RE: Die epigenetische Altersuhr - 2

Epigenetics and aging

Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.

http://advances.sciencemag.org/content/2/7/e1600584


Blood Epigenetic Age may Predict Cancer Incidence and Mortality
http://www.sciencedirect.com/science/art...352396416300421

Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort

Previous studies have developed models predicting methylation age from DNA methylation in blood and other tissues (epigenetic clock) and suggested the difference between DNA methylation and chronological ages as a marker of healthy aging. The goal of this study was to confirm and expand such observations by investigating whether different concepts of the epigenetic clocks in a population-based cohort are associated with cancer, cardiovascular, and all-cause mortality.

https://clinicalepigeneticsjournal.biome...3148-016-0228-z





DNA methylation levels at individual age‐associated CpG sites can be indicative for life expectancy
DNA-methylation (DNAm) levels at age-associated CpG sites can be combined into epigenetic aging signatures to estimate donor age. It has been demonstrated that the difference between such epigenetic age-predictions and chronological age is indicative for of all-cause mortality in later life. In this study, we tested alternative epigenetic signatures and followed the hypothesis that even individual age-associated CpG sites might be indicative for life-expectancy. Using a 99-CpG aging model, a five-year higher age-prediction was associated with 11% greater mortality risk in DNAm profiles of the Lothian Birth Cohort 1921 study. However, models based on three CpGs, or even individual CpGs, generally revealed very high offsets in age-predictions if applied to independent microarray datasets. On the other hand, we demonstrate that DNAm levels at several individual age-associated CpGs seem to be associated with life expectancy - e.g., at CpGs associated with the genesPDE4C and CLCN6. Our results support the notion that small aging signatures should rather be analysed by more quantitative methods, such as site-specific pyrosequencing, as the precision of age-predictions is rather low on independent microarray datasets. Nevertheless, the results hold the perspective that simple epigenetic biomarkers, based on few or individual age-associated CpGs, could assist the estimation of biological age.

https://www.ncbi.nlm.nih.gov/pubmed/26928272

Identifizierung von epigenetischen Masterregulatoren der Alterung im humanen hämatopoietischen System

http://docserv.uni-duesseldorf.de/servle...20Graffmann.pdf




Einfluss bakterieller Erreger auf das Epigenom und die Seneszenz von Wirtszellen

http://www.diss.fu-berlin.de/diss/servle...nxen_online.pdf

Internal 'clock' makes some people age faster and die younger – regardless of lifestyle
Study could explain why even with healthy lifestyles some people die younger than others, and raises future possibility of extending the human lifespan

Scientists have found the most definitive evidence yet that some people are destined to age quicker and die younger than others - regardless of their lifestyle.
The findings could explain the seemingly random and unfair way that death is sometimes dealt out, and raise the intriguing future possibility of being able to extend the natural human lifespan.
“You get people who are vegan, sleep 10 hours a day, have a low-stress job, and still end up dying young,” said Steve Horvath, a biostatistician who led the research at the University of California, Los Angeles. “We’ve shown some people have a faster innate ageing rate.”
A higher biological age, regardless of actual age, was consistently linked to an earlier death, the study found. For the 5% of the population who age fastest, this translated to a roughly 50% greater than average risk of death at any age.
Intriguingly, the biological changes linked to ageing are potentially reversible, raising the prospect of future treatments that could arrest the ageing process and extend the human lifespan.
“The great hope is that we find anti-ageing interventions that would slow your innate ageing rate,” said Horvath. “This is an important milestone to realising this dream.”

https://www.theguardian.com/science/2016...ss-of-lifestyle




DNA methylation-based measures of biological age: meta-analysis predicting time to death
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

http://www.aging-us.com/article/a4YqjiSauBRXHwfiX

Aging and DNA methylation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311512/





Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes
http://www.tandfonline.com/doi/full/10.1...94.2015.1040619




Epigenetic regulation of ageing: linking environmental inputs to genomic stability
Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodelling by environmental stimuli affects several aspects of transcription and genomic stability, with important consequences for longevity, and outline epigenetic differences between the 'mortal soma' and the 'immortal germ line'. Finally, we discuss the inheritance of characteristics of ageing and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases.

http://www.nature.com/nrm/journal/v16/n10/pdf/nrm4048.pdf




Histone methylation makes its mark on longevity
How long organisms live is not entirely written in their
genes. Recent findings reveal that epigenetic factors that
regulate histone methylation, a type of chromatin mod-
ification, can affect lifespan. The reversible nature of
chromatin modifications suggests that therapeutic tar-
geting of chromatin regulators could be used to extend
lifespan and healthspan. This review describes the epi-
genetic regulation of lifespan in diverse model organ-
isms, focusing on the role and mode of action of
chromatin regulators that affect two epigenetic marks,
trimethylated lysine 4 of histone H3 (H3K4me3) and
trimethylated lysine 27 of histone H3 (H3K27me3), in
longevity.

http://web.stanford.edu/group/brunet/Shuo%20Han%202012.pdf





Age-Related Increase of EED Expression in Early Hematopoietic Progenitor Cells is Associated with Global Increase of the Histone Modification H3K27me3.
Human hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood exhibit higher differentiation potential and repopulation capacity compared to adult HSPCs. The molecular basis for these functional differences is currently unknown. Upon screening for epigenetic effector genes being differentially expressed in neonatal and adult HSPC subpopulations, the Polycomb Repressive Complex 2 (PRC2) member EED was identified. Even though EED is expressed at comparable amounts in neonatal and adult multipotent HSPCs, early adult lineage committed progenitors of the lymphomyeloid (LM) and erythromyeloid lineages expressed higher EED amounts than neonatal HPCs. We demonstrate that EED overexpression directly leads to higher H3K27me3 levels, a repressive histone modification that is mediated by the PRC2 complex. Quantitative analysis of H3K27me3 levels by FPLC-based ELISA revealed elevated levels in primary blood cells from adults. Besides quantitative changes, gene ontology analysis of the genome-wide H3K27me3 distribution revealed qualitative changes in adult HSPCs with elevated levels in genes associated with nonhematopoietic development pathways. In contrast, H3K4me3 which labels active chromatin was enriched on hematopoietic genes. In vitro differentiation of EED-transfected neonatal HSPCs revealed aberrant expression of the myelopoietic marker CD14, suggesting that EED affects the lymphoid versus myeloid decision processes within the lymphomyeloid lineage. This is in line with LM progenitors having the most pronounced differences in EED expression. Highlighting the dynamic roles of epigenetic modifications in human hematopoiesis, the present data demonstrate shifts in the PRC2-associated histone modification H3K27me3 from birth to adulthood.

http://online.liebertpub.com/doi/10.1089/scd.2014.0435

Epigenom-Forschung
Ein neuer Dreh in der Epigenetik
Wie wiederentdeckte chemische Marker an DNA und RNA die Genexpressionsforschung aufrütteln.

Zitat

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Eins ist allerding klar: m6A spielt eine grundlegende Rolle bei der Zelldifferenzierung, denn Zellen ohne diese Markierung bleiben in ihrer Entwicklung in einem stammzell- oder vorläuferzellähnlichen Stadium stecken. Dies kann tödlich enden: Als He und Kollegen etwa den m6A-Schreiber bei Mäusen inaktivierten, starben viele Embryos bereits in der Gebärmutter.

Für die Funktion von m6A liefert He eine mögliche Erklärung. Immer wenn eine Zelle von einem Stadium in ein anderes übergeht, wie etwa während des Differenzierungsprozesses, müssen sich auch ihre mRNAs verändern. Diese Variation des mRNA-Gehalts, die He mit dem Begriff "Transkriptom-Switch" (zu Deutsch etwa "Transkriptom-Schalter") umschreibt, erfordert Präzision und sorgfältiges Timing. Die Methylmarkierungen könnten den Zellen die Möglichkeit verschaffen, die Aktivität von mehreren tausend Transkripten zu synchronisieren, meint He.

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http://www.spektrum.de/news/ein-neuer-dr...genetik/1440214

Die Infos aus dem Artikel hören sich stark danach an, als würde auch die Methylierung von Adenosin eine entscheidende Rolle in der Alterung spielen!

Wer weiß, welche anderen Faktoren neben der Methylierung von Cytosin und Adenin sowie der Histon-Acetylierung noch am Zelldifferenzierungs- und Alterungsprogramm (ich vemute mal, die hängen stark zusammen) beteiligt sind...
Ob wir alle Faktoren in absehbarer Zeit identifizieren und auch gut genug verstehen werden?

ich habe gerade gesehen, von Cerascreen gibt es einen Home-Labortest für das Methylierungsalter, den

Cerascreen Genetic Age Test.

Hat jemand schon mal den Test selber gemacht? Oder einen ähnlichen?

Hallo,

es wäre evtl. auch interessant, welchen Einfluss die Aktivität der Mitochondrien bzw. deren Zustand/mtDNA auf die Methylierung der CpG Inseln hat. Eine Regeneration des Thymus könnte die Blutzellen evtl. um > 1 Jahr "verjüngen".

Viele Grüße

Roger

Zitat von Prometheus im Beitrag #46

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Zitat von Scout im Beitrag #42

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ich habe gerade gesehen, von Cerascreen gibt es einen Home-Labortest für das Methylierungsalter, den

Cerascreen Genetic Age Test.

Hat jemand schon mal den Test selber gemacht? Oder einen ähnlichen?

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@Scout

Ich habe inzwischen weiter recherchiert.

"The lab then conducts a methylation analysis using Next Generation Sequencing to determine the methylation state of the DNA. AI software developed at Fraunhofer IME is then used to analyze this data and derive the biological age from the methylation data. Initial tests conducted on approximately 150 subjects have shown that the algorithm works very well. Estimates of biological age for healthy individuals came remarkably close to the actual chronological ages of the subjects."
https://www.izb.fraunhofer.de/en/press/news-01-08-2019.html

So wie das sehe, ist der Test darauf kalibriert, das chronologische Alter anhand der Probe möglichst präzise einzugrenzen.

Das entspricht also in etwa dem Ansatz der Horvath-Uhr, allerdings denke ich, dass an Schleimhautproben andere CpG-Methylierungen eine Rolle spielen als bei der Horvath-Uhr, die auf der Auswertung von Blutproben basiert.

Das Problem ist hier, dass die Auswahl der CpG-Methylierungen nicht primär auf das biologische Alter ausgerichtet ist!

Sinnvoller wäre eigentlich der Ansatz nicht auf das Geburtsjahr zu fokussieren, sondern auf das Mortalitätsrisiko.
Bei der Blutanalyse erzielt man damit präzisere Prognosen zum wahren biologischen Alter: DNAm PhenoAge

P.S.:
Selbstverständlich korrelieren das biologische Alter und das chronologische Alter im Normalfall. Daher wird der Test vermutlich schon brauchbar sein, allerdings entsteht eine gewisse Unschärfe, wenn man im Grunde die DIFFERENZ zwischen biologischen und chonologischen Alter bestimmen möchte.

Habe jetzt mal eine diesbezügliche Anfrage an Cerascreen gestellt.

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Irgendwie scheint mir das sog. "biologische Alter" nicht definiert zu sein.
Was ist eigentlich die Skala? Das chronologische Alter? Irgendwie stimmt da was nicht.

Ja, und die von mir vielgenannte "Psychologie der Messung". Habs dann schwarz auf
weiß, dass ich nicht mehr so lange zu leben habe. Das ist eine tolle Programmierung.
Interventionen? Klar die mach ich auh so umnd bin fest davon überzeugt dass sie
wirken. Wenns nicht gefällt werden die Zellen in betroffenen Gebieten sich melden.

Zitat von Dr.Faust im Beitrag #48

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Irgendwie scheint mir das sog. "biologische Alter" nicht definiert zu sein.
Was ist eigentlich die Skala? Das chronologische Alter? Irgendwie stimmt da was nicht.

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Ich meint das prinzipiell mit den "biologischen Alter". Den Zustand des Körpers und besonders der Zellen
auf einen Wert zu reduzieren ist mir suspekt. Und die Skala soll dann das chronologisch Alter sein. Geht das
überhaupt prinzipiell? Mathematisch gesehen ist der Zustand des Körpers ein hochdimensionaler Vektor.
Der wird dann auf eine eindimensionale Skala projiziert. Das ist keine definierte mathematische Aufgabe,
hat unendlch viele Lösungen. Jeder Autor deknt sich eine andere Projektion aus.