THBD Signaling as a Novel Target for Senolytic Drugs

Researchers here show that THBD signaling inhibition is an approach to selectively destroy senescent cells. There is an approved drug that can do this, vorapaxar, though at first glance its safety profile looks worse than that of dasatinib, the only senolytic so far proven to clear senescent cells in humans. One might wonder how much of vorapaxar's successes in clinical trials are due to clearance of senescent cells versus other mechanisms.

As is the case in many lines of research into cellular senescence, the focus here is on fibrosis, a progressive failure of tissue maintenance in which scar-like deposits form to disrupt tissue structure and function. Senescent cells are implicated in this process, and clearance of senescent cells has been shown to reverse fibrosis in a number of different organs and animal models.

Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis.

Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability.

Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.


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