The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the "SASP Atlas," a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA). Our findings will facilitate the identification of proteins characteristic of senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus, and tissue of origin of senescent cells in vivo.

The senescence-associated secretory phenotype (SASP) has recently emerged as both a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically monitored by a few dozen secreted proteins, 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 soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins, but also includes a subset of proteins elevated in all SASPs. Based on our analyses, we propose several candidate biomarkers of cellular senescence, including GDF15, STC1 and SERPINs. This resource will facilitate identification of proteins that drive specific senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus and tissue of senescent cells in vivo. Figure 4. Renal epithelial cells and fibroblasts express distinct sSASPs. A) Venn diagram comparing proteins increased in the sSASP of senescent fibroblasts vs senescent epithelial cells induced by X-irradiation. B) Venn diagram comparing protein increases in the fibroblast sSASP vs decreases in the epithelial sSASP. C) Pathway and network analysis of proteins highly secreted by senescent fibroblasts and epithelial cells. C) Pathway and network analysis of proteins significantly increased in the fibroblast sSASP but significantly decreased in the epithelial cell sSASP.

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No abstract

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescenceassociated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

The imaginal disc epithelia that give rise to the adult ectoderm of Drosophila can compensate to produce normal adult organs after damage. We looked at the local response to cell death using two genetic methods to elevate cell death rates. During cell competition, sporadic cell death occurs predictably along the boundaries between populations of competing wild-type and Minute/+ cells [1]. Boundaries between Minute/+ and wild type populations showed an unusual degree of mixing, associated with mitotic re-orientation of wild type cells towards M/+ territory that they take over. Apoptosis of M/+ cells was the cue, and re-oriented mitosis required the planar cell polarity genes dachsous, fat, and atrophin genes. Clones mutated for pineapple eye, an essential gene, elevate apoptosis by a non-competitive mechanism [2]. Mitosis was also re-oriented near cells mutant for pineapple eye, likewise dependent on the planar cell polarity genes. These findings show that planar cell polarity genes are required for responses to cell death. Oriented mitosis may help maintain morphology as dividing cells replace those that have been lost.

Wild-type Drosophila cells can remove cells heterozygous for ribosomal protein mutations (known as "Minute" mutant cells) from genetic mosaics, a process termed cell competition. The ribosomal protein S12 was unusual because cells heterozygous for rpS12 mutations were not competed by wild-type, and a viable missense mutation in rpS12 protected Minute cells from cell competition with wild-type cells. Furthermore, cells with Minute mutations were induced to compete with one another by altering the gene dose of rpS12, eliminating cells with more rpS12 than their neighbors. Thus RpS12 has a special function in cell competition that defines the competitiveness of cells. We propose that cell competition between wild-type and Minute cells is initiated by a signal of ribosomal protein haploinsufficiency mediated by RpS12. Since competition between cells expressing different levels of Myc did not require RpS12, other kinds of cell competition may be initiated differently.

Heterozygosity for mutations in ribosomal protein genes frequently leads to a dominant phenotype of retarded growth and small adult bristles in Drosophila (the Minute phenotype). Cells with Minute genotypes are subject to cell competition, characterized by their selective apoptosis and removal in mosaic tissues that contain wild-type cells. Competitive apoptosis was found to depend on the pro-apoptotic reaper, grim and head involution defective genes but was independent of p53. Rp/+ cells are protected by anti-apoptotic baculovirus p35 expression but lacked the usual hallmarks of 'undead' cells. They lacked Dronc activity, and neither expression of dominant-negative Dronc nor dronc knockdown by dsRNA prevented competitive apoptosis, which also continued in dronc null mutant cells or in the absence of the initiator caspases dredd and dream/strica. Only simultaneous knockdown of dronc and dream/strica by dsRNA was sufficient to protect Rp/+ cells from competition. By contrast, Rp/Rp cells were also protected by baculovirus p35, but Rp/Rp death was dronc-dependent, and undead Rp/Rp cells exhibited typical dronc-dependent expression of Wingless. Independence of p53 and unusual dependence on Dream/Strica distinguish competitive cell death from noncompetitive apoptosis of Rp/Rp cells and from many other examples of cell death.