In today’s open access paper, the authors survey the work of the past decade in the use of proteomics to assess the consequences of cellular senescence. Senescent cells accumulate with age, but even in late age they remain a tiny fraction of all cells. The harms caused by the long-term presence of senescent cells occur because these cells secrete a potent mix of inflammatory signals, growth factors, and other molecules that rouse the immune system, promote fibrosis and other dysfunctions in tissue maintenance, encourage other cells to also become senescent, and so forth. This senescence-associated secretory phenotype is actually beneficial in the short term: it assists in wound healing and suppression of cancer, for example. As for so many other areas of biochemistry, too much of a good thing is not a good thing at all.
Work progresses on the commercial development of senolytic therapies capable of selectively destroying senescent cells in old tissues. In animal models of numerous age-related conditions, this class of intervention produces consistent and impressive benefits. It is literally a form of rejuvenation, removing cells that are actively maintaining a degraded, damaging state of an aged metabolism. Many age-related conditions have a strong inflammatory component, and those tested are reversed to a meaningful degree by removal of senescent cells and their pro-inflammatory signaling. Interestingly, this field is presently somewhat ahead of the ability to accurately catalog the presence and effects of senescent cells, but many research groups are working on a better understanding of senescent cells and the senescence-associated secretory phenotype. Give it a few years and the scope of available assays will catch up with the ability to remove senescent cells for therapeutic benefit.
The development of clinical proteomic biomarkers is an emerging and fast-growing field in human biomedical research. Recently, the focus has been developing senescence-based biomarkers of aging, frailty, and age-related diseases. Over the last decade, proteomic studies of human plasma and other biofluids have made significant progress in accurately quantifying proteins and potential biomarkers at increased depth and coverage. One of the most promising areas for these emerging technologies is therapies that target a fundamental aging process known as cellular senescence.
Cellular senescence is widely accepted as a basic driver of aging and age-related diseases. In this complex stress response, cells permanently lose the ability to proliferate and alter distal tissues through systemic and local paracrine effects. Cellular senescence can be triggered by stressors, including genotoxic agents, nutrient deprivation, hypoxia, mitochondrial dysfunction, and oncogene activation. Although senescent cells irreversibly arrest growth, they remain metabolically active and secrete many biologically active molecules, known as the senescence-associated secretory phenotype (SASP). The SASP initiates inflammation, wound healing, and growth responses in nearby cells. With age, the number of senescent cells or ‘senescence burden’ increases, and this increased senescence burden and chronic SASP drive many pathological hallmarks of aging.
Cellular senescence is an example of antagonistic pleiotropy – a trait that is beneficial early in life but detrimental later in life. In healthy tissues, the SASP is typically transient and contributes to tissue homeostasis. In contrast, the chronic presence of senescent cells and a SASP is associated with multiple age-related diseases. Eliminating senescent cells and the SASP is considered a highly promising therapeutic strategy for preventing or treating age-associated diseases and extending health span. To selectively kill senescent cells non-genetically, drugs known as ‘senolytics’ are being developed; additionally, drugs termed senomorphics or senostatics are being developed to mitigate the detrimental effects of senescent cells by modifying the SASP.
To develop clinical therapeutics that target senescent cells, it is critical to have reliable biomarkers to measure the senescent cell burden in humans both to identify patients with an elevated burden and to track the efficacy of the therapeutics. In this review, we will discuss proteomic strategies to discover senescence-derived biomarkers and their great potential for measuring the senescent cell burden. Senescent cells secrete many molecules, and the resulting SASP consists of a complex mixture of both proteins, metabolites, and other molecules. However, thorough investigation is required to determine which SASP protein factors or protein panels qualify as biomarkers to quantitatively assess the senescent cell burden, and subsequently which SASP factors can be used efficiently and accurately as a biomarker for aging and age-related diseases.