Senescence-associated alterations in the extracellular matrix: deciphering their role in the regulation of cellular function

Abstract

The extracellular matrix (ECM) is a dynamic structural network that provides a physical scaffolding, as well as biochemical factors that maintain normal tissue homeostasis and thus its disruption is implicated in many pathological conditions. On the other hand, senescent cells express a particular secretory phenotype, affecting the composition and organization of the surrounding ECM and modulating their microenvironment. As accumulation of senescent cells may be linked to the manifestation of several age-related conditions, senescence-associated ECM alterations may serve as targets for novel anti-ageing treatment modalities. Here we will review characteristic changes in the ECM elicited by cellular senescence and we will discuss the complex interplay between ECM and senescent cells, in relation to normal ageing and selected age-associated pathologies.

Lysine-36 of Drosophila histone H3.3 supports adult longevity

“…Interestingly, brain extracellular region proteins were identified in both sexes. This category of genes is among the hallmarks of the senescence-associated secretory phenotype (SASP), which has been implicated as a driver of numerous age-related disorders ( Naylor et al 2013 ; Mavrogonatou et al 2023 ; Mebratu et al 2023 ). Another prominent GO term category, identified in both males and females, centers around the oxidization and transport of glutathione ( Fig.…”

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging

“…Most importantly, senescent cells present a specific secretome, mainly consisting of soluble chemokines, growth factors, pro-inflammatory mediators, bioactive lipids, MMPs and insoluble ECM components, the “senescence-associated secretory phenotype” (SASP). SASP is regulated by several signaling pathways [e.g., p53, p38 mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) and mammalian target of rapamycin (mTOR)] and is the mediator through which senescent cells exert most of their biological effects on adjacent cells and ECM [ 21 , 22 , 23 ]. Collectively, and based on all above-stated senescence-associated cellular modifications, to be firmly characterized as senescent, cells should assemble many of the following traits: overexpression of p16 INK4a , p21 WAF1 and p53, increased β-galactosidase activity (senescence-associated β-galactosidase, SA-β-Gal), accumulation of the by-product of oxidized proteins, lipids and metals (known as lipofuscin), accumulation of phosphorylated histone H2A.X and senescence-associated heterochromatin foci, down-regulation of lamin B1 or high mobility group box 1, increased oxidative load and altered expression of SASP factors towards a pro-inflammatory and catabolic phenotype [ 22 ].…”

“…By definition, and as opposed to the uncontrolled and indefinite ability of cancer cells to proliferate, cellular senescence may be considered an anticarcinogenic mechanism, while it also plays a beneficial role during normal development, tissue repair and against organ fibrosis [ 24 ]. Nevertheless, accumulation of senescent cells (e.g., due to organismal aging) may severely impair tissue microarchitecture via their SASP, substantially contributing to the manifestation or promotion of age-associated disorders [ 21 , 22 ]. After the first report on the existence of senescent cells in human IVDs by Roberts et al [ 25 ], an enhanced number of senescent cells in aged and degenerated IVDs has been identified and confirmed [ 26 ], even very early in life [ 6 ].…”

A tissue ubiquitous gene set for cellular senescence

“…T cells and epithelial cells are among the top interaction targets of SnCs 12,29 (Figure 2k), consistent across human and mouse (correlation=0.417, Figure 2l, Supplementary Table S4). Several key pathways known as hallmarks of cellular senescence are consistently enriched across tissues (Figure 2m), including COLLAGEN, which is responsible for extracellular matrix remodeling and enlarged phenotypes of senescent cells 30-32 ; LAMININ, corresponding to the loss of laminin B1 that compromises nuclear integrity in senescent cells 1,33 ; MHC-I, which is elevated in senescent cells 34,35 ; and MIF, which is involved in senescence-associated inflammation and oxidative stress response pathways 36,37 . These pathways are again consistent across human and mouse (correlation=0.816, Figure 2n, Supplementary Table S5).…”