Today, we want to spotlight a new publication that charts the senescence-associated secretory phenotype (SASP), which consists of the various secreted signals given out by senescent cells during aging.
Senescent cells and the SASP
As we get older, an increasing number of our cells enter into a state known as senescence. They cease dividing and supporting the tissues and organs of which they are part and, instead, secrete a range of harmful chemical signals. This cocktail of harmful signals is known as the senescence-associated secretory phenotype (SASP).
Senescent cells only make up a small number of the total amount of cells in our bodies, but the pro-inflammatory cytokines, chemokines, and extracellular matrix proteases that they secrete do a great deal of damage and help age-related diseases to develop. If this was not bad enough, the SASP can also cause nearby, healthy cells to become senescent; this means that a relatively small number of senescent cells can cause problems far in excess of their numbers, including the degradation of tissue function, increased levels of chronic inflammation, and a greater lifetime risk of cancer.
Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.
By the time people reach old age, significant numbers of these senescent cells have accumulated in the body, causing chronic inflammation and damage to surrounding cells, tissues, and organs. These senescent cells are one of the hallmarks of aging and are thought to be a key reason why we age and become sick [1-2].
A new class of drugs known as senolytics focuses on removing these cells from the body in order to reduce inflammation and improve tissue function. The hope is that doing so will delay or even prevent certain age-related diseases from developing, as has already been demonstrated in mice [3]. Considering that the SASP is linked to both aging and cancer, there is every reason to be optimistic about senolytics and their potential for increasing healthy human lifespan [4-5].
A new atlas charting the SASP
A new open-access publication from researchers at the Buck Institute for Research on Aging, including Dr. Judith Campisi, is the foundation for a “SASP Atlas” that aims to comprehensively categorize the various secretions that our myriad cell types make [6] This will likely be incredibly useful in tracking the differences in the SASP between various cells.
Essentially, these researchers are creating a database that will collect information about the SASP in one place, giving it the potential to be an incredible scientific resource. The SASP Atlas database is now under construction and we recommend checking it out.
We do not currently fully understand senescent cells and their subtle differences and why these nuances exist in different cells and tissues. We know that transient senescent cells are beneficial in tissue regeneration and, broadly speaking, that persistent senescent cells cause chronic inflammation are a problem, but there is some way to go before we fully understand all that is going on here.
Fortunately, even our incomplete knowledge is allowing us to make good progress and, while somewhat crude, the first generation of senolytics has proven effective in removing senescent cells and reducing the SASP. While these treatments are unable to remove all senescent cells, it is now understood that senescent cells use different pro-survival pathways to avoid destruction, which is why no single drug has yet been able to deal with every senescent cell. This database will include such knowledge and allow senolytics to be increasingly refined, and the goal is for them to become more effective in the near future.
Summary
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.
Conclusion
This new database is a very welcome addition to the research landscape and stands alongside other useful resources, such as the superb HAGR database created by Dr. João Pedro Magalhães and other researchers.
Literature
[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
[2] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.
[3] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236.
[4] Freund, A., Orjalo, A. V., Desprez, P. Y., & Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends in molecular medicine, 16(5), 238-246.
[5] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99.
[6] Basisty, N., Kale, A., Jeon, O., Kuehnemann, C., Payne, T., Rao, C., … & Schilling, B. (2019). A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development. bioRxiv, 604306.
