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

Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16Luc reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin—the most concentrated flavonoid in HK—as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16–CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16–CDK6 interaction.

Sara Zumerle, Miles Sarill, Miriam Saponaro, Manuel Colucci, Liliana Contu, Edoardo Lazzarini, Roberta Sartori, Camilla Pezzini, Anna Rinaldi, Anna Scanu, Jacopo Sgrignani, Patrizia Locatelli, Marianna Sabbadin, Aurora Valdata, Daniela Brina, Isabella Giacomini, Beatrice Rizzo, Alessandra Pierantoni, Saman Sharifi, Silvia Bressan, Claudia Altomare, Yulia Goshovska, Chiara Giraudo, Roberto Luisetto, Luca Iaccarino, Cristina Torcasio, Simone Mosole, Emiliano Pasquini, Andrea Rinaldi, Laura Pellegrini, Gregorio Peron, Matteo Fassan, Stefano Masiero, Andrea Maria Giori, Stefano Dall’Acqua, Johan Auwerx, Pietro Cippà, Andrea Cavalli, Marco Bolis, Marco Sandri, Lucio Barile, Monica Montopoli, Andrea Alimonti