalities at age 26 that they had at age 3 study. These researchers used 10 biologic age markers of subjects at age 38 to find that their biological ages ranged from 28 to 61.

F2.large

Researchers assessed subjects’ pace of aging at ages 26, 32, and 38 with 11 more biomarkers, including leukocyte telomere length. Three of the initial 10 biomarkers weren’t used because measurements were taken only at age 38.

These researchers also assessed physical functioning, physical limitations, cognitive testing, retinal imaging, self-rated health, and facial aging. There was a fascinating graph in the supplementary material of the effect on each of these assessments of successively leaving out each of 18 pace-of-aging biomarkers.

There were three areas I expected to see covered that weren’t addressed in this study:

  1. Where were links back to all relevant measurements and predictions made when these subjects were ages 3, 5, 7..? Other studies of these same subjects made such links, but only cognitive testing was linked back in this study. Were these researchers trying to pretend that these dramatic later-life physical measurements weren’t effects of earlier-life causes?
  2. Where were psychological measurements? Are we to believe that subjects’ states of mind had no relationships to their biomarkers?
  3. I didn’t see any effort to use newer measures such as The degree of epigenetic DNA methylation may be used as a proxy to measure biological age study. I’d expect that these subjects’ historical tissue samples were available. The peer reviewer certainly was familiar with newer biomarkers.

http://www.pnas.org/content/112/30/E4104.full “Quantification of biological aging in young adults”

If research doesn’t provide causal evidence for effects, can epigenetics be forced in to explain everything?

gettingwell4 < 0 Detracted from science, Epigenetics, Telomeres

This 2015 UK bird study found that older mothers had female children who had fewer offspring than did the rest of the house sparrow population. The finding applied also to older fathers and their male children.

In general, if a study didn’t directly demonstrate cause and effect, it isn’t appropriate to force the use of epigenetics to explain everything. That’s what this study did with epigenetic inheritance.

Did the study:

“Demonstrate that this parental age effect..potentially is epigenetically inherited.”

by analyzing DNA across generations?

No!

The researchers ran some numbers that tested the effect of older foster parents where the model’s only other possible explanation was epigenetic inheritance.

Several other things about this study were off:

  • The researchers used the term “fitness” 28 times as shorthand to mean the number of offspring, but only twice was it explained as “reproductive fitness.” This was potentially misleading in some of the contexts of the term’s other uses. For example, several of the cited references used “fitness” in a different context.
  • The researchers went into a long exposition of telomeres, punctuated by citing 11 references, only to say:

    “However it is unclear how telomere dynamics could affect fitness.”

    The next sentence was:

    “An alternative explanation might be the accumulation of deleterious mutations as individuals age.”

    which was additionally irritating because “alternative” assumed that telomeres presented a factual explanation of the study’s findings in the first place. Was this section an artifact of a struggle with the reviewer?

After forcing epigenetic inheritance as an explanatory factor and potentially misleading readers about reproductive fitness and telomeres, the researchers had little basis to conclude that their research had “important implications.”

http://www.pnas.org/content/112/13/4021.full “Reduced fitness in progeny from old parents in a natural population”

Dr. Arthur Janov interview on his 2011 book Life Before Birth: The hidden script that rules our lives

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Epigenetics, Limbic system, Lower brain, Neurochemicals, Primal Therapy, Stress, Telomeres , , , , , ,

Dr. Arthur Janov’s 2011 book “Life Before Birth: The hidden script that rules our lives” describes problems that start in the earliest parts of our lives, when epigenetic changes due to trauma in the womb affect our development.

“The science has changed. When I first started out 44 years ago, there was nobody who could understand it, or agree, especially the professionals. Now all, or a great deal of the current research, is backing up everything I say.

I’m saying that this therapy is really a matter of life and death now. I should probably start at the beginning and say that there’s trauma in the womb. We need to set back the clock so that we take account of trauma that occurs while our mother is carrying that has lifelong consequences for how long we live, for example. There’s a current research study that shows that as you get more traumatized in the womb, your life expectancy is much shorter.

When you get rid of the childhood pain that happened way back when – and there are ways to do it – you will live much longer. So truly, a proper therapy now is a matter of life and death. Not only because your life expectancy is shorter when you have trauma, but you get sick earlier, you have diabetes, Alzheimer’s, all kinds of diseases on your way to your death, which makes life very uncomfortable.

But that’s just part of what we do. The idea is that we found a way to take the pain out of the system, going all the way back. And what we’re finding is that pain starts way, way earlier than we thought.

I used to think that the greatest point was the birth trauma. Well that’s no longer true. Way before the birth trauma there are traumas from the smoking mothers, the anxious mothers, the depressed mothers, that have lifelong effects on the baby, the offspring.”

“https://www.youtube.com/watch?v=dbUhjZhpEyct”

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