RE:News aus der Forschung 2023 - 10

Inhibition of fatty acid oxidation enables heart regeneration in adult mice

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Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia–reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

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https://www.nature.com/articles/s41586-023-06585-5

Kommentar: Wenn sich das bestätigt könnte es ein großer Schritt Richtung Lebensverlängerung werden. Herz-Kreislauf-Erkrankungen sind die Todesursache Nr. 1.

Was ist fatty acid oxidation? Fettsäuteoxidation, Fettverbrennung?
Taugt da Wasserstoff? Oder muss ich irgendeinen Metaboliten, Pyruvat?, Essen.

Zitat von Illuminatus im Beitrag #227

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Was ist fatty acid oxidation? Fettsäuteoxidation, Fettverbrennung?
Taugt da Wasserstoff? Oder muss ich irgendeinen Metaboliten, Pyruvat?, Essen.

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Zu meiner Schande, wenn ich Fettsäureoxidation höre, denke ich irgendwie an oxidierte schlechte Fette in der Zellmembran, aber es ist wohl einfach die Fettverbrennung in den Zellen.
https://medlexi.de/Fetts%C3%A4ureoxidation
Diese Studie schaut halt auch nur auf Herzzellen nach einem Infarkt. Wie Gesund/Robust die Maus war, ist nicht Inhalt der Studie. Infarkte sind nicht gut für Langlebigkeit und auch kein Enzymmangel.
Aber Wasserstoff ist gut bei Ischämie.
https://wasserstofftherapie.de/studien/s...izinisches-gas/
PS....mich hat es aber nicht verjüngt

IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration

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The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium. Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ-signaling completely reverses these aging phenotypes and reinstalls regenerative capacity of the aged intestinal epithelium.

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https://www.nature.com/articles/s41467-023-41683-y

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

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Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

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https://www.nature.com/articles/s41413-023-00283-8

https://www.nature.com/articles/s41551-019-0424-1
Synthetisch glykosylierte Antigene induzieren eine antigenspezifische Toleranz und verhindern das Auftreten von Diabetes

Eine Toleranz zu Impfen geht wohl (Spikes?).
Mich würde die Rolle von Glukosamin (N-Acetylglucosamin) interessieren. Aber ich versteh diese vielen Stoffwechselwegen eh nicht mehr.
Irgendwas mit Blutgruppen?

#231 Ich denke da geht es um künstlich modifizierte Antigene und auch das werden wir mit einfachen Supplements wohl nicht erreichen.

Zitat von version2 im Beitrag Covid-19 Impfstoffbedenken weiter gehts

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Zitat von bul im Beitrag Covid-19 Impfstoffbedenken weiter gehts

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Nach der jeder Injektion wird die Wahrscheinlichkeit immer höher, dass der betroffene Körper tolerant gegen die Spikes wird.

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Warum soll das so sein? Das wäre dann ja bei der Infektion auch so.

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Zitat von Illuminatus im Beitrag #231

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Eine Toleranz zu Impfen geht wohl (Spikes?).

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Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

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Here, we provide the detailed structure of mTOR, its complexes, and the comprehensive role of upstream regulators, as well as downstream effectors of mTOR signaling cascades in the metabolism, biogenesis of biomolecules, immune responses, and autophagy. Additionally, we summarize the potential of long noncoding RNAs (lncRNAs) as an important modulator of mTOR signaling. Importantly, we have highlighted the potential of mTOR signaling in aging, neurological disorders, human cancers, cancer stem cells, and drug resistance. Here, we discuss the developments for the therapeutic targeting of mTOR signaling with improved anticancer efficacy for the benefit of cancer patients in clinics.

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https://www.nature.com/articles/s41392-023-01608-z

Developing a Treatment for Arthritis from Stem Cell Signals

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This is far from the first attempt at treating osteoarthritis using stem cells. We have previously reported on a study finding that injecting mesenchymal stem cells is effective for treating arthritis in guinea pigs, which naturally develop humanlike arthritis symptoms. However, transporting and storing these cells is not easy, and there is a risk of immune rejection [1].

However, previous research has also found that EVs, which are intercellular communication particles taken from these cells, are the driving factor behind their benefits. For example, EVs derived from MSCs have been reported to reduce senescence in mice. Their effects on chondrocytes have also been documented [2]. This research builds upon that work by focusing on the changes induced when these EVs are delivered.

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https://www.lifespan.io/news/developing-...m-cell-signals/

Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells

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Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvβ3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvβ3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.

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https://pubs.acs.org/doi/10.1021/jacs.3c06898

Klingt vielversprechend, mal schauen was draus wird.

Graphene oxide reduces the toxicity of Alzheimer’s proteins
https://www.eurekalert.org/news-releases/1003529

Preprint:

ImAge: an imaging approach to quantitate aging and rejuvenation

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We propose that ImAge represents the first-in-class individual-level biomarker of aging and rejuvenation with single-cell resolution.

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https://www.biorxiv.org/node/3383376.full

Von April, keine Ahnung ob wir die schon hatten:

Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures
https://www.nature.com/articles/s43587-023-00389-y

Zitat von version2 im Beitrag #237

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ImAge: an imaging approach to quantitate aging and rejuvenation

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Zitat von Methusalem im Beitrag #238

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Also "nur" eine weitere Altersuhr.

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Schon klar, die bisherige Altersuhren haben alle ihre Probleme. Gab sogar einen längeren Artikel darüber.

Zitat von Methusalem im Beitrag #240

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Schon klar, die bisherige Altersuhren haben alle ihre Probleme. Gab sogar einen längeren Artikel darüber.

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@version2
Siehe hier:
RE:Rapamycin (6)

Wurde von @Dr.Faust @Prometheus usw. schon diskutiert.

Die Altersuhren haben Probleme. Sie stoppen z. T., sie laufen manchmal vor- und rückwärts usw.

Effects of iron homeostasis on epigenetic age acceleration: a two-sample Mendelian randomization study

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The results of present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10559596/

Kommentar: Könnte zu viel Eisen die epigenetische Alterung beschleunigen?

Noch was zu der Studie aus #235 (Senolyse): https://news.unist.ac.kr/selective-remov...lated-diseases/

Zu viel Eisen muß man aber auch erstmal hinbekommen. Dagegen ist Eisenmangel, zumeist unendeckt, doch eher ein Massenphänomen.

Hallo Tizian,

das ist ein großer Irrtum, denn bei vielen (gesunden) Männern akkumuliert Eisen mit zunehmendem Alter und bei Frauen kann es im Alter auch passieren: Blutspende und/oder Aderlass kann das Problem evtl. beseitigen (je nach Laborwert).

Viele Grüße

Roger

Also ich sehe das anders. Mal abgesehen davon, daß chronischer Eisenmangel praktisch eine Begleiterscheinung von Veganismus & Co. ist, also weltweit Zigmillionen betrifft, wieviele Menschen im zunehmenden Alter sind denn noch wirklich gesund? Geschweige davon, daß Eisenmangel und Anämie zumeist Hand in Hand gehen und sehr viele Menschen betrifft.

Aber ich will da auch gar nicht streiten.

γ-Aminobutyric acids (GABA) and serum GABA/AABA (G/A) ratio as potential biomarkers of physical performance and aging
https://www.nature.com/articles/s41598-023-41628-x

GABA-Level steigen mit zunehmendem Alter.

Apoptotic stress causes mtDNA release during senescence and drives the SASP

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Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

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https://www.nature.com/articles/s41586-023-06621-4

Could Skin Microbiome Transfer Slow Aging?

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Microbiome transplantation is a procedure in which the skin microbiome of a healthy individual is transferred to a cleansed and disinfected area of another person's skin to improve the recipient's skin condition. This method has been used for therapeutic purposes and has shown promising results. However, the research is limited [5].

The influence of other people's microbiomes on the balance of the skin's population of bacteria may have health effects in humans. The transplantation of microbes from healthy and young individuals to others may provide a new opportunity in the field of hygiene to develop therapeutic strategies for maintaining skin health and preventing skin aging.

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https://www.psychologytoday.com/intl/blo...sfer-slow-aging

Intersection clock reveals a rejuvenation event during human embryogenesis
https://onlinelibrary.wiley.com/doi/full...UaFLBR8sNsS7y_g

Anti-Aging Potential of Plants of the Anak Dalam Tribe, Jambi, Indonesia

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Among these plants, Toona sinensis, Curcuma heyneana, Curcuma zedoaria, Curcuma longa, and Kaempferia rotunda are the most commonly used medicinal plants with anti-aging properties. T. sinensis is a tree, while the others are herbs. T. sinensis shows the highest potential for development as an anti-aging agent, with its extracts, active fractions, and bioactive quercetin isolates known to possess strong anti-aging activities both in vitro and in vivo. Furthermore, C. heyneana, C. longa, C. zedoaria, and K. rotunda also show potential for further research, and three of them have demonstrated good potential for in vivo anti-aging activities.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10534538/

A class of anti-inflammatory lipids decrease with aging in the central nervous system

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Lipids contribute to the structure, development, and function of healthy brains. Dysregulated lipid metabolism is linked to aging and diseased brains. However, our understanding of lipid metabolism in aging brains remains limited. Here we examined the brain lipidome of mice across their lifespan using untargeted lipidomics. Co-expression network analysis highlighted a progressive decrease in 3-sulfogalactosyl diacylglycerols (SGDGs) and SGDG pathway members, including the potential degradation products lyso-SGDGs. SGDGs show an age-related decline specifically in the central nervous system and are associated with myelination. We also found that an SGDG dramatically suppresses LPS-induced gene expression and release of pro-inflammatory cytokines from macrophages and microglia by acting on the NF-κB pathway. The detection of SGDGs in human and macaque brains establishes their evolutionary conservation. This work enhances interest in SGDGs regarding their roles in aging and inflammatory diseases and highlights the complexity of the brain lipidome and potential biological functions in aging.
(...)
Future studies are required to determine whether administering SGDGs can inhibit neuroinflammation in vivo and further mechanisms by which SGDGs inhibit the production of pro-inflammatory cytokines. These studies will provide insights into developing new therapeutics to treat inflammation and age-related diseases.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898107/

Kommentar: Kommt mir so vor als hätten wir die schon gehabt, aber ich konnte über die Suche nichts dergleichen finden.