Late‐Life Treatment with the Senolytic ABT‐263 Reverses Aortic Stiffening and Improves Endothelial Function with Aging

Abstract

Advancing age is the primary risk factor for the development of cardiovascular diseases (CVD), driven largely by age‐related arterial dysfunction. Two key manifestations of arterial dysfunction with advancing age are aortic stiffening and vascular endothelial dysfunction. Excessive reactive oxygen species (ROS)‐induced oxidative stress is a major macro‐mechanistic process causing arterial dysfunction during aging; however, the upstream mechanistic event(s) driving oxidative stress are incompletely understood. A rapidly emerging candidate is cellular senescence, a state of irreversible cell‐cycle arrest that can be cleared with senolytics. Purpose We tested the hypotheses that late‐life treatment with the senolytic ABT‐263 (ABT) would: 1) reverse age‐related aortic stiffening by reducing aortic intrinsic mechanical wall stiffness (elastic modulus [EM]); and 2) increase endothelial function by increasing nitric oxide (NO) bioavailability and reducing oxidative stress. Methods Old (27 mo) male C57BL6/N mice were treated with vehicle ([V]; 10% EtOH, 30% PEG400 and 60% Phosal 50 PG; n = 7) or ABT (50 mg/kg/day in [V]; n = 6) by oral gavage using a 1 week on – 2 weeks off – 1 week on dosing paradigm. A cohort of young adult mice (6 mo; n = 5) served as a young control (YC) reference group. Aortic pulse wave velocity (PWV), an in vivo measure of aortic stiffness, was measured pre‐ and post‐treatment. Aortic elastic modulus was assessed by performing stress‐strain testing in excised aortic rings. Endothelial function was assessed via ex vivo carotid artery endothelial‐dependent dilation (EDD) with increasing concentrations of acetylcholine (ACh). NO bioavailability (ACh in the presence of the NO‐synthase inhibitor, L‐NAME) and the role of excessive ROS in regulating EDD (ACh with the addition of the ROS scavenger, TEMPOL) were assessed as potential mechanisms. Results Aortic stiffness. ABT reversed aortic PWV in old mice (pre: 456 ± 7 vs post: 375 ± 11 cm/sec, P = 0.0003), to levels of YC (348 ± 13 cm/sec; P = 0.14 vs. ABT), whereas no effect was observed in the [V]‐treated group. Reduced aortic PWV with ABT was accompanied by lower aortic EM (V: 2738 ± 152 kPa, ABT: 2228 ± 155 kPa, YC: 2120 ± 362 kPa; P = 0.03). Endothelial function. ABT‐treated mice had greater peak EDD relative to [V]‐treated animals and comparable to YC (ABT: 94 ± 3% vs. V: 78 ± 5%, P = 0.01; YC: 91 ±2). Group differences in peak EDD were abolished in the presence of L‐NAME, suggesting that ABT rescued EDD by restoring NO bioavailability. TEMPOL restored peak EDD in [V]‐treated old mice to YC levels (92 ±5%, P = 0.003 vs. ACh alone), while having no effect in ABT or YC animals, suggesting that ABT selectively ameliorated the tonic ROS‐related suppression of EDD with aging. Conclusion Cellular senescence is mechanistically implicated in age‐related arterial dysfunction, and treatment with the senolytic compound ABT‐263 may be a therapeutic strategy for improving arterial function, with the potential for reducing CVD risk with aging.

Anthracycline chemotherapy‐mediated vascular dysfunction as a model of accelerated vascular aging

“…Our preliminary results indicate that treatment of old mice with the senolytic ABT-263 (aka Navitoclax) reverses the age-related increase in aortic PWV and increases vascular endothelial function to levels observed in young adult mice. 101 Our observations are consistent with previous findings that treatment of old mice with the senolytic cocktail dasatinib plus quercetin can increase vascular endothelial function in old mice. 102 As previously mentioned, DOXO increases cellular senescence in a variety of cell and tissue types, including cardiac tissue, but the role of cellular senescence in mediating DOXO-induced vascular dysfunction remains to be determined.…”

“…184 Our preliminary results suggest that ABT-263 administration to old mice reverses aortic stiffening and improves EDD with aging in mice. 101 However, the influence of ABT-263 on vascular senescence and function in the setting of anthracycline chemotherapy has yet to be determined.…”

Cellular senescence: a key therapeutic target in aging and diseases

“…Treating DKD patients with a 3-day oral course of D+Q resulted in a reduction of SA-β-galpositive and p16 INK4a -and p21 CIP1 -expressing cells in adipose and skin biopsies. Further, examination of patient blood samples also Navitoclax (ABT-263), a compound targeting one type of SCAPs, the BCL-2 family of proteins, is another extensively studied senolytic compound showing comparable outcomes to D+Q and fisetin in multiple mouse models (Table 2) (60,61,161,162,(166)(167)(168)(169)(170). Although navitoclax showed diverse benefits in many preclinical tests, its translational potential is still limited by its platelet toxicity (171,172).…”

Could angiotensin‐II induced T‐cell senescence exacerbate age‐related vascular dysfunction?

“…Future studies could examine the direct role of Ang II on T-cells with ageing, and how suppression of Ang II could affect T-cell senescence. Additionally, clearance of senescent cells via senolytics have shown to ameliorate age-related vascular dysfunction (Mahoney et al 2021). Future studies could explore the role of T-cell senescence by using transgenic mouse models to genetically clear the senescent T-cells from old mice.…”

“…Additionally, clearance of senescent cells via senolytics have shown to ameliorate age‐related vascular dysfunction (Mahoney et al . 2021). Future studies could explore the role of T‐cell senescence by using transgenic mouse models to genetically clear the senescent T‐cells from old mice.…”