Cellular Senescence in the Cardiovascular and Metabolic Diseases of Aging

In today's open access paper, the authors review what is known of the role of cellular senescence in the common cardiovascular and metabolic conditions of aging, with a focus on senescence in the vascular system. The accumulation of senescent cells over time is one of the root causes of aging: a process that takes place as a side-effect of the normal operation of cellular metabolism, and that produces slow decline, damage, and systems failure. Research over the past few years has directly connected the growing number of senescent cells in older individuals with age-related disease of the lungs, vascular system, joints, and most of the major organs. Removing senescent cells has been shown to extend life in mice, and partially reverse a number of age-related conditions in other animal studies. Human studies have started, and will be expanding this year and next.

Senescence is a state in which cells cease to replicate, and begin to generate a range of inflammatory and other signal molecules. These cells appear to be important in embryonic development, helping to define shape and structure of tissue, and also play a transient role in regeneration from injury. All somatic cells in the body ultimately reach the Hayflick limit on cell divisions and become senescent, a part of the grand design of multicellular life in which only a few cells are permitted unlimited replication, the first and most important defense against cancer. Cells also become senescent in response to mutational damage or a toxic environment, another defense against cancer. In all of these scenarios, all but a tiny fraction of newly senescent cells quickly destroy themselves.

Unfortunately, a few senescent cells manage to linger, and the signals generated by those few cells ultimately fatally disrupt the function of organs. They cause chronic inflammation, harmful alterations in the processes of tissue maintenance that induce fibrosis, and many other issues linked to an accelerated progression of aging and age-related disease. In the cardiovascular system, evidence points to cellular senescence to be a driver of the calcification that contributes to stiffness and hypertension, and senescent foam cells accelerate the construction of atherosclerotic plaques that narrow and weaken blood vessel walls. The combination of these two processes - high blood pressure and weakened blood vessels - causes a sizable fraction of all human death. Addressing the varied causes of both will go a long way to pushing back the consequences of aging, and destroying senescent cells is the first such approach to enter earnest development.

Vascular Senescence in Cardiovascular and Metabolic Diseases

In aging societies, the discrepancy between the total lifespan and the healthy lifespan is becoming a major problem. Chronological aging is associated with a higher prevalence of age-related diseases, including heart failure, diabetes, and atherosclerotic disorders with or without various comorbidities, resulting in impairment of the quality of life by limitation of normal activities. Thus, aging is associated with several undesirable processes. The mechanisms of aging and age-associated disorders are complex, and thus cannot be comprehended by a simple approach. However, recent studies have indicated a pivotal role of cellular senescence in the progression of age-related disorders.

p53 signaling is thought to have a central role in cellular senescence. Somatic cells have a finite lifespan and eventually enter a state of irreversible growth arrest termed "replicative senescence." Telomeres are repetitive nucleotide sequences located at the terminals of mammalian chromosomes that undergo incomplete replication during cell division, resulting in telomere shortening. Because telomeres are essential for chromosomal stability and DNA replication, DNA damage is recognized when telomere shortening exceeds the physiological range and this triggers cellular senescence, mainly via the p53 or p16 signaling pathways. "Stress-induced premature senescence" is another type of cellular senescence that is triggered by various stress signals. It is also mediated via the p53 or p16 signaling pathways.

It was reported that p53 is increased in the failing heart, in aged vessels, and in the visceral fat of patients with obesity or heart failure. Studies have indicated a pathological role of p53-induced cellular senescence in aging and age-related disorders, including heart failure, atherosclerotic disease, obesity, and diabetes. However, there is controversy about the role of p53 in aging and age-related diseases. In some settings, p53 signaling has been shown to have a beneficial effect by suppression of aging; various reports suggest that the p53/p21 signaling pathways regulate cellular senescence in a context-dependent manner.

Interestingly, it was recently reported that elimination of senescent cells by genetic manipulation inhibited age-related degenerative changes in several organs of mice, such as the heart and kidneys. Other studies have identified several pharmacological agents that selectively damage and remove senescent cells, and these compounds have been described as "senolytic agents". For example, an inhibitor of anti-apoptotic proteins (ABT263) depletes senescent bone marrow hematopoietic stem cells and senescent muscle cells in a chronological aging model, leading to rejuvenation of these tissues. Studies have shown that senescent cells damage their local environment and promote tissue remodeling in age-related disorders, suggesting that inhibition of cellular senescence and/or elimination of senescent cells could be potential next generation therapies for diseases associated with aging.

Reactive oxygen species and chronic low-grade sterile inflammation are two major contributors to the progression of age-related vascular dysfunction. Senescent cells accumulate in the arteries with aging irrespective of whether or not a person has age-related vascular disorders. Along with aging, vascular tissues of rodents and humans show elevation of the levels of p16, p21, phosphorylated p38, and double-stranded DNA breaks, in association with high SA-β Gal activity. It was reported that expression of p53 and p21 is increased in the arteries of elderly persons, together with structural breakdown of telomeres known as telomere uncapping.

Endothelial cells and vascular smooth muscle cells (VSMCs) from patients with abdominal aortic aneurysm (AAA) have the phenotypic features commonly observed in senescent cells. Hypertension is an established risk factor for atherosclerotic diseases, and it was reported that binding of p53 to the p21 promoter is increased in the arteries of hypertensive patients. While telomere length is comparable between patients with hypertension and controls, telomere uncapping is 2-fold higher in hypertensive patients. A murine model of genomic instability demonstrated senescence of endothelial cells and VSMCs in the aorta, along with impaired vasodilation, increased vascular stiffness, and hypertension.

Endothelial cells are critically important for maintaining vascular homeostasis and are involved in various biological functions, including angiogenesis, blood pressure regulation, coagulation, and systemic metabolism. Aged endothelial cells develop a dysfunctional phenotype that is characterized by reduced proliferation and migration, decreased expression of angiogenic molecules, and low production of nitric oxide (NO), which is synthetized by NO synthase (NOS) and mediates vasodilatation. Senescent endothelial cells have been found in atherosclerotic plaque. An autopsy study of patients with ischemic heart disease revealed that SA-β-gal activity is increased in the coronary arteries. In the coronary arteries, SA-β-gal activity is high in cells located on the luminal surface (probably endothelial cells). Both endothelial nitric oxide synthase (eNOS) and NO activity are reduced in these cells compared to young cells.

One of the problems related to an increase of senescent cells is development of the senescence-associated secretory phenotype, which is characterized by production of pro-inflammatory cytokines with a causal role in tissue remodeling. In human arterial endothelial cells with replicative senescence, levels of H2O2 and O2- are high and NO production is reduced. High ROS levels in senescent endothelial cells are thought to accelerate senescence. Aging is reported to be linked with increased circulating levels of pro-inflammatory cytokines, such as interleukin-6, tumor necrosis factor alpha, and monocyte chemoattractant protein-1. It is highly possible that accumulation of senescent endothelial cells in the arteries of elderly persons induces chronic sterile inflammation and vascular remodeling, increasing susceptibility to atherosclerotic diseases.

In conclusion, senescence of vascular cells promotes the development of age-related disorders, including heart failure, diabetes, and atherosclerotic diseases, while suppression of vascular cell senescence ameliorates phenotypic features of aging in various models. Recent findings have indicated that specific depletion of senescent cells reverses age-related changes. Although the biological networks contributing to maintenance of homeostasis are extremely complex, it seems reasonable to explore senolytic agents that can act on specific cellular components or tissues. Several clinical trials of senolytic agents are currently ongoing.

Survivors of hematopoietic stem cell transplantation are prone to premature aging, and one pilot clinical study is designed to test whether dasatinib and quercetin (D + Q) can suppress aging in these patients (NCT02652052). Another clinical trial is testing whether D + Q reduces pro-inflammatory cells obtained by skin biopsy in patients with idiopathic pulmonary fibrosis (NCT02874989). Furthermore, a clinical trial is ongoing to determine whether D + Q can reduce the senescent cell burden and frailty in patients with chronic kidney disease, as well as improving the function of adipose tissue-derived mesenchymal stem cells (NCT02848131). So far, only D + Q has been assessed in the clinical setting, and none of the current clinical trials are testing whether senolytic agents can inhibit cardiovascular disorders. However, depletion of senescent cells was demonstrated to suppress pathological progression of atherosclerotic plaque in rodents, suggesting that senolytic agents could become a next generation therapy for cardiovascular disorders.

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