Oral Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development (#182)

Nathan Basisty 1 , Abhijit Kale 1 , Okhee Jeon 1 , Chisaka Kuehnemann 1 , Therese Payne 1 , Chirag Rao 1 , Anja Holtz 1 , Samah Shah 1 , Luigi Ferrucci 2 , Judy Campisi 1 3 , Birgit Schilling 1
  1. The Buck Institute for Research on Aging, Novato, CALIFORNIA, United States
  2. National Institute on Aging, Baltimore, Maryland, United States
  3. Lawrence Berkeley Laboratory, Berkeley, California, United States


Introduction: The senescence-associated secretory phenotype (SASP) has recently emerged as both a driver of, and promising therapeutic target for, a multitude of chronic age-related conditions, ranging from neurodegeneration to cancer.  The complexity of the SASP has been greatly underappreciated and a small set of factors cannot explain the diverse phenotypes it produces in vivo.  Here, we present ‘SASP Atlas’, a comprehensive proteomic database of SASPs, including a novel exosome SASP phenotype, driven by multiple inducers of senescence in different human cell types. We also propose that SASP proteins are promising biomarkers to assess senescent cell burden in aging and disease.

Methods: Secretomes of senescent cells were characterized by comparing the secreted soluble (sSASP) and exosome (eSASP) proteins of irradiation-, oncogenic RAS-, or HIV drug atazanavir-induced senescent human fibroblasts to non-senescent controls. Secreted proteins and exosomes were obtained from the medium of cells cultured for 24 hours in serum-free conditions. Data-independent acquisitions (DIA) were performed on a TripleTOF 6600.

Results: While 172 proteins increased in all inducers and 53 proteins increased in all inducers and cell types, the SASP of each inducer and cell type were largely distinct, totaling over 1000 unique proteins. CXCL1, MMP1, and STC1 were consistently among the top increased proteins in response to all inducers. Senescent cells, on average, secreted larger exosomes containing a highly distinct set of proteins compared with the soluble secretome, including proteins involved in G-protein and RAS signaling, prostaglandin regulation and the complement system.

Discussion: Together, the data demonstrate that the SASP is a complex and highly diverse set of secretory phenotypes, including a unique exosome SASP. This resource will aid in identifying the proteins that drive senescence-associated phenotypes and provide comprehensive catalogs of potential biomarkers for assessing the burden and origin of senescent cells in vivo.