The power of proteomics to monitor senescence-associated secretory phenotypes and beyond: toward clinical applications

Abstract

Introduction: Cellular senescence is a rapidly growing field with potential relevance for the treatment of multiple human diseases. In the last decade, cellular senescence and the senescence-associated secretory phenotype (SASP) have emerged as central drivers of aging and many chronic diseases, including cancer, neurodegeneration, heart disease and osteoarthritis. Major efforts are underway to develop drugs that selectively eliminate senescent cells (senolytics) or alter the SASP (senomorphics) to treat age-related diseases in humans. The translation of senescence-targeting therapies into humans is still in early stages. Nonetheless, it is clear that proteomic approaches will facilitate the discovery of important SASP proteins, development of senescence- and SASP-derived biomarkers, and identification of therapeutic targets for senolytic and senomorphic drugs.

Areas covered: We review recent proteomic studies of cellular senescence and their translational relevance and, particularly, characterization of the secretory phenotype and preclinical development of biomarkers (from 2008-2020, PubMed). We focus on emerging areas, such as the heterogeneity of senescent cells and the SASP, extracellular vesicles released by senescent cells, and validating biomarkers of aging in vivo.

Expert opinion: Proteomic and multi-omic approaches will be important for the development of senescence-based biomarkers to facilitate and monitor future therapeutic interventions that target senescent cells.

Keywords: Aging; biomarkers; clinical proteomics; data-independent acquisition; plasma; secretome; senescence; senescence-associated secretory phenotype; senolytics; senomorphics.

Figure 1:. Pipeline for the development of senescence-based biomarkers of aging and disease.

In phase 1, discovery, the secretomes (SASP) of senescent cells are characterized in cell-culture systems to generate biomarker candidates that can be tailored to specific biological contexts, based on the disease and cell type. Multiple cell types and senescence-inducing stimuli (e.g., genotoxic/oncogenic/metabolic stress) can be interrogated, and the most robust biomarkers of all conditions used for later stages of biomarker development. In step 2, verification, biomarker candidates are filtered, based on whether they can be detected in plasma (or other biofluids), and biomarker assays are developed based on the most reproducible and quantitative peptide(s) from each protein biomarker candidate. Finally, these biomarkers are interrogated in human cohorts in step 3, validation. Cohorts for step 3 should be chosen so that they contain subjects with high and low senescent cell burdens, and ideally, an intervention that either increases or reduces senescent cell burden. Examples of cohorts with variable senescence burden are old and young individuals, and doxorubicin-treated patients and untreated patients (or before and after doxorubicin treatment).