A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development

Abstract

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.

The Aging Metabolome—Biomarkers to Hub Metabolites

“…[ 42,43 ] A number of hallmarks of senescent cells have been recognized (including upregulated expression of p16 Ink4A and/or p21) [ 44 ] of which the senescence‐associated secretory phenotype (SASP) is a well‐characterized one. [ 45 ] It is important to note that depending on the tissues of origin and inducers of senescence, cells display a range of non‐overlapping hallmarks including secreted SASP factors (e.g., TGF‐β, IL‐6, and IL‐8). An important feature of senescent cells is also their dysregulated metabolome.…”

Single-cell analyses identify tobacco smoke exposure-associated, dysfunctional CD16+ CD8 T cells with high cytolytic potential in peripheral blood

“…(Kandhaya-Pillai et al, 2017). CST3, which increased in smoker monocytes, is associated with subclinical atherosclerosis (Chung et al, 2018) and cellular senescence (Basisty et al, 2019). Among the monocyte smoking DEGs, we also identified TNFSF13B, a critical regulator of atherogenic B cell proliferation and differentiation (Kyaw et al, 2013a).…”

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

“…Combined, the findings presented in our model recapitulate the major elements described in the pathogenesis of IPF. For instance, the presence of senescence phenotype in lung epithelium has emerged as a major contributor to aging and multiple respiratory diseases, including lung fibrosis (3,24,28). We reported the presence of cellular senescence markers, such as p21, p53, γ-H2AX and SA-βgal staining, which along with the expression of SASP components represent a source of chronic profibrotic signaling through the activation of Il-6, Mcp1, TNF-α, and IL-1α.…”