Application of senescence reporter mouse models in panvascular diseases

Abstract

Vascular ageing accelerates panvascular diseases such as atherosclerosis, age-related arterial stiffening, pulmonary hypertension and cerebral microvascular dysfunction, yet the causal roles of senescent cells remain uncertain. This review aims to clarify those roles by systematically mapping the technological evolution, functional features and disease-specific applications of senescence reporter mouse models. We categorize senescence reporter mouse models into senescence tracing models and senescence eliminating models, and track three successive generations that progressively increased temporal, spatial and functional specificity. First-generation luciferase lines enabled non-invasive whole-body imaging; second-generation fluorescent reporters delivered single cell resolution; third-generation dual recombinase systems achieved lineage tracing and conditional clearance. In parallel, elimination platforms advanced from global ATTAC (apoptosis through targeted activation of Caspase) and trimodality reporter constructs to cell-type-restricted designs. Across atherosclerosis, arterial stiffening, pulmonary vascular remodeling and cerebral microvascular dysfunction, targeted removal or longitudinal tracking of cyclin-dependent kinase inhibitor 2A, CDKN2A (p16^Ink4a) or cyclin-dependent kinase inhibitor 1A, CDKN1A (p21^Waf1/Cip1) positive cells revealed both shared and tissue-specific pathogenic mechanisms, and provided genetic gold standards for benchmarking senolytic drugs. We highlight remaining gaps, particularly the reliance on single biomarkers (p16, p21, p53) that may miss heterogeneous senescent subsets, and propose integrating multi-omics profiling, artificial intelligence-assisted image analysis and next-generation dual recombinase tools to refine mechanistic insight and enable precise anti-senescence interventions in panvascular disease.

Keywords

Vascular ageing / cellular senescence / senescence reporter mice / dual recombinase systems / panvascular diseases

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