RE: Senolysis, Reloaded - 4

Zitat von Prometheus im Beitrag #18

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Nimmt man allerdings einen mTOR-Inhibitor hinzu, wandelt sich das Bild, und auf einmal wirkt die Senolyse:

Zitat

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Bemerkenswerterweise führt die Kombination von ABT-263 und MCL-1-Inhibitoren zu einer synthetischen Letalität seneszenter Melanozyten, und ihre topische Anwendung reicht aus, um Nävi bei männlichen Mäusen zu beseitigen. [...]Der mTOR-Inhibitor PP242 reicht aus, um den MCL-1-Spiegel zu senken und seneszente Melanozyten für die toxische Wirkung von ABT-263 zu sensibilisieren.

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Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression
https://www.nature.com/articles/s41467-022-35657-9

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Das Senolytikum könnte auch unerwünschte Auswirkungen haben:

The senolytic drug ABT-263 accelerates ovarian aging in older female mice

Zitat

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ABT-263 treatment did not rescue abnormal estrus cycles and sex hormonal levels, or inhibit the formation of multinucleated giant cells and ovarian stromal cell apoptosis in aged ovaries. However, it reduced ovarian fibrosis and preserved the steroidogenic gene expression of ovarian stromal cells in aged ovaries. Importantly, ABT-263 treatment further depleted ovarian follicles in aged mice. In conclusion, ABT-263 treatment accelerated the depletion of ovarian follicles in aged mice, suggesting that senolytic drugs for reproductively old female may adversely affect female fertility.

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https://www.nature.com/articles/s41598-024-73828-4

Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline
https://onlinelibrary.wiley.com/doi/10.1111/acel.14340

Comparable anti-ageing efficacies of a multi-ingredient nutraceutical and a senolytic intervention in old mice
https://www.biorxiv.org/content/10.1101/...ZZL02-rGN_VANlw

Development of novel flavonoid senolytics through phenotypic drug screening and drug design

Zitat

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Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging. Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.

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https://www.biorxiv.org/content/10.1101/2024.10.27.620529v1

Senescent Cells Promote Cartilage Regeneration in Rats

Zitat

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Cellular senescence is widely known to have negative effects, to the point that it is one of the hallmarks of aging. In fact, rather than protecting cartilage, cellular senescence has been reported to damage it in the progression of osteoarthritis [1]. However, the idea that senescence is beneficial for regeneration is not a new concept [2], and it has been found to assist wound healing in mice [3]. Understanding everything involved in this complex relationship is not easy, and one of the factors appears to be windows of time [4].

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https://www.lifespan.io/news/senescent-c...ration-in-rats/

Kommentar: Mir fiel bei Nutzung eines Senolytikums auch auf, dass einige Hautstellen langsamer regenerierten. Also evtl. lieber erstmal abwarten bis alles verheilt ist, bevor man Senolytika nutzt. Das ist kein medizinischer Rat.

Zitat von version2 im Beitrag #81

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Senescent Cells Promote Cartilage Regeneration in Rats

Zitat

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Cellular senescence is widely known to have negative effects, to the point that it is one of the hallmarks of aging. In fact, rather than protecting cartilage, cellular senescence has been reported to damage it in the progression of osteoarthritis [1]. However, the idea that senescence is beneficial for regeneration is not a new concept [2], and it has been found to assist wound healing in mice [3]. Understanding everything involved in this complex relationship is not easy, and one of the factors appears to be windows of time [4].

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https://www.lifespan.io/news/senescent-c...ration-in-rats/

Kommentar: Mir fiel bei Nutzung eines Senolytikums auch auf, dass einige Hautstellen langsamer regenerierten. Also evtl. lieber erstmal abwarten bis alles verheilt ist, bevor man Senolytika nutzt. Das ist kein medizinischer Rat.

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Ja bei Fisetin fiel mir das auch auf.

Cell senescence in cardiometabolic diseases
https://www.nature.com/articles/s41514-0...TIiErCjBe_K33xQ

Goodbye, senescent cells: CAR-T cells unleashed to fight ageing
https://www.nature.com/articles/s41580-0...4sZwx4yQ1iCRC5g

Chronic social stress induces p16-mediated senescent cell accumulation in mice
https://www.nature.com/articles/s43587-024-00743-8

TGFβ Hemmung ist hier wichtig.

Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ
https://www.nature.com/articles/s41556-0...wwF4n8-R_PEdZlw

Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing
https://www.nature.com/articles/s43587-0...I2eyyLwSG8dBahw

Emerging insights in senescence: pathways from preclinical models to therapeutic innovations
https://www.nature.com/articles/s41514-0...vzh1-_RuXkrNy3Q

Emerging insights in senescence: pathways from preclinical models to therapeutic innovations
https://www.nature.com/articles/s41514-0...vzh1-_RuXkrNy3Q

The role of high mobility group proteins in cellular senescence mechanisms
https://www.frontiersin.org/journals/agi...IEqZVudpoVQ4LmQ

Cellular senescence in Alzheimer’s disease: from physiology to pathology
https://translationalneurodegeneration.b...oVZ3M4IqrhHWMUg

Hallo Speedy,

die Seneszenz in den Stammzellnischen ist besonders tragisch und in einigen Fällen können die Stammzellen wieder reaktiviert werden (siehe auch "Alzheimer jetzt stoppen!", Bruce Fife). Dr. Nehls würde u.a. Vitamin D, Low Dose Lithium und Omega3 Fettsäuren empfehlen.

Viele Grüße

Roger

Myricetin wäre ein natürlicher zum Beispiel. Wer täglich eine Handvoll Walnüsse verzehrt beugt dem ganzen was vor dann.

Connectivity Map and perturbation-based sensitivity analysis identifies MEK inhibitors as senolytics in human lung fibroblasts
https://www.biorxiv.org/content/10.1101/...Eas4RV0qx1iiIuA

Zitat von version2 im Beitrag #75

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Zitat

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This indicates that oleandrin has a more substantial senolytic effect than ouabain in replicative senescence and therapy-induced senescence in epithelial cancer cells (Fig. 4c and Supplementary Fig. 9b, d, e). Importantly, treatment of oncogene-induced and replicative senescent cells with 10 nM oleandrin induced an evident increase in caspase-3/7 activity when compared to control cells, as well as cells treated with oleandrin and periplocin, confirming that oleandrin induces apoptosis in senescent cells at lower concentrations than ouabain

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Noch was zum Ouabain (hatten wir noch nicht): https://www.ncbi.nlm.nih.gov/core/lw/2.0...3_Fig8_HTML.jpg

Via:
https://www.longecity.org/forum/topic/11...kes-the-poison/

Zitat

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g-Strophanthin (kurz Strophanthin, von στροφή, „Strophe“, hier im Sinne von „Wendung, Schlängelung“, und ἄνϑος, „Blüte“, bezieht sich auf die lang ausgezogenen, gedrehten Spitzen der Blütenblätter bestimmter Strophanthusarten) auch Ouabain, ist ein Cardenolid-Glykosid, das als Herzglykosid früher zur Behandlung von Herzkrankheiten mit Herzschwäche eingesetzt wurde.[6][7] Das Aglycon ist g-Strophanthidin (Ouabagenin). Strophanthin wirkt auf Rezeptoren am Enzym Na+/K+-ATPase (Natrium-Kalium-Pumpe) und kann in höheren Dosen tödlich wirken.

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https://de.wikipedia.org/wiki/G-Strophanthin

Cellular senescence in acute human infectious disease: a systematic review
https://www.frontiersin.org/journals/agi...24.1500741/full

Unclogging the immune system: Scientists use immunotherapy to remove aging cell buildup
https://medicalxpress.com/news/2024-12-u...rapy-aging.html

An antibiotic that mediates immune destruction of senescent cancer cells
https://www.pnas.org/doi/10.1073/pnas.24...ub%20%200pubmed

Identifying novel aging-related diagnostic and prognostic models and aging-targeted drugs for sepsis patients
https://pubmed.ncbi.nlm.nih.gov/39732977/

Senescence as a Molecular Target in Skin Aging and Disease
https://www.sciencedirect.com/science/ar...NwA4SJFWShshvXA