Emerging clinical evidence implicates cellular senescence in the pathogenesis of various inflammatory conditions including inflammatory bowel diseases (IBDs), demonstrating that the intestinal stem cell crypts of patients with early Crohn’s disease exhibit markers positive for cell cycle inhibitor proteins. This phenomenon coupled with chronic systemic inflammation, a term coined “inflammaging," triggers many age-related pathologies and accelerates mortality. Our research evaluates the efficacy of interventions that target these death-resistant senescent cells to improve overall health and vitality. Particularly, we investigated the effects of Fisetin, a potent flavanoid with senolytic properties, in a dextran sodium sulfate (DSS) induced mouse model of colitis. Our findings reveal that Fisetin significantly inhibits senescence and inflammation in the colon while simultaneously enhancing the relative abundance of beneficial microbes, especially Akkermansia muciniphila, showcasing its potential for managing IBDs. Additionally, given the profound restoration of the microbiome and the central role of resident microbes in the production of metabolites essential for facilitating immunomodulation, we extended our investigations to further explore the effects of fecal microbiota transplant (FMT) from long-living Ames dwarf mice, characterized by low inflammatory status, into normal mice. Our results show notable shifts in microbial diversity, indicating that FMT may combat dysbiosis, a precursor to several conditions, including autoimmune, metabolic, and neurodegenerative diseases. Lastly, our exploration of potential anti-aging pharmacological interventions including Metformin (MF) and Trodusquemine (MSI-1436) during the postnatal window has demonstrated robust transcriptomic alterations of key biomarkers in the GH/Igf1 axis, such as Pi3k, Akt, and Mtor, suggesting delayed aging and improved liver function in young mice. These epigenetic changes underscore that early-life pharmacological interventions may forestall the onset of age-related metabolic disorders. All in all, there remains an urgent need for breakthroughs that can enhance healthspan to ensure that the rapidly growing population of older adults enjoys life in these extended years

La sénescence cellulaire est un mécanisme naturel de suppression tumorale défini par un arrêt stable de la prolifération. Bien que presque toujours mutées dans au moins une des voies déclenchant la sénescence (ex : p53/p21 ou p16/Rb), les cellules cancéreuses conservent souvent la capacité d’y entrer en réponse au traitement. Cette sénescence induite par la thérapie (SIT) peut être ciblée pharmacologiquement pour en renforcer les effets positifs. Une approche émergente consiste à combiner un traitement anticancéreux induisant la sénescence à un sénolytique, agent éliminant spécifiquement les cellules sénescentes. Dans le contexte du cancer de la prostate (CP), différents types de SIT ont déjà été observées dans de multiples modèles exposés à différents traitements. Cependant, le manque de données comparant ces phénotypes souligne le besoin d’analyses plus systématiques. De plus, la sensibilité aux sénolytiques des cellules du CP en état de SIT n’a pas encore été évaluée dans ces contextes. Dans cette étude, nous avons évalué les destins cellulaires des lignées du CP après exposition à trois traitements pertinents au niveau clinique : l’irradiation et l’olaparib, deux inducteurs de dommages à l’ADN et l’enzalutamide, un anti-androgène. Dépendamment de la lignée, les traitements par irradiation et olaparib ont mené à une réponse dirigée principalement vers la sénescence ou vers une réponse mixte de mort cellulaire, de catastrophe mitotique et de sénescence. Dans tous les cas, ceux-ci ont déclenché un phénotype sénescent classique et convertible en mort cellulaire par des sénolytiques inhibiteurs des antiapoptotiques de la famille Bcl-2. D’autre part, le traitement à l’enzalutamide a déclenché un phénotype semblable à la sénescence se distinguant par sa réversibilité, son absence de dommages à l’ADN et son insensibilité à ces mêmes sénolytiques. Globalement, nos résultats soulignent l’importance du contexte thérapeutique dans l’élaboration des stratégies de manipulation de la SIT du CP. Ils constituent également une justification robuste à l’étude préclinique des traitements combinant la radiothérapie ou l’olaparib à des inhibiteurs des antiapoptotiques de la famille Bcl-2 dans le contexte du CP. / Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. Although almost always mutated in at least one of the senescence pathways genes (e.g., p53/p21 or p16/Rb), cancer cells often retain the ability to become senescent in response to treatment. This therapy-induced senescence (TIS) can be pharmacologically targeted to enhance its positive effects. An emerging approach is to combine senescence-inducing cancer treatment with senolytics, compounds that specifically eliminate senescent cells. In the context of prostate cancer (PCa), different types of TIS have already been observed in multiple models exposed to different treatments. However, the lack of data comparing these phenotypes highlights the need for more systematic analyses. In addition, the senolytic sensitivity of TIS PCa cells has not yet been evaluated in these settings. In this study, we evaluated the cell fates of PCa cell lines after exposure to three clinically relevant treatments: irradiation and olaparib, two DNA damage inducers, and enzalutamide, an anti-androgen. Depending on the cell line, irradiation and olaparib treatments led to a response mainly directed towards senescence or toward a mixed response of cell death, mitotic catastrophe and senescence. In all cases, these treatments triggered a classic senescent phenotype that was convertible to cell death by senolytic inhibitors of the Bcl-2 family antiapoptotics. On the other hand, treatment with enzalutamide triggered a senescence-like phenotype, distinguishable by its reversibility, absence of DNA damage and insensitivity to these same senolytics. Overall, our results underscore the importance of the therapeutic context in the development of PCa-TIS manipulation strategies. They also provide a robust rationale for the preclinical study of treatments that combine radiotherapy or olaparib with Bcl-2 family antiapoptotic inhibitors in the PCa context.