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