Cathepsin L activates Notch1 signaling through direct proteolytic cleavage, triggering a cascade that induces endothelial senescence and accelerates atherosclerosis development. This ligand-independent mechanism identifies a previously unrecognized pathway linking cellular aging to vascular disease and opens therapeutic targets for senescence-based interventions in atherosclerosis prevention.
Key Points
- Cathepsin L directly cleaves Notch1 independent of canonical ligand binding
- CUX1/p16 activation drives endothelial senescence associated with plaque formation
- Blocking this pathway reduces atherosclerotic lesions in mouse models
Longevity Analysis
Vascular senescence represents a convergence point between aging and atherosclerosis—the primary driver of mortality in developed populations. This research identifies a specific enzymatic mechanism that accelerates this process, meaning interventions targeting cathepsin L activity or Notch1 cleavage could theoretically slow both vascular aging and atherosclerotic progression. The finding that blocking the downstream senescence signal (CUX1) prevents plaque formation suggests that senescence itself, not just its byproducts, actively drives disease. For practitioners, this shifts the lens from managing cholesterol or inflammation alone to addressing the underlying cellular aging process that permits vascular degeneration—a distinction with significant implications for prevention strategies in midlife and beyond.
Original published by Wiley Aging Cell, by Yuwei Wu, Lili Lu, Shaoyang Yan, Zewen Du, Danli Jiang, Ting Wu, Qichao Wu, Jie Liu, Johny Ebin, Wei Sun, Partha Dutta, Jay Xiaojun Tan, Jonathan K. Alder, Gang Li .