Dataset Information

Senolytics improve the neurogenic potential of non-glial progenitors and neurorepair in the dorsal pallium of aged killifish independent of inflammation

ABSTRACT: With advancing age, senescent cells accumulate as they are not efficiently cleared by the immune system anymore. Via a senescence-associated secretory phenotype, chronic senescent cells alter the microenvironment, creating an unfavorable milieu for neurogenesis and neurorepair. Using an innovative and rapid aging model, the African turquoise killifish, we have previously demonstrated a dramatic decline in neurogenic potential of non-glial progenitors with age. Even after traumatic brain injury, progenitor proliferation and neuron production was very low in aged killifish in comparison to young adult killifish, and overall neurorepair was incomplete. In the present study, we validated if the senolytic cocktail dasatinib and quercetin (D+Q) could reboot the neurogenic output by clearing chronic senescent cells from the aged killifish brain to re-create the necessary supportive environment. Our results confirm that the aged killifish telencephalon holds a very high senescent cell burden, which we could diminish by short-term systemic D+Q treatment. As a consequence of D+Q administration, proliferation of non-glial progenitors increased and more new neurons were generated and migrated into the parenchyma after injury. Injury-induced inflammation and glial scarring, a phenomenon only seen in aged killifish, remained unaltered. Senolytic treatment with D+Q might thus hold promise for improving brain function in aged populations, and is especially interesting for reviving the neurogenic potential of an already aged central nervous system.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Nothobranchius Furzeri

TISSUE(S): Brain

SUBMITTER: Kurt Boonen

LAB HEAD: Lut Arckens

PROVIDER: PXD036437 | Pride | 2023-07-20

REPOSITORIES: pride

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Publications

A short dasatinib and quercetin treatment is sufficient to reinstate potent adult neuroregenesis in the aged killifish.

Van Houcke Jolien J Mariën Valerie V Zandecki Caroline C Ayana Rajagopal R Pepermans Elise E Boonen Kurt K Seuntjens Eve E Baggerman Geert G Arckens Lutgarde L

NPJ Regenerative medicine 20230616 1

The young African turquoise killifish has a high regenerative capacity, but loses it with advancing age, adopting several aspects of the limited form of mammalian regeneration. We deployed a proteomic strategy to identify pathways that underpin the loss of regenerative power caused by aging. Cellular senescence stood out as a potential brake on successful neurorepair. We applied the senolytic cocktail Dasatinib and Quercetin (D + Q) to test clearance of chronic senescent cells from the aged kill ...[more]

PMID: 37328477

Similar Datasets

Project description:Senolytic drugs are designed to selectively clear senescent cells (SnCs) that accumulate with injury or aging. In a mouse model of osteoarthritis (OA), senolysis yields a pro-regenerative response. However, recent research studies showed that the therapeutic benefit is reduced in aged mice. Increased oxidative stress (redox) mediates metabolic dysregulation and accumulation of posttranslational modifications (PTM) on proteins from the cartilage and is one of the major hallmarks of advanced age. This research investigated whether the senolytic treatment differentially affects oxidative load in the joints from young and aged animals. We employed label-free quantitative (LFQ) analysis of changes in the protein expression profiles and associated carbonylated PTMs in the extracted joint proteins. Our proteomic survey focused to a set of PTMs described as advanced glycation-end products (AGEs) or advanced lipooxidation-end products (ALEs), known to accumulate during aging and age-associated diseases. AGEs and ALEs are the result of non-enzymatic reactions of protein with reducing sugars, or with oxidized sugar or lipid degradation products, which may alter and sometimes crosslink the positively charged amino acids lysine and arginine on proteins. Our proteomic dataset supported detection of several AGEs and ALEs, including the adducts 4-ONE (4-oxononenal), 4-ONE+Delta:H(-2)O(-1) (dehydrated 4-oxononenal Michael adduct), carboxyethyl, carboxymethyl, 3-deoxyglucosone derived dihydroxyimidazoline, G-H1 (glyoxal-derived hydroimidazolone), HNE (4-hydroxynonenal), several carbonylated adducts including proline to pyrrolidinone or pyrrolidone Other detected modifications of note include mono-oxidation and di-oxidation products, including tryptophan to kynurenine. We also detected lysine-epsilon-gly-gly (GlyGly), which marks ubiquitylated sites, indicating potential substrates of proteasome-dependent degradation. The grand total PTM change was negative for treated aged OA mice but positive for treated young OA mice, regardless of whether summed across modifications or across proteins. In other words, senolytic treatment reduced oxidation associated PTMs more effectively in aged OA mice than in young OA mice. The LFQ proteomics analysis was complemented with new biophysical computational tools aimed to predict the stability of carbonylated proteins extracted from the joints. The biophysical model predicted divergent proteomic responses between young and aged animals. Altogether, our results showed that senolysis reduces overall oxidative stress in the aged arthritic joints in vivo.

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