The presence of growing numbers of lingering senescent cells is one of the root causes of aging. Vast numbers of cells become senescent every day, but near all are quickly removed, either via programmed cell death or the actions of the immune system. A tiny number survive, however, and that alone would eventually be enough to cause age-related disease and death. While senescent cells never rise to very large fractions of all of the cells in a given tissue, they cause considerable harm via a potent mix of secreted signals known as the senescence-associated secretory phenotype, or SASP. The SASP causes chronic inflammation and destructive remodeling of the nearby extracellular matrix. Further, it changes the behavior of other cells for the worse, including increasing their chances of becoming senescent.
In today's open access paper, researchers present the start of a new database that will categorize the many molecules making up the SASP for various cell types. Since nothing is simple in biochemistry, the SASP is undoubtedly meaningfully different from tissue to tissue and cell type to cell type. Why does the SASP exist? Senescent cells have important transient roles in wound healing and in regulating the growth of embryonic tissues. Here the signals are beneficial, involved in growth and regeneration, and senescent cells are cleared from the site after they have served their purpose. Further, senescence in response to DNA damage or a toxic environment is a defense against cancer, in that senescent cells cease to replicate, encourage nearby cells to do the same, and rouse the immune system into greater activity - exactly the sort of strategy that should put a halt to cancer in its earliest stages.
Unfortunately, that the clearance of senescent cells is imperfect, and some always linger, ensures that the SASP becomes a cause of aging. Signals that are beneficial in specific contexts in the short term become harmful when continually present. In old tissues, the secretions of senescent cells actively maintain a degraded, dysfunction state of cellular metabolism and tissue function. This is why senolytic treatments capable of selectively removing some fraction of senescent cells are proving to be so very effective for a very wide range of age-related diseases in animal studies. Fortunately, no great understanding of the SASP is needed to make progress in this form of treatment; we know that removing chronic SASP is beneficial, and that should be the primary focus of development.
The senescence-associated secretory phenotype (SASP) has recently emerged as both a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically monitored by a few dozen secreted proteins, has been greatly underappreciated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present 'SASP Atlas', a comprehensive proteomic database of soluble and exosome 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. Based on our analyses, we propose several candidate biomarkers of cellular senescence, including GDF15, STC1, and SERPINs. This resource will facilitate identification of proteins that drive specific senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus and tissue of senescent cells in vivo.
Cellular senescence is a complex stress response that causes an essentially irreversible arrest of cell proliferation and development of a multi-component senescence-associated secretory phenotype (SASP). The SASP consists of myriad cytokines, chemokines, growth factors, and proteases that initiate inflammation, wound healing, and growth responses in nearby cells and tissues. In young and healthy tissues, the SASP is typically transient and tends to contribute to the preservation or restoration of tissue homeostasis. However, the increase in senescent cells with age and a chronic SASP are now known to be key drivers of many pathological hallmarks of aging, including chronic inflammation, tumorigenesis, impaired stem cell renewal, and others.
Using either or both of two transgenic mouse models that allow the selective elimination of senescent cells, or compounds that mimic the effect of these transgenes, data from several laboratories strongly support the idea that the presence of senescent cells drives multiple age-related phenotypes and pathologies, including age-related atherosclerosis, osteoarthritis, cancer metastasis and cardiac dysfunction, myeloid skewing in the bone marrow, kidney dysfunction, and overall decrements in healthspan.
Several types of stress elicit a senescence and secretory response, which in turn can drive multiple phenotypes and pathologies associated with aging in mammals. Some of these stressors have shared effects. For example, telomere attrition resulting from repeated cell division (replicative senescence), elevated reactive oxygen species, chromatin disruption, and even the activation of certain oncogenes all can cause genotoxic stress, as can a number of therapeutic drug treatments, such as anti-cancer chemotherapies and certain highly active antiretroviral therapies for HIV treatment or prevention. However, whether these stressors produce similar or distinct SASPs is at present poorly characterized. Therefore, a comprehensive characterization of SASP components is critical to understanding how senescent response can drive such diverse pathological phenotypes in vivo. It is also a critical step in clarifying how various stimuli, all acting through senescence, differentially affect health.