Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies

SIMPLE SUMMARY: The accumulation of senescent cells is now widely known to be a driver of aging and many age-related pathologies, such as neurodegeneration and type 2 diabetes, among others. Targeting senescent cells for selective removal or altering the proteins they release are promising therapeutic strategies against age-related diseases. However, the biology of senescent cells is complex, dynamic, and heterogeneous. In order to better identify pathology-driving senescent cells and develop therapies to alter their complex biology or drive them toward cell death, a detailed and comprehensive understanding of senescence-associated proteins and the mechanisms that enable senescent cells to evade cell death is required. Major developments in proteomic workflows over the past decade have enabled an increasingly comprehensive, quantitative, and specific molecular profiling and interrogation of cellular mechanisms. In this review, we discuss the current state of translational senescence research and how modern proteomic technologies, particularly mass spectrometry-based proteomics, can accelerate our understanding of the fundamental mechanisms that drive senescence and robustly probe the proteomic phenotypes of heterogenous populations of senescent cells. We will focus on how these fundamental biological insights will ultimately accelerate the development of senescence-targeting therapies, or senotherapeutics. ABSTRACT: Cellular senescence is a state of irreversible growth arrest with profound phenotypic changes, including the senescence-associated secretory phenotype (SASP). Senescent cell accumulation contributes to aging and many pathologies including chronic inflammation, type 2 diabetes, cancer, and neurodegeneration. Targeted removal of senescent cells in preclinical models promotes health and longevity, suggesting that the selective elimination of senescent cells is a promising therapeutic approach for mitigating a myriad of age-related pathologies in humans. However, moving senescence-targeting drugs (senotherapeutics) into the clinic will require therapeutic targets and biomarkers, fueled by an improved understanding of the complex and dynamic biology of senescent cell populations and their molecular profiles, as well as the mechanisms underlying the emergence and maintenance of senescence cells and the SASP. Advances in mass spectrometry-based proteomic technologies and workflows have the potential to address these needs. Here, we review the state of translational senescence research and how proteomic approaches have added to our knowledge of senescence biology to date. Further, we lay out a roadmap from fundamental biological discovery to the clinical translation of senotherapeutic approaches through the development and application of emerging proteomic technologies, including targeted and untargeted proteomic approaches, bottom-up and top-down methods, stability proteomics, and surfaceomics. These technologies are integral for probing the cellular composition and dynamics of senescent cells and, ultimately, the development of senotype-specific biomarkers and senotherapeutics (senolytics and senomorphics). This review aims to highlight emerging areas and applications of proteomics that will aid in exploring new senescent cell biology and the future translation of senotherapeutics.