Senolysis, Reloaded - 2

Mid-old cells are a potential target for anti-aging interventions in the elderly

Zitat

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The biological process of aging is thought to result in part from accumulation of senescent cells in organs. However, the present study identified a subset of fibroblasts and smooth muscle cells which are the major constituents of organ stroma neither proliferative nor senescent in tissues of the elderly, which we termed “mid-old status” cells. Upregulation of pro-inflammatory genes (IL1B and SAA1) and downregulation of anti-inflammatory genes (SLIT2 and CXCL12) were detected in mid-old cells. In the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Remarkably, the microenvironmental change and the functional decline of mid-old cells could be reversed by a young cell-originated protein, SLIT2. Our data identify functional reversion of mid-old cells as a potential method to prevent or ameliorate aspects of aging-related tissue dysfunction.
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In summary, these findings demonstrate that SLIT2 protein functions as an anti-aging molecule in aged mice.
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Can SLIT2 extend lifespan? Although our mouse sample size was small (n = 4, each), we administered PBS or rmSLIT2 injections once a week to 23-month-old mice and measured longevity. However, we did not observe evidence that SLIT2 extends lifespan, which is a major drawback of this study. Nonetheless, we believe that further investigation using a larger sample size of aged mice is necessary to draw conclusive results.

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https://www.nature.com/articles/s41467-023-43491-w

Hallo,

Ketone, ALA und AMPK/SIRT1 Aktivatoren können häufig auch zur Senolyse genutzt werden.

Viele Grüße

Roger

Hat schon mal jemand FOXO4-DRI experimentell diesbezüglich eingestetzt und wie sind die Erfahrungen? Vor allem im direkten Vergleich zu High-dose Fisetin oder zur Quercetin/Langer Pfeffer Kombi.

Älteres Paper was wir aber hier noch nicht hatten mein ich.

Extracts of Cistanche deserticola Can Antagonize Immunosenescence and Extend Life Span in Senescence-Accelerated Mouse Prone 8 (SAM-P8) Mice
https://www.ncbi.nlm.nih.gov/pmc/article...S9sDSkljuCRANeI

Traditional herbs: mechanisms to combat cellular senescence
https://www.aging-us.com/article/205269/...NdWuPpz3S7I#r15

Senolytics enhance longevity in Caenorhabditis elegans by altering betaine metabolism
https://www.biorxiv.org/content/10.1101/2023.12.19.572398v1

Cellular senescence in brain aging and cognitive decline
https://www.frontiersin.org/articles/10....23.1281581/full

Zitat von Prometheus im Beitrag #33

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Natürliche Substanzen, die potentiell senolytisch wirken könnten:

•3,4'-dihydroxypropiophenone
• baicalein
• α, β-dehydrocurvularin
•lovastatin
•luteolin
•phloretin

Quelle:

Natural Products as a Major Source of Candidates for Potential Senolytic Compounds obtained by in silico Screening
https://doi.org/10.2174/1573406419666221019153537

Kommentar Prometheus: In silico-Daten sind nicht unbedingt die beste Evidenz. Allerdings könnte durchaus etwas dran sein, zum Beispiel gibt es für Luteolin weitere Indizien für eine senolytische Aktivität.

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#33
Zum erwähnten Phloretin hatten wir bislang noch nichts hier im Forum glaube ich. Bekannt ist es in erster Linie als Inhaltsstoff in einem patentierten Gesichtspflege Produkt was zu horrenden Preisen angeboten wird.

Phloretin, as a Potent Anticancer Compound: From Chemistry to Cellular Interactions
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787340/

Phloretin enhances remyelination by stimulating oligodendrocyte precursor cell differentiation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674257/

Phloretin ameliorates diabetes-induced endothelial injury through AMPK-dependent anti-EndMT pathway
https://pubmed.ncbi.nlm.nih.gov/35381340/

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging
https://www.biorxiv.org/content/10.1101/2024.01.14.575313v1

Zitat von Speedy im Beitrag #37

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CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging
https://www.biorxiv.org/content/10.1101/2024.01.14.575313v1

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Flavonoid 4,4'-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy
https://www.sciencedirect.com/science/ar...4184?via%3Dihub

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Zitat

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Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells (‘senolytics’) partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

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https://www.nature.com/articles/s43587-023-00560-5

Klingt sehr gut, aber man sollte die "Competing Interests" beachten.

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice
https://jbiomedsci.biomedcentral.com/art...kg48W2sle8yd3y8

These: Bei einer idealen Verjüngung müsste man keine Senolytika nehmen, weil der Körper selbst effektiv seneszente Zellen entfernt. Noch sind wir nicht da und ob Menschen die kaum/keinen Thymus mehr haben überhaupt wieder dahin gelangen werden?

Bioinformatics procedure for investigating senolytic (anti‐aging) agents: A digital signal processing technique

Zitat

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Our results show that the peptides have different degrees of senolytic (anti‐aging) activity, depending on their affinity for CR3 and BDB, or FOXO4 and DRI. We found that enhanced senescence 2 (ES2) has a higher affinity for CR3 and BDB than FOXO4 and DRI, and that the interaction between CR3 and BDB is crucial for aging. Therefore, ES2 and other CR3‐based peptides are more potent senolytics than FOXO4‐based peptides. Our findings are consistent with previous studies and reveal new insights into the mechanisms of senescence and senolytics. ES2 is considered the best senolytic candidate, as it is 3–7 times more effective than DRI.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10792327/

Kommentar: Dies scheint mir vor allem eine theoretische Arbeit zu sein, deren Ergebnisse noch in vitro und ggf. in vivo zu überprüfen wären.

Hallo,

mit einer prof. Jodtherapie beim Privatarzt/HP kann man u.a. die Schadstoffe aus dem Thymus verdrängen. Ergothionein und/oder Ketone können evtl. die Mitochondrien in den seneszenten Zellen reaktivieren und die stark geschädigten Zellen gehen ganz natürlich durch Apoptose unter. Benachbarte Zellen können sich bei geringen Schäden erholen, wenn sie nicht mehr durch Ammoniak geschädigt werden.

Viele Grüße

Roger

Zitat von Roger im Beitrag #43

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Hallo,

mit einer prof. Jodtherapie beim Privatarzt/HP kann man u.a. die Schadstoffe aus dem Thymus verdrängen. Ergothionein und/oder Ketone können evtl. die Mitochondrien in den seneszenten Zellen reaktivieren und die stark geschädigten Zellen gehen ganz natürlich durch Apoptose unter. Benachbarte Zellen können sich bei geringen Schäden erholen, wenn sie nicht mehr durch Ammoniak geschädigt werden.

Viele Grüße

Roger

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Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions
https://www.aging-us.com/article/205581/text

Senotherapeutics to Counteract Senescent Cells Are Prominent Topics in the Context of Anti-Ageing Strategies
https://www.mdpi.com/1422-0067/25/3/1792

Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction
https://academic.oup.com/edrv/advance-ar...421?login=false