Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress.

Background: Mechanisms underlying doxorubicin chemotherapy-induced aortic stiffening are incompletely understood.

Objectives: To determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in mediating doxorubicin-induced aortic stiffening and the influence of senolytic therapy.

Methods: Aortic stiffness (aortic pulse wave velocity) and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir.

Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress.

Background: Mechanisms underlying Doxorubicin (Doxo) chemotherapy-induced aortic stiffening are incompletely understood.

Objectives: Determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in mediating Doxo-induced aortic stiffening and the influence of senolytic therapy.

Methods: Aortic stiffness (aortic pulse-wave velocity [PWV]), and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir [GCV].

Late Life Supplementation of 25-Hydroxycholesterol Reduces Aortic Stiffness and Cellular Senescence in Mice.

Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age-related aortic stiffening is driven, in part, by cellular senescence-a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25-hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice.

Methylglyoxal-induced glycation stress promotes aortic stiffening: Putative mechanistic roles of oxidative stress and cellular senescence.

Background: Here, we assessed the role of the advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1 in aortic stiffening and explored the potential of a glycation stress-lowering compound (Gly-Low) to mitigate these effects.

Methods: Young (3-6 month) C57BL/6 mice were supplemented with MGO (in water) and Gly-Low (in chow). Aortic stiffness was assessed in vivo via pulse wave velocity (PWV) and ex vivo through elastic modulus.

The influence of a human macronutrient-matched diet on phenotypes in old mice.

Preclinical rodent models are essential research tools for improving understanding of physiological aging processes in humans. However, the translatability of findings obtained leveraging rodent models to humans is limited, likely due in part to differences in macronutrient composition of the diets. Here, we investigated the impact of a 3-month diet intervention in old male C57BL/6JN mice in which the macronutrient composition was aligned with that of a midlife/older adult in the United States, compared to a traditional rodent diet, and assessed various phenotypes that are typically altered with aging.

The bottlenose dolphin (): a novel model for studying healthy arterial aging.

Endothelial function declines with aging and independently predicts future cardiovascular disease (CVD) events. Diving also impairs endothelial function in humans. Yet, dolphins, being long-lived mammals adapted to diving, undergo repetitive cycles of tissue hypoxia-reoxygenation and disturbed shear stress without manifesting any apparent detrimental effects, as CVD is essentially nonexistent in these animals.

Klotho enhances diastolic function in aged hearts through Sirt1-mediated pathways.

Aging leads to a progressive decline in cardiac function, increasing the risk of heart failure with preserved ejection fraction (HFpEF). This study elucidates the impact of α-Klotho, an anti-aging hormone, on cardiac diastolic dysfunction and explore its downstream mechanisms. Aged wild-type and heterozygous Klotho-deficient mice received daily injection of soluble α-Klotho (sKL) for 10 weeks, followed by a comprehensive assessment of heart function by echocardiography, intracardiac pressure catheter, exercise tolerance, and cardiac pathology.

Socioeconomic status as a potential mediator of arterial aging in marginalized ethnic and racial groups: current understandings and future directions.

Cardiovascular diseases (CVDs) are the leading cause of death in the United States. However, disparities in CVD-related morbidity and mortality exist as marginalized racial and ethnic groups are generally at higher risk for CVDs (Black Americans, Indigenous People, South and Southeast Asians, Native Hawaiians, and Pacific Islanders) and/or development of traditional CVD risk factors (groups above plus Hispanics/Latinos) relative to non-Hispanic Whites (NHW). In this comprehensive review, we outline emerging evidence suggesting these groups experience accelerated arterial dysfunction, including vascular endothelial dysfunction and large elastic artery stiffening, a nontraditional CVD risk factor that may predict risk of CVDs in these groups with advancing age.

Role of the circulating milieu in age-related arterial dysfunction: a novel ex vivo approach.

The circulating milieu, bioactive molecules in the bloodstream, is altered with aging and interfaces constantly with the vasculature. This anatomic juxtaposition suggests that circulating factors may actively modulate arterial function. Here, we developed a novel, translational experimental model that allows for direct interrogation of the influence of the circulating milieu on age-related arterial dysfunction (aortic stiffening and endothelial dysfunction).

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment.

Background: Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction.

Methods: We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263.

Female C57BL/6N mice are a viable model of aortic aging in women.

The aorta stiffens with aging in both men and women, which predicts cardiovascular mortality. Aortic wall structural and extracellular matrix (ECM) remodeling, induced in part by chronic low-grade inflammation, contribute to aortic stiffening. Male mice are an established model of aortic aging.

Aging, aerobic exercise, and cardiovascular health: Barriers, alternative strategies and future directions.

Age-associated cardiovascular (CV) dysfunction, namely arterial dysfunction, is a key antecedent to the development of CV disease (CVD). Arterial dysfunction with aging is characterized by impaired vascular endothelial function and stiffening of the large elastic arteries, each of which is an independent predictor of CVD. These processes are largely mediated by an excess production of reactive oxygen species (ROS) and an increase in chronic, low-grade inflammation that ultimately leads to a reduction in bioavailability of the vasodilatory molecule nitric oxide.