A natural extract from Salvia haenkei (HK) significantly extends lifespan and healthspan in naturally aged mice by targeting cellular senescence. HK treatment reduced age-induced inflammation, fibrosis, and senescence markers across multiple tissues, improved muscle strength, and increased fur thickness. It also mitigated chemotherapeutic-induced senescence, as shown in p16-LUC reporter mice. Mass spectrometry identified luteolin, a flavonoid in HK, as a key compound that disrupts the p16-CDK6 interaction, a mechanism underlying senescence. HK treatment improved physical appearance, bone health, kidney function, and muscle strength in aged mice. It also reduced doxorubicin-induced senescence and cardiotoxicity, as evidenced by decreased p16-positive cells and improved cardiac function. Luteolin, the main component of HK, was shown to inhibit senescence by disrupting the p16-CDK6 interaction, as confirmed by surface plasmon resonance and proximity ligation assays. These findings suggest that HK and its component luteolin could be valuable for developing therapies to combat aging and age-related diseases.A natural extract from Salvia haenkei (HK) significantly extends lifespan and healthspan in naturally aged mice by targeting cellular senescence. HK treatment reduced age-induced inflammation, fibrosis, and senescence markers across multiple tissues, improved muscle strength, and increased fur thickness. It also mitigated chemotherapeutic-induced senescence, as shown in p16-LUC reporter mice. Mass spectrometry identified luteolin, a flavonoid in HK, as a key compound that disrupts the p16-CDK6 interaction, a mechanism underlying senescence. HK treatment improved physical appearance, bone health, kidney function, and muscle strength in aged mice. It also reduced doxorubicin-induced senescence and cardiotoxicity, as evidenced by decreased p16-positive cells and improved cardiac function. Luteolin, the main component of HK, was shown to inhibit senescence by disrupting the p16-CDK6 interaction, as confirmed by surface plasmon resonance and proximity ligation assays. These findings suggest that HK and its component luteolin could be valuable for developing therapies to combat aging and age-related diseases.