Senolytics Block Chemotherapy-Driven Artery Stiffening in Mice

Cancer survivors treated with anthracycline chemotherapy face elevated lifetime cardiovascular disease risk, with large-artery stiffening acting as a critical early driver. Doxorubicin (Doxo), the most widely used anthracycline, increases aortic pulse wave velocity (PWV)—the gold-standard measure of arterial stiffness—but the upstream mechanisms remain incompletely understood. This study investigated whether cellular senescence, the stress-induced state of permanent cell-cycle arrest that unleashes a pro-inflammatory secretome (SASP), is a primary mediator of Doxo-induced aortic stiffening, and whether senolytics could prevent it.

Two complementary mouse studies were conducted in young adult (4–6 month) p16-3MR mice, a validated transgenic model enabling selective genetic elimination of p16-positive senescent cells with ganciclovir (GCV). In Study 1, a single Doxo injection (10 mg/kg IP) raised aortic PWV by 17% (362 to 425 cm/sec), an effect completely abolished by GCV treatment (348 cm/sec post-treatment). In Study 2, the FDA-recognized senolytic ABT263 administered by oral gavage after Doxo similarly prevented the PWV increase (404 cm/sec Doxo-vehicle vs. 342 cm/sec Doxo-ABT263). Crucially, neither intervention altered blood pressure, confirming the stiffening effects were blood-pressure independent.

To establish a causal role for the circulating SASP milieu specifically, the team incubated aortic rings from healthy donor mice in plasma collected from each treatment group. Plasma from Doxo-treated mice induced measurable ex vivo aortic stiffening (increased elastic modulus) compared to control plasma, whereas plasma from Doxo-GCV or Doxo-ABT263 mice did not—directly implicating circulating SASP factors as effectors of vascular damage.

Mechanistic analyses pointed to glycation stress as a key downstream pathway. Advanced glycation end-products (AGEs) were elevated in Doxo plasma, and pharmacological inhibition of the receptor for AGEs (RAGE) significantly attenuated plasma-induced ex vivo aortic stiffening. This highlights a receptor-mediated, non-crosslinking glycation mechanism—distinct from the better-studied structural protein crosslinking pathway—as a novel driver of chemotherapy-associated vascular aging.

These findings carry strong translational implications. Both GCV (genetic) and ABT263 (pharmacological) senolytics fully protected against Doxo-induced arterial stiffening without affecting blood pressure, demonstrating target engagement and proof-of-principle efficacy. Targeting the senescence–SASP–glycation axis with senolytics or RAGE inhibitors may represent actionable strategies to reduce cardiovascular morbidity in the growing population of cancer survivors exposed to anthracycline chemotherapy.