Systemic Senolysis in Naturally Aged Mice Using a FAST-PLV Gene Therapy Approach

Approaches to eliminate senescent cells in vivo using transgenic mouse models have demonstrated significant improvements in lifespan, reduction in cancer incidence, and amelioration of age-related degeneration. These approaches require, however, that the organism be genetically engineered from the embryo and/or repeatedly dosed for the organism’s lifespan, making them challenging to implement in humans using current technologies. To overcome these limitations, we developed a clinically viable senolytic gene therapy consisting of a suicide gene, inducible caspase 9 (iCasp9), under control of the early senescence and tumor suppressive p53 promoter or the late senescence p16 ^Ink4a promoter. In vitro , this gene therapy selectively activates in senescent cells and induces caspase-9-dependent apoptosis. When formulated in the FAST-PLV platform and administered systemically to aged mice, the burden of senescent cells was significantly reduced in various tissues, leading to a 123% increase in post-treatment survival for animals given a combination of p16 and p53 targeted senolytic gene therapies. Treated mice showed significantly reduced frailty, increased physical function, and improved heart health. Gross necropsy indicated a 3-fold reduced tumor incidence. In summary, we demonstrate a novel and redosable senolytic genetic medicine approach that improves healthspan by targeting senescent cells based on their transcriptional activity.