Clearance of Stress-Induced Premature Senescent Cells Alleviates the Formation of Abdominal Aortic Aneurysms

Abstract

Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRβ/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRβ/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.

Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice

“…Additionally, navitoclax treatment of Ang II-induced premature senescent VSMCs in vitro also reduced the expression of Mmp2 and Mmp9. These studies indicate that senescence could be targeted to prevent or reduce aneurysm development 57 . Importantly, specifically targeting senescent cells as a form of therapy also shows potential for translation to the clinic, as senescence of VSMCs has been identified in the aortas of patients with Marfan syndrome.…”

Senolytic and senomorphic secondary metabolites as therapeutic agents in Drosophila melanogaster models of Parkinson’s disease

“…Senolytic secondary metabolites selectively target senescent cells for induced apoptosis or programmed death, ultimately leading to their clearance from tissues and possible replacement with healthy cells ( 81 ). Senolytics have shown exciting promise in pre-clinical and clinical studies for their ability to enhance tissue regenerative capacity and alleviate age-related pathologies ( 82 ).…”

“…The mechanism of action and efficacy of senolytic secondary metabolites vary depending on the metabolite and cellular environment ( 81 , 83 , 84 ). For example, in response to cellular stress, some senolytic secondary metabolites will activate either the intracellular p53 or P16 INK4A pathways, leading to a senescent cellular state ( 85 ).…”