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Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction accelerates\ atherogenesis. Circ. Res. \n126, 298 314 \(2020\).\r:71)/F 4/H/N/Rect[321.155 554.855 326.251 542.444]/Subtype/Link/Type/Annot>> endobj 4 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:12. Ridker, P. M. etal. Antiinflammatory therapy with canakinumab for atheroscle\ rotic disease. N. Engl. \nJ. Med. 377, 1119 1131 \(2017\).\r:72)/F 4/H/N/Rect[225.318 543.855 230.296 531.444]/Subtype/Link/Type/Annot>> endobj 5 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:13. Ridker, P. M. etal. Modulation of the interleukin-6 signalling pathway and i\ ncidence rates of atherosclerotic events and all- cause mortality: analyses from the Canakinumab Anti- Inflammatory Thrombosis O\ utcomes Study \(CANTOS\). Eur. Heart J.:73)/F 4/H/N/Rect[206.852 499.855 211.948 487.444]/Subtype/Link/Type/Annot>> endobj 6 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:Fig. 1 | Ageing-related processes that promote atherogenesis: IL-6 as a potenti\ al shared pathway. Ageing promotes the development and progression of atherosclerosis through different mechanisms, which mi\ ght be related to age- induced elevati:74)/F 4/H/N/Rect[265.351 433.855 269.705 421.444]/Subtype/Link/Type/Annot>> endobj 7 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:14. Bennett, M. R. & Clarke, M. C. H. Killing the old: cell senescence in atheros\ clerosis. Nat. Rev. Cardiol. 14, 8 9 \(2017\).\r:75)/F 4/H/N/Rect[236.757 290.855 241.852 278.444]/Subtype/Link/Type/Annot>> endobj 8 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:15. McElhaney, J. E., Kuchel, G. A., Zhou, X., Swain, S. L. & Haynes, L. 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Nature 532, 380 384 \(2016\).\r:136)/F 4/H/N/Rect[545.622 213.855 550.658 201.444]/Subtype/Link/Type/Annot>> endobj 75 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:67. Esplin, B. L. etal. Chronic exposure to a TLR ligand injures hematopoietic s\ tem cells. J. Immunol. 186, 5367 5375 \(2011\).\r:137)/F 4/H/N/Rect[405.387 180.855 410.653 168.444]/Subtype/Link/Type/Annot>> endobj 76 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:68. Claesson, M. J. etal. Gut microbiota composition correlates with diet and he\ alth in the elderly. Nature 488, 178 184 \(2012\).\r:138)/F 4/H/N/Rect[414.049 169.855 419.031 157.444]/Subtype/Link/Type/Annot>> endobj 77 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:60. Ho, Y.-H. etal. Remodeling of bone marrow hematopoietic stem cell niches p\ romotes myeloid cell expansion during premature or physiological aging. 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Circulation 108, 457 463 \(2003\).\r:182)/F 4/H/N/Rect[317.205 455.855 322.208 443.444]/Subtype/Link/Type/Annot>> endobj 266 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:11. Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction accelerate\ s atherogenesis. Circ. Res. \n126, 298 314 \(2020\).\r:183)/F 4/H/N/Rect[184.286 389.855 189.33 377.444]/Subtype/Link/Type/Annot>> endobj 267 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:82. Du, W. etal. Age- associated vascular inflammation promotes monocytosis dur\ ing atherogenesis. Aging Cell 15, 766 777 \(2016\).\r:184)/F 4/H/N/Rect[190.501 389.855 195.545 377.444]/Subtype/Link/Type/Annot>> endobj 268 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:82. Du, W. etal. Age- associated vascular inflammation promotes monocytosis du\ ring atherogenesis. Aging Cell 15, 766 777 \(2016\).\r:185)/F 4/H/N/Rect[291.415 345.855 296.518 333.444]/Subtype/Link/Type/Annot>> endobj 269 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:84. Belmin, J. etal. Increased production of tumor necrosis factor and interleuk\ in-6 by arterial wall of aged rats. Am. J. Physiol. 268, H2288 H2293 \(1995\).\r:186)/F 4/H/N/Rect[297.719 345.855 302.822 333.444]/Subtype/Link/Type/Annot>> endobj 270 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:85. Qian, F. etal. Age- associated elevation in TLR5 leads to increased inflamma\ tory responses in the elderly. Aging Cell 11, 104 110 \(2011\).\r:187)/F 4/H/N/Rect[218.157 312.855 223.199 300.444]/Subtype/Link/Type/Annot>> endobj 271 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:57. Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellul\ ar senescence and the senescent secretory phenotype: therapeutic opportunities. \nJ. Clin. 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Yu, E. P. K. etal. Mitochondrial respiration is reduced in atheroscleros\ is, promoting necrotic core formation and reducing relative fibrous cap thickness. Arterioscler. Thromb. Vasc. Biol. 37, 232\ 2 2332 \(2017\).\r:214)/F 4/H/N/Rect[307.112 411.974 312.19 399.444]/Subtype/Link/Type/Annot>> endobj 302 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:10. Yu, E. P. K. etal. Mitochondrial respiration is reduced in atherosclero\ sis, promoting necrotic core formation and reducing relative fibrous cap thickness. Arterioscler. Thromb. Vasc. Biol. 37, 23\ 22 2332 \(2017\).\r:215)/F 4/H/N/Rect[201.891 378.974 206.959 366.444]/Subtype/Link/Type/Annot>> endobj 303 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:25. Lpez- Otn, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. \ The hallmarks of aging. Cell 153, 1194 1217 \(2013\).\r:216)/F 4/H/N/Rect[325.445 334.855 330.667 322.444]/Subtype/Link/Type/Annot>> endobj 304 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:101. Brcena, C., Mayoral, P. & Quirs, P. M. in International Review of Cell and M\ olecular Biology Vol. 340 Ch. 2 \(eds. Lpez- Otn, C. & Galluzzi, L.\) 35 77 \(Academic, 2018\).\r:217)/F 4/H/N/Rect[331.927 334.855 339.761 322.444]/Subtype/Link/Type/Annot>> endobj 305 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:102. Vendrov, A. E. etal. NOX4 NADPH oxidase- dependent mitochondrial oxidative \ stress in aging- associated cardiovascular disease. Antioxid. Redox Signal. 23, 1389 1409 \(2015\).\r:218)/F 4/H/N/Rect[273.583 257.855 281.325 245.444]/Subtype/Link/Type/Annot>> endobj 306 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:103. Vendrov, A. E. etal. Attenuated superoxide dismutase 2 activity induces ath\ erosclerotic plaque instability during aging in hyperlipidemic mice. J. Am. Heart Assoc. 6, e006775 \(2017\).\r:219)/F 4/H/N/Rect[202.27 235.855 209.759 223.444]/Subtype/Link/Type/Annot>> endobj 307 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:99. Ballinger, S. W. etal. Mitochondrial integrity and function in atherogenesi\ s. Circulation 106, 544 549 \(2002\).\r:220)/F 4/H/N/Rect[194.586 224.855 199.586 212.444]/Subtype/Link/Type/Annot>> endobj 308 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:100. Yu, E. etal. Mitochondrial DNA damage can promote atherosclerosis independ\ ently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher- risk plaques i\ n humans. Circulation 128, 702 712:221)/F 4/H/N/Rect[282.566 191.855 290.074 179.444]/Subtype/Link/Type/Annot>> endobj 309 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:104. Goszcz, K. etal. Antioxidants in cardiovascular therapy: panacea or false h\ ope? Front. Cardiovasc. Med. 2, 29 \(2015\).\r:222)/F 4/H/N/Rect[167.994 158.855 175.621 146.444]/Subtype/Link/Type/Annot>> endobj 310 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:105. Cherubini, A. etal. Role of antioxidants in atherosclerosis: epidemiologica\ l and clinical update. Curr. Pharm. Des. 11, 2017 2032 \(2005\).\r:223)/F 4/H/N/Rect[176.812 158.855 184.439 146.444]/Subtype/Link/Type/Annot>> endobj 311 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:11. Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction accelerat\ es atherogenesis. Circ. Res. \n126, 298 314 \(2020\).\r:224)/F 4/H/N/Rect[424.108 334.855 429.203 322.444]/Subtype/Link/Type/Annot>> endobj 312 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:11. Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction accelera\ tes atherogenesis. Circ. Res. \n126, 298 314 \(2020\).\r:225)/F 4/H/N/Rect[455.924 312.855 461.166 300.444]/Subtype/Link/Type/Annot>> endobj 313 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:Box 1 | Mitophagy\rDuring homeostasis, damaged mitochondria are recycled via mitop\ hagy, which is a specialized subset of macroautophagy \(see the figure\). Mitophagy reduces the production of mitochondrial dama\ ge- associated molecular patterns \(mtDAM:226)/F 4/H/N/Rect[496.589 279.855 501.245 267.444]/Subtype/Link/Type/Annot>> endobj 314 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:106. LaRocca, T. J., Hearon, C. M. Jr., Henson, G. D. \n& Seals, D. R. Mitochondri\ al quality control and age-associated arterial stiffening. Exp. Gerontol. 58, 78 82 \(2014\).\r:227)/F 4/H/N/Rect[420.363 235.855 428.307 223.444]/Subtype/Link/Type/Annot>> endobj 315 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:11. Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction acceler\ ates atherogenesis. Circ. Res. \n126, 298 314 \(2020\).\r:228)/F 4/H/N/Rect[409.908 202.855 415.23 190.444]/Subtype/Link/Type/Annot>> endobj 316 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:11. Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction accele\ rates atherogenesis. Circ. Res. \n126, 298 314 \(2020\).\r:229)/F 4/H/N/Rect[545.563 158.855 550.658 146.444]/Subtype/Link/Type/Annot>> endobj 317 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:87. Song, Y. etal. Aging enhances the basal production \nof IL-6 and CCL2 in vas\ cular smooth muscle cells. Arterioscler. Thromb. Vasc. 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Immun\ ol. 7, 41 \(2016\).\r:255)/F 4/H/N/Rect[465.689 477.855 470.784 465.444]/Subtype/Link/Type/Annot>> endobj 448 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:16. Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age- dependent dysregulat\ ion of innate immunity. \nNat. Rev. Immunol. 13, 875 887 \(2013\).\r:256)/F 4/H/N/Rect[471.98 477.855 477.076 465.444]/Subtype/Link/Type/Annot>> endobj 449 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:116. Baylis, D., Bartlett, D. B., Patel, H. P. & Roberts, H. C. Understanding how\ we age: insights into inflammaging. Longev. Healthspan 2, 8 \(2013\).\r:257)/F 4/H/N/Rect[478.272 477.855 485.915 465.444]/Subtype/Link/Type/Annot>> endobj 450 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:117. Thevaranjan, N. etal. Age- associated microbial dysbiosis promotes intestin\ al permeability, systemic inflammation, and macrophage dysfunction. 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Res. 123, \n825 848 \(2018\).\r:261)/F 4/H/N/Rect[539.322 422.855 544.397 410.444]/Subtype/Link/Type/Annot>> endobj 454 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:30. Ungvari, Z., Tarantini, S., Donato, A. J., Galvan, V. \n& Csiszar, A. Mechani\ sms of vascular aging. Circ. Res. 123, 849 867 \(2018\).\r:262)/F 4/H/N/Rect[545.583 422.855 550.658 410.444]/Subtype/Link/Type/Annot>> endobj 455 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:119. Wang, G. C. & Casolaro, V. Immunologic changes in frail older adults. Trans\ l. Med. UniSa 9, 1 6 \(2014\).\r:263)/F 4/H/N/Rect[425.428 389.855 433.436 377.444]/Subtype/Link/Type/Annot>> endobj 456 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:57. Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellu\ lar senescence and the senescent secretory phenotype: therapeutic opportunities. \nJ. Clin. Invest. 123, 966 972 \(2013\).\r:\ 264)/F 4/H/N/Rect[521.595 389.855 526.934 377.444]/Subtype/Link/Type/Annot>> endobj 457 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:86. Csiszar, A. etal. Age- associated proinflammatory secretory phenotype in v\ ascular smooth muscle cells from the non- human primate Macaca mulatta: reversal by resveratrol treatment. J. Gerontol. A Bio\ l. Sci. Med. Sci. 67, 811 820 \(2012:265)/F 4/H/N/Rect[528.252 389.855 533.591 377.444]/Subtype/Link/Type/Annot>> endobj 458 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:87. Song, Y. etal. Aging enhances the basal production \nof IL-6 and CCL2 in v\ ascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 32, 103 109 \(2012\).\r:266)/F 4/H/N/Rect[534.909 389.855 540.248 377.444]/Subtype/Link/Type/Annot>> endobj 459 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:Box 2 | IL-6 signalling\rIL-6 can signal via a classic signalling pathway and a t\ rans- signalling pathway \(see the figure\). In the classic IL-6 signalling pathway, IL-6 engages the membrane- bound IL-6 rece\ ptor \(IL-6R\) and subsequently interacts :267)/F 4/H/N/Rect[495.02 345.855 499.679 333.444]/Subtype/Link/Type/Annot>> endobj 460 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:120. Rose- John, S., Winthrop, K. & Calabrese, L. The role of IL-6 in host defenc\ e against infections: immunobiology and clinical implications. Nat. Rev. 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A., Sakkinen, P., Conze, D., Hardin, N. \n& Tracy, R. Interleukin-6\ exacerbates early atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 19, 2364 2367 \(1999\).\r:271)/F 4/H/N/Rect[542.867 136.855 550.658 124.444]/Subtype/Link/Type/Annot>> endobj 464 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:80. Madan, M., Bishayi, B., Hoge, M. & Amar, S. Atheroprotective role of interle\ ukin-6 in diet- and/or pathogen- associated atherosclerosis using an ApoE heterozygote murine model. 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؛kx.cڤygYj>ZjulP7tI[z;w]銀z 7Ӽ }.D(]3㇨Ӭ`bz`bٸ=Dg~*4.NC" gQW=R=ǁru_ E+dgS: + `̽ͱx.~]a#'፧ KUc@'pCX& YsmB_aJ=ϸܞYOTc)m`7E' ^@R{Ae eZ\zJSBjru7!Obٮ-꺴\<Wt[<;ZT\]egsn}̪vj^nͤЉ-j\>k6oinwxЉ7} r3MԢwvTyx+Ǹj,^Oݰ;`mŧ??.uͰ<kʍx<`x#~~/yIJmKn9p_"/⫽<3O <㷴d6q%+?%kUJ3[WJ}D Hg zF b饖2V'FNn'8WY`vugm+:n*0mEM+ޥZ 廱 endstream endobj 467 0 obj <> endobj 468 0 obj [469 0 R 470 0 R 471 0 R 472 0 R 473 0 R 474 0 R 475 0 R 476 0 R 477 0 R 478 0 R 479 0 R 480 0 R 481 0 R 482 0 R 483 0 R 484 0 R] endobj 469 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:122. Schuett, H. etal. Transsignaling of interleukin-6 crucially contributes to \ atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 32, 281 290 \(2012\).\r:273)/F 4/H/N/Rect[235.736 356.974 243.15 344.444]/Subtype/Link/Type/Annot>> endobj 470 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:122. Schuett, H. etal. Transsignaling of interleukin-6 crucially contributes to\ atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 32, 281 290 \(2012\).\r:274)/F 4/H/N/Rect[331.82 345.974 339.761 333.444]/Subtype/Link/Type/Annot>> endobj 471 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:Fig. 2 | IL-6 as a potential therapeutic target in age-related atherosclerosis.\ IL-6 is upregulated in multiple tissues \nthat have important roles in the increase in atherogenesis with ageing. Therefore\ , blockade of IL-6 might be an effectiv:275)/F 4/H/N/Rect[335.228 235.855 339.912 223.444]/Subtype/Link/Type/Annot>> endobj 472 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:123. Scott, L. J. Tocilizumab: a review in rheumatoid arthritis. Drugs 77, 18\ 65 1879 \(2017\).\r:276)/F 4/H/N/Rect[177.562 180.855 185.204 168.444]/Subtype/Link/Type/Annot>> endobj 473 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:124. Kang, S., Tanaka, T., Narazaki, M. & Kishimoto, T. Targeting interleukin-6 s\ ignaling in clinic. Immunity 50, 1007 1023 \(2019\).\r:277)/F 4/H/N/Rect[186.4 180.855 194.043 168.444]/Subtype/Link/Type/Annot>> endobj 474 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:120. Rose- John, S., Winthrop, K. & Calabrese, L. The role of IL-6 in host defe\ nce against infections: immunobiology and clinical implications. Nat. Rev. Rheumatol. 13, 399 409 \(2017\).\r:278)/F 4/H/N/Rect[255.324 147.855 263.066 135.444]/Subtype/Link/Type/Annot>> endobj 475 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:12. Ridker, P. M. etal. Antiinflammatory therapy with canakinumab for atheros\ clerotic disease. N. Engl. \nJ. Med. 377, 1119 1131 \(2017\).\r:279)/F 4/H/N/Rect[270.47 125.855 275.566 113.444]/Subtype/Link/Type/Annot>> endobj 476 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:13. Ridker, P. M. etal. Modulation of the interleukin-6 signalling pathway an\ d incidence rates of atherosclerotic events and all- cause mortality: analyses from the Canakinumab Anti- Inflammatory Thrombosi\ s Outcomes Study \(CANTOS\). Eur. Heart:280)/F 4/H/N/Rect[276.762 125.855 281.857 113.444]/Subtype/Link/Type/Annot>> endobj 477 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:125. Pawar, A. etal. Risk of serious infections in tocilizumab versus other biol\ ogic drugs in patients with rheumatoid arthritis: a multidatabase cohort study. Ann. Rheum. Dis. 78, 456 464 \(2019\).\r:281)/F 4/H/N/Rect[283.012 114.855 290.527 102.444]/Subtype/Link/Type/Annot>> endobj 478 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:56. Kirkland, J. L. & Tchkonia, T. Cellular senescence: \na translational perspec\ tive. EBioMedicine 21, 21 28 \(2017\).\r:282)/F 4/H/N/Rect[217.7 59.8547 222.875 47.4439]/Subtype/Link/Type/Annot>> endobj 479 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:126. Xu, M. etal. Senolytics improve physical function \nand increase lifespan in\ old age. Nat. Med. 24, \n1246 1256 \(2018\).\r:283)/F 4/H/N/Rect[492.85 312.855 500.642 300.444]/Subtype/Link/Type/Annot>> endobj 480 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:127. Roos, C. M. etal. Chronic senolytic treatment alleviates established vasomo\ tor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973 977 \(2016\).\r:284)/F 4/H/N/Rect[501.887 312.855 509.679 300.444]/Subtype/Link/Type/Annot>> endobj 481 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:128. Soukas, A. A., Hao, H. & Wu, L. Metformin as anti- aging therapy: is it for \ everyone? Trends Endocrinol. Metab. 30, 745 755 \(2019\).\r:285)/F 4/H/N/Rect[383.832 290.855 391.475 278.444]/Subtype/Link/Type/Annot>> endobj 482 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:129. Miller, R. A. etal. Rapamycin, but not resveratrol \nor simvastatin, extends\ life span of genetically heterogeneous mice. J. Gerontol. Ser. A Biol. Sci. \nMed. Sci. 66A, 191 201 \(2011\).\r:286)/F 4/H/N/Rect[463.872 279.855 471.838 267.444]/Subtype/Link/Type/Annot>> endobj 483 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:130. Michiels, C. F., Kurdi, A., Timmermans, J.-P., \nDe Meyer, G. R. Y. & Martine\ t, W. Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy. \ Atherosclerosis 251, 319 327 \(2016\):287)/F 4/H/N/Rect[416.835 224.855 424.596 212.444]/Subtype/Link/Type/Annot>> endobj 484 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevCardio_431.indd:11. Tyrrell, D. J. etal. Age- associated mitochondrial dysfunction a\ ccelerates atherogenesis. Circ. 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N5|l:W*]aߵZ.u7L$Y{ˡt붶;mRhUhR~!cb1|vndE_d )nZ'©-NGgSLU=_5Jeс`,hI$vOVbٙ+1ͰKhKyVzY1) jBk0^+E )U"e0x|(i.lu]s%o \_]$i endstream endobj 957 0 obj <>stream HU[r! iួ&`YvL3~X>#6ۚHc;awۿOـ?? |LN?Ah3-ꩇ;FXsMc2\E/sB(Hj>̆Pc-(;e6yxNt}!xuߠC]#!w]9a;nmr'z{im2tVt$f)9= y[iS!b۪ob͉O7hcNu!+M('ձ?踢QMN:RwBpD%DZ6*Ʊ,5׀P2pZ崵^MT;&LߪBP( BP( W{- endstream endobj 958 0 obj <> endobj 959 0 obj <> endobj 960 0 obj <> endobj 961 0 obj <> endobj 962 0 obj <> endobj 963 0 obj <> endobj 964 0 obj <> endobj 965 0 obj <> endobj 966 0 obj <> endobj 967 0 obj <> endobj 968 0 obj <> endobj 969 0 obj <<>> endobj 970 0 obj <>stream application/pdf doi:10.1038/s41569-020-0431-7 Springer US Nature Reviews Cardiology, doi:10.1038/s41569-020-0431-7 Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6 Daniel J. Tyrrell Daniel R. Goldstein 10.1038/s41569-020-0431-7 http://dx.doi.org/10.1038/s41569-020-0431-7 journal Nature Reviews Cardiology © 2020, Springer Nature Limited 1759-5010 10.1038/s41569-020-0431-7 springer.com springerlink.com 2010-04-23 True 10.1038/s41569-020-0431-7 springer.com springerlink.com Springer 2020-12-08T10:36:19+05:30 2020-12-08T10:35:33+05:30 2020-12-08T10:36:19+05:30 True VoR uuid:bbdf91c4-3616-48c7-b6a1-f79432596e52 uuid:1b493060-ab63-4974-8f4d-de5e40d22302 default 1 converted uuid:6ca2d043-da28-43cd-8b59-6960eaa882fa converted to PDF/A-2b pdfToolbox 2020-12-08T10:36:19+05:30 2 B Daniel R. Goldstein http://orcid.org/0000-0001-6695-979X http://ns.adobe.com/pdf/1.3/ pdf Adobe PDF Schema internal A name object indicating whether the document has been modified to include trapping information Trapped Text http://ns.adobe.com/pdfx/1.3/ pdfx pdfx internal ID of PDF/X standard GTS_PDFXVersion Text internal Conformance level of PDF/X standard GTS_PDFXConformance Text internal Company creating the PDF Company Text internal Date when document was last modified SourceModified Text external Mirrors crossmark:CrosMarkDomains CrossMarkDomains Seq Text internal Mirrors crossmark:DOI doi Text http://ns.adobe.com/xap/1.0/mm/ xmpMM XMP Media Management Schema internal UUID based identifier for specific incarnation of a document InstanceID URI internal The common identifier for all versions and renditions of a document. 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In lieu of using #other please reach out to the PRISM group at info@prismstandard.org to request addition of your term to the Aggregation Type Controlled Vocabulary. aggregationType Text external Copyright copyright Text external The Digital Object Identifier for the article. The DOI may also be used as the dc:identifier. If used as a dc:identifier, the URI form should be captured, and the bare identifier should also be captured using prism:doi. If an alternate unique identifier is used as the required dc:identifier, then the DOI should be specified as a bare identifier within prism:doi only. If the URL associated with a DOI is to be specified, then prism:url may be used in conjunction with prism:doi in order to provide the service endpoint (i.e. the URL). doi Text external ISSN for an electronic version of the issue in which the resource occurs. Permits publishers to include a second ISSN, identifying an electronic version of the issue in which the resource occurs (therefore e(lectronic)Issn. If used, prism:eIssn MUST contain the ISSN of the electronic version. See prism:issn. issn Text external Title of the magazine, or other publication, in which a resource was/will be published. Typically this will be used to provide the name of the magazine an article appeared in as metadata for the article, along with information such as the article title, the publisher, volume, number, and cover date. Note: Publication name can be used to differentiate between a print magazine and the online version if the names are different such as “magazine” and “magazine.com.” publicationName Text external This element provides the url for an article or unit of content. The attribute platform is optionally allowed for situations in which multiple URLs must be specified. PRISM recommends that a subset of the PCV platform values, namely “mobile” and “web”, be used in conjunction with this element. NOTE: PRISM recommends against the use of the #other value allowed in the PRISM Platform controlled vocabulary. In lieu of using #other please reach out to the PRISM group at prism-wg@yahoogroups.com to request addition of your term to the Platform Controlled Vocabulary. url Text http://springernature.com/ns/xmpExtensions/2.0/ sn Springer Nature ORCID Schema external Author information: contains the name of each author and his/her ORCID (ORCiD: Open Researcher and Contributor ID). 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