Selective targeting of cancer and senescence via shared metabolic shifts extends lifespan of old mice.

Eliminating both senescent and cancer cells through pharmacological intervention presents a powerful therapeutic strategy against aging and tumor progression. Navitoclax has emerged as a promising candidate with both senolytic and antitumor activity, but its clinical application remains limited due to dose-dependent thrombocytopenia and tumor-specific resistance. To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells. We demonstrate that DMA effectively ablates different types of senescent and cancer cells in vitro by exacerbating their defects in ATP production. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues.