Increasing evidence shows a direct link between fibrosis in the extracellular matrix and cellular senescence.
Mounting evidence suggests a direct link between cellular senescence and tissue damage due to the deposition of extracellular matrix (ECM) components, a condition also known as fibrosis. Notably, elimination of senescent cells alleviates fibrosis in animal models . However, the relevance of this interplay between senescent cells and ECM components in aging and age-related diseases remains poorly understood.
Longevity.Technology: In a review article recently published in the journal Clinical Science, Blokland et al. indicate that ECM stiffening, a major characteristic of fibrosis and an emerging hallmark of aging , may cause cellular senescence. They also point out that the direct regulation of cellular senescence by ECM may represent a key mechanistic link between fibrosis, cellular senescence, and aging .
Deposition of collagen and other ECM components is the leading cause of organ dysfunction associated with fibrosis. Although the cause of ECM deposition remains unknown, studies suggest that cellular senescence may play a key role in fibrosis.
Increased ECM stiffness due to alterations in ECM composition and increased cross-linking of the ECM components is the main feature of fibrosis. In fact, the mechanical characteristics of ECM and ECM stiffening play a more important role in fibrotic diseases than ECM deposition. Increased cross-linking of ECM fibres has been associated with resistance to proteolytic degradation by matrix metallopeptidases. These alterations in proteolytic degradation significantly impact cellular functions, particularly in fibroblasts. The increased activation and proliferation of fibroblast due to ECM stiffening links ECM alterations to tissue damage in fibrotic disease [3, 4].
“The cell cycle arrest is needed to reduce the amount of collagen that the cells synthesize. Matrix metalloproteinases included in SASP destroy excessive collagen, while pro-inflammatory cytokines attract immune cells to finalize the cleanup.”
Additionally, ECM stiffening promotes the activation of transforming growth factor-β (TGF-β), which is known to induce cellular senescence in numerous cell types, favouring the onset of age-related diseases. Interestingly, senolytic agents (e.g., quercetin and dasatinib) have been shown to alleviate fibrosis in animal models, in addition to eliminating senescent cells . The ability of senolytics to reduce fibrosis is believed to be mediated through the modulation of senescence-associated secretory phenotype (SASP) and inflammaging .
“The cell cycle arrest is needed to reduce the amount of collagen that the cells synthesize. Matrix metalloproteinases included in SASP destroy excessive collagen, while pro-inflammatory cytokines attract immune cells to finalize the cleanup. The anti-fibrotic nature of cellular senescence has been demonstrated in multiple studies,” said Alexander Fedintsev, a scientist at the Moscow Institute of Physics and Technology working on the identification of aging biomarkers . “My bet is that cells can sense the excess of collagen via ECM stiffening, and if the stiffness exceeds a certain threshold, this might launch the cellular senescence sequence. But the increase in stiffness is exactly what happens during normal aging due to non-enzymatic cross-link formation!”
The results of the first human pilot study of senolytics have recently been published in the journal EBioMedicine (ClinicalTrials.gov: NCT02874989) . The study has shown that quercetin and dasatinib significantly improved the physical condition of patients with idiopathic pulmonary fibrosis. Furthermore, the senolytic treatment reduced the levels of IL-6, MMP, and TIMP2, which are implicated in ECM remodelling and fibrosis.
Notwithstanding promising preliminary data showing that targeting senescence may be a promising therapeutic approach for patients with fibrotic diseases, randomized large-cohort controlled trials are warranted to confirm the clinical usefulness of senolytics for patients with fibrosis and other senescence-related diseases.