Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice

The accumulation of senescent cells within tissues contributes to age-related diseases through the senescence-associated secretory phenotype (SASP). To fight senescence and maintain a healthy tissue microenvironment, the quest for longevity-promoting compounds has resulted in promising discoveries from botanical sources. Here we show that daily administration with a low dose of Haenkenium (HK), a standardized extract of Salvia haenkei, extended the lifespan and healthspan of aged C57BL/6 mice by delaying senescence and consequently ameliorating systemic inflammation and fibrosis markers in multiple tissues including skin, muscle, cartilage, and kidney. Additionally, treated aged mice displayed increased muscle strength, vitality, and thicker fur coverage than age-matched controls. Notably, HK treatment also effectively reduced doxorubicin (Doxo)-induced senescence in p16LUC reporter mice and protected against Doxo-induced cardiotoxicity. The composition of HK was analyzed by UPLC-QTOF-MS, which revealed multiple polyphenols that were then screened for their putative anti-senescence activity in vitro. Among these, luteolin, luteolin- 7-O-glucuronide and 3,4-dicaffeoylquinic were identified as HK-derived constituents with comparable activity to HK. Mechanistically, we report that luteolin could disrupt the p16-CDK6 interaction, which was validated by surface plasmon resonance (SPR) and by in situ proximity ligation assay in vitro. Our findings suggest that phytoconstituents such as luteolin can alter the senescence phenotype by disrupting the activity of p16 which subsequently is associated with improved longevity in mice.