Applying Proteomics to the Development of Senolytic Therapies

A cell can enter a senescent state in response to various forms of damage and stress, including the short telomeres that occur when reaching the Hayflick limit on cellular replication. A senescent cell ceases to replicate and secretes pro-inflammatory signals, attracting the attention of the immune system. Senescent cells help to suppress cancer by pointing the immune system to areas of potential risk in tissue, and are a part of the response to injury, aiding in regeneration. Senescent cells are normally destroyed by the immune system shortly after creation, but the pace of destruction slows down with age, allowing the number of lingering senescent cells to increase over time. The signals that are helpful in the short term become harmful when present constantly for the long term, disrupting tissue function.

Senolytic therapies are those that can selectively destroy senescent cells, and seem the most straightforward approach to treating this contribution to degenerative aging. Animal studies in which senescent cells are destroyed have demonstrated a rapid, sizable reversal of many measures of aging and age-related disease. The data is impressive. Researchers are looking into other approaches, though, such as suppression of inflammatory signaling or prevention of the senescent state, under the general heading of senotherapeutics. Proteomic analysis plays a sizable role in this area of research and development, as noted in today's open access paper. While first generation senolytic drugs are being tested at some pace in the clinic, largely the dasatinib and quercetin combination, readily available to many via off-label prescriptions, very little effort is spend on that in comparison to the search for novel ways to destroy or change the behavior of senescent cells. This is unfortunate; more of an effort should be made to determine whether existing, low-cost senolytics could be highly beneficial in human patients.

Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies

Aging comprises a cascade of underlying cellular and molecular processes, commonly referred to as the hallmarks of aging, that lead to a gradual loss of function and increased susceptibility to diseases. One of the most studied hallmarks of aging, cellular senescence, is a key driver of aging and age-related diseases. Cellular senescence is a complex stress response resulting from a variety of sub-lethal stresses that permanently alter the state of a cell. Three of the defining features of senescence are a permanent arrest of cell proliferation, an increased secretion of a variety of bioactive molecules known as the senescence-associated secretory phenotype (SASP), and a resistance to apoptosis. Despite an arrest of cell growth, senescent cells remain metabolically active and secrete a robust SASP that comprises bioactive molecules, including metabolites, proteins, and lipids. The chronic presence of senescent cells and the SASP are connected to various age-related disorders such as cancer, diabetes, neurodegeneration, osteoarthritis, and cardiovascular disease. Therefore, the elimination of senescent cells and the SASP are promising approaches for combating age-related diseases and improving healthspan.

Causal linkage among aging, cellular senescence, and age-related diseases has caused the emergence of 'senotherapeutics', a catch-all term that refers to therapeutic interventions that target senescent cells. Two common classes of pharmacological senotherapeutics include senolytics and senomorphics. Senolytics are chemical compounds that selectively kill senescent cells. Non-pharmacological senotherapeutic approaches, such as vaccines or immunotherapies, are also proposed options for the selective elimination of senescent cells. Interventions that reduce the upstream inducers of senescence, such as DNA damage, ROS, inflammation, or metabolic imbalance, likely confer senotherapeutic benefits by reducing the initiation of senescence. Additionally, targeting cell populations that drive senescence, such as aged immune cells, may reduce senescent cell burden. Senomorphics are the agents that can block or otherwise modulate the SASP to reduce its detrimental activity and mitigate aging phenotypes. The discovery of the SASP and its potency as a driver of aging have greatly increased interest in its comprehensive characterization, both to explore new mechanisms of aging and identify new biomarkers that indicate 'senescence burden', a useful metric for the clinical translation of senotherapeutic approaches.

Protein biomarkers are essential due to their diagnostic, prognostic, and predictive power, as well as identifying and stratifying patients for treatment and measuring the efficacy of therapies. Mass spectrometry-based proteomics is a powerful, versatile, and robust technology used for comprehensively quantifying and discovering proteins with unrivaled specificity. Given the robust and heterogeneous proteomic phenotypes associated with senescence and the SASP, the discovery and profiling of their proteomic signatures require the large-scale, unbiased, and quantitative abilities that mass spectrometry can provide. The presence of senescence-associated proteins in circulation in recent studies also suggests the use of proteomic technologies will be required for the detection and quantification of senescence biomarkers in blood. Numerous innovations in mass spectrometry workflows for biomarker and drug discovery have been made in recent years, opening new opportunities to accelerate the development of senotherapeutics.

Here, we review the available technologies for identifying, validating, and prioritizing protein biomarkers and therapeutic targets identified via mass spectrometry and how these technologies may be leveraged for the clinical translation of senotherapeutics. We describe the technological advancements that have enabled researchers to address challenges inherent to the proteomic analysis of blood, such as the wide dynamic range of protein concentrations, and discuss multiple workflows that can be leveraged for the discovery of senescence biomarkers, senolytic targets, and cell-surface proteins. We also highlight how modern mass spectrometry-based technologies will open the door for future clinical applications, develop translationally relevant approaches to quantify aging and cellular senescence, and develop therapeutics for enhancing human healthspan.

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