Abstract
Hypertension has been described as a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype of arteries from hypertensive patients and animals remain elusive. Cellular senescence is an age-related physiologic process in which cells undergo irreversible growth arrest. Although controlled senescence negatively regulates cell proliferation and promotes tissue regeneration, uncontrolled senescence can contribute to disease pathogenesis by presenting the senescence-associated secretory phenotype, in which molecules such as proinflammatory cytokines, matrix metalloproteases, and reactive oxygen species are released into tissue microenvironments. This review will address and critically evaluate the current literature on the role of cellular senescence in hypertension, with particular emphasis on cells types that mediate and modulate vascular function and structure.
Keywords: blood pressure, cellular senescence, hypertension, vascular aging
PREMATURE VASCULAR AGING IN HYPERTENSION
Our desire to reverse (or at least delay) the aging process has long been the focus of biomedical research and homeopathic medicine. However, whether the lifespan of an individual organism relates to the longevity of its constituent cells, tissues, and organs is still obscure. In this sense, plants present a unique perspective in the search for a definitive answer to this most fundamental question. For example, deciduous trees are mostly made up of dead tissues; the canopy is renewed and discarded every year, root systems turn over, and reproduction takes place repeatedly over decades, centuries or even millennia.1 This phenomenon is regulated by senescence and presents a clear disconnect between the lifespan of the whole and the parts. Given that senescence is an important physiologic process to control cell proliferation and rejuvenate tissues and organs in humans, this disassociation could also be present in the process of human pathophysiology, including cardiovascular diseases.
Generally, the increase in cardiovascular events as we age is attributable to the natural decline in organ function.2 Within the context of hypertension, age is considered a major risk factor and the prevalence of hypertension increases with age, irrespective of biological sex.3 In hypertension however, the decline in vascular function and aged phenotype are premature in their onset and particularly pronounced.4,5 As a result, vascular age determination, as opposed to chronological age per se, has now been introduced into clinical guidelines for cardiovascular disease prevention.6 Nonetheless, what precisely defines vascular aging is broad and can encompass many of the vascular maladaptations presented in hypertensive patients and animals, including:
1) Hypercontractility: Defects in the regulation of vascular smooth muscle cell calcium (e.g., increased calcium entry and storage, impaired intracellular calcium buffering capacity, and decreased calcium extrusion) and a switch in the abundance of endothelium-derived provasoconstrictive factors relative to provasodilatory factors.
2) Stiffening and remodeling: Changes in vascular distensibility and cross-section area due to calcification, actin polymerization, fibrosis, and extracellular matrix deposition.
3) Inflammation and oxidative stress: Immune cell and non-immune cell exacerbated generation of proinflammatory cytokines, chemokines, adhesion molecules, and reactive oxygen species (ROS) relative to proresolving factors such as lipoxins, resolvins, and protectins.
Therefore, hypertension is a condition of vascular aging and the factors that contribute to the deterioration of vascular function as we age are accelerated in hypertension4,5 (Figure 1). Nonetheless, identification of these age-associated factors and their mechanisms remain elusive.
CELLULAR SENESCENCE IS AN AGE-ASSOCIATED PHYSIOLOGIC PROCESS
Cellular senescence is a conserved mechanism among somatic cell types that induces irreversible cell-cycle arrest in response to excessive or prolonged stress or replicative exhaustion. Evolutionarily, senescence is a protective mechanism to prevent the transmission of genomic defects to the next generation. Moreover, controlled senescence actually promotes tissue regeneration and function via the recruitment of immune cells and clearance of senescent cells.7,8 However, aged tissues or tissues from diseased animals are not able to efficiently complete this sequence of events, thereby resulting in the accumulation of senescent cells.7
The number of stimuli that trigger senescence is constantly increasing and specific mechanisms of vascular cell senescence in the context of hypertension or prohypertensive stimuli will be discussed later in this review. Broadly, senescent stimuli can be classified into either damage-induced senescence (e.g., DNA damage and telomere alterations, epigenetic depression of the cyclin-dependent kinase inhibitor 2A locus, ROS, oncogenic signaling/tumor suppressor inactivation) or developmentally programmed senescence (e.g., developmental cues, polyploidization, and cell fusion).9 These triggers generally result in the activation of p53 and convergence on the cyclin-dependent kinase inhibitors p15, p16, p21, and p27. The inhibition of cyclin-dependent kinase–cyclin complexes causes proliferative arrest, and the crucial component responsible for the implementation of senescence is the hypophosphorylated form of retinoblastoma (Rb) protein.10
One specific means by which senescent cells can contribute to the development and/or maintenance of pathophysiology is by mediation of inflammation and oxidative stress. Upon the onset of senescence, senescent cells develop heightened secretory activity known as the senescence-associated secretory phenotype (SASP).11 This phenotype is characterized by the secretion of proinflammatory cytokines and chemokines, ROS, growth factors, proteases, plasminogen activator inhibitor-1, but never anti-inflammatory or proresolving factors, into the local tissue environment.11 Although the SASP pattern may vary according to cell type, as well as the particular stress or damage that induces senescence,12 physiologically, this proinflammatory/pro-oxidative milieu signals the recruitment of phagocytes to infiltrate tissues and clear out the senescent cells. Thus, the mitostatic effect of uncontrolled senescence is counterbalanced by the effects of the SASP and this can contribute to the pathophysiology of disease. In fact, this phenomenon is already known to occur in endothelial cells13 and vascular smooth muscle cells14; thus, it is logical to hypothesize that senescent cells contribute to vascular inflammation in hypertension (Figure 2). Nonetheless, determining whether senescence primarily drives pathophysiology or is a secondary bystander is difficult.
Although understanding the mechanistic relationship between senescence and pathophysiology is a focus of great interest, there is already evidence supporting the therapeutic approach of targeting senescence for the treatment and reversal of disease.15,16 Agents that prevent the activation of specific mechanisms of senescence, such as those involving telomerase, DNA-damage repair machinery, cell-cycle checkpoint kinases, and tumor suppressors, are all known to reduce indices of pathophysiology.15,16
CELLULAR SENESCENCE IS A WIDESPREAD PHENOTYPE IN HYPERTENSION
Although senescence has been linked with age for many years,17,18 only recently was it reported that the removal of senescent cells does indeed delay chronological and premature aging, increase lifespan, and rejuvenate organ function,19–21 including the vasculature22 and kidneys.20 Nonetheless, our understanding of senescence in hypertension-associated end-organ dysfunction, beyond phenotypic recognition, is far from complete. Almost all forms of experimental hypertension and hypertensive patients show cellular senescence in various organs as an indicator of end-organ damage. To the best of our knowledge, Table 1 presents a list of investigations that reported senescence in an established experimental model of hypertension or after exposure to prohypertensive stimuli. Overall, these studies generally indicate a pressure-dependent association between increased cellular senescence and hypertension,23,24 with angiotensin II being the predominant prosenescence factor.25 Furthermore, antihypertensive therapy has been shown to reduce indices of senescence.24 Nonetheless, it currently unknown if removal of senescent cells does indeed lower (or prevent) hypertension.
Table 1.
Experimental model of hypertension | Tissue/cell type | Reference | |
---|---|---|---|
Aldosterone | Kidney | 26 | |
VSMCs | 27 | ||
Angiotensin II | Aorta | 28 | |
Endothelial cells | 29 | ||
EPCs | 30–35 | ||
Endothelial cells | 36 | ||
Kidney | 24,37 | ||
Myocardium | 38 | ||
VSMCs | 25,39–41, | ||
Dahl Salt-sensitive rats | Aorta | 42 | |
Myocardium | 43,44 | ||
VSMCs | 45 | ||
Deoxycorticosterone acetate rats | Coronary arteries | 24 | |
Kidney | 24 | ||
Myocardium | 24 | ||
Human patient samples | Endothelial cells | 46 | |
EPCs | 47 | ||
Kidney | 24,48 | ||
Leukocytes | 48 | ||
VSMCs | 28,49,50 | ||
Nitric oxide inhibition | Aorta | 51 | |
EPCs | 52 | ||
Endothelial cells | 53,54 | ||
Spontaneously hypertensive rats | Aorta | 55,56 | |
EPCs | 35,47,57,58 | ||
Microvascular endothelial cells | 59 | ||
Myocardium | 60 | ||
Miscellaneous | Senescence inducer | ||
Activated Ras | VSMCs | 61 | |
Hydrogen peroxide | Endothelial cells | 62,63 | |
Indoxyl sulfate | VSMCs | 45 | |
Tert-butyl hydroperoxide or l-buthionine-[S,R]-sulphoximine | Endothelial cells | 64 | |
Tumor necrosis factor α | Endothelial cells | 65 |
Abbreviations: EPC, endothelial progenitor cell; VSMC, vascular smooth muscle cell.
VASCULAR CELL SENESCENCE CAN MEDIATE THE AGING PHENOTYPE
It is well established that a host of prohypertensive stimuli can cause senescence of vascular cells and induce many of the vascular aging phenotypes defined earlier. Table 2 presents a compilation of seminal investigations that reported senescent vascular cells mediating a characteristic of the aged phenotype. Studies that demonstrated an association, but not causality, between a vascular aging phenotype and senescence were not surveyed in this list due to an overabundance of literature.
Table 2.
Vascular age phenotype | Tissue/cell type | Model | Reference | |
---|---|---|---|---|
Hypercontractility | Endothelial vasoactive factors | Aorta | Senescence-accelerated mice | 66,67 |
Mesenteric resistance arteries | Senescence-accelerated mice + Western diet | 68 | ||
Endothelial cells | Replicative senescence | 69 | ||
Endothelial cells | Telomere inhibition-induced senescence | 70 | ||
Endothelial cells | Replicative senescence | 71–73 | ||
Other | PVAT | Obese (db/db) mice | 74 | |
Stiffening and remodeling | Actin polymerization | Endothelial cells | Replicative senescence | 75 |
Endothelial cells | Replicative senescence | 76,77 | ||
VSMCs | Replicative senescence | 78 | ||
Calcification | Aorta | Hypercholesterolemic mice | 22 | |
VSMCs | Replicative senescence | 79–81 | ||
Fibrosis | Aortic valves | Senescence-accelerated mice | 82 | |
Fibroblasts | Replicative senescence or ionizing radiation-induced senescence | 83,84 | ||
ECM deposition | Endothelial cells | Replicative senescence | 76,85,86 | |
Inflammation and oxidative stress | Cytokines and chemokines | Endothelial cells | Replicative senescence | 13 |
VSMCs | Activated Ras-induced senescence | 61 | ||
VSMCs | Replicative senescence and bleomycin-induced senescence | 14 | ||
Cell adhesion | Endothelial cells | Replicative senescence | 87 | |
Endothelial cells | Replicative senescence | 69 | ||
Endothelial cells | Telomere inhibition | 70 | ||
Impaired resolution | Fibroblasts | Bleomycin or ionizing radiation | 88 | |
Myofibroblasts | Bleomycin | 89 | ||
ROS | Endothelial cells | Replicative senescence | 90 | |
Endothelial cells | Replicative senescence | 91,92 | ||
Pulmonary artery endothelial cells | Replicative senescence | 93 |
Abbreviations: ECM, extracellular matrix; PVAT, perivascular adipose tissue; ROS, reactive oxygen species; VSMC, vascular smooth muscle cell.
From these investigations, it is possible to extrapolate that senescence of vascular cells contributes to the aged phenotype and probably contributes to the maintenance of hypertension. This collection of basic science literature supports the observations that the onset of senescence is dependent on relative age (as opposed to chronological age) and appears earlier in patients with longer exposure to a cardiovascular disease risk factors, particularly hypertension.46
BEYOND VASCULAR SENESCENCE IN HYPERTENSION
Hypertension is a complex condition that is driven by multiorgan dysfunction. In addition to endothelial cells and vascular smooth muscle cells of the vasculature, perivascular adipose tissue (PVAT), the kidneys, the brain, and the immune system have well-defined roles in facilitating increases in blood pressure, and recently, gut dysbiosis has also been revealed to contribute. Therefore, cellular senescence in these other organs and cell types could also contribute to the pathogenesis of hypertension-associated premature vascular aging.
Perivascular adipose tissue
Analogous to the SASP, PVAT is well known to secrete a variety of factors ranging from adipokines, gaseous molecules, and angiotensin 1–7 to ROS, proinflammatory cytokines, and angiotensin II.94 Given the close proximity of PVAT to cells of the vasculature, paracrine cross-talk can easily occur, and this can influence vascular function. Generally, PVAT from healthy animals secretes anticontractile factors,95 whereas PVAT from hypertensive animals not only loses this anticontractile phenotype,96 but it also generates of hyper-contractile factors.97,98 Nonetheless, the mechanisms underlying this phenotypic switch are still being revealed. Recently, it was observed that adipose tissue senescence, via mineralocorticoid receptor activation, contributed to increased arterial contractile responses.74 This illustrates that senescent PVAT can mediate premature vascular aging by promoting hypercontractility.
Kidneys
As indicated in Table 1, renal senescence is present in aldosterone, angiotensin II, and deoxycorticosterone acetate models of hypertension, as well as human hypertensive patients. Uncontrolled senescence would not only affect renal function, but also probably contribute to the high frequency of end-stage renal disease in the elderly adults.99,100
Brain
Most of the literature on cellular senescence in the brain has focused on its ability to mediate neurodegeneration.101,102 Hypertension has also been established to cause and contribute to neurodegeneration.103,104 Therefore, it is plausible that the 2 phenomena are not mutually exclusive and that increased neuronal senescence in hypertension could be an underlying factor. Furthermore, while it is unlikely that senescent neurons drive increases sympathetic tone, we hypothesize that the SASP of other senescent brain cells (e.g., glial cells or neural stem cells) could propagate inflammation in surrounding (non-senescent) tissues that could then mediate neurogenic hypertension. Beyond neurons, it has been observed that angiotensin II induces senescence in astrocytes via ROS.105 The downstream effects of astrocyte senescence on hypertension could be far reaching given their multifunctional role in brain homeostasis (e.g., blood–brain barrier integrity, extracellular ion balance, and inflammation).
T cells
Uncontrolled immune system activation, including monocytes/macrophages,106 natural killer cells,107 dendritic cells,108 T cells,109 and γ-δ T cells,110 has been well ascribed in the pathogenesis of hypertension. In particular, T cells have been the focus of a great deal of research.111 Nonetheless, what precisely activates T cells to mediate inflammation and further increases in blood pressure has yet to be fully elucidated. It has been observed that immunosenescent (CD28null and CD57+) cytotoxic T cells are increased in patients with hypertension.112 An outstanding question that remained from this study was whether senescent T cells present a heightened production of cytokine and chemokines (SASP), beyond their normal proinflammatory capacity. Moreover, whether these other immune cells involved in the development and/or maintenance of hypertension (i.e., monocytes/macrophages, dendritic cells, or γ-δ T cells) present a senescent phenotype has not been reported. On the other hand, it has been observed that senescent natural killer cells can promote vascular remodeling and angiogenesis,113 thus demonstrating the evolutionarily conserved function of senescence on vascular homeostasis.7,8
Gut
Gut dysbiosis has recently come to prominence as a novel mediator of organs important for the control of blood pressure.114 Therefore, it is obvious that hypertension-associated dysbiosis is associated with hypertension-associated premature vascular aging.30 Importantly however, alterations in the composition and diversity of microbiota via gut senescence have been revealed as a mechanistic cause of disease.115 We hypothesize that this gut senescence mechanism also exists in hypertension, accelerating the decline in vascular function. Supporting this idea are the observations that longevity in mice is promoted by a probiotic-induced suppression of colonic senescence116 and that decreased gut microbial diversity promotes a physiologic decline in organ function that cannot be solely attributed to chronological aging per se.117 Nonetheless, direct evidence of a gut senescence-vascular axis in hypertension remains to be confirmed.
NOVEL MECHANISMS UNDERLYING VASCULAR SENESCENCE IN HYPERTENSION
In hypertension, cells of the vasculature are continually exposed to stress and damage from autocrine, paracrine, and endocrine sources. Therefore, novel mechanisms of senescence in hypertension are vast. Nonetheless, we wish to highlight autophagy, endoplasmic reticulum stress and proteotoxicity, and telomere uncapping as 3 potentially novel prosenescence mechanisms of particular relevance to the hypertension field.
Autophagy is the evolutionarily conserved catabolic process essential for both maintaining homeostasis via the removal of damaged proteins and organelles and to provide micronutrients during times of stress.118 Importantly, autophagy has also been implicated as a modulator of longevity,119 and it is also known that its induction can extend lifespan.120 Therefore, it is tempting to suggest that a decline in autophagy contributes to aged phenotype of the vasculature associated with hypertension. This notion is supported by studies that showed an upregulation of autophagy reversed several phenotypes of vascular aging in old mice121,122 and our own studies observing that spontaneously hypertensive rats have decreased autophagic activity in resistance arteries.123 Precisely how autophagy induction reduces the aged vascular phenotype is the focus of intense research,124–126 and only one original investigation has demonstrated that upregulation of autophagy decreases vasculature senescence.127 Right now our understanding is centered on the premise that the accumulation of dysfunctional and decaying organelles and misfolded proteins leads to a state of oxidative stress that subsequently quenches nitric oxide bioavailabilty121,122 (Figure 3) and also uncouples endothelial nitric oxide synthase.128 Nonetheless, given the close association of autophagy with metabolism and energy homeostasis, we hypothesize that upregulation of autophagy imparts influence on metabolic sensors (e.g., AKT and AMPK) and thereby can modulate vascular function through these mechanisms.
Although organelle recycling and protein misfolding is an inevitable consequence of normal cellular function, the unfolded protein response and multiple proteostasis systems are devoted to the refolding, repair, or clearance of damaged proteins, including autophagy.129 However, when the unfolded protein response and proteostasis systems do not function effectively, dysfunctional organelles accumulate and misfolded proteins are vulnerable to aggregation.130 In hypertension, our group has previously revealed that alleviation of endoplasmic reticulum stress and the unfolded protein response lowers blood pressure and improves vascular function and structure in hypertensive rats.131,132 However, the proteotoxicity that occurs as a consequence of endoplasmic reticulum stress is only beginning to emerge in hypertension133,134 and nothing is currently known about its contribution to vascular senescence in hypertension.
Telomeres are protective structures present at the ends of chromosomes important for preventing genome instability. It is well established that cellular senescence can be triggered by telomere shortening,135 and a number of reviews have focused on the contribution of telomere shortening to vascular cell senescence and cardiovascular disease,136,137 including hypertension.138 However, there is increasing evidence that the exposure of chromosome ends, or “telomere uncapping,” is more pathophysiologically relevant.139 This is supported with evidence demonstrating that vascular telomere uncapping and senescence are linked to hypertension independently of mean telomere length, and telomere uncapping is associated with hypertension to a greater degree than mean telomere length.140 Furthermore, it has been observed that telomeric repeat-binding factor 2 (a protein that plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes) deletion leads to telomere uncapping, increased senescence signaling, elevated blood pressure, and impaired endothelium-dependent vasodilation.141 Overall, these investigations reveal that arterial telomere uncapping is an important inducer of senescence within the context of hypertension-associated premature vascular aging and telomere uncapping contributes to the development and maintenance of high blood pressure. Nonetheless, telomere uncapping does not necessarily apply to other organ systems involved in the pathogenesis of hypertension.
CONCLUSION
Age is not considered to be a modifiable risk factor for cardiovascular disease such as physical inactivity, dietary excess, or smoking. Unfortunately though, it outranks all those, as a predictor of clinical events.142 Age is a major risk factor for hypertension,3 and premature aging (relative actual chronological age) is commonly observed in the vasculature of hypertensive animals.4,5 Nonetheless, the factors and molecular mechanism underlying this phenotype remain elusive. Senescence is age-associated phenomenon important for homeostasis.7 However, if senescence becomes excessive and uncontrolled, it could contribute to the genesis and/or maintenance of hypertension via acceleration of relative vascular age.46 Enhancing our understanding of cellular senescence, beyond phenotypic recognition, could further refine the vascular age determination as a prognostic and diagnostic index of cardiovascular disease risk, as well as offer an alternative therapeutic target to hypertensive patients resistant to all currently available treatments (Figure 4).
ACKNOWLEDGMENT
This work was supported by the American Heart Association (18POST34060003) and National Institutes of Health (K99GM118885, PO1HL134604, and R01HL143082).
DISCLOSURE
The authors declared no conflict of interest.
REFERENCES
- 1. Thomas H. Senescence, ageing and death of the whole plant. New Phytol 2013; 197:696–711. [DOI] [PubMed] [Google Scholar]
- 2. Faconti L, Bruno RM, Ghiadoni L, Taddei S, Virdis A. Ventricular and vascular stiffening in aging and hypertension. Curr Hypertens Rev 2015; 11:100–109. [DOI] [PubMed] [Google Scholar]
- 3. Writing Group Members , Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; American Heart Association Statistics Committee, Stroke Statistics Subcommittee . Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38–360. [DOI] [PubMed] [Google Scholar]
- 4. Abeywardena MY, Jablonskis LT, Head RJ. Age- and hypertension-induced changes in abnormal contractions in rat aorta. J Cardiovasc Pharmacol 2002; 40:930–937. [DOI] [PubMed] [Google Scholar]
- 5. Guzik TJ, Touyz RM. Oxidative stress, inflammation, and vascular aging in hypertension. Hypertension 2017; 70:660–667. [DOI] [PubMed] [Google Scholar]
- 6. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvänne M, Scholte Op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F; Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice; European Association for Cardiovascular Prevention and Rehabilitation . European guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Atherosclerosis 2012; 223:1–68. [DOI] [PubMed] [Google Scholar]
- 7. Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, Rodríguez-Baeza A, Varela-Nieto I, Ruberte J, Collado M, Serrano M. Programmed cell senescence during mammalian embryonic development. Cell 2013; 155:1104–1118. [DOI] [PubMed] [Google Scholar]
- 8. Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J, Keyes WM. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 2013; 155:1119–1130. [DOI] [PubMed] [Google Scholar]
- 9. 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. [DOI] [PubMed] [Google Scholar]
- 10. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev 2014; 28:99–114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 2010; 5:99–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 2010; 16:238–246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Maier JA, Voulalas P, Roeder D, Maciag T. Extension of the life-span of human endothelial cells by an interleukin-1 alpha antisense oligomer. Science 1990; 249:1570–1574. [DOI] [PubMed] [Google Scholar]
- 14. Gardner SE, Humphry M, Bennett MR, Clarke MC. Senescent vascular smooth muscle cells drive inflammation through an interleukin-1α-dependent senescence-associated secretory phenotype. Arterioscler Thromb Vasc Biol 2015; 35:1963–1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 2015; 21:1424–1435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Riera CE, Dillin A. Can aging be ‘drugged’? Nat Med 2015; 21:1400–1405. [DOI] [PubMed] [Google Scholar]
- 17. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965;37:614–636. [DOI] [PubMed] [Google Scholar]
- 18. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585–621. [DOI] [PubMed] [Google Scholar]
- 19. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016; 530:184–189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017; 169:132–147.e16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 2016; 22:78–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016; 15:973–977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Chiu CL, Hearn NL, Paine D, Steiner N, Lind JM. Does telomere shortening precede the onset of hypertension in spontaneously hypertensive mice? Twin Res Hum Genet 2016; 19:422–429. [DOI] [PubMed] [Google Scholar]
- 24. Westhoff JH, Hilgers KF, Steinbach MP, Hartner A, Klanke B, Amann K, Melk A. Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a. Hypertension 2008; 52:123–129. [DOI] [PubMed] [Google Scholar]
- 25. Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, Nagai T, Kaneko S, Komuro I. Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 2006; 114:953–960. [DOI] [PubMed] [Google Scholar]
- 26. Fan YY, Kohno M, Hitomi H, Kitada K, Fujisawa Y, Yatabe J, Yatabe M, Felder RA, Ohsaki H, Rafiq K, Sherajee SJ, Noma T, Nishiyama A, Nakano D. Aldosterone/mineralocorticoid receptor stimulation induces cellular senescence in the kidney. Endocrinology 2011; 152:680–688. [DOI] [PubMed] [Google Scholar]
- 27. Min LJ, Mogi M, Iwanami J, Li JM, Sakata A, Fujita T, Tsukuda K, Iwai M, Horiuchi M. Cross-talk between aldosterone and angiotensin II in vascular smooth muscle cell senescence. Cardiovasc Res 2007; 76:506–516. [DOI] [PubMed] [Google Scholar]
- 28. Vafaie F, Yin H, O’Neil C, Nong Z, Watson A, Arpino JM, Chu MW, Wayne Holdsworth D, Gros R, Pickering JG. Collagenase-resistant collagen promotes mouse aging and vascular cell senescence. Aging Cell 2014; 13:121–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Kim MY, Kang ES, Ham SA, Hwang JS, Yoo TS, Lee H, Paek KS, Park C, Lee HT, Kim JH, Han CW, Seo HG. The PPARδ-mediated inhibition of angiotensin II-induced premature senescence in human endothelial cells is SIRT1-dependent. Biochem Pharmacol 2012; 84:1627–1634. [DOI] [PubMed] [Google Scholar]
- 30. Karbach SH, Schonfelder T, Brandao I, Wilms E, Hormann N, Jackel S, Schuler R, Finger S, Knorr M, Lagrange J, Brandt M, Waisman A, Kossmann S, Schafer K, Munzel T, Reinhardt C, Wenzel P. Gut microbiota promote angiotensin II-induced arterial hypertension and vascular dysfunction. J Am Heart Assoc 2016;5:e003698. doi: 10.1161/JAHA.116.003698 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Imanishi T, Hano T, Nishio I. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens 2005; 23:97–104. [DOI] [PubMed] [Google Scholar]
- 32. Imanishi T, Hano T, Nishio I. Estrogen reduces angiotensin II-induced acceleration of senescence in endothelial progenitor cells. Hypertens Res 2005; 28:263–271. [DOI] [PubMed] [Google Scholar]
- 33. Imanishi T, Kobayashi K, Kuroi A, Ikejima H, Akasaka T. Pioglitazone inhibits angiotensin II-induced senescence of endothelial progenitor cell. Hypertens Res 2008; 31:757–765. [DOI] [PubMed] [Google Scholar]
- 34. Zhou Z, Hu CP, Wang CJ, Li TT, Peng J, Li YJ. Calcitonin gene-related peptide inhibits angiotensin II-induced endothelial progenitor cells senescence through up-regulation of klotho expression. Atherosclerosis 2010; 213:92–101. [DOI] [PubMed] [Google Scholar]
- 35. Zhou Z, Peng J, Wang CJ, Li D, Li TT, Hu CP, Chen XP, Li YJ. Accelerated senescence of endothelial progenitor cells in hypertension is related to the reduction of calcitonin gene-related peptide. J Hypertens 2010; 28:931–939. [DOI] [PubMed] [Google Scholar]
- 36. Shan H, Bai X, Chen X. Angiotensin II induces endothelial cell senescence via the activation of mitogen-activated protein kinases. Cell Biochem Funct 2008; 26:459–466. [DOI] [PubMed] [Google Scholar]
- 37. Weber GJ, Purkayastha B, Ren L, Pushpakumar S, Sen U. Hypertension exaggerates renovascular resistance via miR-122-associated stress response in aging. J Hypertens 2018; 36:2226–2236. [DOI] [PubMed] [Google Scholar]
- 38. Misaka T, Suzuki S, Miyata M, Kobayashi A, Ishigami A, Shishido T, Saitoh S, Kubota I, Takeishi Y. Senescence marker protein 30 inhibits angiotensin II-induced cardiac hypertrophy and diastolic dysfunction. Biochem Biophys Res Commun 2013; 439:142–147. [DOI] [PubMed] [Google Scholar]
- 39. Ichiki T, Miyazaki R, Kamiharaguchi A, Hashimoto T, Matsuura H, Kitamoto S, Tokunou T, Sunagawa K. Resveratrol attenuates angiotensin II-induced senescence of vascular smooth muscle cells. Regul Pept 2012; 177:35–39. [DOI] [PubMed] [Google Scholar]
- 40. Min LJ, Mogi M, Iwanami J, Li JM, Sakata A, Fujita T, Tsukuda K, Iwai M, Horiuchi M. Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition. Hypertension 2008; 51:1339–1344. [DOI] [PubMed] [Google Scholar]
- 41. Mistry Y, Poolman T, Williams B, Herbert KE. A role for mitochondrial oxidants in stress-induced premature senescence of human vascular smooth muscle cells. Redox Biol 2013; 1:411–417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Adijiang A, Higuchi Y, Nishijima F, Shimizu H, Niwa T. Indoxyl sulfate, a uremic toxin, promotes cell senescence in aorta of hypertensive rats. Biochem Biophys Res Commun 2010; 399:637–641. [DOI] [PubMed] [Google Scholar]
- 43. Louhelainen M, Merasto S, Finckenberg P, Vahtola E, Kaheinen P, Leskinen H, Levijoki J, Pollesello P, Haikala H, Mervaala EM. Effects of calcium sensitizer OR-1986 on a cardiovascular mortality and myocardial remodelling in hypertensive Dahl/Rapp rats. J Physiol Pharmacol 2009; 60:41–47. [PubMed] [Google Scholar]
- 44. Takahashi K, Takatsu M, Hattori T, Murase T, Ohura S, Takeshita Y, Watanabe S, Murohara T, Nagata K. Premature cardiac senescence in DahlS.Z-Lepr(fa)/Lepr(fa) rats as a new animal model of metabolic syndrome. Nagoya J Med Sci 2014; 76:35–49. [PMC free article] [PubMed] [Google Scholar]
- 45. Muteliefu G, Shimizu H, Enomoto A, Nishijima F, Takahashi M, Niwa T. Indoxyl sulfate promotes vascular smooth muscle cell senescence with upregulation of p53, p21, and prelamin A through oxidative stress. Am J Physiol Cell Physiol 2012; 303:C126–C134. [DOI] [PubMed] [Google Scholar]
- 46. Voghel G, Thorin-Trescases N, Farhat N, Nguyen A, Villeneuve L, Mamarbachi AM, Fortier A, Perrault LP, Carrier M, Thorin E. Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors. Mech Ageing Dev 2007; 128:662–671. [DOI] [PubMed] [Google Scholar]
- 47. Imanishi T, Moriwaki C, Hano T, Nishio I. Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension. J Hypertens 2005; 23:1831–1837. [DOI] [PubMed] [Google Scholar]
- 48. De Vusser K, Pieters N, Janssen B, Lerut E, Kuypers D, Jochmans I, Monbaliu D, Pirenne J, Nawrot T, Naesens M. Telomere length, cardiovascular risk and arteriosclerosis in human kidneys: an observational cohort study. Aging (Albany, NY) 2015; 7:766–775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 2006; 99:156–164. [DOI] [PubMed] [Google Scholar]
- 50. Bennett MR, Macdonald K, Chan SW, Boyle JJ, Weissberg PL. Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. Circ Res 1998; 82:704–712. [DOI] [PubMed] [Google Scholar]
- 51. Boe AE, Eren M, Murphy SB, Kamide CE, Ichimura A, Terry D, McAnally D, Smith LH, Miyata T, Vaughan DE. Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-l-arginine methyl ester-induced hypertension and vascular senescence. Circulation 2013; 128:2318–2324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Li J, Yu L, Zhao Y, Fu G, Zhou B. Thymosin β4 reduces senescence of endothelial progenitor cells via the PI3K/Akt/eNOS signal transduction pathway. Mol Med Rep 2013; 7:598–602. [DOI] [PubMed] [Google Scholar]
- 53. Bode-Böger SM, Scalera F, Martens-Lobenhoffer J. Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc Med 2005; 10(Suppl 1):S65–S71. [DOI] [PubMed] [Google Scholar]
- 54. Scalera F, Borlak J, Beckmann B, Martens-Lobenhoffer J, Thum T, Täger M, Bode-Böger SM. Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl L-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol 2004; 24:1816–1822. [DOI] [PubMed] [Google Scholar]
- 55. Han X, Ling S, Gan W, Sun L, Duan J, Xu JW. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-d-glucoside ameliorates vascular senescence and improves blood flow involving a mechanism of p53 deacetylation. Atherosclerosis 2012; 225:76–82. [DOI] [PubMed] [Google Scholar]
- 56. Sueta D, Koibuchi N, Hasegawa Y, Toyama K, Uekawa K, Katayama T, Ma M, Nakagawa T, Waki H, Maeda M, Ogawa H, Kim-Mitsuyama S. Blood pressure variability, impaired autonomic function and vascular senescence in aged spontaneously hypertensive rats are ameliorated by angiotensin blockade. Atherosclerosis 2014; 236:101–107. [DOI] [PubMed] [Google Scholar]
- 57. de Nigris F, Balestrieri ML, Williams-Ignarro S, D’Armiento FP, Lerman LO, Byrns R, Crimi E, Palagiano A, Fatigati G, Ignarro LJ, Napoli C. Therapeutic effects of autologous bone marrow cells and metabolic intervention in the ischemic hindlimb of spontaneously hypertensive rats involve reduced cell senescence and CXCR4/Akt/eNOS pathways. J Cardiovasc Pharmacol 2007; 50:424–433. [DOI] [PubMed] [Google Scholar]
- 58. Imanishi T, Kobayashi K, Hano T, Nishio I. Effect of estrogen on differentiation and senescence in endothelial progenitor cells derived from bone marrow in spontaneously hypertensive rats. Hypertens Res 2005; 28:763–772. [DOI] [PubMed] [Google Scholar]
- 59. Nurmi L, Heikkilä HM, Vapaatalo H, Kovanen PT, Lindstedt KA. Downregulation of Bradykinin type 2 receptor expression in cardiac endothelial cells during senescence. J Vasc Res 2012; 49:13–23. [DOI] [PubMed] [Google Scholar]
- 60. Li WQ, Tan SL, Li XH, Sun TL, Li D, Du J, Wei SS, Li YJ, Zhang BK. Calcitonin gene-related peptide inhibits the cardiac fibroblasts senescence in cardiac fibrosis via up-regulating klotho expression. Eur J Pharmacol 2019; 843:96–103. [DOI] [PubMed] [Google Scholar]
- 61. Minamino T, Yoshida T, Tateno K, Miyauchi H, Zou Y, Toko H, Komuro I. Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis. Circulation 2003; 108:2264–2269. [DOI] [PubMed] [Google Scholar]
- 62. Oeseburg H, Iusuf D, van der Harst P, van Gilst WH, Henning RH, Roks AJ. Bradykinin protects against oxidative stress-induced endothelial cell senescence. Hypertension 2009; 53:417–422. [DOI] [PubMed] [Google Scholar]
- 63. Suo R, Zhao ZZ, Tang ZH, Ren Z, Liu X, Liu LS, Wang Z, Tang CK, Wei DH, Jiang ZS. Hydrogen sulfide prevents H2O2-induced senescence in human umbilical vein endothelial cells through SIRT1 activation. Mol Med Rep 2013; 7:1865–1870. [DOI] [PubMed] [Google Scholar]
- 64. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 2004; 117:2417–2426. [DOI] [PubMed] [Google Scholar]
- 65. Carracedo J, Buendía P, Merino A, Madueño JA, Peralbo E, Ortiz A, Martín-Malo A, Aljama P, Rodríguez M, Ramírez R. Klotho modulates the stress response in human senescent endothelial cells. Mech Ageing Dev 2012; 133:647–654. [DOI] [PubMed] [Google Scholar]
- 66. Lloréns S, de Mera RM, Pascual A, Prieto-Martín A, Mendizábal Y, de Cabo C, Nava E, Jordán J. The senescence-accelerated mouse (SAM-P8) as a model for the study of vascular functional alterations during aging. Biogerontology 2007; 8:663–672. [DOI] [PubMed] [Google Scholar]
- 67. Novella S, Dantas AP, Segarra G, Novensà L, Bueno C, Heras M, Hermenegildo C, Medina P. Gathering of aging and estrogen withdrawal in vascular dysfunction of senescent accelerated mice. Exp Gerontol 2010; 45:868–874. [DOI] [PubMed] [Google Scholar]
- 68. Jiménez-Altayó F, Onetti Y, Heras M, Dantas AP, Vila E. Western-style diet modulates contractile responses to phenylephrine differently in mesenteric arteries from senescence-accelerated prone (SAMP8) and resistant (SAMR1) mice. Age (Dordr) 2013; 35:1219–1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ Res 2001; 89:793–798. [DOI] [PubMed] [Google Scholar]
- 70. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 2002; 105:1541–1544. [DOI] [PubMed] [Google Scholar]
- 71. Sato I, Kaji K, Morita I, Nagao M, Murota S. Augmentation of endothelin-1, prostacyclin and thromboxane A2 secretion associated with in vitro ageing in cultured human umbilical vein endothelial cells. Mech Ageing Dev 1993; 71:73–84. [DOI] [PubMed] [Google Scholar]
- 72. Sato I, Morita I, Kaji K, Ikeda M, Nagao M, Murota S. Reduction of nitric oxide producing activity associated with in vitro aging in cultured human umbilical vein endothelial cell. Biochem Biophys Res Commun 1993; 195:1070–1076. [DOI] [PubMed] [Google Scholar]
- 73. Neubert K, Haberland A, Kruse I, Wirth M, Schimke I. The ratio of formation of prostacyclin/thromboxane A2 in HUVEC decreased in each subsequent passage. Prostaglandins 1997; 54:447–462. [DOI] [PubMed] [Google Scholar]
- 74. Lefranc C, Friederich-Persson M, Braud L, Palacios-Ramirez R, Karlsson S, Boujardine N, Motterlini R, Jaisser F, Nguyen Dinh Cat A. MR (mineralocorticoid receptor) induces adipose tissue senescence and mitochondrial dysfunction leading to vascular dysfunction in obesity. Hypertension 2019; 73:458–468. [DOI] [PubMed] [Google Scholar]
- 75. Cavallaro U, Castelli V, Del Monte U, Soria MR. Phenotypic alterations in senescent large-vessel and microvascular endothelial cells. Mol Cell Biol Res Commun 2000; 4:117–121. [DOI] [PubMed] [Google Scholar]
- 76. Kamino H, Hiratsuka M, Toda T, Nishigaki R, Osaki M, Ito H, Inoue T, Oshimura M. Searching for genes involved in arteriosclerosis: proteomic analysis of cultured human umbilical vein endothelial cells undergoing replicative senescence. Cell Struct Funct 2003; 28:495–503. [DOI] [PubMed] [Google Scholar]
- 77. Krouwer VJ, Hekking LH, Langelaar-Makkinje M, Regan-Klapisz E, Post JA. Endothelial cell senescence is associated with disrupted cell-cell junctions and increased monolayer permeability. Vasc Cell 2012; 4:12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Absher M, Woodcock-Mitchell J, Mitchell J, Baldor L, Low R, Warshaw D. Characterization of vascular smooth muscle cell phenotype in long-term culture. In Vitro Cell Dev Biol 1989; 25:183–192. [DOI] [PubMed] [Google Scholar]
- 79. Burton DG, Giles PJ, Sheerin AN, Smith SK, Lawton JJ, Ostler EL, Rhys-Williams W, Kipling D, Faragher RG. Microarray analysis of senescent vascular smooth muscle cells: a link to atherosclerosis and vascular calcification. Exp Gerontol 2009; 44:659–665. [DOI] [PubMed] [Google Scholar]
- 80. Bielak-Zmijewska A, Wnuk M, Przybylska D, Grabowska W, Lewinska A, Alster O, Korwek Z, Cmoch A, Myszka A, Pikula S, Mosieniak G, Sikora E. A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta. Biogerontology 2014; 15:47–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81. Nakano-Kurimoto R, Ikeda K, Uraoka M, Nakagawa Y, Yutaka K, Koide M, Takahashi T, Matoba S, Yamada H, Okigaki M, Matsubara H. Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition. Am J Physiol Heart Circ Physiol 2009; 297:H1673–H1684. [DOI] [PubMed] [Google Scholar]
- 82. Chen J, Fan J, Wang S, Sun Z. Secreted klotho attenuates inflammation-associated aortic valve fibrosis in senescence-accelerated mice P1. Hypertension 2018; 71:877–885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6:2853–2868. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 2009; 11:973–979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Kumazaki T, Robetorye RS, Robetorye SC, Smith JR. Fibronectin expression increases during in vitro cellular senescence: correlation with increased cell area. Exp Cell Res 1991; 195:13–19. [DOI] [PubMed] [Google Scholar]
- 86. Kumazaki T, Kobayashi M, Mitsui Y. Enhanced expression of fibronectin during in vivo cellular aging of human vascular endothelial cells and skin fibroblasts. Exp Cell Res 1993; 205:396–402. [DOI] [PubMed] [Google Scholar]
- 87. Maier JA, Statuto M, Ragnotti G. Senescence stimulates U937-endothelial cell interactions. Exp Cell Res 1993; 208:270–274. [DOI] [PubMed] [Google Scholar]
- 88. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 2017; 8:14532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 2014; 6:231ra47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90. Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res 2004; 94:768–775. [DOI] [PubMed] [Google Scholar]
- 91. Deshpande SS, Qi B, Park YC, Irani K. Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence. Arterioscler Thromb Vasc Biol 2003; 23:e1–e6. [DOI] [PubMed] [Google Scholar]
- 92. Unterluggauer H, Hampel B, Zwerschke W, Jansen-Dürr P. Senescence-associated cell death of human endothelial cells: the role of oxidative stress. Exp Gerontol 2003; 38:1149–1160. [DOI] [PubMed] [Google Scholar]
- 93. Xin MG, Zhang J, Block ER, Patel JM. Senescence-enhanced oxidative stress is associated with deficiency of mitochondrial cytochrome c oxidase in vascular endothelial cells. Mech Ageing Dev 2003; 124:911–919. [DOI] [PubMed] [Google Scholar]
- 94. Szasz T, Webb RC. Perivascular adipose tissue: more than just structural support. Clin Sci (Lond) 2012; 122:1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95. Soltis EE, Cassis LA. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin Exp Hypertens A 1991; 13:277–296. [DOI] [PubMed] [Google Scholar]
- 96. Gálvez B, de Castro J, Herold D, Dubrovska G, Arribas S, González MC, Aranguez I, Luft FC, Ramos MP, Gollasch M, Fernández Alfonso MS. Perivascular adipose tissue and mesenteric vascular function in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 2006; 26:1297–1302. [DOI] [PubMed] [Google Scholar]
- 97. Gao YJ, Takemori K, Su LY, An WS, Lu C, Sharma AM, Lee RM. Perivascular adipose tissue promotes vasoconstriction: the role of superoxide anion. Cardiovasc Res 2006; 71:363–373. [DOI] [PubMed] [Google Scholar]
- 98. Gálvez-Prieto B, Bolbrinker J, Stucchi P, de Las Heras AI, Merino B, Arribas S, Ruiz-Gayo M, Huber M, Wehland M, Kreutz R, Fernandez-Alfonso MS. Comparative expression analysis of the renin-angiotensin system components between white and brown perivascular adipose tissue. J Endocrinol 2008; 197:55–64. [DOI] [PubMed] [Google Scholar]
- 99. Sturmlechner I, Durik M, Sieben CJ, Baker DJ, van Deursen JM. Cellular senescence in renal ageing and disease. Nat Rev Nephrol 2017; 13:77–89. [DOI] [PubMed] [Google Scholar]
- 100. Melk A. Senescence of renal cells: molecular basis and clinical implications. Nephrol Dial Transplant 2003; 18:2474–2478. [DOI] [PubMed] [Google Scholar]
- 101. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK. Cellular senescence and the aging brain. Exp Gerontol 2015; 68:3–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102. Kritsilis M, V Rizou S, Koutsoudaki PN, Evangelou K, Gorgoulis VG, Papadopoulos D. Ageing, cellular senescence and neurodegenerative disease. Int J Mol Sci. 2018;19:2937. doi: 10.3390/ijms19102937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103. Goel R, Bhat SA, Rajasekar N, Hanif K, Nath C, Shukla R. Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: protection by angiotensin converting enzyme inhibition. Pharmacol Biochem Behav 2015; 133:132–145. [DOI] [PubMed] [Google Scholar]
- 104. Kruyer A, Soplop N, Strickland S, Norris EH. Chronic hypertension leads to neurodegeneration in the TgSwDI mouse model of Alzheimer’s disease. Hypertension 2015; 66:175–182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105. Liu G, Hosomi N, Hitomi H, Pelisch N, Fu H, Masugata H, Murao K, Ueno M, Matsumoto M, Nishiyama A. Angiotensin II induces human astrocyte senescence through reactive oxygen species production. Hypertens Res 2011; 34:479–483. [DOI] [PubMed] [Google Scholar]
- 106. Wenzel P, Knorr M, Kossmann S, Stratmann J, Hausding M, Schuhmacher S, Karbach SH, Schwenk M, Yogev N, Schulz E, Oelze M, Grabbe S, Jonuleit H, Becker C, Daiber A, Waisman A, Münzel T. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation 2011; 124:1370–1381. [DOI] [PubMed] [Google Scholar]
- 107. Kossmann S, Schwenk M, Hausding M, Karbach SH, Schmidgen MI, Brandt M, Knorr M, Hu H, Kröller-Schön S, Schönfelder T, Grabbe S, Oelze M, Daiber A, Münzel T, Becker C, Wenzel P. Angiotensin II-induced vascular dysfunction depends on interferon-γ-driven immune cell recruitment and mutual activation of monocytes and NK-cells. Arterioscler Thromb Vasc Biol 2013; 33:1313–1319. [DOI] [PubMed] [Google Scholar]
- 108. Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J 2nd, Harrison DG. DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest 2014; 124:4642–4656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204:2449–2460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110. Caillon A, Mian MOR, Fraulob-Aquino JC, Huo KG, Barhoumi T, Ouerd S, Sinnaeve PR, Paradis P, Schiffrin EL. γδ T cells mediate angiotensin II-induced hypertension and vascular injury. Circulation 2017; 135:2155–2162. [DOI] [PubMed] [Google Scholar]
- 111. McCarthy CG, Goulopoulou S, Webb RC. Paying the toll for inflammation. Hypertension 2019; 73:514–521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112. Youn JC, Yu HT, Lim BJ, Koh MJ, Lee J, Chang DY, Choi YS, Lee SH, Kang SM, Jang Y, Yoo OJ, Shin EC, Park S. Immunosenescent CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension. Hypertension 2013; 62:126–133. [DOI] [PubMed] [Google Scholar]
- 113. Rajagopalan S, Long EO. Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling. Proc Natl Acad Sci USA 2012; 109:20596–20601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114. Galla S, Chakraborty S, Mell B, Vijay-Kumar M, Joe B. Microbiotal-host interactions and hypertension. Physiology (Bethesda) 2017; 32:224–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499:97–101. [DOI] [PubMed] [Google Scholar]
- 116. Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS One 2011; 6:e23652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117. O’Toole PW, Jeffery IB. Gut microbiota and aging. Science 2015; 350:1214–1215. [DOI] [PubMed] [Google Scholar]
- 118. Abada A, Elazar Z. Getting ready for building: signaling and autophagosome biogenesis. EMBO Rep 2014; 15:839–852. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119. Yen WL, Klionsky DJ. How to live long and prosper: autophagy, mitochondria, and aging. Physiology (Bethesda) 2008; 23:248–262. [DOI] [PubMed] [Google Scholar]
- 120. Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 2013; 4:2300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121. LaRocca TJ, Henson GD, Thorburn A, Sindler AL, Pierce GL, Seals DR. Translational evidence that impaired autophagy contributes to arterial ageing. J Physiol 2012; 590:3305–3316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. LaRocca TJ, Gioscia-Ryan RA, Hearon CM Jr, Seals DR. The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev 2013; 134:314–320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123. McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res 2015; 107:119–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 124. Nussenzweig SC, Verma S, Finkel T. The role of autophagy in vascular biology. Circ Res 2015; 116:480–488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 125. Abdellatif M, Sedej S, Carmona-Gutierrez D, Madeo F, Kroemer G. Autophagy in cardiovascular aging. Circ Res 2018; 123:803–824. [DOI] [PubMed] [Google Scholar]
- 126. Sasaki Y, Ikeda Y, Iwabayashi M, Akasaki Y, Ohishi M. The impact of autophagy on cardiovascular senescence and diseases. Int Heart J 2017; 58:666–673. [DOI] [PubMed] [Google Scholar]
- 127. Xu XJ, Zhao WB, Feng SB, Sun C, Chen Q, Ni B, Hu HY. Celastrol alleviates angiotensin II-mediated vascular smooth muscle cell senescence via induction of autophagy. Mol Med Rep 2017; 16:7657–7664. [DOI] [PubMed] [Google Scholar]
- 128. Zhang JX, Qu XL, Chu P, Xie DJ, Zhu LL, Chao YL, Li L, Zhang JJ, Chen SL. Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation. Biochim Biophys Acta Mol Cell Res 2018; 1865:709–720. [DOI] [PubMed] [Google Scholar]
- 129. Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000; 10:524–530. [DOI] [PubMed] [Google Scholar]
- 130. Ayyadevara S, Balasubramaniam M, Gao Y, Yu LR, Alla R, Shmookler Reis R. Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes. Aging Cell 2015; 14:35–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131. Spitler KM, Webb RC. Endoplasmic reticulum stress contributes to aortic stiffening via proapoptotic and fibrotic signaling mechanisms. Hypertension 2014; 63:e40–e45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132. Spitler KM, Matsumoto T, Webb RC. Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 2013; 305:H344–H353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133. Ayyadevara S, Mercanti F, Wang X, Mackintosh SG, Tackett AJ, Prayaga SV, Romeo F, Shmookler Reis RJ, Mehta JL. Age- and hypertension-associated protein aggregates in mouse heart have similar proteomic profiles. Hypertension 2016; 67:1006–1013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134. Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Atkinson JB, Fogo AB, Prinsen JK, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT. Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology? J Am Heart Assoc 2014; 3:e001384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135. Herbig U, Jobling WA, Chen BP, 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. [DOI] [PubMed] [Google Scholar]
- 136. Minamino T, Komuro I. Role of telomeres in vascular senescence. Front Biosci 2008; 13:2971–2979. [DOI] [PubMed] [Google Scholar]
- 137. Fyhrquist F, Saijonmaa O, Strandberg T. The roles of senescence and telomere shortening in cardiovascular disease. Nat Rev Cardiol 2013; 10:274–283. [DOI] [PubMed] [Google Scholar]
- 138. Fuster JJ, Díez J, Andrés V. Telomere dysfunction in hypertension. J Hypertens 2007; 25:2185–2192. [DOI] [PubMed] [Google Scholar]
- 139. Morgan RG, Donato AJ, Walker AE. Telomere uncapping and vascular aging. Am J Physiol Heart Circ Physiol 2018; 315:H1–H5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140. Morgan RG, Ives SJ, Walker AE, Cawthon RM, Andtbacka RH, Noyes D, Lesniewski LA, Richardson RS, Donato AJ. Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping. J Hypertens 2014; 32:1293–1299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 141. Morgan RG, Walker AE, Trott DW, Machin DR, Henson GD, Reihl KD, Cawthon RM, Denchi EL, Liu Y, Bloom SI, Phuong TT, Richardson RS, Lesniewski LA, Donato AJ. Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress. J Mol Cell Cardiol 2019; 127:74–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142. Sniderman AD, Furberg CD. Age as a modifiable risk factor for cardiovascular disease. Lancet 2008; 371:1547–1549. [DOI] [PubMed] [Google Scholar]