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Simple Summary: The aim of this study was to explore the potential impact of red ginseng (RG) on age-associated cellular senescence through in vitro, ex vivo, and 19-month-old aged mouse models. In addition to enhancing insulin homeostasis, RG supplementation modified the canonical cellular senescence pathway and inhibited apoptotic markers. Moreover, RG significantly reduced the senescence-associated inflammatory pathway in the liver. Finally, the RG treatment mitigated cellular senescence in primary hepatocytes and mouse embryonic fibroblasts. In conclusion, these findings suggest that RG has a positive influence on the aging process by regulating hepatic cellular senescence and age-related phenotypes. Cellular senescence is defined as an irreversible cell cycle arrest accompanied by morphological and physiological alterations during aging. Red ginseng (RG), processed from fresh ginseng (Panax ginseng C.A. Meyer) with a one-time steaming and drying process, is a well-known beneficial herbal medicine showing antioxidant, anti-inflammatory, and anti-aging properties. The current study aimed to investigate the benefits of RG in alleviating hepatic cellular senescence and its adverse effects in 19-month-old aged mice. We applied two different intervention methods and durations to compare RG's effects in a time-dependent manner: (1) oral gavage injection for 4 weeks and (2) ad libitum intervention for 14 weeks. We observed that 4-week RG administration was exerted to maintain insulin homeostasis against developing age-associated insulin insensitivity and suppressed cellular senescence pathway in the liver and primary hepatocytes. Moreover, with remarkable improvement of insulin homeostasis, 14-week RG supplementation downregulated the activation of c-Jun N-terminal kinase (JNK) and its downstream transcriptional factor nuclear factor-κB (NF-κB) in aged mice. Lastly, RG treatment significantly reduced the senescence-associated β-galactosidase (SA-β-gal)-positive cells in primary hepatocytes and ionizing radiation (IR)-exposed mouse embryonic fibroblasts (MEFs). Taken together, we suggest that RG can be a promising candidate for a senolytic substance by preventing hepatic cellular senescence. [ABSTRACT FROM AUTHOR]

Simple Summary: The goal of this study was to examine if BG impacts the aging process, specifically cellular senescence, using in vitro and aged mouse models. Primary mouse embryonic fibroblasts (MEFs) and aged mice (18 months old) showed that BG supplementation retarded cellular senescence. Of note, BG-supplemented aged mice had remarkedly altered hepatic genes involved in the aging process as it caused less activation of the canonical senescence pathway. These observations demonstrated that BG positively impacts the age-related phenotype by controlling the expression of cellular senescence in the liver and other metabolic organs such as skeletal muscle and white adipose tissue. Cellular senescence, one of the hallmarks of aging, refers to permanent cell cycle arrest and is accelerated during the aging process. Black ginseng (BG), prepared by a repeated steaming and drying process nine times from fresh ginseng (Panax ginseng C.A. Meyer), is garnering attention for herbal medicine due to its physiological benefits against reactive oxygen species (ROS), inflammation, and oncogenesis, which are common cues to induce aging. However, which key nodules in the cellular senescence process are regulated by BG supplementation has not been elucidated yet. In this study, we investigated the effects of BG on cellular senescence using in vitro and aged mouse models. BG-treated primary mouse embryonic fibroblasts (MEFs) in which senescence was triggered by ionizing radiation (IR) expressed less senescence-associated β-galactosidase (SA-β-gal)-positive stained cells. In our aged mice (18 months old) study, BG supplementation (300 mg/kg) for 4 weeks altered hepatic genes involved in the aging process. Furthermore, we found BG supplementation downregulated age-related inflammatory genes, especially in the complement system. Based on this observation, we demonstrated that BG supplementation led to less activation of the canonical senescence pathway, p53-dependent p21 and p16, in multiple metabolic organs such as liver, skeletal muscle and white adipose tissue. Thus, we suggest that BG is a potential senolytic candidate that retards cellular senescence. [ABSTRACT FROM AUTHOR]