Systematic Screening of Cell Death Pathways in Search of New Senolytics
Senolytic drugs capable of clearing senescent cells from the bodies of older people will be a very important part of the medicine of tomorrow. A burden of senescent cells contributes significantly to aging, and removing them produces quite rapid and profound rejuvenation in animal models. If taking the small molecule drug approach, a diversity of senolytics will likely be needed in order to clear most senescent cells from most tissues, due to differences in drug biodistribution and biochemistry of senescence between tissue types. The search for new senolytic drug targets and drug compounds has been underway in earnest for a few years, and researchers are starting to become more rigorous and systematic, as demonstrated here.
Selectively ablating senescent cells ("senolysis") is an evolving therapeutic approach for age-related diseases. Current senolytics are limited to local administration by potency and side effects. While genetic screens could identify senolytics, current screens are underpowered for identifying genes that regulate cell death due to limitations in screen methodology.
Here, we establish Death-seq, a positive selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263, a BH3 mimetic. SMAC mimetics, enhancers of cell death in our screens, synergize with ABT-199, another BH3 mimetic that is not senolytic alone, clearing senescent cells in models of age-related disease while sparing human platelets, avoiding the thrombocytopenia associated with ABT-263.
In summary, Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identify drug targets for diverse pathological states such as senescence, cancer, and neurodegeneration.