Digging Deeper into the Senescence-Associated Secretory Phenotype
Given the importance of lingering senescent cells in the progression of degenerative aging, researchers continue to dig deeper into the biochemistry of these errant cells and their disruptive influence on tissue function. Here find a representative example of this work, in which the senescence-associated secretory phenotype is analyzed, in part to find better universal markers of senescence, and in part to find better therapeutic targets that are common across different cell types and causes of senescence.
DNA damage resulting from genotoxic injury can initiate cellular senescence, a state characterized by alterations in cellular metabolism, lysosomal activity, and the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). Senescence can have beneficial effects on our bodies, such as anti-cancer properties, wound healing, and tissue development, which are attributed to the SASP produced by senescent cells in their intermediate stages. However, senescence can also promote cancer and aging, primarily due to the pro-inflammatory activity of SASP.
Studying senescence is complex due to various factors involved. Genotoxic stimuli cause random damage to cellular macromolecules, leading to variations in the senescent phenotype from cell to cell, despite a shared program. Furthermore, senescence is a dynamic process that cannot be analyzed as a static endpoint, adding further complexity. Investigating SASP is particularly intriguing as it reveals how a senescence process triggered in a few cells can spread to many others, resulting in either positive or negative consequences for health.
Senescence is a dynamic process influenced by a variety of factors, which greatly affects SASP composition and functions. However, to our knowledge, there is no comprehensive secretome analysis that considers these influences. In this study, we performed a meta-analysis of 70 protein lists from 20 studies to clarify the induction process of senescence. The analysis revealed the following points: I) The IGF and IGFBP signaling pathways are representative common factors in senescent cells. II) The RUNX1 and UCH deubiquitination that regulates proteasome activity were enriched at the very early stage (1-3 days). III) SASP of the middle stage and late stage were enriched inflammatory pathway related protein, including IL-1, IL-4, IL-12, IL-13, and NF-kb. IV) There is a change in carbohydrate metabolism towards glycolysis during senescence induction. V) Senescent fibroblasts subjected to oncogene-induced senescence were found to be distinct from other senescent cells.
IGFBPs have been extensively linked to senescent cells. Studies have demonstrated that these IGFBPs can induce senescence at both the cellular and individual levels when administered to either the culture medium or living organisms. In our analysis, we consistently detected IGFBP4 and IGFBP7 in all datasets at the late stage. Furthermore, the IGF and IGFBP signaling pathway emerged as a common pathway in both the middle and late stages, irrespective of the type of stressor. These findings align with previous analyses and underscore the significant role of the IGF and IGFBP pathway in senescence. They suggest that factors associated with this pathway could serve as a universal marker for identifying senescent cells.