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Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics

Yeaeun Han, Sung Young Kim

Experimental & Molecular Medicine · 2023 · Review · CC BY

doi:10.1038/s12276-022-00906-w

Abstract

Senescence compromises the essential role that the endothelium plays in maintaining vascular homeostasis, so promoting endothelial dysfunction and the development of age-related vascular diseases. Their biological and clinical significance calls for strategies for identifying and therapeutically targeting senescent endothelial cells. While senescence and endothelial dysfunction have been studied extensively, distinguishing what is distinctly endothelial senescence remains a barrier to overcome for an effective approach to addressing it. Here, we review the mechanisms underlying endothelial senescence and the evidence for its clinical importance. Furthermore, we discuss the current state and the limitations in the approaches for the detection and therapeutic intervention of target cells, suggesting potential directions for future research.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Age-related endothelial dysfunction, regarded as a prominent precursor to the development of cardiovascular diseases (CVDs),, can be characterized by a shift toward a vasoconstrictive, proinflammatory and prothrombotic environment, resulting in impaired regulation of vascular homeostasis. Endothelial dysfunction can be largely explained by endothelial senescence, which has been implicated in the development of various age-related CVDs, including stroke, vascular dementia, macular degeneration, obstructive sleep apnea, atherosclerosis,, myocardial infarction, pulmonary hypertension–, hypertension, diabetes,, renal failure, peripheral arterial disease, erectile dysfunction and diabetic foot (Fig. 1). The “geroscience hypothesis” aptly summarizes the idea that as aging is the main driver of multiple interrelated diseases, targeting key aging contributors may prevent the onset or mitigate the severity of multimorbidity. Therefore, there are great clinical motivations and implications for research into endothelial senescence.

In this review, we discuss the key alterations found in endothelial senescence and its clinical potential in vascular diseases. The investigation into the clinical applications of endothelial senescence is characterized by two objectives: detecting and targeting senescence. By utilizing endothelial senescence as a molecular biomarker, it may be possible to describe the degree of endothelial dysfunction. Upon detection, senescent cells can be treated to reverse damage and recover endothelial function. Finally, we discuss the latest advances in detection approaches and in senotherapeutics, with a special focus on endothelial cells (ECs) and potential therapeutic applications of these advances to CVDs.

Key pathways involved in endothelial senescence

Senescence serves as a blanket term that encompasses a wide range of states of stable cell cycle arrest states associated with various biological contexts and stimuli. Although such heterogeneity complicates the precise characterization or quantification of senescence, its implication in major age-related diseases makes it critical to investigate for a better understanding of their pathogenesis and the search for therapeutic venues. Rather than a simplistic approach in which various unique types of senescence are understood in the limited confines of generalized senescence, it may be useful to consider the individual features of a particular type of senescence in a defined physiological context.

While endothelial senescence has certain features that can be uniquely attributed to it, it shares several core mechanisms with other types of senescence. Endothelial senescence is triggered by a variety of senescence stressors that include replicative and oxidative stress, oncogenic activation, telomere attrition, DNA damage, and mitochondrial dysfunction. Mitochondrial dysfunction in senescent ECs can be characterized by decreased mitochondrial mass and alterations in the mitochondrial composition and electron transport chain (ETC). It has been demonstrated that the activity of complex IV and cytochrome c oxidase, components of the mitochondrial ETC, declines with age, and the resulting impairment increases mitochondrial oxidative stress. In turn, oxidative stress can accelerate telomere shortening and induce DNA damage in ECs. Regardless of the type of stressor, senescent pathways converge on cell cycle arrest, which is primarily mediated by two main tumor suppressive pathways involving p53/p21WAF1 and/or p16Ink4A/RB. Senescent cells acquire the senescence-associated secretory phenotype (SASP), which includes chemokines, cytokines, growth factors, and insoluble factors. While the SASP is heterogeneous and can vary by the type of cell and stimuli, a unique feature of endothelial SASP is its characterization by regulators of arterial dysfunction, including increased levels of reactive oxygen species (ROS) and reduced nitric oxide (NO).

Impaired redox homeostasis characterized by reduced NO production and increased oxidative stress is widely recognized as a key defining feature of endothelial senescence (Fig. 2). NO is a critical vasodilatory factor that has also been observed in reduction in endothelial dysfunction, owing to age-related impairment of endothelial nitric oxide synthase (eNOS) and decreased levels of the eNOS cofactors tetrahydrobiopterin (BH4) and L-arginine. It has been reported that hyperglycemia, hyperuricemia, and hyperlipidemia inhibit eNOS production, while FGF21 has been shown to delay endothelial senescence by enhancing eNOS in mice and in a SIRT1-dependent manner in human umbilical vein endothelial cells (HUVECs),. Diminished NO bioavailability may lead to impaired angiogenesis, reduced levels of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α), and dysregulation in related metabolic processes such as the NAD+ biosynthetic pathway and NAD+-dependent protein deacetylase sirtuin-1 (SIRT1) in the sirtuin family. Critical cellular sensors, adenosine monophosphate-activated protein kinase (AMPK), which senses the cell energy status, and mammalian target of rapamycin (mTOR), which senses the cell nutritional status, can modulate endothelial function and are altered during endothelial senescence. In endothelial senescence, protein kinase B (Akt) has been reported to be constitutively activated and to promote cell arrest in a p53/p21-dependent manner through the inhibition of the transcription factor FOXO3a,. Inhibition of mTOR has been associated with enhanced endothelium-dependent dilation and higher levels of NO. Another energy-sensitive metabolic sensor, sirtuin, plays an essential role in facilitating endothelial function through the regulation of the transcription factors FOXO, p53, and NFκB as well as in producing NO through the deacetylation of eNOS,,. SIRT1 can further protect the endothelium by mediating the level of plasminogen activator inhibitor-1 (PAI-1), which can be increased via SIRT1 inhibition and is often increased in endothelial senescence and dysfunction.

The renin/angiotensin system (RAS) is another key component of vascular tone regulation, which is altered in endothelial senescence. The altered RAS can be identified by increased angiotensin-converting enzyme 1 (ACE1), angiotensin II (Ang II), and angiotensin II type-1 receptor (AT-1), which have been shown to induce fibrosis, inflammation, and oxidative stress in aged mouse thoracic aorta. In conjunction with increased endothelin-1, a vasoconstrictor peptide produced by ECs,, the altered RAS exerts vasoconstrictive pressure on the vasculature.

Another cause of vasoconstrictive stress is derived from the uncoupling of eNOS (Fig. 3). The cause of eNOS uncoupling can be attributed to the limited availability of its cofactors such as L-arginine and BH4. Uncoupled eNOS and NADPH oxidase (NOX) can produce superoxide. While superoxide can be scavenged by superoxide dismutases, it has a higher affinity for NO and binds to it to form peroxynitrite (ONOO−), a toxic and reactive nitrogen species with strong oxidizing action. ONOO−can oxidizes BH4 into 7,8-dihydrobiopterin (BH2) and damage zinc-thiolate clusters of eNOS, further driving eNOS uncoupling, ultimately increasing ROS and reducing NO. It has been observed that dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR), two enzymes responsible for the regeneration of BH4 from BH2, are impaired in senescence, further amplifying NO deficiency in a feed-forward loop. DHFR, a DNA-synthesizing enzyme, is attenuated in senescent cells. Likewise, deficiency of MTHFR, an enzyme critical for the conversion of homocysteine to methionine, can lead to eNOS uncoupling in a BH4-dependent manner. Interestingly, it has been reported that inhibition of s-adenosylhomocysteine hydrolase leads to senescence in HUVECs. As evidenced by the role of the components of folate metabolism in endothelial senescence, it is possible that folate metabolism, which is altered in cancer and targeted for therapy, may also be critically involved in endothelial senescence. Further studies are needed to examine the key factors of folate metabolism, such as methylenetetrahydrofolate dehydrogenase, to elucidate the underlying mechanisms, which remain largely unknown.

Although much remains to be explored regarding the metabolic shifts in endothelial senescence, these shifts appear to play a crucial role in senescence. It is well-established that senescent cells are metabolically active,. However, the main source of energy in senescent ECs is still a matter of debate. Different studies of replicative senescence in HUVECs have reported conflicting results, showing that (1) glycolysis decreased with a decline in the expression of nuclear factor E2-related factor 2 (NRF2), a regulator of endothelial proliferation and glycolysis; (2) the rate of glycolysis and the expression of glycolytic enzymes (hexokinase, LDH, aldolase, GAPDH, and pyruvate kinase) did not change significantly; and (3) glycolysis was increased with increased expression of lactate dehydrogenase A and decreased expression of pyruvate dehydrogenase kinase 1-4. While the latter two studies both noted an increase in glucose consumption and lactate production, the former study did not see a correlation between these two changes and suggested glutaminolysis is the alternative energy source for senescent ECs. The same study showed that the inhibition of glutaminase (GLS) induced premature senescence in HUVECs. Supporting this finding, it was demonstrated that inhibition of GLS1 reduced the proliferative capacity and increased ROS in HUVECs. Studies have shown that senescent cells are associated with lower levels of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, and of D-3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the committed step in de novo serine biosynthesis and regulates the critical steps of one-carbon metabolism. G6PD and PHGDH play essential roles in redox homeostasis, mediating the production of NADPH, and the downregulation of these enzymes may significantly contribute to increased ROS in endothelial senescence,.

Endothelial senescence in vascular diseases

Occupying the inner walls of blood vessels, ECs are subject to constant stresses from hemodynamic forces and various substances carried through the flowing blood. Studies have shown that ECs positioned near arterial geometries such as bifurcations and curvatures in human tissue samples or otherwise exposed to disrupted blood flow, undergo higher cell turnover and replicative senescence. Spikes in the partial oxygen pressure and the concentration of hormones and nutrients, which are notably increased during routine activities that cause abrupt metabolic changes in the body, such as exercising and eating, can lead to senescence. It has been demonstrated that high partial oxygen pressure can induce cellular senescence–, while culturing ECs in elevated levels of insulin, glucose, or uric acid showed reduced proliferative potential and accelerated onset of senescence. High levels of glucose or other reducing sugars can introduce advanced glycation end-products (AGEs) into the circulation, and these AGEs can bind to and stimulate ECs, generating ROS. Similarly, the levels of advanced oxidation protein products (AOPPs), which can be increased by AGEs, tend to be high in uremic patients and have been shown to induce senescence in HUVECs. Other substances, such as circulating microparticles (MPs), which are shed from the membrane following a variety of stimuli and are circulated through the bloodstream, can lead to endothelial dysfunction by mediating NO and ROS production,. It has been observed that exposure to MPs from acute coronary syndrome patients induces endothelial senescence through Ang 2, ACE1, and AT-1 of the altered RAS system.

Endothelial senescence has been observed in multiple vascular organs, including the brain and the kidney, undermining critical functions of these organs and has thus been implicated in the development of CVDs. In the brain, cerebrovascular ECs comprise the blood‒brain barrier (BBB) and the neurovascular unit, and senescent phenotypes have been associated with increased BBB permeability and neurovascular uncoupling. Proinflammatory SASP factors, such as interleukin 6 (IL-6) and interleukin 1β (IL-1β), are upregulated during aging and cerebrovascular diseases. Moreover, altered expression of proteases and protease regulators, such as matrix metalloproteinases (MMPs), can compromise tight junction integrity in the endothelium, all of which may contribute to a leaky BBB and ultimately to cerebrovascular diseases. A comparison of kidneys in old and young mice showed that SASP factors contributing to glomerulosclerosis in old mice, such as PAI-1, IL-1β, IL-6, or MMPs, were upregulated, and PAI-1 expressed by glomerular ECs may mediate crosstalk with podocytes to induce podocyte detachment and apoptosis. The same study showed that endothelial senescence, as represented by high PAI-1 expression, was a negative prognostic marker for kidney transplantation, as recipients with PAI-1-positive kidneys were more likely to develop severe cases of glomerulosclerosis independent of other known clinical covariates.

Various key features of endothelial senescence enhance susceptibility to the development of CVDs, where reduced capacity for replication and NO production and increased inflammation lead to pathophysiological consequences that can result in endothelial dysfunction. Several studies have linked reduced replicative capacity and senescence in endothelial cells to reduced angiogenesis, such as impaired neovascularization, as observed in senescent HUVECs, telomerase-deficient mice and SIRT1-silenced mice. In turn, reduced angiogenic potential can lead to impaired wound healing and neovascularization, which are crucial to recovery from tissue damage, which may predispose patients to subsequent cardiovascular pathologies. Proinflammatory cytokines contribute to vascular inflammation, which has been associated with atherogenesis and atherosclerosis. Remodeling of the extracellular matrix (ECM) was shown to be disrupted in senescent ECs. ECM degradation by MMPs, which are SASP factors, may result in arterial stiffening, exacerbated by reduced eNOS levels, and an increase in the risk of hypertension. Vasodilators and related factors, such as NO, prostacyclin, and eNOS, have been observed to be decreased in senescent ECs. The ensuing endothelial dysfunction due to this reduction in NO bioavailability and loss of vascular tone has been implicated in cardiovascular events.

Several genetic disorders further demonstrate the interconnectedness between senescence and CVD pathology. Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by the accumulation of progerin, a mutant form of lamin A (LMNA),, primarily in the vasculature, including the endothelium,. Similarly, Werner syndrome is caused by a mutation in the Werner syndrome helicase (WRN) gene, a DNA helicase gene that has been reported to play a critical role in endothelial homeostasis. These diseases manifest as accelerated aging and premature death, often due to cardiovascular complications, predominantly via atherosclerosis,. It has been observed that HGPS-derived ECs exhibited senescence traits, and that the expression of progerin in ECs induced inflammation and senescence, whereas deletion of LMNA in mice resulted in senescence-associated cardiomyopathy with increased SA-β-gal staining intensity and SASP protein levels. Notably, deficient levels of G6PD, which has been shown to increase ROS and adhesion molecule levels in HUVECs, has been identified as a risk factor for CVDs in elderly subjects,.

Detection of endothelial senescence

Biomarkers frequently used to detect senescent ECs are features that have been broadly established across different types of cellular senescence. A common method to identify senescent cells is by examining their lysosomal content. SA-β-gal staining represents the activity of the lysosomal enzyme beta-galactosidase, which is detectable at the suboptimal cellular pH of 6.0. Beta-galactosidase has been detected in CVD tissue samples from aged retinal blood vessels, atherosclerotic plaques in aorta and coronary arteries,, and adipose tissue obtained from obese subjects. Other biomarkers, such as cyclin-dependent kinase (CDK) inhibitors and telomere length, have been implicated in the pathogenesis of various CVDs. Indeed, it has been reported that telomere length was negatively correlated with atherosclerotic grade in humans, p16Ink4A limited cell proliferation, and regeneration in response to pancreatic islet injury in mice, and p53 was elevated in patients with congestive heart failure or hypertrophic cardiomyopathy. Despite its broad use as a biomarker, increased SA-β-gal activity is not unique to senescent cells; it has been observed in cells induced to quiescence through serum starvation or confluence. Similarly, while a high level of p16Ink4A is a fairly well-established biomarker that is found consistently across aged human tissues, it has also been observed in cells with inactivated RB, such as cancer cells, but absent in cells undergoing certain forms of senescence in vitro,. To improve the detection of senescent cells, it is common to assess the levels of multiple markers, such as staining for SA-β-gal and γH2AX, which indicates DNA damage response activation. Nevertheless, the lack of specificity of endothelial senescence biomarkers raises the question of whether the cells identified to date are truly senescent, and the search for a more precise characterization of senescence that caters to different cellular and physiological contexts remains an ongoing challenge.

Moreover, there are challenges to detecting senescent cells outside of a laboratory setting, which limit the clinical exploration of in vivo senescence in patients. The traditional methods of senescence detection rely on immunohistochemical staining of frozen or fixed tissues, which requires physical collection of tissues ex vivo. The need for in situ methods of measuring senescence has led to the development of liquid biopsy, a noninvasive approach that provides an alternative source of senescence identification. Components studied in liquid biopsy include circulating cells, extracellular vesicles, nucleosomes, and various glycoproteins and antigens, which can serve as viable biomarkers. Circulating ECs, which include endothelial progenitor cells (EPCs) and blood outgrowth endothelial cells (BOECs), hold much promise as potential markers of endothelial senescence measured through liquid biopsy. It is well-established that EPCs actively contribute to cardiovascular homeostasis and are used as tools to study endothelial dysfunction. There have been attempts to use EPCs for their vascular regenerative ability to treat related diseases, such as coronary artery disease and liver cirrhosis. Accumulating evidence supports the idea that dysfunction and a reduction of EPCs are associated with cardiovascular risk factors such as aging, hypertension–, coronary artery disease, and diabetes. Senescent EPCs have been observed in preeclampsia, and senescent circulating BOECs in smokers and chronic obstructive pulmonary disease patients. Moreover, ECs secrete circulating microparticles, as observed in aging porcine coronary artery ECs and senescent mouse aortic ECs. Known as endothelial microparticles (EMPs), these small extracellular vesicles (approximately 100–1000 nm) possess cellular reprogramming potential and procoagulant, proinflammatory tendencies. Moreover, they play a crucial role in the paracrine induction of senescence and propagation of vascular aging,. An increase in EMP levels has been associated with various CVDs, such as stroke, hypertension,, heart failure, and acute coronary syndrome, demonstrating their potential as a diagnostic biomarker. Other promising biomarkers to be utilized in liquid biopsy include AOPPs, which have been shown to induce senescence in HUVECs, and AGEs, known to stimulate ECs and promote diabetes through oxidative stress. While liquid biopsy can offer valuable information that spans various aspects of circulatory biology that can be observed and quantified across space and time, technical challenges remain in actual implementation of liquid biopsy. The low abundance of target components in the bloodstream, the lack of standardized protocols and platforms for analysis and interpretation, and high costs of setup, present significant barriers to the research and technical development of liquid biopsy. Further research is needed to elucidate how potential markers for liquid biopsy can be used to detect senescence and to search for innovative ways to overcome the limitations.

Therapeutic opportunities for endothelial senescence

Potential clinical implications of senescence have galvanized research into therapeutic approaches targeting senescent cells. Considerable progress has been made in two groups of senotherapeutics, senolytics, and senomorphics, in which a few of the compounds have entered clinical trials. Meanwhile, senescence immunotherapy has attracted interest for its potential in senotherapy and its efficacy in boosting the effectiveness of other treatments. We discuss the recent development and limitations of senotherapeutics and introduce several areas in which potential senotherapeutic targets have been identified.

Senolytics eliminate senescent cells by inducing apoptosis by targeting pathways such as BCL-2 family members, p53 and p38 MAPK (Table 1). Dasatinib is a tyrosine kinase inhibitor (TKI) that acts on a number of tyrosine kinases, including the Bcr-Abl and Src kinases. It is known for its initial efficacy in treating chronic myelogenous leukemia, and has been repurposed as a senolytic. It has been demonstrated that quercetin, a Bcl-xL-inhibiting flavonoid, and dasatinib, individually or in combination, are effective at reducing the number of senescent HUVECs, and improving health and cardiac function in vivo– and in idiopathic pulmonary fibrosis patients, where the treatment has led to enhanced physical functions and modest changes in SASP levels. These promising results have led to a series of clinical trials focused on CVDs, including coronary artery diseases and idiopathic pulmonary fibrosis (Table 1). Fisetin has been reported to selectively induce apoptosis in HUVECs,, and three Bcl-xL inhibitors, A1331852, A1155463, and navitoclax, have been shown to induce apoptosis selectively in senescent HUVECs, and in mice, with health improvements–. Recently, senolytics inhibiting glutaminolysis, arginine metabolism, and angiopoietin-like 2 (ANGPTL2), a SASP factor, have shown some potential. Nevertheless, much more evidence is needed to advocate for the clinical usage of senolytics. In 2018, the National Institute on Aging’s Interventions Testing Program, considered the gold standard for testing longevity drugs, ran a series of studies on fisetin with genetically heterogeneous mice—as opposed to inbred mice commonly used in research—in three independent laboratories. The results showed that fisetin provided no benefits in extending lifespan or clearing senescent cells. Similarly, despite numerous studies illustrating the in vitro and in vivo efficacy of quercetin, a study showed that quercetin induced cell death in both senescent and nonsenescent primary human coronary artery ECs, showing little specificity for senescence.

Moreover, generations of cancer therapeutics have shown that even drugs once believed to be the most innovative, such as TKIs, are inevitably associated with the risk of acquired resistance to therapy, potentially leading to a more intractable population of surviving tumor cells. Certainly, there is a need for consistent results from independent laboratories as well as longitudinal follow-up studies to observe the long-term effects of these drugs. The use of senolytics can result in far-reaching consequences on the body, as they may not be necessarily cell- or tissue-specific. Targets of senolytics include pathways that are involved in various biological processes in addition to senescence, and inhibition of one pathway may lead to the activation of another, as pathways are not entirely independent of one another and engage in crosstalk. Neglecting the interconnectedness of pathways may create the risk of unexpected adverse events.

Senomorphics are administered with the intention of attenuating the effects of detrimental senescent functions such as SASP, rather than removing senescent cells altogether. Senomorphics target certain components of the SASP factors or pathways that lead to the production of SASP factors, through NF-κB, JAK, SIRT1, and mTOR. Ruxolitinib is a JAK1/2 inhibitor approved by the FDA to treat myelofibrosis, and metformin and resveratrol have been shown to attenuate acquisition of the senescent phenotype via NF-ƙB inhibition,. The three aforementioned senomorphics showed in vitro and in vivo efficacy in ECs– and aged mice–. Rapamycin, which inhibits mTOR, has demonstrated inhibitory effects on SASP acquisition and inflammation in senescent pulmonary vascular ECs as well as in mice, which showed cardiac improvement,. Furthermore, FGF21, a SIRT1 activator, reduced senescent phenotypes in HUVECs, protected the immune system against senescence, and extended the lifespan of mice. A caveat with senomorphics is the need for regular administration, as they do not eliminate the source of SASP, highlighting the need to investigate the long-term effects of senomorphics through longitudinal studies, as with senolytics. It is worth noting that while the overall benefits of senomorphics remain to be proven, studies have shown that regular consumption of certain senomorphics, such as metformin and D-glucosamine, has extended the lifespan of participants.

Senescence immunotherapy mediates senescent clearance by taking advantage of the immune system. While this area of therapeutics needs further research and validation in endothelial senescence, it has been shown in liver ECs that SASP-induced endothelial phenotype plays a critical role in recruiting immunocytes in an endothelium-dependent manner and that the immune surveillance of senescent cells is mediated through two distinct EC pathways that depend on the NF-κB component RELA and inducible T-cell costimulator ligand (ICOSLG), suggesting possible targets for immunotherapy. Senescence immunotherapy may be an effective complement to existing drugs and treatments. For example, it can be utilized through antibodies targeting senescence-specific antigens to elicit immune responses against senescent cells and thus enhance the antitumor effects of cytotoxic drugs. A recent study reported on D9-HMSN@RSV, which consists of an antibody to CD9, a cell surface protein reported being upregulated in endothelial senescence and atherosclerosis, conjugated to mesoporous silica nanoparticles (MSNs) to deliver rosuvastatin (RSV), an HMG-CoA reductase inhibitor. CD9-HMSN@RSV produced positive results both in vitro and in vivo: it attenuated SASP acquisition, cleared senescent endothelial cells, and inhibited both the buildup of senescent plaque and the progression of atherosclerosis in mice. Another example of effective cotreatment involves the use of chimeric antigen receptor (CAR) T cells, where CAR T cells made to recognize urokinase-type plasminogen activator receptor (uPAR)—a cell surface protein widely upregulated in senescent cells—improved outcomes in lung adenocarcinoma and liver fibrosis in mice. As certain SASP factors can facilitate immune responses, senescence-inducing therapy, followed by senescence immunotherapy, may be viable treatment for various refractory diseases by creating a more immunologically responsive environment. In an experiment with mouse models of pancreatic ductal adenocarcinoma, it was shown that vascular remodeling and endothelial activation mediated by therapy-induced senescence led to the accumulation of T cells in immunologically unresponsive tumors, potentiating PD-1 inhibitor immunotherapy. Combined, these studies suggest that along with further research into endothelium-specific immunological features, the advent of senescence immunotherapy may be potentially applicable to endothelial senescence and CVDs.

Future perspectives and conclusions

Certain compounds with a hormetic antiaging effect offer new possibilities for senotherapy. Gilbert syndrome (GS) is a genetic disorder characterized by mild hyperbilirubinemia caused by changes in UGT1A1, which encodes the enzyme required for the breakdown of bilirubin. Individuals with GS experience a lower incidence of CVDs, including coronary artery diseases and stroke,. While serum bilirubin has been reported to gradually and naturally increase with age and can be cytotoxic at high levels, a moderately elevated level of bilirubin can be effectively antioxidant and anti-inflammatory, leading to improved endothelial function. Interestingly, knockdown of biliverdin reductase A (BLVRA), an enzyme that converts biliverdin to bilirubin, induced senescence, whereas its overexpression restored certain nonsenescent features in senescent cells. Although the narrow therapeutic window necessitates further research into its clinical viability, bilirubin is a promising candidate for endothelial senescence therapeutics.

Another promising venue worthy of further research lies in targeting nucleocytoplasmic trafficking (NCT). A study of postmitotic cells in rats revealed the presence of extremely long-lived proteins associated with nuclear pore complex (NPC) over the observational period, a striking contrast to the majority of proteins, which are usually turned over in a matter of days. Along with nuclear transport receptors (NTRs) and Ran, NPC comprises the NCT, a specialized machinery involved in the transport of macromolecules, such as signaling proteins and messenger ribonucleoproteins (mRNPs). It has been reported that a set of genes associated with NCT—as well as genes associated with the machinery responsible for transport of mRNA, the transcription-export (TREX) complex—is downregulated in various types of senescence, including endothelial senescence,. A recent study showed that senescent lens epithelial cells showed concomitant downregulation of a group of NCT genes and failure of the nuclear translocation of BLVRA and NRF2, suggesting a possible role for NCT in the impaired delivery of these two proteins. A recent study into the disruption of the NCT machinery in fibroblasts revealed a phenotype resembling replicative senescence, indicating that several potential senescence drivers in the NCT may be leveraged for senescence therapy. Further studies are needed to understand the mechanisms and validate the utility of NCT and TREX factors.

Still, whether or not the elimination of senescent cells is indeed beneficial is yet to be determined. In a study of stress-induced senescence in pulmonary microvascular ECs in mice, senescent cells were removed via the senolytic agent ABT263, leading to a reversal in blood vessel remodeling and pulmonary arterial hypertension. However, a study of p16Ink4A–Cre knockin mice presented contrasting results. The genetic elimination of cells, mainly liver vascular ECs, with high levels of p16Ink4A with an ablator line (Rosa26-DTA) caused blood tissue barrier disruption, liver fibrosis, and health deterioration in some mice, as the removed senescent cells were not replaced. Additionally, a study on the effect of navitoclax in atherosclerosis presented contradictory results in which the number of senescent cells and the degree of atherogenesis were reduced in culture but the senescence marker levels were not reduced in vivo. Moreover, many of the studies of EC senescence tend to be based on HUVECs, at least utilized in the preliminary study. Although a cost-effective and accessible option, HUVECs are collected from the immune-privileged environment of fetal tissues and therefore harbor several fundamental differences compared to adult endothelial cells. These differences present the possibility that results from HUVECs may not necessarily be accurate representations of adult vascular pathophysiology and suggest that we may need to find a cell line that better represents in vivo conditions.

Much remains to be explored and further validated in endothelial senescence research. The conflicting results from senescence studies highlight the need to refine the biomarkers to each pathophysiological context, as no single marker can be used to identify senescent cells conclusively. Most likely, collecting a set of markers—those that are universal and those that are more specific—and adjusting them to fulfill different purposes will be necessary. For example, encapsulation of navitoclax, a senolytic associated with thrombocytopenia, with beads coated with galactooligosaccharides, which respond to β-galactosidase activity, has led to the clearance of senescent cells and showed low toxicity. This emphasizes the importance of the detection of senescent cells and the delivery of senotherapeutics. Senotherapeutics targeting senescent ECs not only target age-associated deterioration but also lead to improvements in cardiovascular function, which are areas of great interest in view of the burgeoning aging population worldwide. In summary, further exploration into the molecular mechanisms and precise characterization of endothelial senescence and how these mechanisms can be manipulated for therapeutics could have a meaningful impact on developing treatments for vascular diseases.

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  22. 22.

    Spyridopoulos I, Isner JM, Losordo DW. Oncogenic ras induces premature senescence in endothelial cells: role of p21(Cip1/Waf1). Basic Res. Cardiol. 2002;97:117-124.

    Not in our library10.1007/s003950200001

  23. 23.

    Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc. Natl Acad. Sci. USA. 1995;92:11190-11194.

    Not in our library10.1073/pnas.92.24.11190

  24. 24.

    Zhan H, Suzuki T, Aizawa K, Miyagawa K, Nagai R. Ataxia telangiectasia mutated (ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence. J. Biol. Chem. 2010;285:29662-29670.

    Not in our library10.1074/jbc.m110.125138

  25. 25.

    Dai D-F, Rabinovitch PS, Ungvari Z. Mitochondria and cardiovascular aging. Circ. Res. 2012;110:1109-1124.

    Not in our library10.1161/circresaha.111.246140

  26. 26.

    Ungvari Z, et al. Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H2121-H2128.

    Not in our library10.1152/ajpheart.00012.2008

  27. 27.

    Kurz DJ, et al. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J. Cell Sci. 2004;117:2417-2426.

    Not in our library10.1242/jcs.01097

  28. 28.

    Donato AJ, Morgan RG, Walker AE, Lesniewski LA. Cellular and molecular biology of aging endothelial cells. J. Mol. Cell. Cardiol. 2015;89:122-135.

    Not in our library10.1016/j.yjmcc.2015.01.021

  29. 29.

    Faget DV, Ren Q, Stewart SA. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer. 2019;19:439-453.

    Not in our library10.1038/s41568-019-0156-2

  30. 30.

    Ungvari Z, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat. Rev. Cardiol. 2018;15:555-565.

    Not in our library10.1038/s41569-018-0030-z

  31. 31.

    Du XL, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. 2001;108:1341-1348.

    Not in our library10.1172/jci11235

  32. 32.

    Jia G, Aroor AR, Jia C, Sowers JR. Endothelial cell senescence in aging-related vascular dysfunction. Biochim. Biophys. Acta Mol. Basis Dis. 2019;1865:1802-1809.

    Not in our library10.1016/j.bbadis.2018.08.008

  33. 33.

    Tian F, et al. κ-opioid receptor stimulation improves endothelial function via Akt-stimulated NO production in hyperlipidemic rats. Sci. Rep. 2016;6:26807.

    Not in our library10.1038/srep26807

  34. 34.

    Ying L, et al. Fibroblast growth factor 21 Ameliorates diabetes-induced endothelial dysfunction in mouse aorta via activation of the CaMKK2/AMPKα signaling pathway. Cell Death Dis. 2019;10:665.

    Not in our library10.1038/s41419-019-1893-6

  35. 35.

    Yan J, et al. Fibroblast growth factor 21 delayed endothelial replicative senescence and protected cells from H2O2-induced premature senescence through SIRT1. Am. J. Transl. Res. 2017;9:4492-4501.

    Not in our library

  36. 36.

    Miyauchi H, et al. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J. 2004;23:212-220.

    Not in our library10.1038/sj.emboj.7600045

  37. 37.

    Astle MV, et al. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene. 2012;31:1949-1962.

    Not in our library10.1038/onc.2011.394

  38. 38.

    Khor E-S, Wong P-F. The roles of MTOR and miRNAs in endothelial cell senescence. Biogerontology. 2020;21:517-530.

    Not in our library10.1007/s10522-020-09876-w

  39. 39.

    Mattagajasingh I, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA. 2007;104:14855-14860.

    Not in our library10.1073/pnas.0704329104

  40. 40.

    Donato AJ, et al. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J. Physiol. 2011;589:4545-4554.

    Not in our library10.1113/jphysiol.2011.211219

  41. 41.

    Ota H, et al. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell. Cardiol. 2007;43:571-579.

    Not in our library10.1016/j.yjmcc.2007.08.008

  42. 42.

    Yoon HE, et al. Age-associated changes in the vascular renin-angiotensin system in mice. Oxid. Med. Cell. Longev. 2016;2016:6731093.

    Not in our library10.1155/2016/6731093

  43. 43.

    Uryga AK, Bennett MR. Ageing induced vascular smooth muscle cell senescence in atherosclerosis. J. Physiol. 2016;594:2115-2124.

    Not in our library10.1113/jp270923

  44. 44.

    Freeman BD, Machado FS, Tanowitz HB, Desruisseaux MS. Endothelin-1 and its role in the pathogenesis of infectious diseases. Life Sci. 2014;118:110-119.

    Not in our library10.1016/j.lfs.2014.04.021

  45. 45.

    Zeiher AM, Ihling C, Pistorius K, Schächinger V, Schaefer HE. Increased tissue endothelin immunoreactivity in atherosclerotic lesions associated with acute coronary syndromes. Lancet. 1994;344:1405-1406.

    Not in our library10.1016/s0140-6736(94)90571-1

  46. 46.

    Đambić, V., Pojatić, Đ., Stažić, A. & Kibel, A. Significance of the renin-angiotensin system in clinical conditions. in Selected Chapters from the Renin-Angiotensin System (ed. Kibel, A.) (IntechOpen, 2020).

    Not in our library

  47. 47.

    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 1996;271:C1424-C1437.

    Not in our library10.1152/ajpcell.1996.271.5.c1424

  48. 48.

    Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113:1708-1714.

    Not in our library10.1161/circulationaha.105.602532

  49. 49.

    Kietadisorn R, Juni RP, Moens AL. Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities. Am. J. Physiol. Endocrinol. Metab. 2012;302:E481-E495.

    Not in our library10.1152/ajpendo.00540.2011

  50. 50.

    Lemarié CA, et al. Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1. Am. J. Physiol. Heart Circ. Physiol. 2011;300:H745-H753.

    Not in our library10.1152/ajpheart.00321.2010

  51. 51.

    You Y, et al. Inhibition of S-adenosylhomocysteine hydrolase induces endothelial senescence via hTERT downregulation. Atherosclerosis. 2022;353:1-10.

    Not in our library10.1016/j.atherosclerosis.2022.06.002

  52. 52.

    Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 2007;8:729-740.

    Not in our library10.1038/nrm2233

  53. 53.

    Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer. 2010;10:51-57.

    Not in our library10.1038/nrc2772

  54. 54.
    MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells · 2018
    Not checked
  55. 55.

    Kuosmanen SM, et al. NRF2 regulates endothelial glycolysis and proliferation with miR-93 and mediates the effects of oxidized phospholipids on endothelial activation. Nucleic Acids Res. 2018;46:1124-1138.

    Not in our library10.1093/nar/gkx1155

  56. 56.

    Unterluggauer H, et al. Premature senescence of human endothelial cells induced by inhibition of glutaminase. Biogerontology. 2008;9:247-259.

    Not in our library10.1007/s10522-008-9134-x

  57. 57.

    Stabenow LK, et al. Oxidative glucose metabolism promotes senescence in vascular endothelial cells. Cells. 2022;11:2213.

    Not in our library10.3390/cells11142213

  58. 58.

    Peyton KJ, et al. Glutaminase-1 stimulates the proliferation, migration, and survival of human endothelial cells. Biochem. Pharmacol. 2018;156:204-214.

    Not in our library10.1016/j.bcp.2018.08.032

  59. 59.

    Leopold JA, Zhang Y-Y, Scribner AW, Stanton RC, Loscalzo J. Glucose-6-phosphate dehydrogenase overexpression decreases endothelial cell oxidant stress and increases bioavailable nitric oxide. Arterioscler. Thromb. Vasc. Biol. 2003;23:411-417.

    Not in our library10.1161/01.atv.0000056744.26901.ba

  60. 60.

    Park HS, Kim SY. Endothelial cell senescence: a machine learning-based meta-analysis of transcriptomic studies. Ageing Res. Rev. 2021;65:101213.

    Not in our library10.1016/j.arr.2020.101213

  61. 61.

    Parsanathan R, Jain SK. Glucose-6-phosphate dehydrogenase deficiency increases cell adhesion molecules and activates human monocyte-endothelial cell adhesion: protective role of l-cysteine. Arch. Biochem. Biophys. 2019;663:11-21.

    Not in our library10.1016/j.abb.2018.12.023

  62. 62.

    Vandekeere S, et al. Serine synthesis via PHGDH is essential for heme production in endothelial cells. Cell Metab. 2018;28:573-587.e13.

    Not in our library10.1016/j.cmet.2018.06.009

  63. 63.

    Bloom, S. I., Islam, M. T., Lesniewski, L. A. & Donato, A. J. Mechanisms and consequences of endothelial cell senescence. Nat. Rev. Cardiol. 10.1038/s41569-022-00739-0 (2022).

    Not in our library10.1038/s41569-022-00739-0

  64. 64.

    Kotla S, et al. Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein. JCI Insight. 2019;4:e124867.

    Not in our library10.1172/jci.insight.124867

  65. 65.

    Warboys CM, et al. Disturbed flow promotes endothelial senescence via a p53-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 2014;34:985-995.

    Not in our library10.1161/atvbaha.114.303415

  66. 66.

    Parrinello S, et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell Biol. 2003;5:741-747.

    Not in our library10.1038/ncb1024

  67. 67.

    Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc. Natl Acad. Sci. USA. 1995;92:4337-4341.

    Not in our library10.1073/pnas.92.10.4337

  68. 68.

    von Zglinicki T, Saretzki G, Döcke W, Lotze C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp. Cell Res. 1995;220:186-193.

    Not in our library10.1006/excr.1995.1305

  69. 69.

    Rogers SC, Zhang X, Azhar G, Luo S, Wei JY. Exposure to high or low glucose levels accelerates the appearance of markers of endothelial cell senescence and induces dysregulation of nitric oxide synthase. J. Gerontol. A Biol. Sci. Med. Sci. 2013;68:1469-1481.

    Not in our library10.1093/gerona/glt033

  70. 70.

    Maeda M, Hayashi T, Mizuno N, Hattori Y, Kuzuya M. Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase. PLoS ONE. 2015;10:e0123169.

    Not in our library10.1371/journal.pone.0123169

  71. 71.

    Yu M-A, Sánchez-Lozada LG, Johnson RJ, Kang D-H. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J. Hypertens. 2010;28:1234-1242.

    Not in our library

  72. 72.

    Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr. Diab. Rep. 2014;14:453.

    Not in our library10.1007/s11892-013-0453-1

  73. 73.
    The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases · 2017
    No notice
  74. 74.

    Chen Y, et al. p53 SUMOylation mediates AOPP-induced endothelial senescence and apoptosis evasion. Front. Cardiovasc. Med. 2021;8:795747.

    Not in our library10.3389/fcvm.2021.795747

  75. 75.

    Morel O, Jesel L, Freyssinet J-M, Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler. Thromb. Vasc. Biol. 2011;31:15-26.

    Not in our library10.1161/atvbaha.109.200956

  76. 76.

    Brodsky SV, Zhang F, Nasjletti A, Goligorsky MS. Endothelium-derived microparticles impair endothelial function in vitro. Am. J. Physiol. Heart Circ. Physiol. 2004;286:H1910-H1915.

    Not in our library10.1152/ajpheart.01172.2003

  77. 77.

    Mostefai HA, et al. Phosphatidylinositol 3-kinase and xanthine oxidase regulate nitric oxide and reactive oxygen species productions by apoptotic lymphocyte microparticles in endothelial cells. J. Immunol. 2008;180:5028-5035.

    Not in our library10.4049/jimmunol.180.7.5028

  78. 78.

    Abbas M, et al. Endothelial microparticles from acute coronary syndrome patients induce premature coronary artery endothelial cell aging and thrombogenicity: role of the Ang II/AT1 receptor/NADPH oxidase-mediated activation of MAPKs and PI3-kinase pathways. Circulation. 2017;135:280-296.

    Not in our library10.1161/circulationaha.116.017513

  79. 79.

    Graves SI, Baker DJ. Implicating endothelial cell senescence to dysfunction in the ageing and diseased brain. Basic Clin. Pharmacol. Toxicol. 2020;127:102-110.

    Not in our library10.1111/bcpt.13403

  80. 80.

    Wang W-J, Cai G-Y, Chen X-M. Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget. 2017;5:64520-64533.

    Not in our library10.18632/oncotarget.17327

  81. 81.

    Cohen C, et al. Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1. EMBO Mol. Med. 2021;13:e14146.

    Not in our library10.15252/emmm.202114146

  82. 82.

    Erusalimsky JD. Vascular endothelial senescence: from mechanisms to pathophysiology. J. Appl. Physiol. 2009;106:326-332.

    Not in our library10.1152/japplphysiol.91353.2008

  83. 83.

    Yang J, et al. Human endothelial cell life extension by telomerase expression. J. Biol. Chem. 1999;274:26141-26148.

    Not in our library10.1074/jbc.274.37.26141

  84. 84.

    Franco S, Segura I, Riese HH, Blasco MA. Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res. 2002;62:552-559.

    Not in our library

  85. 85.

    Potente M, et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007;21:2644-2658.

    Not in our library10.1101/gad.435107

  86. 86.

    Lähteenvuo J, Rosenzweig A. Effects of aging on angiogenesis. Circ. Res. 2012;110:1252-1264.

    Not in our library10.1161/circresaha.111.246116

  87. 87.

    Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler. Thromb. Vasc. Biol. 2005;25:932-943.

    Not in our library10.1161/01.atv.0000160548.78317.29

  88. 88.

    Kaess BM, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012;308:875-881.

    Not in our library10.1001/2012.jama.10503

  89. 89.

    Hoffmann J, et al. Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli: important role of nitric oxide. Circ. Res. 2001;89:709-715.

    Not in our library10.1161/hh2001.097796

  90. 90.

    Nakajima M, et al. Aging decreases the production of PGI2 in rat aortic endothelial cells. Exp. Gerontol. 1997;32:685-693.

    Not in our library10.1016/s0531-5565(97)00089-2

  91. 91.

    Matsushita H, et al. eNOS activity is reduced in senescent human endothelial cells: Preservation by hTERT immortalization. Circ. Res. 2001;89:793-798.

    Not in our library10.1161/hh2101.098443

  92. 92.

    Taddei S, Virdis A, Ghiadoni L, Versari D, Salvetti A. Endothelium, aging, and hypertension. Curr. Hypertens. Rep. 2006;8:84-89.

    Not in our library10.1007/s11906-006-0045-4

  93. 93.

    Eriksson M, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003;423:293-298.

    Not in our library10.1038/nature01629

  94. 94.

    Goldman RD, et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA. 2004;101:8963-8968.

    Not in our library10.1073/pnas.0402943101

  95. 95.

    McClintock D, Gordon LB, Djabali K. Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody. Proc. Natl Acad. Sci. USA. 2006;103:2154-2159.

    Not in our library10.1073/pnas.0511133103

  96. 96.

    Olive M, et al. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler. Thromb. Vasc. Biol. 2010;30:2301-2309.

    Not in our library10.1161/atvbaha.110.209460

  97. 97.

    Laarmann K, Kress JM, Kaina B, Fritz G. Werner syndrome (WRN) DNA helicase and base excision repair (BER) factors maintain endothelial homeostasis. DNA Repair. 2019;73:17-27.

    Not in our library10.1016/j.dnarep.2018.10.005

  98. 98.

    Prakash A, et al. Cardiac abnormalities in patients with Hutchinson-Gilford progeria syndrome. JAMA Cardiol. 2018;3:326-334.

    Not in our library10.1001/jamacardio.2017.5235

  99. 99.

    Xu S, Jin Z-G. Hutchinson-Gilford progeria syndrome: cardiovascular pathologies and potential therapies. Trends Biochem. Sci. 2019;44:561-564.

    Not in our library10.1016/j.tibs.2019.03.010

  100. 100.

    Kato H, Maezawa Y. Atherosclerosis and cardiovascular diseases in progeroid syndromes. J. Atheroscler. Thromb. 2022;29:439-447.

    Not in our library10.5551/jat.rv17061

  101. 101.

    Unable to find information for 9014341.

    Not in our library

  102. 102.

    Mojiri A, et al. Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice. Eur. Heart J. 2021;42:4352-4369.

    Not in our library10.1093/eurheartj/ehab547

  103. 103.

    Bidault G, et al. Progerin expression induces inflammation, oxidative stress and senescence in human coronary endothelial cells. Cells. 2020;9:1201.

    Not in our library10.3390/cells9051201

  104. 104.

    Rouhi L, et al. Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype. J. Cardiovasc. Aging. 2022;2:30.

    Not in our library10.20517/jca.2022.14

  105. 105.

    Dore MP, Portoghese M, Pes GM. The elderly with glucose-6-phosphate dehydrogenase deficiency are more susceptible to cardiovascular disease. J. Atheroscler. Thromb. 2021;28:604-610.

    Not in our library10.5551/jat.56531

  106. 106.

    Thomas JE, et al. Glucose-6-phosphate dehydrogenase deficiency is associated with cardiovascular disease in U.S. military centers. Tex. Heart Inst. J. 2018;45:144-150.

    Not in our library10.14503/thij-16-6052

  107. 107.

    Lee BY, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5:187-195.

    Not in our library10.1111/j.1474-9726.2006.00199.x

  108. 108.

    López-Luppo M, et al. Cellular senescence is associated with human retinal microaneurysm formation during aging. Invest. Ophthalmol. Vis. Sci. 2017;58:2832-2842.

    Not in our library10.1167/iovs.16-20312

  109. 109.

    Vasile E, Tomita Y, Brown LF, Kocher O, Dvorak HF. Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J. 2001;15:458-466.

    Not in our library10.1096/fj.00-0051com

  110. 110.

    Villaret A, et al. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes. 2010;59:2755-2763.

    Not in our library10.2337/db10-0398

  111. 111.

    Ogami M, et al. Telomere shortening in human coronary artery diseases. Arterioscler. Thromb. Vasc. Biol. 2004;24:546-550.

    Not in our library10.1161/01.atv.0000117200.46938.e7

  112. 112.

    Okuda K, et al. Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosis. Atherosclerosis. 2000;152:391-398.

    Not in our library10.1016/s0021-9150(99)00482-7

  113. 113.

    Krishnamurthy J, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443:453-457.

    Not in our library10.1038/nature05092

  114. 114.

    Song H, Conte JV, Foster AH, McLaughlin JS, Wei C. Increased p53 protein expression in human failing myocardium. J. Heart Lung Transplant. 1999;18:744-749.

    Not in our library10.1016/s1053-2498(98)00039-4

  115. 115.

    Predmore JM, et al. Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. Circulation. 2010;121:997-1004.

    Not in our library10.1161/circulationaha.109.904557

  116. 116.

    Yang N-C, Hu M-L. The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp. Gerontol. 2005;40:813-819.

    Not in our library10.1016/j.exger.2005.07.011

  117. 117.

    Tuttle CSL, Luesken SWM, Waaijer MEC, Maier AB. Senescence in tissue samples of humans with age-related diseases: a systematic review. Ageing Res. Rev. 2021;68:101334.

    Not in our library10.1016/j.arr.2021.101334

  118. 118.

    Shapiro GI, et al. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995;55:505-509.

    Not in our library

  119. 119.

    Yamakoshi K, et al. Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. J. Cell Biol. 2009;186:393-407.

    Not in our library10.1083/jcb.200904105

  120. 120.

    Herbig U, Jobling WA, Chen BPC, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell. 2004;14:501-513.

    Not in our library10.1016/s1097-2765(04)00256-4

  121. 121.
    Quantitative identification of senescent cells in aging and disease · 2017
    No notice
  122. 122.

    Kustanovich A, Schwartz R, Peretz T, Grinshpun A. Life and death of circulating cell-free DNA. Cancer Biol. Ther. 2019;20:1057-1067.

    Not in our library10.1080/15384047.2019.1598759

  123. 123.

    Pompilio G, et al. Endothelial progenitor cells and cardiovascular homeostasis: clinical implications. Int. J. Cardiol. 2009;131:156-167.

    Not in our library10.1016/j.ijcard.2008.08.033

  124. 124.

    Medina RJ, O’Neill CL, O’Doherty TM, Wilson SEJ, Stitt AW. Endothelial progenitors as tools to study vascular disease. Stem Cells Int. 2012;2012:346735.

    Not in our library10.1155/2012/346735

  125. 125.

    Zhu J, et al. Safety and efficacy of autologous thymosin β4 pre-treated endothelial progenitor cell transplantation in patients with acute ST segment elevation myocardial infarction: a pilot study. Cytotherapy. 2016;18:1037-1042.

    Not in our library10.1016/j.jcyt.2016.05.006

  126. 126.

    D’Avola D, et al. Phase 1-2 pilot clinical trial in patients with decompensated liver cirrhosis treated with bone marrow-derived endothelial progenitor cells. Transl. Res. 2017;188:80-91.e2.

    Not in our library10.1016/j.trsl.2016.02.009

  127. 127.

    Jie KE, Goossens MHJ, van Oostrom O, Lilien MR, Verhaar MC. Circulating endothelial progenitor cell levels are higher during childhood than in adult life. Atherosclerosis. 2009;202:345-347.

    Not in our library10.1016/j.atherosclerosis.2008.05.012

  128. 128.

    Tepper OM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106:2781-2786.

    Not in our library10.1161/01.cir.0000039526.42991.93

  129. 129.

    Umemura T, et al. Aging and hypertension are independent risk factors for reduced number of circulating endothelial progenitor cells. Am. J. Hypertens. 2008;21:1203-1209.

    Not in our library10.1038/ajh.2008.278

  130. 130.

    Vasa M, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ. Res. 2001;89:E1-E7.

    Not in our library10.1161/hh1301.093953

  131. 131.

    Wang Y, Lim R, Nie G. Elevated circulating HtrA4 in preeclampsia may alter endothelial expression of senescence genes. Placenta. 2020;90:71-81.

    Not in our library10.1016/j.placenta.2019.12.012

  132. 132.
    Dysfunction of Endothelial Progenitor Cells from Smokers and Chronic Obstructive Pulmonary Disease Patients Due to Increased DNA Damage and Senescence · 2013
    No notice
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    Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments · 2022
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    Talpaz M, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 2006;354:2531-2541.

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    Fan T, Du Y, Zhang M, Zhu AR, Zhang J. Senolytics cocktail dasatinib and quercetin alleviate human umbilical vein endothelial cell senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-dependent manner. Gerontology. 2022;68:920-934.

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    Hohmann MS, Habiel DM, Coelho AL, Verri WA, Hogaboam CM. Quercetin enhances ligand-induced apoptosis in senescent idiopathic pulmonary fibrosis fibroblasts and reduces lung fibrosis in vivo. Am. J. Respir. Cell Mol. Biol. 2019;60:28-40.

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    Salaami O, et al. Antidiabetic effects of the senolytic agent dasatinib. Mayo Clin. Proc. 2021;96:3021-3029.

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  153. 153.
    New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463 · 2017
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    Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28.

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    Moncsek A, et al. Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2-/-) mice. Hepatology. 2018;67:247-259.

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    Chang J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 2016;22:78-83.

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    Childs BG, et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016;354:472-477.

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    Johmura Y, et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. 2021;371:265-270.

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    Miller RA, et al. An Aging Interventions Testing Program: study design and interim report. Aging Cell. 2007;6:565-575.

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    Rosenzweig SA. Acquired resistance to drugs targeting tyrosine kinases. Adv. Cancer Res. 2018;138:71-98.

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    Harrison CN, Talpaz M, Mead AJ. Ruxolitinib is effective in patients with intermediate-1 risk myelofibrosis: a summary of recent evidence. Leuk. Lymphoma. 2016;57:2259-2267.

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    Moiseeva O, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013;12:489-498.

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    Csiszar A, et al. Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. Am. J. Physiol. Heart Circ. Physiol. 2006;291:H1694-H1699.

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    Xia L, et al. Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms. Br. J. Pharmacol. 2008;155:387-394.

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    Shen X, et al. Resveratrol prevents endothelial progenitor cells from senescence and reduces the oxidative reaction via PPAR‑γ/HO‑1 pathways. Mol. Med. Rep. 2016;14:5528-5534.

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    Arunachalam G, Samuel SM, Marei I, Ding H, Triggle CR. Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1. Br. J. Pharmacol. 2014;171:523-535.

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    Xu M, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA. 2015;112:E6301-E6310.

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    Sin TK, et al. Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis. J. Physiol. 2015;593:1887-1899.

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    Kim EN, et al. The protective effect of resveratrol on vascular aging by modulation of the renin-angiotensin system. Atherosclerosis. 2018;270:123-131.

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    Sena CM, et al. Metformin restores endothelial function in aorta of diabetic rats. Br. J. Pharmacol. 2011;163:424-437.

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    Houssaini A, et al. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight. 2018;3:e93203.

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    Flynn JM, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013;12:851-862.

    Not in our library10.1111/acel.12109

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    Dietary rapamycin supplementation reverses age‐related vascular dysfunction and oxidative stress, while modulating nutrient‐sensing, cell cycle, and senescence pathways · 2016
    No notice
  180. 180.

    Youm Y-H, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc. Natl Acad. Sci. USA. 2016;113:1026-1031.

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    The starvation hormone, fibroblast growth factor-21, extends lifespan in mice · 2012
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    Hoare M, et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 2016;18:979-992.

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    Yin K, et al. Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance. Genes Dev. 2022;36:533-549.

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    Cho JH, et al. CD9 induces cellular senescence and aggravates atherosclerotic plaque formation. Cell Death Differ. 2020;27:2681-2696.

    Not in our library10.1038/s41418-020-0537-9

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    Pham LM, et al. Targeting and clearance of senescent foamy macrophages and senescent endothelial cells by antibody-functionalized mesoporous silica nanoparticles for alleviating aorta atherosclerosis. Biomaterials. 2021;269:120677.

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    Amor C, et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature. 2020;583:127-132.

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    Ruscetti M, et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell. 2020;181:424-441.e21.

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    Rigato I, Ostrow JD, Tiribelli C. Bilirubin and the risk of common non-hepatic diseases. Trends Mol. Med. 2005;11:277-283.

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    Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study) · 2018
    Not checked
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    Boland BS, Dong MH, Bettencourt R, Barrett-Connor E, Loomba R. Association of serum bilirubin with aging and mortality. J. Clin. Exp. Hepatol. 2014;4:1-7.

    Not in our library10.1016/j.jceh.2014.01.003

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    Vítek L, Ostrow JD. Bilirubin chemistry and metabolism; harmful and protective aspects. Curr. Pharm. Des. 2009;15:2869-2883.

    Not in our library10.2174/138161209789058237

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    Nitti M, Furfaro AL, Mann GE. Heme oxygenase dependent bilirubin generation in vascular cells: a role in preventing endothelial dysfunction in local tissue microenvironment? Front. Physiol. 2020;11:23.

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    Kim SY, Kang HT, Choi HR, Park SC. Biliverdin reductase A in the prevention of cellular senescence against oxidative stress. Exp. Mol. Med. 2011;43:15-23.

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    Savas JN, Toyama BH, Xu T, Yates JR, Hetzer MW. Extremely long-lived nuclear pore proteins in the rat brain. Science. 2012;335:942.

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  195. 195.

    Ori A, et al. Integrated transcriptome and proteome analyses reveal organ-specific proteome deterioration in old rats. Cell Syst. 2015;1:224-237.

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  196. 196.

    Kim SY, et al. Senescence-related functional nuclear barrier by down-regulation of nucleo-cytoplasmic trafficking gene expression. Biochem. Biophys. Res. Commun. 2010;391:28-32.

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  197. 197.

    Kim SY, et al. Global transcriptional downregulation of TREX and nuclear trafficking machinery as pan-senescence phenomena: evidence from human cells and tissues. Exp. Mol. Med. 2020;52:1351-1359.

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  198. 198.

    Huang Y, et al. Biliverdin reductase A protects lens epithelial cells against oxidative damage and cellular senescence in age-related cataract. Oxid. Med. Cell. Longev. 2022;2022:5628946.

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    Park J-H, et al. Disruption of nucleocytoplasmic trafficking as a cellular senescence driver. Exp. Mol. Med. 2021;53:1092-1108.

    Not in our library10.1038/s12276-021-00643-6

  200. 200.

    Grosse L, et al. Defined p16 high senescent cell types are indispensable for mouse healthspan. Cell Metab. 2020;32:87-99.e6.

    Not in our library10.1016/j.cmet.2020.05.002

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    Garrido AM, et al. Efficacy and limitations of senolysis in atherosclerosis. Cardiovasc. Res. 2022;118:1713-1727.

    Not in our library10.1093/cvr/cvab208

  202. 202.

    French LE, et al. Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. J. Cell Biol. 1996;133:335-343.

    Not in our library10.1083/jcb.133.2.335

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    Tan PH, et al. Phenotypic and functional differences between human saphenous vein (HSVEC) and umbilical vein (HUVEC) endothelial cells. Atherosclerosis. 2004;173:171-183.

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    Kile BT. The role of apoptosis in megakaryocytes and platelets. Br. J. Haematol. 2014;165:217-226.

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    A versatile drug delivery system targeting senescent cells · 2018
    No notice

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