ApoptoSENS at Buck Institute for Aging Research

 

Targeting senescent cells and their secretions

Senescence is a genetic program which normal dividing cells invoke in order to prevent excessive cellular growth. This is initially a protective mechanism, preventing cells undergoing stresses such as DNA damage from becoming cancerous, and keeping the wound-healing response from overstepping its bounds and generating an overgrowth of fibrous connective tissue. Senescence stops such cells from dividing; the problem is that some senescent cells persist long after their usefulness has expired, ignoring signals for programmed cell death (apoptosis) while growing larger and, often, secreting various inflammatory molecules that disrupt the environment in which neighboring cells have to function. These inflammatory molecules can have many effects, from the induction of an immune response to the degradation of the extracellular environment and alteration of the behavior of neighboring cells. Targeting senescent cells both for elimination and for the modulation of their secretions is the focus of a major extramural project of SENS Research Foundation.
 
This project is being performed by doctoral candidate Kevin Perrott in Dr. Judith Campisi's laboratory at the Buck Institute for Research on Aging. Dr. Campisi is a noted pioneer in the field of senescence, having been the first to develop an assay able to identify senescent cells. Subsequently it was her lab which discovered their pro-inflammatory secretions, called the "Senescence Associated Secretory Phenotype", or SASP. In the course of his thesis work in Dr. Campisi's lab, Perrott is using high-throughput screening methods to identify and characterize novel substances able to either induce senescent cells to commit suicide, or to alter the SASP, mitigating its deleterious impact by lowering the secretion of IL-6 and other pro-inflammatory markers.
 
The Prestwick Library was the first source of compounds which were screened. Its more than 1400 compounds were applied to irradiated cells and their non-irradiated controls, and the cells' viability and secretion of IL-6 were examined. So far, no candidates have emerged which selectively kill senescent cells, but there have been a handful that are able to reduce the pro-inflammatory nature of the SASP. These compounds are being followed up on to determine their mechanisms of action and ultimately their effects in mouse models. Other much larger libraries of compounds are now being pursued with an eye to the genetic elements underlying their effects on the SASP, and a focus on those with the greatest potential therapeutic effects.
 
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