RE: News aus der Forschung - 12

Remodeling of cytoskeleton, chromatin and gene expression during mechanical rejuvenation of aged human dermal fibroblasts

Zitat

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Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been explored. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood. Here, we studied the cytoskeletal, genome-wide chromatin and transcriptional changes in young, aged and mechanically rejuvenated fibroblasts using immunofluorescence, RNA-seq and Hi-C experiments. The mechanically rejuvenated aged fibroblasts, that had partially reset their transcription to a younger cell state, showed a local reorganization of the inter-chromosomal contacts and lamina-associated domains. Interestingly, the observed chromatin reorganization correlated with the transcriptional changes. Immunofluorescence experiments in the rejuvenated state confirmed increased acto-myosin contractility like younger fibroblasts. In addition, the rejuvenated contractile properties were maintained over multiple cell passages. Overall, our results give an overview of how changes in the cytoskeleton, chromatin, and gene activity are connected to aging and rejuvenation.

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https://pubmed.ncbi.nlm.nih.gov/39630645/

Neferine Attenuates Aging-Related Liver Dysfunction by Suppressing Cellular Aging via Mitochondrial Reactivation

Zitat

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Pharmacological analyses revealed that neferine-induced autophagy via the death-associated protein kinase 1 (DAPK1) and c-Jun N-terminal kinase (JNK) signaling pathways despite the lack of AMP activated protein kinase (AMPK) signaling activation. Furthermore, neferine stimulated ATP production and β-oxidation activity in aging cells. Our in vivo experiments demonstrated that oral administration of neferine rejuvenated aging liver tissue, suppressed fatty acid accumulation in the liver, and reduced senescence-associated β-galactosidase activity. Thus, neferine rejuvenated aging cells and liver tissue by inducing autophagy to reactivate mitochondrial function.

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https://www.jstage.jst.go.jp/article/bpb...-00477/_article

Kommentar: Zum Alkaloid Neferin finden sich wenig informationen. Anscheinend kommt es im Heiligen Lotus vor? https://institut-der-gesundheit.com/lexikon/heiliger-lotus


Senolytics rejuvenate aging cardiomyopathy in human cardiac organoids

Zitat

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Methods: We employed human iPSC-derived cardiac organoids (hCOs/hCardioids) to model doxorubicin(DOXO)-induced cardiomyopathy in an aged context. hCardioids were treated with DOXO and subsequently with a combination of two senolytics: dasatinib (D) and quercetin (Q).

Results: DOXO-treated hCardioids exhibited significantly increased oxidative stress, DNA damage (pH2AX), cellular senescence (p16INK4A) and decreased cell proliferation associated with a senescence-associated secretory phenotype (SASP). DOXO-treated hCardioids were considerably deprived of cardiac progenitors and displayed reduced cardiomyocyte proliferation as well as contractility. These distinctive aging-associated characteristics were confirmed by global RNA-sequencing analysis. Treatment with D+Q reversed these effects, reducing oxidative stress and senescence markers, alleviating SASP, and restoring hCardioids viability and function. Additionally, senolytics replenished cardiac progenitors and reversed the cardiomyocyte proliferation deficit.

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https://pubmed.ncbi.nlm.nih.gov/39622416/

RANKL treatment restores thymic function and improves T cell-mediated immune responses in aged mice

Zitat

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Here, we identified that the receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) axis in the thymus is altered during aging. Using a conditional transgenic mouse model, we demonstrated that endothelial cells depend on RANK signaling for their cellularity and functional maturation. Decreased RANKL availability during aging resulted in a decline in cellularity and function of both endothelial cells and thymic epithelial cells, contributing to thymic involution. We then found that, whereas RANKL neutralization in young mice mimicked thymic involution, exogenous RANKL treatment in aged mice restored thymic architecture as well as endothelial cell and epithelial cell abundance and functional properties. Consequently, RANKL improved T cell progenitor homing to the thymus and boosted T cell production. This cascade of events resulted in peripheral T cell renewal and effective antitumor and vaccine responses in aged mice. Furthermore, we conducted a proof-of-concept study that showed that RANKL stimulates endothelial cells and epithelial cells in human thymic organocultures. Overall, our findings suggest that targeting the RANK-RANKL axis through exogenous RANKL administration could represent a therapeutic strategy to rejuvenate thymic function and improve T cell immunity during aging.

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https://pubmed.ncbi.nlm.nih.gov/39630886/

Kommentar: Wo kriegt man jetzt RANKL hier?


Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative-Inflammatory State: A Randomized Controlled Trial
https://pmc.ncbi.nlm.nih.gov/articles/PMC11591374/#abstract1

Kommentar: Funding beachten.

Discovery of Thermodynamic Control Variables that Independently Regulate Healthspan and Maximum Lifespan
https://www.biorxiv.org/content/10.1101/...QLfdly37oW2zGDw

Zitat von Prometheus im Beitrag #278

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Zitat von Speedy im Beitrag #277

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Discovery of Thermodynamic Control Variables that Independently Regulate Healthspan and Maximum Lifespan
https://www.biorxiv.org/content/10.1101/...QLfdly37oW2zGDw

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Die Frage ist: Welche neuen Perspektiven eröffnet diese Sichtweise für die Lebensverlängerung?

In der Publikation wird erwähnt, das Maßnahmen zur Verringerung der effektiven Temperatur aussichtsreich zur Verlängerung der medianen Lebensspanne sind. Welche sind das?

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Zitat

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This implies that aging is driven by rare, high-energy transitions on rugged energy landscape, most likely simultaneous and hence practically irreversible failures in highly redundant systems. While the overall rate of damage accumulation and hence the maximum lifespan does not depend on the effective temperature driving the noise in leading pathways, effective temperature does influence both initial mortality rate and the mortality rate doubling time – thereby shaping the survival curve.

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Mir fehlt das physikalische Wissen, um dem Paper im Detail zu folgen. Es klingt doch recht theoretisch. Vielleicht sollte man sich lieber auf solche Forschung konzentrieren, die Lösungen vorschlägt?

Zitat von version2 im Beitrag #279

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Vielleicht sollte man sich lieber auf solche Forschung konzentrieren, die Lösungen vorschlägt?

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Hallo Prometheus,

beim großen Mausohr altern die Zellen nicht (siehe auch Link): das Reparaturgen, die Autophagie und die Qualitätskontrolle der Mitochondrien sind fast dauerhaft aktiviert (Heteroplasmie wird nur bei Krankheiten oder Verletzungen beobachtet) etc.

VG

Roger

Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis
https://www.nature.com/articles/s41586-0...gLjC9wCAZB87VFg

Human body’s ageing ‘clock’ ticks faster after heat stress
https://www.nature.com/articles/d41586-0...8YWOLZEEMo_pMEg

Zitat von Prometheus im Beitrag #285

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Interessant - einerseits logisch, weil z.B. auch die Sterblichkeit in Hitzeperioden ansteigt. Andererseits bedeutet es auch , dass eine über längere Zeit zu warme Umgebungstemperatur offenbar schneller suprahometische Effekte hat als ich dachte. Die Cut off Werte von 26.7 °C bzw. 32.2 °C sind erstaunlich niedrig, ich hätte das erst bei Außentemperaturen über der Körpertemperatur erwartet!

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Too old for healthy aging? Exploring age limits of longevity treatments
https://www.nature.com/articles/s44324-0...AYkt-YhSOmzxRGA

Kein Sport, keine Kälte etc. mehr im hohen Alter?

Hallo Ununheilig,

man sollte die o.g. Aussagen nicht verallgemeinern. Statistisch gesehen ist der Stoffwechsel im Alter zunehmend geschwächt und in diesen Fällen ist leider nur noch ein leichtes, angepasstes Training möglich (Pacing): "Übertraining" ist schädlich für den Körper. Man kann den Körper jedoch in einigen Fällen reaktivieren (Ketose, NEM etc.) und bei einer erfolgreichen Strategie ist evtl. eine langsame Steigerung der Trainingsleistung möglich.

VG

Roger

Lithocholic acid phenocopies anti-ageing effects of calorie restriction
https://www.nature.com/articles/s41586-024-08329-5

Aged neurons don’t register energy need
https://www.science.org/doi/10.1126/science.adu4935

Scientists steer the development of stem cells to regenerate and repair organs
https://phys.org/news/2024-12-scientists...irZRAqCbW-rXvCQ

Canagliflozin treatment prevents follicular exhaustion and attenuates hallmarks of ovarian aging in genetically heterogenous mice
https://link.springer.com/article/10.1007/s11357-024-01465-w

Zitat von Prometheus im Beitrag #297

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Transcriptome Analysis Reveals Norathyriol Prolongs the Lifespan via Regulating Metabolism in C. elegans
https://www.mdpi.com/2218-1989/14/12/716

Kommentar Prometheus: Wirkt auf mehrere Pathways gleichzeitig (mTOR/IGF-1, SIRT-1/AMPK/SREBP-1 etc) und reduziert die Lipofuscin-Ansammlung in C. elegans.

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