Background/Objective: Aging is a significant risk factor for chronic diseases and disability, yet effective anti-aging interventions remain elusive. We explored the potential of 3-hydroxybutyrate (3HB), an endogenous metabolite with established safety, to modulate longevity in mice. Methods: In this study, we employed 2BS and WI-38 cell models, a yeast model, and naturally aging mouse models to investigate the effects of 3HB on aging in various systems. Additionally, we utilized RNA sequencing and metabolomics technologies to explore the potential mechanisms underlying the action of 3HB. Results: Our findings demonstrate that 3HB supplementation effectively delays cellular senescence, extending yeast lifespan by 51.3% and the median lifespan of naturally senescent mice by 21.0%. Notably, 3HB prolonged healthy lifespan in mice while mitigating age-related tissue morphology changes and organ senescence. Mechanistically, we identified that 3HB’s anti-aging properties are mediated through its ability to delay cellular senescence and metabolic reprogramming, while promoting the production of beneficial metabolites like trigoneline and isoguvacine. Conclusions: These findings highlight the promising therapeutic potential of 3HB as an anti-aging intervention and provide novel insights into its underlying mechanisms.

Chicory (Cichorium intybus L.) is a widely used nutritional and medicinal plant, whose roots are an important commercial source of inulin, while the aerial parts are often discarded during industrial processing. This study systematically compared chicory polysaccharides (CPs) extracted from aerial parts (CP-A) and roots (CP-R) with respect to their compositional features and cytoprotective effects in an oxygen–glucose deprivation/reperfusion (OGD/R)-induced H9c2 cell injury model. CP-A and CP-R differed in molecular weight distribution and monosaccharide composition, with CP-R exhibiting a higher molecular weight and fructose content. Despite these differences, both fractions significantly improved cell viability and reduced oxidative and biochemical injury markers. Integrated proteomic and transcriptomic analyses indicated that CP-A and CP-R were associated with the modulation of stress-responsive signaling networks, prominently involving oxidative stress-linked MAPK/NF-κB pathways. These findings demonstrate comparable cytoprotective activities of polysaccharide-rich fractions from roots and aerial parts and support the valorization of chicory aerial biomass as a potential source of functional ingredients for cardiovascular health.