RE:News aus der Forschung 2023 - 9

Pig kidney keeps working for over a month in brain-dead man’s body
https://www.theguardian.com/us-news/2023...uman-transplant

Kommentar: Sehr spannend, hier wurde ein genetisch modifiziertes Schwein genutzt, damit die Niere nicht abgestoßen wird. Ich frage mich allerdings wie lange so ein Organ hält, denn Schweine leben ja normalerweise nur 15-20 Jahre.

NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates

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Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.

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https://www.science.org/doi/10.1126/scitranslmed.add1951

Kommentar: Ein neuer Stern am Senolytika-Himmel?

Therapeutic potential of nitric oxide in vascular aging due to the promotion of angiogenesis

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The decrease in angiogenesis that occurs with aging significantly contributes to the higher incidence and mortality of cardiovascular diseases among the elderly.
(...)
Nitric oxide (NO) has been thoroughly investigated for its function in regulating angiogenesis and is an important factor that can counteract endothelial cell senescence.

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https://onlinelibrary.wiley.com/doi/10.1111/cbdd.14248

Endothelial FoxM1 reactivates aging-impaired endothelial regeneration for vascular repair and resolution of inflammatory lung injury

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Expression of forkhead box M1 (FoxM1), an important mediator of endothelial regeneration in young mice, was not induced in lungs of aged mice. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of the FOXM1 gene driven by an endothelial cell (EC)–specific promoter reactivated endothelial regeneration, normalized vascular repair and resolution of inflammation, and promoted survival in aged mice after sepsis challenge. In addition, treatment with the FDA-approved DNA demethylating agent decitabine was sufficient to reactivate FoxM1-dependent endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival.

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https://www.science.org/doi/10.1126/scitranslmed.abm5755

Kommentar: FOXM1 ist bei jungen Mäusen aktiv, bei älteren nicht. Führt man es älteren zu, verbessert sich deren Endothel-Regeneration. Zudem konnte durch Gabe von Decitabin die Expression von FOXM1 erhöht werden. So verstehe ich das jedenfalls.

Nature's Design Paradox: Aging as an Inherent Software Flaw
https://gethealthspan.com/blog/articles/...ag5mxkelxk5exd/

Kommentar: Netter Artikel der die Theorie der epigenetischen Alterung durch logische Argumente wahrscheinlicher erscheinen lässt. Alterung wird als fortgesetztes Wachstumsprogramm beschrieben, das nach der Reproduktionszeit etwas aus dem Ruder laufen würde. Insbesondere das Argument der Vorhersagbarkeit (predictability) hat mich überzeugt. Nicht ganz zu ende gedacht hingegen erscheinen die negativen Ausführungen zu IGF-1/GH sowie die Lobhudelei auf Rapamycin und Metformin. Denn das dürfte zwar ein längeres Leben bringen, aber nicht in einem jüngeren Körper. Oder wie soll das gehen, ohne junge Werte dieser Hormone?
Bis es eine gute Möglichkeit zum epigenetischen Reset gibt wird das Rätselraten um die exakten Mechanismen hinter der Alterung wohl vorerst weiter gehen.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment
https://www.ahajournals.org/doi/10.1161/...ONAHA.123.21392

Kommentar: Mäusestudie.

Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

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it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging.
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We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data. We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.

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https://www.biorxiv.org/content/10.1101/2023.08.06.552148v1

Kommentar: Lassen wir uns bald alle Schweineblut(plasma) verabreichen, um jünger zu werden? Ist AA vielleicht doch satanisch? "You will injekt ze Pigblood!"

Zitat von Prometheus im Beitrag #205

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Leider kein Volltextzugriff. Womit bzw wie wurde die Senolyse durchgeführt? Wie wurde die Gefäßsteifigkeit vorher/nachher gemessen?

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Zitat

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genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6 N mice with the senolytic ABT-263.
(...)
aortic stiffness assessed by aortic pulse wave velocity

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https://www.ahajournals.org/doi/10.1161/...ONAHA.123.21392

#206 Danke für den Kontext.

Zitat von version2 im Beitrag #200

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Also: Systemische Verabreichung von PF4 = gut für das gealterte Mäusehirn.

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Histone mark age of human tissues and cells
https://www.biorxiv.org/content/10.1101/2023.08.21.554165v2

A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model
https://www.nature.com/articles/s41467-023-40546-w

Intermittent Fasting Improves Alzheimer’s Pathology

Zitat

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Mice on a time-restricted feeding schedule had better memory and less accumulation of amyloid proteins in the brain compared to controls

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https://today.ucsd.edu/story/intermitten...imers-pathology


Stanford Medicine-led research identifies gene ‘fingerprint’ for brain aging

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A study in mice finds that white matter — the tissue that transmits messages around the brain — shows the greatest changes as the animals age.

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https://med.stanford.edu/news/all-news/2...ging-genes.html

#208: In der Studie steht:

Zitat

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PF4—a chemokine released from platelets and involved in coagulation and immunomodulatory functions—is elevated in the blood serum after neutral blood exchange in aged mice (a systemic rejuvenating intervention) as well as therapeutic plasma exchange in humans (a similar human clinical procedure).

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Insofern weiß ich nicht, was Fälle von NW bei Geimpften nun damit zu tun haben, aber vielleicht versteh ich auch nicht wirklich was du meinst.

#208
Zumindest ist mehr PF4, wenn man dazu viel Antikörper hat schlecht. Aber wenn man das Blut
verdünnt mit Plasma ist ja auch weniger Antikörper da.
Ach was weiß ich, was ich gestern gemeint habe.

Longevity gene from naked mole rats extends lifespan of mice

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The successful transfer of a gene that produces HMW-HA paves the way for improving the health and lifespan of humans, too.

In a groundbreaking endeavor, researchers at the University of Rochester have successfully transferred a longevity gene from naked mole rats to mice, resulting in improved health and an extension of the mouse’s lifespan.

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https://www.rochester.edu/newscenter/gen...ifespan-565032/

Kommentar: Im Median lebten die dann anscheinend 4,4% länger. Ich hätte mehr erwartet, aber es ist ja auch nur ein Gen. Jetzt bitte noch die verbesserte DNA-Reperatur vom Grönlandwal transferieren.

Phytosterols reverse antiretroviral-induced hearing loss, with potential implications for cochlear aging
https://journals.plos.org/plosbiology/ar...al.pbio.3002257

#213
Interessant. Müsste man ebenfalls tiefer analysieren.

Extracellular Vesicles in Young Serum Contribute to the Restoration of Age-Related Brain Transcriptomes and Cognition in Old Mice

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We have previously demonstrated that circulating extracellular vesicles (EVs) are essential to the beneficial effect of young serum on the skeletal muscle regenerative cascade. Here, we show that infusions of young serum significantly improve age-associated memory deficits, and that these effects are abolished after serum depletion of EVs.

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https://www.mdpi.com/1422-0067/24/16/12550

Biotech on $4m mission to extend healthspan by 20 years based on biomarkers of aging in Phase 3 trial by the end of this decade.

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The company’s immediate scientific objective is to decode all rejuvenation programs present in human cells, to build an atlas of disease and rejuvenation targets for clinical translation.

“We have a bold mission of extending human healthspan by 20 years based on biomarkers of aging in a Phase 3 trial by the end of this decade. Embryonic stem cells hold the key to unlocking rejuvenation biology,” said Mark Kotter, clock.bio’s Founder.

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https://longevity.technology/news/clock-...s-human-genome/

Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems

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Individuals, organs, tissues, and cells age in diverse ways throughout the lifespan. Epigenetic clocks attempt to quantify differential aging between individuals, but they typically summarize aging as a single measure, ignoring within-person heterogeneity. Our aim was to develop novel systems-based methylation clocks that, when assessed in blood, capture aging in distinct physiological systems. We combined supervised and unsupervised machine learning methods to link DNA methylation, system-specific clinical chemistry and functional measures, and mortality risk. This yielded a panel of 11 system-specific scores– Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone, and Metabolic. Each system score predicted a wide variety of outcomes, aging phenotypes, and conditions specific to the respective system, and often did so more strongly than existing epigenetic clocks that report single global measures. We also combined the system scores into a composite Systems Age clock that is predictive of aging across physiological systems in an unbiased manner. Finally, we showed that the system scores clustered individuals into unique aging subtypes that had different patterns of age-related disease and decline. Overall, our biological systems based epigenetic framework captures aging in multiple physiological systems using a single blood draw and assay and may inform the development of more personalized clinical approaches for improving age-related quality of life

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https://www.biorxiv.org/content/10.1101/...8904v1.full.pdf

Kommentar: Das geht in Richtung Altersmessung je nach Gewebe/Organ, spannend. Vielleicht kann man damit dann eines Tages spezifische Verjüngung erreichen.

Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial
https://www.nature.com/articles/s41591-023-02543-w

Boosting T cell immunity against cytomegalovirus: a potential strategy combating human aging and age-related diseases
https://www.nature.com/articles/s41392-023-01590-6

Kommentar: Interessante Studie, leider für mich nicht ganz verständlich.

Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism

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Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues.

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https://link.springer.com/article/10.1007/s11357-023-00915-1

Kommentar: Hier wurde die Alterung unter Einfluss von geroprotektiven Maßnahmen (AA-Maßnahmen) der normalen Alterung gegenübergestellt.

Dynamic lipidome alterations associated with human health, disease and ageing
https://www.nature.com/articles/s42255-023-00880-1

Falls wir das noch nicht hatten:

Robust Mouse Rejuvenation
https://www.levf.org/projects/robust-mou...nation-study-1/

Zitat von Prometheus im Beitrag #220

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Aber was bei PUFA und Omega 3-Fettsäuren funktioniert, könnte wohl auch mit Large TAG, 22:6 FA, 20:5 FA, 18:3 FA und18:2 Fa und 16:1 FA funktionieren...

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Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages

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Aging is characterized by gradual immune dysfunction and increased disease risk. Genomic instability is considered central to the aging process, but the underlying mechanisms of DNA damage are insufficiently defined. Cells in confined environments experience forces applied to their nucleus, leading to transient nuclear envelope rupture (NER) and DNA damage. Here, we show that Lamin A/C protects lung alveolar macrophages (AMs) from NER and hallmarks of aging. AMs move within constricted spaces in the lung. Immune-specific ablation of lamin A/C results in selective depletion of AMs and heightened susceptibility to influenza virus-induced pathogenesis and lung cancer growth. Lamin A/C-deficient AMs that persist display constitutive NER marks, DNA damage and p53-dependent senescence. AMs from aged wild-type and from lamin A/C-deficient mice share a lysosomal signature comprising CD63. CD63 is required to limit damaged DNA in macrophages. We propose that NER-induced genomic instability represents a mechanism of aging in AMs.

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https://www.nature.com/articles/s43587-023-00488-w

Addressing the complexities in measuring cyclodextrin-sterol binding constants: A multidimensional study
https://www.sciencedirect.com/science/ar...144861723008251

Kommentar: Behandelt Atherosklerose.

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans
https://journals.plos.org/plosgenetics/a...al.pgen.1010938

T cell exhaustion is associated with cognitive status and amyloid accumulation in Alzheimer’s disease
https://www.nature.com/articles/s41598-023-42708-8

Preprints:

Urolithin A induces cardioprotection and enhanced mitochondrial quality during natural aging and heart failure
https://www.biorxiv.org/content/10.1101/2023.08.22.554375v1

ASK1 promotes inflammation in senescence and aging
https://www.biorxiv.org/content/10.1101/2023.09.20.558729v1

Abnehm-Medikament erleichtert Lernen bei Übergewicht
Liraglutid wirkt sich positiv auf die Gehirnaktivität bei Menschen mit Adipositas aus

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Um unser Verhalten steuern zu können, muss das Gehirn in der Lage sein, Assoziationen zu bilden. Dabei wird beispielsweise ein neutraler äußerer Reiz mit einer Konsequenz verknüpft, die auf diesen Reiz folgt (z.B. die Herdplatte leuchtet rot – man kann sich die Hand verbrennen). Dadurch lernt das Gehirn, welche Konsequenzen unser Umgang mit dem ersten Reiz hat. Das assoziative Lernen ist die Grundlage für die Bildung neuronaler Verknüpfungen und verleiht Reizen eine motivierende Kraft. Es wird wesentlich von einer Hirnregion gesteuert, dem dopaminergen Mittelhirn. Diese Region hat viele Rezeptoren für körpereigene Hormone wie z.B. Insulin und kann damit unser Verhalten an die physiologischen Bedürfnisse unseres Körpers anpassen.

Doch was passiert, wenn die Insulinsensitivität im Körper durch Übergewicht verringert ist? Verändert sich dadurch unsere Gehirnaktivität, unsere Fähigkeit, Verknüpfungen zu erlernen, und somit unser Verhalten zu steuern? Forschende des Max-Planck-Instituts für Stoffwechselforschung haben nun bei Probanden mit normalem Körpergewicht (hohe Insulinsensitivität) und Probanden mit Adipositas (verminderte Insulinsensitivität) gemessen, wie gut das Lernen von Assoziationen funktioniert und welchen Einfluss das Abnehm-Medikament Liraglutid darauf hat.

Geringere Fähigkeit, sensorische Reize miteinander zu verknüpfen

„Diese Ergebnisse sind von grundlegender Bedeutung. Wir zeigen hier, dass grundlegende Verhaltensweisen wie das assoziative Lernen nicht nur von äußeren Umweltbedingungen abhängen, sondern auch vom Stoffwechselzustand des Körpers. Ob jemand Übergewicht hat oder nicht, bestimmt also auch, wie das Gehirn lernt, sensorische Signale zuzuordnen und welcher Antrieb dabei entsteht. Die Zustandsnormalisierung, die wir durch das Medikament bei Adipositas erreichen, passt also zu den Ergebnissen von Studien, dass durch diese Medikamente wieder ein normales Sättigungsgefühl vermittelt wird und die Menschen infolge weniger essen und damit abnehmen“, sagt Studienleiter Marc Tittgemeyer vom Max-Planck-Institut für Stoffwechselforschung.

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https://www.mpg.de/20744597/0815-neur-ab...ositas-153735-x