A proteomic atlas of senescence-associated secretomes for aging biomarker development

Abstract

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.

Cellular senescence: friend or foe to respiratory viral infections?

“…On the other hand, in the short term, the SASP promotes wound healing that is required to respond to acute cellular damage [12,13,40]. Importantly, the specific characteristics of the SASP may be dependent on the cell type and the mechanism of senescence induction [41]. For example, the SASP associated with fibroblasts contains significantly more SASP factors than the SASP associated with renal epithelial cells [41].…”

Nicotine in Senescence and Atherosclerosis

“…The composition of the secretome depends on the cell type and inducer, as recently reported by Basisty et al [161]. RAS overexpression, X-irradiation, and atazanavir, a drug used in cancer treatment, induced the expression of known markers, such as SA-β-gal, IL-6, and p16INK4A, as well as specific markers, depending on the cell type.…”

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

“…Drugs targeting IL-6 have been included among the potential strategies to inhibit the deleterious consequences of the senescence-associated secretory phenotype (SASP), the secretome produced by senescent cells [31,32]. The SASP includes cytokines, chemokines, proteases, and growth factors, recently collected in a proteomic database [29], which functionally links the accumulation of senescent cells with its pathological processes [33,34]. However, the SASP appears to be beneficial or deleterious, depending on the biological context.…”

“…Indeed, understanding the biological mechanisms that are the basis of the higher susceptibility to death in elderly people may be important to plan preventive and therapeutic strategies in the current pandemic, as well as for the future emergence of similar pandemic viruses for which vaccines are unavailable. Blocker of IL-6R, IL-6 is among the most common SASP factor [28,29] Hydroxychloroquine and azithromycin Clinical Trial (NCT04322396) and other pilot studies…”