Mild Uncoupling of Mitochondria Synergistically Enhances Senolytic Specificity and Sensitivity of BH3 Mimetics

Despite immense potential as anti-aging interventions, applications of current senolytics are limited due to low sensitivity and specificity. We demonstrate the specific loss of complex I-linked coupled respiration and the inability to maintain mitochondrial membrane potential upon respiratory stimulation as a specific vulnerability of senescent cells. Further decreasing the mitochondrial membrane potential of senescent cells with a mitochondrial uncoupler synergistically enhances the in vitro senolytic efficacy of BH3 mimetic drugs, including Navitoclax, by up to two orders of magnitude, whereas non-senescent cells remain unaffected. Moreover, a short-term intervention combining the mitochondrial uncoupler BAM15 with Navitoclax at a dose two orders of magnitude lower than typically used rescues radiation-induced premature aging in an in vivo mouse model, as demonstrated by reduced frailty and improved cognitive function for at least eight months. Our study shows compromised mitochondrial functional capacity is a senescence-specific vulnerability that can be targeted by mild uncoupling in vitro and in vivo.