Targeting cellular senescence with Salvia haenkei: in vitro, in vivo and human clinical insights on a senotherapeutic of botanical origin

Aging is a multicellular degenerative process encompassing multiple molecular pathways. The accumulation of senescent cells within tissues is one such hallmark that contributes to the formation of age-related diseases through the senescence-associated secretory phenotype (SASP). To mitigate senescence burden 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 the Bolivian botanical Salvia haenkei (SH), 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 was identified as HK-derived constituents with comparable activity to HK in a model of senescence induction by UV-B in human fibroblasts. 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. Considering the putative benefits of HK in vivo on lifespan and healthspan, a randomized, open-label, parallel-arm, clinical trial was then conducted in older healthy humans with the aim of establishing the safety and efficacy of HK as a nutraceutical supplement. HK modulated serum markers of the SASP, indicating its potential utility for further development. In sum, these findings suggest that polyphenol-rich botanical extracts such as HK can alter the senescence phenotype by disrupting the activity of p16 which subsequently is associated with improved longevity in mice with a positive outcome for human nutraceutical development.