血管老化和中风的炎症分子介导物和途径：综述

Ter Horst, R.; Jaeger, M.; Smeekens, S.P.; Oosting, M.; Swertz, M.A.; Li, Y.; Kumar, V.; Diavatopoulos, D.A.; Jansen, A.F.M.; Lemmers, H.; Toenhake-Dijkstra, H.; van Herwaarden, A.E.; Janssen, M.; van der Molen, R.G.; Joosten, I.; Sweep, F.C.G.J.; Smit, J.W.; Netea-Maier, R.T.; Koenders, M.M.J.F.; Xavier, R.J.; van der Meer, J.W.M.; Dinarello, C.A.; Pavelka, N.; Wijmenga, C.; Notebaart, R.A.; Joosten, L.A.B.; Netea, M.G. Host and environmental factors influencing individual human cytokine responses. Cell, 2016, 167(4), 1111-1124.e13.
[http://dx.doi.org/10.1016/j.cell.2016.10.018] [PMID: 27814508]

Rea, J.N.M.; Carvalho, A.; McNerlan, S.E.; Alexander, H.D.; Rea, I.M. Genes and life-style factors in BELFAST nonagenarians: nature, nurture and narrative. Biogerontology, 2015, 16(5), 587-597.
[http://dx.doi.org/10.1007/s10522-015-9567-y] [PMID: 25773008]

Liu, Y-Z.; Wang, Y-X.; Jiang, C-L. Inflammation: the common pathway of stress-related diseases. Front. Hum. Neurosci., 2017, 11, 316.
[http://dx.doi.org/10.3389/fnhum.2017.00316] [PMID: 28676747]

Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell, 2010, 140(6), 771-776.
[http://dx.doi.org/10.1016/j.cell.2010.03.006] [PMID: 20303867]

Abe, K.; Hashimoto, Y.; Yatsushiro, S.; Yamamura, S.; Bando, M.; Hiroshima, Y.; Kido, J.; Tanaka, M.; Shinohara, Y.; Ooie, T.; Baba, Y.; Kataoka, M. Simultaneous immunoassay analysis of plasma IL-6 and TNF-α on a microchip. PLoS One, 2013, 8(1), e53620.
[http://dx.doi.org/10.1371/journal.pone.0053620] [PMID: 23326472]

Battle, A.; Khan, Z.; Wang, S.H.; Mitrano, A.; Ford, M.J.; Pritchard, J.K.; Gilad, Y. Genomic variation. Impact of regulatory variation from RNA to protein. Science, 2015, 347(6222), 664-667.
[http://dx.doi.org/10.1126/science.1260793] [PMID: 25657249]

Kubiczkova, L.; Sedlarikova, L.; Hajek, R.; Sevcikova, S. TGF-β - an excellent servant but a bad master. J. Transl. Med., 2012, 10, 183.
[http://dx.doi.org/10.1186/1479-5876-10-183] [PMID: 22943793]

Franceschi, C.; Bonafè, M.; Valensin, S.; Olivieri, F.; De Luca, M.; Ottaviani, E.; De Benedictis, G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci., 2000, 908, 244-254.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb06651.x] [PMID: 10911963]

Franceschi, C.; Capri, M.; Monti, D.; Giunta, S.; Olivieri, F.; Sevini, F.; Panourgia, M.P.; Invidia, L.; Celani, L.; Scurti, M.; Cevenini, E.; Castellani, G.C.; Salvioli, S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev., 2007, 128(1), 92-105.
[http://dx.doi.org/10.1016/j.mad.2006.11.016] [PMID: 17116321]

Franceschi, C.; Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(Suppl. 1), S4-S9.
[http://dx.doi.org/10.1093/gerona/glu057] [PMID: 24833586]

Chung, H.Y.; Cesari, M.; Anton, S.; Marzetti, E.; Giovannini, S.; Seo, A.Y.; Carter, C.; Yu, B.P.; Leeuwenburgh, C. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev., 2009, 8(1), 18-30.
[http://dx.doi.org/10.1016/j.arr.2008.07.002] [PMID: 18692159]

Rea, I.M.; Gibson, D.S.; McGilligan, V.; McNerlan, S.E.; Alexander, H.D.; Ross, O.A. Age and age-related diseases: role of inflammation triggers and cytokines. Front. Immunol., 2018, 9, 586.
[http://dx.doi.org/10.3389/fimmu.2018.00586] [PMID: 29686666]

Fredman, G.; Hellmann, J.; Proto, J.D.; Kuriakose, G.; Colas, R.A.; Dorweiler, B.; Connolly, E.S.; Solomon, R.; Jones, D.M.; Heyer, E.J.; Spite, M.; Tabas, I. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun., 2016, 7, 12859.
[http://dx.doi.org/10.1038/ncomms12859] [PMID: 27659679]

Forsey, R.J.; Thompson, J.M.; Ernerudh, J.; Hurst, T.L.; Strindhall, J.; Johansson, B.; Nilsson, B-O.; Wikby, A. Plasma cytokine profiles in elderly humans. Mech. Ageing Dev., 2003, 124(4), 487-493.
[http://dx.doi.org/10.1016/S0047-6374(03)00025-3] [PMID: 12714257]

Ferrucci, L.; Harris, T.B.; Guralnik, J.M.; Tracy, R.P.; Corti, M.C.; Cohen, H.J.; Penninx, B.; Pahor, M.; Wallace, R.; Havlik, R.J. Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc., 1999, 47(6), 639-646.
[http://dx.doi.org/10.1111/j.1532-5415.1999.tb01583.x] [PMID: 10366160]

Wei, J.; Xu, H.; Davies, J.L.; Hemmings, G.P. Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci., 1992, 51(25), 1953-1956.
[http://dx.doi.org/10.1016/0024-3205(92)90112-3] [PMID: 1453878]

Fichtlscherer, S.; Rosenberger, G.; Walter, D.H.; Breuer, S.; Dimmeler, S.; Zeiher, A.M. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation, 2000, 102(9), 1000-1006.
[http://dx.doi.org/10.1161/01.CIR.102.9.1000] [PMID: 10961964]

Lind, L.; Siegbahn, A.; Hulthe, J.; Elmgren, A. C-reactive protein and e-selectin levels are related to vasodilation in resistance, but not conductance arteries in the elderly: the prospective investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Atherosclerosis, 2008, 199(1), 129-137.
[http://dx.doi.org/10.1016/j.atherosclerosis.2007.09.038] [PMID: 17991470]

Mattace-Raso, F.U.S.; van der Cammen, T.J.M.; van der Meer, I.M.; Schalekamp, M.A.D.H.; Asmar, R.; Hofman, A.; Witteman, J.C.M. C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis, 2004, 176(1), 111-116.
[http://dx.doi.org/10.1016/j.atherosclerosis.2004.04.014] [PMID: 15306182]

Joseph, V.A.; John, K.F.; Martin, L.G.; Michelle, K.J.; Joseph, M.M.; Izabella, L.; Birgitta, L.T.; Shuxia, F.; Ewa, O.; Peter, W.W.F.; Ramachandran, V.S.; Gary, M.F.; Emelia, B.J. Brachial artery vasodilator function and systemic inflammation in the framingham offspring study. Circulation, 2004, 110, 3604-3609.

Schnabel, R.; Larson, M.G.; Dupuis, J.; Lunetta, K.L.; Lipinska, I.; Meigs, J.B.; Yin, X.; Rong, J.; Vita, J.A.; Newton-Cheh, C.; Levy, D.; Keaney, J.F., Jr; Vasan, R.S.; Mitchell, G.F.; Benjamin, E.J. Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension, 2008, 51(6), 1651-1657.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.105668] [PMID: 18426996]

Tchalla, A.E.; Wellenius, G.A.; Travison, T.G.; Gagnon, M.; Iloputaife, I.; Dantoine, T.; Sorond, F.A.; Lipsitz, L.A. Circulating vascular cell adhesion molecule-1 is associated with cerebral blood flow dysregulation, mobility impairment, and falls in older adults. Hypertension, 2015, 66(2), 340-346.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05180] [PMID: 26056332]

Walker, A.E.; Seibert, S.M.; Donato, A.J.; Pierce, G.L.; Seals, D.R. Vascular endothelial function is related to white blood cell count and myeloperoxidase among healthy middle-aged and older adults. Hypertension, 2010, 55(2), 363-369.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.145870] [PMID: 20048194]

Puz, P.; Lasek-Bal, A.; Ziaja, D.; Kazibutowska, Z.; Ziaja, K. Inflammatory markers in patients with internal carotid artery stenosis. Arch. Med. Sci., 2013, 9(2), 254-260.
[http://dx.doi.org/10.5114/aoms.2013.34533] [PMID: 23671435]

Giacconi, R.; Cipriano, C.; Albanese, F.; Boccoli, G.; Saba, V.; Olivieri, F.; Franceschi, C.; Mocchegiani, E. The -174G/C polymorphism of IL-6 is useful to screen old subjects at risk for atherosclerosis or to reach successful ageing. Exp. Gerontol., 2004, 39(4), 621-628.
[http://dx.doi.org/10.1016/j.exger.2003.12.013] [PMID: 15050298]

Freitas, W.M.; Quaglia, L.A.; Santos, S.N.; Soares, A.A.S.; Japiassú, A.V.T.; Boaventura, V.; dos Santos Barros, E.; Córdova, C.; Nóbrega, O.T.; Sposito, A.C. Association of systemic inflammatory activity with coronary and carotid atherosclerosis in the very elderly. Atherosclerosis, 2011, 216(1), 212-216.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.01.040] [PMID: 21316055]

Machado-Silva, W.; Henriques, A.D.; Souza, G.D.; Gomes, L.; Ferreira, A.P.; Brito, C.J.; Córdova, C.; Moraes, C.F.; Nóbrega, O.T. Serum immune mediators independently associate with atherosclerosis in the left (but not right) carotid territory of older individuals. J. Stroke Cerebrovasc. Dis., 2016, 25(12), 2851-2858.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.07.047] [PMID: 27554076]

Koh, S.J.; Kim, J.Y.; Hyun, Y.J.; Park, S.H.; Chae, J.S.; Park, S.; Kim, J-S.; Youn, J.C.; Jang, Y.; Lee, J.H. Association of serum RANTES concentrations with established cardiovascular risk markers in middle-aged subjects. Int. J. Cardiol., 2009, 132(1), 102-108.
[http://dx.doi.org/10.1016/j.ijcard.2007.10.038] [PMID: 18190991]

Rodríguez-Mañas, L.; El-Assar, M.; Vallejo, S.; López-Dóriga, P.; Solís, J.; Petidier, R.; Montes, M.; Nevado, J.; Castro, M.; Gómez-Guerrero, C.; Peiró, C.; Sánchez-Ferrer, C.F. Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation. Aging Cell, 2009, 8(3), 226-238.
[http://dx.doi.org/10.1111/j.1474-9726.2009.00466.x] [PMID: 19245678]

Samuel, M.; Tardif, J-C.; Khairy, P.; Roubille, F.; Waters, D.D.; Grégoire, J.C.; Pinto, F.J.; Maggioni, A.P.; Diaz, R.; Berry, C.; Koenig, W.; Ostadal, P.; Lopez-Sendon, J.; Gamra, H.; Kiwan, G.S.; Dubé, M-P.; Provencher, M.; Orfanos, A.; Blondeau, L.; Kouz, S.; L’Allier, P.L.; Ibrahim, R.; Bouabdallaoui, N.; Mitchell, D.; Guertin, M-C.; Lelorier, J. Cost-effectiveness of low-dose colchicine after myocardial infarction in the colchicine cardiovascular outcomes trial (COLCOT). Eur. Heart J. Qual. Care Clin. Outcomes, 2020, •••, qcaa045.
[http://dx.doi.org/10.1093/ehjqcco/qcaa045]

Nidorf, S.M.; Fiolet, A.T.L.; Mosterd, A.; Eikelboom, J.W.; Schut, A.; Opstal, T.S.J.; The, S.H.K.; Xu, X-F.; Ireland, M.A.; Lenderink, T.; Latchem, D.; Hoogslag, P.; Jerzewski, A.; Nierop, P.; Whelan, A.; Hendriks, R.; Swart, H.; Schaap, J.; Kuijper, A.F.M.; van Hessen, M.W.J.; Saklani, P.; Tan, I.; Thompson, A.G.; Morton, A.; Judkins, C.; Bax, W.A.; Dirksen, M.; Alings, M.; Hankey, G.J.; Budgeon, C.A.; Tijssen, J.G.P.; Cornel, J.H.; Thompson, P.L. Colchicine in patients with chronic coronary disease. N. Engl. J. Med., 2020, 383(19), 1838-1847.
[http://dx.doi.org/10.1056/NEJMoa2021372] [PMID: 32865380]

Tong, D.C.; Quinn, S.; Nasis, A.; Hiew, C.; Roberts-Thomson, P.; Adams, H.; Sriamareswaran, R.; Htun, N.M.; Wilson, W.; Stub, D.; van Gaal, W.; Howes, L.; Collins, N.; Yong, A.; Bhindi, R.; Whitbourn, R.; Lee, A.; Hengel, C.; Asrress, K.; Freeman, M.; Amerena, J.; Wilson, A.; Layland, J. Colchicine in patients with acute coronary syndrome: the australian COPS randomized clinical trial. Circulation, 2020, 142(20), 1890-1900.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050771] [PMID: 32862667]

Ridker, P.M.; Devalaraja, M.; Baeres, F.M.M.; Engelmann, M.D.M.; Hovingh, G.K.; Ivkovic, M.; Lo, L.; Kling, D.; Pergola, P.; Raj, D.; Libby, P.; Davidson, M. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet, 2021, 397(10289), 2060-2069.
[http://dx.doi.org/10.1016/S0140-6736(21)00520-1] [PMID: 34015342]

Ershler, W.B. Interleukin-6: a cytokine for gerontologists. J. Am. Geriatr. Soc., 1993, 41(2), 176-181.
[http://dx.doi.org/10.1111/j.1532-5415.1993.tb02054.x] [PMID: 8426042]

Ershler, W.B.; Keller, E.T. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu. Rev. Med., 2000, 51, 245-270.
[http://dx.doi.org/10.1146/annurev.med.51.1.245] [PMID: 10774463]

Weiss, T.W.; Arnesen, H.; Seljeflot, I. Components of the interleukin-6 transsignalling system are associated with the metabolic syndrome, endothelial dysfunction and arterial stiffness. Metabolism, 2013, 62(7), 1008-1013.
[http://dx.doi.org/10.1016/j.metabol.2013.01.019] [PMID: 23428306]

Puzianowska-Kuźnicka, M.; Owczarz, M.; Wieczorowska-Tobis, K.; Nadrowski, P.; Chudek, J.; Slusarczyk, P.; Skalska, A.; Jonas, M.; Franek, E.; Mossakowska, M. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun. Ageing, 2016, 13, 21.
[http://dx.doi.org/10.1186/s12979-016-0076-x] [PMID: 27274758]

Van Epps, P.; Oswald, D.; Higgins, P.A.; Hornick, T.R.; Aung, H.; Banks, R.E.; Wilson, B.M.; Burant, C.; Graventstein, S.; Canaday, D.H. Frailty has a stronger association with inflammation than age in older veterans. Immun. Ageing, 2016, 13, 27.
[http://dx.doi.org/10.1186/s12979-016-0082-z] [PMID: 27777599]

Varadhan, R.; Yao, W.; Matteini, A.; Beamer, B.A.; Xue, Q-L.; Yang, H.; Manwani, B.; Reiner, A.; Jenny, N.; Parekh, N.; Fallin, M.D.; Newman, A.; Bandeen-Roche, K.; Tracy, R.; Ferrucci, L.; Walston, J. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(2), 165-173.
[http://dx.doi.org/10.1093/gerona/glt023] [PMID: 23689826]

Hubbard, R.E.; O’Mahony, M.S.; Savva, G.M.; Calver, B.L.; Woodhouse, K.W. Inflammation and frailty measures in older people. J. Cell. Mol. Med., 2009, 13(9B), 3103-3109.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00733.x] [PMID: 19438806]

Alemán, H.; Esparza, J.; Ramirez, F.A.; Astiazaran, H.; Payette, H. Longitudinal evidence on the association between interleukin-6 and C-reactive protein with the loss of total appendicular skeletal muscle in free-living older men and women. Age Ageing, 2011, 40(4), 469-475.
[http://dx.doi.org/10.1093/ageing/afr040] [PMID: 21565862]

Ridker, P.M.; Rifai, N.; Stampfer, M.J.; Hennekens, C.H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation, 2000, 101(15), 1767-1772.
[http://dx.doi.org/10.1161/01.CIR.101.15.1767] [PMID: 10769275]

Miwa, K.; Okazaki, S.; Sakaguchi, M.; Mochizuki, H.; Kitagawa, K. Interleukin-6, interleukin-6 receptor gene variant, small-vessel disease and incident dementia. Eur. J. Neurol., 2016, 23(3), 656-663.
[http://dx.doi.org/10.1111/ene.12921] [PMID: 26725994]

Spoto, B.; Mattace-Raso, F.; Sijbrands, E.; Leonardis, D.; Testa, A.; Pisano, A.; Pizzini, P.; Cutrupi, S.; Parlongo, R.M.; D’Arrigo, G.; Tripepi, G.; Mallamaci, F.; Zoccali, C. Association of IL-6 and a functional polymorphism in the IL-6 gene with cardiovascular events in patients with CKD. Clin. J. Am. Soc. Nephrol., 2015, 10(2), 232-240.
[http://dx.doi.org/10.2215/CJN.07000714] [PMID: 25492254]

Di Bona, D.; Vasto, S.; Capurso, C.; Christiansen, L.; Deiana, L.; Franceschi, C.; Hurme, M.; Mocchegiani, E.; Rea, M.; Lio, D.; Candore, G.; Caruso, C. Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res. Rev., 2009, 8(1), 36-42.
[http://dx.doi.org/10.1016/j.arr.2008.09.001] [PMID: 18930842]

Soerensen, M.; Dato, S.; Tan, Q.; Thinggaard, M.; Kleindorp, R.; Beekman, M.; Suchiman, H.E.D.; Jacobsen, R.; McGue, M.; Stevnsner, T.; Bohr, V.A.; de Craen, A.J.M.; Westendorp, R.G.J.; Schreiber, S.; Slagboom, P.E.; Nebel, A.; Vaupel, J.W.; Christensen, K.; Christiansen, L. Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age (Dordr.), 2013, 35(2), 487-500.
[http://dx.doi.org/10.1007/s11357-011-9373-7] [PMID: 22234866]

Swerdlow, D.I.; Holmes, M.V.; Kuchenbaecker, K.B.; Engmann, J.E.L.; Shah, T.; Sofat, R.; Guo, Y.; Chung, C.; Peasey, A.; Pfister, R.; Mooijaart, S.P.; Ireland, H.A.; Leusink, M.; Langenberg, C.; Li, K.W.; Palmen, J.; Howard, P.; Cooper, J.A.; Drenos, F.; Hardy, J.; Nalls, M.A.; Li, Y.R.; Lowe, G.; Stewart, M.; Bielinski, S.J.; Peto, J.; Timpson, N.J.; Gallacher, J.; Dunlop, M.; Houlston, R.; Tomlinson, I.; Tzoulaki, I.; Luan, J.; Boer, J.M.A.; Forouhi, N.G.; Onland-Moret, N.C.; van der Schouw, Y.T.; Schnabel, R.B.; Hubacek, J.A.; Kubinova, R.; Baceviciene, M.; Tamosiunas, A.; Pajak, A.; Topor-Madry, R.; Malyutina, S.; Baldassarre, D.; Sennblad, B.; Tremoli, E.; de Faire, U.; Ferrucci, L.; Bandenelli, S.; Tanaka, T.; Meschia, J.F.; Singleton, A.; Navis, G.; Mateo Leach, I.; Bakker, S.J.L.; Gansevoort, R.T.; Ford, I.; Epstein, S.E.; Burnett, M.S.; Devaney, J.M.; Jukema, J.W.; Westendorp, R.G.J.; Jan de Borst, G.; van der Graaf, Y.; de Jong, P.A.; Mailand-van der Zee, A-H.; Klungel, O.H.; de Boer, A.; Doevendans, P.A.; Stephens, J.W.; Eaton, C.B.; Robinson, J.G.; Manson, J.E.; Fowkes, F.G.; Frayling, T.M.; Price, J.F.; Whincup, P.H.; Morris, R.W.; Lawlor, D.A.; Smith, G.D.; Ben-Shlomo, Y.; Redline, S.; Lange, L.A.; Kumari, M.; Wareham, N.J.; Verschuren, W.M.M.; Benjamin, E.J.; Whittaker, J.C.; Hamsten, A.; Dudbridge, F.; Delaney, J.A.C.; Wong, A.; Kuh, D.; Hardy, R.; Castillo, B.A.; Connolly, J.J.; van der Harst, P.; Brunner, E.J.; Marmot, M.G.; Wassel, C.L.; Humphries, S.E.; Talmud, P.J.; Kivimaki, M.; Asselbergs, F.W.; Voevoda, M.; Bobak, M.; Pikhart, H.; Wilson, J.G.; Hakonarson, H.; Reiner, A.P.; Keating, B.J.; Sattar, N.; Hingorani, A.D.; Casas, J.P. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet, 2012, 379(9822), 1214-1224.
[http://dx.doi.org/10.1016/S0140-6736(12)60110-X] [PMID: 22421340]

Davies, R.; Choy, E. Clinical experience of IL-6 blockade in rheumatic diseases - implications on IL-6 biology and disease pathogenesis. Semin. Immunol., 2014, 26(1), 97-104.
[http://dx.doi.org/10.1016/j.smim.2013.12.002] [PMID: 24389239]

Ferrucci, L.; Corsi, A.; Lauretani, F.; Bandinelli, S.; Bartali, B.; Taub, D.D.; Guralnik, J.M.; Longo, D.L. The origins of age-related proinflammatory state. Blood, 2005, 105(6), 2294-2299.
[http://dx.doi.org/10.1182/blood-2004-07-2599] [PMID: 15572589]

Sims, J.E.; Smith, D.E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol., 2010, 10(2), 89-102.
[http://dx.doi.org/10.1038/nri2691] [PMID: 20081871]

McNerlan, S.E.; Rea, I.M.; Alexander, H.D. A whole blood method for measurement of intracellular TNF-alpha, IFN-gamma and IL-2 expression in stimulated CD3+ lymphocytes: differences between young and elderly subjects. Exp. Gerontol., 2002, 37(2-3), 227-234.
[http://dx.doi.org/10.1016/S0531-5565(01)00188-7] [PMID: 11772508]

O’Mahony, L.; Holland, J.; Jackson, J.; Feighery, C.; Hennessy, T.P.; Mealy, K. Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin. Exp. Immunol., 1998, 113(2), 213-219.
[http://dx.doi.org/10.1046/j.1365-2249.1998.00641.x] [PMID: 9717970]

Armstrong, M.E.; Alexander, H.D.; Ritchie, J.L.; McMillan, S.A.; Rea, I.M. Age-related alterations in basal expression and in vitro, tumour necrosis factor alpha mediated, upregulation of CD11b. Gerontology, 2001, 47(4), 180-185.
[http://dx.doi.org/10.1159/000052795] [PMID: 11408721]

Bruunsgaard, H.; Skinhøj, P.; Pedersen, A.N.; Schroll, M.; Pedersen, B.K. Ageing, tumour necrosis factor-α (TNF-α) and atherosclerosis. Clin. Exp. Immunol., 2000, 121(2), 255-260.
[http://dx.doi.org/10.1046/j.1365-2249.2000.01281.x] [PMID: 10931139]

Ridker Paul, M. Rifai Nader; Pfeffer Marc; Sacks Frank; Lepage serge; braunwald eugene. elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction. Circulation, 2000, 101, 2149-2153.
[http://dx.doi.org/10.1161/01.CIR.101.18.2149]

Nilsson, L.; Szymanowski, A.; Swahn, E.; Jonasson, L. Soluble TNF receptors are associated with infarct size and ventricular dysfunction in ST-elevation myocardial infarction. PLoS One, 2013, 8(2), e55477.
[http://dx.doi.org/10.1371/journal.pone.0055477] [PMID: 23405158]

Ruparelia, N.; Chai, J.T.; Fisher, E.A.; Choudhury, R.P. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat. Rev. Cardiol., 2017, 14(3), 133-144.
[http://dx.doi.org/10.1038/nrcardio.2016.185] [PMID: 27905474]

Shamim, D.; Laskowski, M. Inhibition of inflammation mediated through the tumor necrosis factor α biochemical pathway can lead to favorable outcomes in Alzheimer disease. J. Cent. Nerv. Syst. Dis., 2017, 9, 1179573517722512.
[http://dx.doi.org/10.1177/1179573517722512] [PMID: 28811745]

Di Iorio, A.; Ferrucci, L.; Sparvieri, E.; Cherubini, A.; Volpato, S.; Corsi, A.; Bonafè, M.; Franceschi, C.; Abate, G.; Paganelli, R. Serum IL-1beta levels in health and disease: a population-based study. ‘The InCHIANTI study’. Cytokine, 2003, 22(6), 198-205.
[http://dx.doi.org/10.1016/S1043-4666(03)00152-2] [PMID: 12890453]

2012. Meta-Analysis, A. PLoS One, 2012, 7, e45641. Associations between interleukin-1 gene polymorphisms and coronary heart disease risk.
[http://dx.doi.org/10.1371/journal.pone.0045641] [PMID: 23029154]

Yoshimura, A.; Wakabayashi, Y.; Mori, T. Cellular and molecular basis for the regulation of inflammation by TGF-beta. J. Biochem., 2010, 147(6), 781-792.
[http://dx.doi.org/10.1093/jb/mvq043] [PMID: 20410014]

Rea, I.M.; Maxwell, L.D.; McNerlan, S.E.; Alexander, H.D.; Curran, M.D.; Middleton, D.; Ross, O.A. Killer immunoglobulin-like receptors (KIR) haplogroups A and B track with natural killer cells and cytokine profile in aged subjects: observations from octo/nonagenarians in the belfast elderly longitudinal free-living aging study (BELFAST). Immun. Ageing, 2013, 10(1), 35.
[http://dx.doi.org/10.1186/1742-4933-10-35] [PMID: 23957956]

Krieglstein, K.; Miyazono, K.; ten Dijke, P.; Unsicker, K. TGF-β in aging and disease. Cell Tissue Res., 2012, 347(1), 5-9.
[http://dx.doi.org/10.1007/s00441-011-1278-3] [PMID: 22183203]

Pastrana, J.L.; Sha, X.; Virtue, A.; Mai, J.; Cueto, R.; Lee, I.A.; Wang, H.; Yang, X. Regulatory T cells and atherosclerosis. J. Clin. Exp. Cardiolog, 2012, 2012, 012.

Burks, T.N.; Cohn, R.D. Role of TGF-β signaling in inherited and acquired myopathies. Skelet. Muscle, 2011, 1(1), 19.
[http://dx.doi.org/10.1186/2044-5040-1-19] [PMID: 21798096]

Baugé, C.; Girard, N.; Lhuissier, E.; Bazille, C.; Boumediene, K. Regulation and role of TGFβ signaling pathway in aging and osteoarthritis joints. Aging Dis., 2013, 5(6), 394-405.
[PMID: 25489490]

Doyle, K.P.; Cekanaviciute, E.; Mamer, L.E.; Buckwalter, M.S. TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. J. Neuroinflammation, 2010, 7, 62.
[http://dx.doi.org/10.1186/1742-2094-7-62] [PMID: 20937129]

Mallat, Z.; Gojova, A.; Marchiol-Fournigault, C.; Esposito, B.; Kamaté, C.; Merval, R.; Fradelizi, D.; Tedgui, A. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ. Res., 2001, 89(10), 930-934.
[http://dx.doi.org/10.1161/hh2201.099415] [PMID: 11701621]

Tran, D.Q. TGF-β: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J. Mol. Cell Biol., 2012, 4(1), 29-37.
[http://dx.doi.org/10.1093/jmcb/mjr033] [PMID: 22158907]

Ouyang, W.; Rutz, S.; Crellin, N.K.; Valdez, P.A.; Hymowitz, S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol., 2011, 29, 71-109.
[http://dx.doi.org/10.1146/annurev-immunol-031210-101312] [PMID: 21166540]

Commins, S.; Steinke, J.W.; Borish, L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J. Allergy Clin. Immunol., 2008, 121(5), 1108-1111.
[http://dx.doi.org/10.1016/j.jaci.2008.02.026] [PMID: 18405958]

Sansoni, P.; Vescovini, R.; Fagnoni, F.; Biasini, C.; Zanni, F.; Zanlari, L.; Telera, A.; Lucchini, G.; Passeri, G.; Monti, D.; Franceschi, C.; Passeri, M. The immune system in extreme longevity. Exp. Gerontol., 2008, 43(2), 61-65.
[http://dx.doi.org/10.1016/j.exger.2007.06.008] [PMID: 17870272]

Rink, L.; Cakman, I.; Kirchner, H. Altered cytokine production in the elderly. Mech. Ageing Dev., 1998, 102(2-3), 199-209.
[http://dx.doi.org/10.1016/S0047-6374(97)00153-X] [PMID: 9720652]

Didion, S.P.; Kinzenbaw, D.A.; Schrader, L.I.; Chu, Y.; Faraci, F.M. Endogenous interleukin-10 inhibits angiotensin II-induced vascular dysfunction. Hypertension, 2009, 54(3), 619-624.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.137158] [PMID: 19620507]

Kinzenbaw, D.A.; Chu, Y.; Peña Silva, R.A.; Didion, S.P.; Faraci, F.M. Interleukin-10 protects against aging-induced endothelial dysfunction. Physiol. Rep., 2013, 1(6), e00149.
[http://dx.doi.org/10.1002/phy2.149] [PMID: 24400151]

Fichtlscherer, S.; Breuer, S.; Heeschen, C.; Dimmeler, S.; Zeiher, A.M. Interleukin-10 serum levels and systemic endothelial vasoreactivity in patients with coronary artery disease. J. Am. Coll. Cardiol., 2004, 44(1), 44-49.
[http://dx.doi.org/10.1016/j.jacc.2004.02.054] [PMID: 15234404]

Lio, D.; Scola, L.; Crivello, A.; Colonna-Romano, G.; Candore, G.; Bonafé, M.; Cavallone, L.; Marchegiani, F.; Olivieri, F.; Franceschi, C.; Caruso, C. Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10 -1082 promoter SNP and its interaction with TNF-α -308 promoter SNP. J. Med. Genet., 2003, 40(4), 296-299.
[http://dx.doi.org/10.1136/jmg.40.4.296] [PMID: 12676903]

Westendorp, R.G.; Langermans, J.A.; Huizinga, T.W.; Elouali, A.H.; Verweij, C.L.; Boomsma, D.I.; Vandenbroucke, J.P.; Vandenbrouke, J.P. Genetic influence on cytokine production and fatal meningococcal disease. Lancet, 1997, 349(9046), 170-173.
[http://dx.doi.org/10.1016/S0140-6736(96)06413-6] [PMID: 9111542]

Lakoski, S.G.; Liu, Y.; Brosnihan, K.B.; Herrington, D.M. Interleukin-10 concentration and coronary heart disease (CHD) event risk in the estrogen replacement and atherosclerosis (ERA) study. Atherosclerosis, 2008, 197(1), 443-447.
[http://dx.doi.org/10.1016/j.atherosclerosis.2007.06.033] [PMID: 17706223]

Welsh, P.; Murray, H.M.; Ford, I.; Trompet, S.; de Craen, A.J.M.; Jukema, J.W.; Stott, D.J.; McInnes, I.B.; Packard, C.J.; Westendorp, R.G.J.; Sattar, N. Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk. Arterioscler. Thromb. Vasc. Biol., 2011, 31(10), 2338-2344.
[http://dx.doi.org/10.1161/ATVBAHA.111.231795] [PMID: 21757655]

Csiszar, A.; Ungvari, Z.; Edwards, J.G.; Kaminski, P.; Wolin, M.S.; Koller, A.; Kaley, G. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ. Res., 2002, 90(11), 1159-1166.
[http://dx.doi.org/10.1161/01.RES.0000020401.61826.EA] [PMID: 12065318]

Ungvari, Z.; Orosz, Z.; Labinskyy, N.; Rivera, A.; Xiangmin, Z.; Smith, K.; Csiszar, A. Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am. J. Physiol. Heart Circ. Physiol., 2007, 293(1), H37-H47.
[http://dx.doi.org/10.1152/ajpheart.01346.2006] [PMID: 17416599]

Csiszar, A.; Ungvari, Z.; Koller, A.; Edwards, J.G.; Kaley, G. Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging. Physiol. Genomics, 2004, 17(1), 21-30.
[http://dx.doi.org/10.1152/physiolgenomics.00136.2003] [PMID: 15020720]

Pearson, K.J.; Baur, J.A.; Lewis, K.N.; Peshkin, L.; Price, N.L.; Labinskyy, N.; Swindell, W.R.; Kamara, D.; Minor, R.K.; Perez, E.; Jamieson, H.A.; Zhang, Y.; Dunn, S.R.; Sharma, K.; Pleshko, N.; Woollett, L.A.; Csiszar, A.; Ikeno, Y.; Le Couteur, D.; Elliott, P.J.; Becker, K.G.; Navas, P.; Ingram, D.K.; Wolf, N.S.; Ungvari, Z.; Sinclair, D.A.; de Cabo, R. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab., 2008, 8(2), 157-168.
[http://dx.doi.org/10.1016/j.cmet.2008.06.011] [PMID: 18599363]

Csiszar, A.; Ungvari, Z.; Koller, A.; Edwards, J.G.; Kaley, G. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J., 2003, 17(9), 1183-1185.
[http://dx.doi.org/10.1096/fj.02-1049fje] [PMID: 12709402]

Cernadas, M.R.; de Miguel, L.S.; García-Durán, M. González-Fernández, F.; Millás, I.; Montón, M.; Rodrigo, J.; Rico, L.; Fernández, P.; de Frutos, T.; Rodríguez-Feo, J.A. Expression of constitutive and inducible nitric oxide synthases in the vascular wall of young and aging rats. Circ. Res., 1998, 83, 279-286.

Wang, M.; Zhang, J.; Jiang, L-Q.; Spinetti, G.; Pintus, G.; Monticone, R.; Kolodgie, F.D.; Virmani, R.; Lakatta, E.G. Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension, 2007, 50(1), 219-227.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.089409] [PMID: 17452499]

Miles, E.A.; Rees, D.; Banerjee, T.; Cazzola, R.; Lewis, S.; Wood, R.; Oates, R.; Tallant, A.; Cestaro, B.; Yaqoob, P.; Wahle, K.W.J.; Calder, P.C. Age-related increases in circulating inflammatory markers in men are independent of BMI, blood pressure and blood lipid concentrations. Atherosclerosis, 2008, 196(1), 298-305.
[http://dx.doi.org/10.1016/j.atherosclerosis.2006.11.002] [PMID: 17118371]

Csiszar, A.; Labinskyy, N.; Smith, K.; Rivera, A.; Orosz, Z.; Ungvari, Z. Vasculoprotective effects of anti-tumor necrosis factor-α treatment in aging. Am. J. Pathol., 2007, 170(1), 388-398.
[http://dx.doi.org/10.2353/ajpath.2007.060708] [PMID: 17200210]

Arenas, I.A.; Xu, Y.; Davidge, S.T. Age-associated impairment in vasorelaxation to fluid shear stress in the female vasculature is improved by TNF-alpha antagonism. Am. J. Physiol. Heart Circ. Physiol., 2006, 290(3), H1259-H1263.
[http://dx.doi.org/10.1152/ajpheart.00990.2005] [PMID: 16284227]

Straub, R.H.; Schradin, C. Chronic inflammatory systemic diseases: An evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol. Med. Public Health, 2016, 2016(1), 37-51.
[http://dx.doi.org/10.1093/emph/eow001] [PMID: 26817483]

Beyer, I.; Mets, T.; Bautmans, I. Chronic low-grade inflammation and age-related sarcopenia. Curr. Opin. Clin. Nutr. Metab. Care, 2012, 15(1), 12-22.
[http://dx.doi.org/10.1097/MCO.0b013e32834dd297] [PMID: 22108098]

Sanada, F.; Taniyama, Y.; Muratsu, J.; Otsu, R.; Shimizu, H.; Rakugi, H.; Morishita, R. Source of chronic inflammation in aging. Front. Cardiovasc. Med., 2018, 5, 12.
[http://dx.doi.org/10.3389/fcvm.2018.00012] [PMID: 29564335]

Zhang, Q.; Raoof, M.; Chen, Y.; Sumi, Y.; Sursal, T.; Junger, W.; Brohi, K.; Itagaki, K.; Hauser, C.J. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature, 2010, 464(7285), 104-107.
[http://dx.doi.org/10.1038/nature08780] [PMID: 20203610]

Dall’Olio, F.; Vanhooren, V.; Chen, C.C.; Slagboom, P.E.; Wuhrer, M.; Franceschi, C. N-glycomic biomarkers of biological aging and longevity: a link with inflammaging. Ageing Res. Rev., 2013, 12(2), 685-698.
[http://dx.doi.org/10.1016/j.arr.2012.02.002] [PMID: 22353383]

Wang, G.C.; Kao, W.H.L.; Murakami, P.; Xue, Q-L.; Chiou, R.B.; Detrick, B.; McDyer, J.F.; Semba, R.D.; Casolaro, V.; Walston, J.D.; Fried, L.P. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am. J. Epidemiol., 2010, 171(10), 1144-1152.
[http://dx.doi.org/10.1093/aje/kwq062] [PMID: 20400465]

Kinross, J.; Nicholson, J.K. Gut microbiota: Dietary and social modulation of gut microbiota in the elderly. Nat. Rev. Gastroenterol. Hepatol., 2012, 9(10), 563-564.
[http://dx.doi.org/10.1038/nrgastro.2012.169] [PMID: 22945446]

Toward, R.; Montandon, S.; Walton, G.; Gibson, G.R. Effect of prebiotics on the human gut microbiota of elderly persons. Gut Microbes, 2012, 3(1), 57-60.
[http://dx.doi.org/10.4161/gmic.19411] [PMID: 22555548]

Claesson, M.J.; Cusack, S.; O’Sullivan, O.; Greene-Diniz, R.; de Weerd, H.; Flannery, E.; Marchesi, J.R.; Falush, D.; Dinan, T.; Fitzgerald, G.; Stanton, C.; van Sinderen, D.; O’Connor, M.; Harnedy, N.; O’Connor, K.; Henry, C.; O’Mahony, D.; Fitzgerald, A.P.; Shanahan, F.; Twomey, C.; Hill, C.; Ross, R.P.; O’Toole, P.W. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc. Natl. Acad. Sci. USA, 2011, 108(Suppl. 1), 4586-4591.
[http://dx.doi.org/10.1073/pnas.1000097107] [PMID: 20571116]

Shaw, A.C.; Goldstein, D.R.; Montgomery, R.R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol., 2013, 13(12), 875-887.
[http://dx.doi.org/10.1038/nri3547] [PMID: 24157572]

Aw, D.; Silva, A.B.; Palmer, D.B. Immunosenescence: emerging challenges for an ageing population. Immunology, 2007, 120(4), 435-446.
[http://dx.doi.org/10.1111/j.1365-2567.2007.02555.x] [PMID: 17313487]

Gruver, A.L.; Hudson, L.L.; Sempowski, G.D. Immunosenescence of ageing. J. Pathol., 2007, 211(2), 144-156.
[http://dx.doi.org/10.1002/path.2104] [PMID: 17200946]

de Magalhães, J.P.; Passos, J.F. Stress, cell senescence and organismal ageing. Mech. Ageing Dev., 2018, 170, 2-9.
[http://dx.doi.org/10.1016/j.mad.2017.07.001] [PMID: 28688962]

Ungvari, Z.; Tarantini, S.; Hertelendy, P.; Valcarcel-Ares, M.N.; Fülöp, G.A.; Logan, S.; Kiss, T.; Farkas, E.; Csiszar, A.; Yabluchanskiy, A. Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience, 2017, 39(1), 33-42.
[http://dx.doi.org/10.1007/s11357-017-9964-z] [PMID: 28299642]

Roos, C.M.; Zhang, B.; Palmer, A.K.; Ogrodnik, M.B.; Pirtskhalava, T.; Thalji, N.M.; Hagler, M.; Jurk, D.; Smith, L.A.; Casaclang-Verzosa, G.; Zhu, Y.; Schafer, M.J.; Tchkonia, T.; Kirkland, J.L.; Miller, J.D. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell, 2016, 15(5), 973-977.
[http://dx.doi.org/10.1111/acel.12458] [PMID: 26864908]

Bhayadia, R.; Schmidt, B.M.W.; Melk, A.; Hömme, M. Senescence-induced oxidative stress causes endothelial dysfunction. J. Gerontol. A Biol. Sci. Med. Sci., 2016, 71(2), 161-169.
[http://dx.doi.org/10.1093/gerona/glv008] [PMID: 25735595]

Rossman, M.J.; Kaplon, R.E.; Hill, S.D.; McNamara, M.N.; Santos-Parker, J.R.; Pierce, G.L.; Seals, D.R.; Donato, A.J. Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function. Am. J. Physiol. Heart Circ. Physiol., 2017, 313(5), H890-H895.
[http://dx.doi.org/10.1152/ajpheart.00416.2017] [PMID: 28971843]

Sanada, F.; Taniyama, Y.; Azuma, J.; Iekushi, K.; Dosaka, N.; Yokoi, T.; Koibuchi, N.; Kusunoki, H.; Aizawa, Y.; Morishita, R. Hepatocyte growth factor, but not vascular endothelial growth factor, attenuates angiotensin II-induced endothelial progenitor cell senescence. Hypertension, 2009, 53(1), 77-82.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.108.120725] [PMID: 19047582]

Tchkonia, T.; Zhu, Y.; van Deursen, J.; Campisi, J.; Kirkland, J.L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest., 2013, 123(3), 966-972.
[http://dx.doi.org/10.1172/JCI64098] [PMID: 23454759]

He, S.; Sharpless, N.E. Senescence in health and disease. Cell, 2017, 169(6), 1000-1011.
[http://dx.doi.org/10.1016/j.cell.2017.05.015] [PMID: 28575665]

Ungvari, Z.; Podlutsky, A.; Sosnowska, D.; Tucsek, Z.; Toth, P.; Deak, F.; Gautam, T.; Csiszar, A.; Sonntag, W.E. Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J. Gerontol. A Biol. Sci. Med. Sci., 2013, 68(12), 1443-1457.
[http://dx.doi.org/10.1093/gerona/glt057] [PMID: 23689827]

Childs, B.G.; Baker, D.J.; Wijshake, T.; Conover, C.A.; Campisi, J.; van Deursen, J.M. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 2016, 354(6311), 472-477.
[http://dx.doi.org/10.1126/science.aaf6659] [PMID: 27789842]

Baker, D.J.; Wijshake, T.; Tchkonia, T.; LeBrasseur, N.K.; Childs, B.G.; van de Sluis, B.; Kirkland, J.L.; van Deursen, J.M. Clearance of P16INK4A-positive senescent cells delays ageing-associated disorders. Nature, 2011, 479(7372), 232-236.
[http://dx.doi.org/10.1038/nature10600] [PMID: 22048312]

Colón-Emeric, C.S.; Whitson, H.E.; Pavon, J.; Hoenig, H. Functional decline in older adults. Am. Fam. Physician, 2013, 88(6), 388-394.
[PMID: 24134046]

Freund, A.; Patil, C.K.; Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J., 2011, 30(8), 1536-1548.
[http://dx.doi.org/10.1038/emboj.2011.69] [PMID: 21399611]

Kang, C.; Xu, Q.; Martin, T.D.; Li, M.Z.; Demaria, M.; Aron, L.; Lu, T.; Yankner, B.A.; Campisi, J.; Elledge, S.J. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science, 2015, 349(6255), aaa5612.
[http://dx.doi.org/10.1126/science.aaa5612] [PMID: 26404840]

Morgan, R.G.; Ives, S.J.; Lesniewski, L.A.; Cawthon, R.M.; Andtbacka, R.H.I.; Noyes, R.D.; Richardson, R.S.; Donato, A.J. Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries. Am. J. Physiol. Heart Circ. Physiol., 2013, 305(2), H251-H258.
[http://dx.doi.org/10.1152/ajpheart.00197.2013] [PMID: 23666675]

Song, Y.; Shen, H.; Schenten, D.; Shan, P.; Lee, P.J.; Goldstein, D.R. Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 2012, 32(1), 103-109.
[http://dx.doi.org/10.1161/ATVBAHA.111.236349] [PMID: 22034510]

Bailey-Downs, L.C.; Tucsek, Z.; Toth, P.; Sosnowska, D.; Gautam, T.; Sonntag, W.E.; Csiszar, A.; Ungvari, Z. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation. J. Gerontol. A Biol. Sci. Med. Sci., 2013, 68(7), 780-792.
[http://dx.doi.org/10.1093/gerona/gls238] [PMID: 23213032]

Tucsek, Z.; Toth, P.; Sosnowska, D.; Gautam, T.; Mitschelen, M.; Koller, A.; Szalai, G.; Sonntag, W.E.; Ungvari, Z.; Csiszar, A. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(10), 1212-1226.
[http://dx.doi.org/10.1093/gerona/glt177] [PMID: 24269929]

Tucsek, Z.; Toth, P.; Tarantini, S.; Sosnowska, D.; Gautam, T.; Warrington, J.P.; Giles, C.B.; Wren, J.D.; Koller, A.; Ballabh, P.; Sonntag, W.E.; Ungvari, Z.; Csiszar, A. Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(11), 1339-1352.
[http://dx.doi.org/10.1093/gerona/glu080] [PMID: 24895269]

Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol., 1956, 11(3), 298-300.
[http://dx.doi.org/10.1093/geronj/11.3.298] [PMID: 13332224]

Daiber, A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim. Biophys. Acta, 2010, 1797(6-7), 897-906.
[http://dx.doi.org/10.1016/j.bbabio.2010.01.032] [PMID: 20122895]

Bedard, K.; Krause, K-H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev., 2007, 87(1), 245-313.
[http://dx.doi.org/10.1152/physrev.00044.2005] [PMID: 17237347]

Csiszar, A.; Wang, M.; Lakatta, E.G.; Ungvari, Z. Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J. Appl. Physiol., 2008, 105(4), 1333-1341.
[http://dx.doi.org/10.1152/japplphysiol.90470.2008] [PMID: 18599677]

Takac, I.; Schröder, K.; Brandes, R.P. The Nox family of NADPH oxidases: friend or foe of the vascular system? Curr. Hypertens. Rep., 2012, 14(1), 70-78.
[http://dx.doi.org/10.1007/s11906-011-0238-3] [PMID: 22071588]

Babior, B.M.; Lambeth, J.D.; Nauseef, W. The neutrophil NADPH oxidase. Arch. Biochem. Biophys., 2002, 397(2), 342-344.
[http://dx.doi.org/10.1006/abbi.2001.2642] [PMID: 11795892]

Nguyen, G.T.; Green, E.R.; Mecsas, J. Neutrophils to the ROScue: mechanisms of NADPH oxidase activation and bacterial resistance. Front. Cell. Infect. Microbiol., 2017, 7, 373.
[http://dx.doi.org/10.3389/fcimb.2017.00373] [PMID: 28890882]

Drummond, G.R.; Sobey, C.G. Endothelial NADPH oxidases: which NOX to target in vascular disease? Trends Endocrinol. Metab., 2014, 25(9), 452-463.
[http://dx.doi.org/10.1016/j.tem.2014.06.012] [PMID: 25066192]

Youn, J-Y.; Zhang, J.; Zhang, Y.; Chen, H.; Liu, D.; Ping, P.; Weiss, J.N.; Cai, H. Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase. J. Mol. Cell. Cardiol., 2013, 62, 72-79.
[http://dx.doi.org/10.1016/j.yjmcc.2013.04.019] [PMID: 23643589]

Cho, K-J.; Seo, J-M.; Kim, J-H. Bioactive lipoxygenase metabolites stimulation of NADPH oxidases and reactive oxygen species. Mol. Cells, 2011, 32(1), 1-5.
[http://dx.doi.org/10.1007/s10059-011-1021-7] [PMID: 21424583]

Kienhöfer, J.; Häussler, D.J.F.; Ruckelshausen, F.; Muessig, E.; Weber, K.; Pimentel, D.; Ullrich, V.; Bürkle, A.; Bachschmid, M.M. Association of mitochondrial antioxidant enzymes with mitochondrial DNA as integral nucleoid constituents. FASEB J., 2009, 23(7), 2034-2044.
[http://dx.doi.org/10.1096/fj.08-113571] [PMID: 19228881]

Sohal, R.S.; Orr, W.C. The redox stress hypothesis of aging. Free Radic. Biol. Med., 2012, 52(3), 539-555.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.445] [PMID: 22080087]

Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature, 2011, 469(7329), 221-225.
[http://dx.doi.org/10.1038/nature09663] [PMID: 21124315]

Tschopp, J. Mitochondria: Sovereign of inflammation? Eur. J. Immunol., 2011, 41(5), 1196-1202.
[http://dx.doi.org/10.1002/eji.201141436] [PMID: 21469137]

Abais, J.M.; Xia, M.; Zhang, Y.; Boini, K.M.; Li, P-L. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid. Redox Signal., 2015, 22(13), 1111-1129.
[http://dx.doi.org/10.1089/ars.2014.5994] [PMID: 25330206]

Hasegawa, Y.; Saito, T.; Ogihara, T.; Ishigaki, Y.; Yamada, T.; Imai, J.; Uno, K.; Gao, J.; Kaneko, K.; Shimosawa, T.; Asano, T.; Fujita, T.; Oka, Y.; Katagiri, H. Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation, 2012, 125(9), 1122-1133.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.054346] [PMID: 22302838]

Csiszar, A.; Labinskyy, N.; Jimenez, R.; Pinto, J.T.; Ballabh, P.; Losonczy, G.; Pearson, K.J.; de Cabo, R.; Ungvari, Z. Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1. Mech. Ageing Dev., 2009, 130(8), 518-527.
[http://dx.doi.org/10.1016/j.mad.2009.06.004] [PMID: 19549533]

Chen, H-Z.; Wang, F.; Gao, P.; Pei, J-F.; Liu, Y.; Xu, T-T.; Tang, X.; Fu, W-Y.; Lu, J.; Yan, Y-F.; Wang, X-M.; Han, L.; Zhang, Z-Q.; Zhang, R.; Zou, M-H.; Liu, D-P. Age-Associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm. Circ. Res., 2016, 119(10), 1076-1088.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.308895] [PMID: 27650558]

Gano, L.B.; Donato, A.J.; Pasha, H.M.; Hearon, C.M., Jr; Sindler, A.L.; Seals, D.R. The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am. J. Physiol. Heart Circ. Physiol., 2014, 307(12), H1754-H1763.
[http://dx.doi.org/10.1152/ajpheart.00377.2014] [PMID: 25326534]

Ungvari, Z.; Bailey-Downs, L.; Gautam, T.; Sosnowska, D.; Wang, M.; Monticone, R.E.; Telljohann, R.; Pinto, J.T.; de Cabo, R.; Sonntag, W.E.; Lakatta, E.G.; Csiszar, A. Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-kappaB activation in the nonhuman primate Macaca mulatta. J. Gerontol. A Biol. Sci. Med. Sci., 2011, 66(8), 866-875.
[http://dx.doi.org/10.1093/gerona/glr092] [PMID: 21622983]

Ungvari, Z.; Bailey-Downs, L.; Sosnowska, D.; Gautam, T.; Koncz, P.; Losonczy, G.; Ballabh, P.; de Cabo, R.; Sonntag, W.E.; Csiszar, A. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am. J. Physiol. Heart Circ. Physiol., 2011, 301(2), H363-H372.
[http://dx.doi.org/10.1152/ajpheart.01134.2010] [PMID: 21602469]

Ungvari, Z.; Bailey-Downs, L.; Gautam, T.; Jimenez, R.; Losonczy, G.; Zhang, C.; Ballabh, P.; Recchia, F.A.; Wilkerson, D.C.; Sonntag, W.E.; Pearson, K.; de Cabo, R.; Csiszar, A. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am. J. Physiol. Heart Circ. Physiol., 2011, 300(4), H1133-H1140.
[http://dx.doi.org/10.1152/ajpheart.00402.2010] [PMID: 21217061]

Suh, J.H.; Shenvi, S.V.; Dixon, B.M.; Liu, H.; Jaiswal, A.K.; Liu, R-M.; Hagen, T.M. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc. Natl. Acad. Sci. USA, 2004, 101(10), 3381-3386.
[http://dx.doi.org/10.1073/pnas.0400282101] [PMID: 14985508]

Mostoslavsky, R.; Chua, K.F.; Lombard, D.B.; Pang, W.W.; Fischer, M.R.; Gellon, L.; Liu, P.; Mostoslavsky, G.; Franco, S.; Murphy, M.M.; Mills, K.D.; Patel, P.; Hsu, J.T.; Hong, A.L.; Ford, E.; Cheng, H-L.; Kennedy, C.; Nunez, N.; Bronson, R.; Frendewey, D.; Auerbach, W.; Valenzuela, D.; Karow, M.; Hottiger, M.O.; Hursting, S.; Barrett, J.C.; Guarente, L.; Mulligan, R.; Demple, B.; Yancopoulos, G.D.; Alt, F.W. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 2006, 124(2), 315-329.
[http://dx.doi.org/10.1016/j.cell.2005.11.044] [PMID: 16439206]

Valcarcel-Ares, M.N.; Gautam, T.; Warrington, J.P.; Bailey-Downs, L.; Sosnowska, D.; de Cabo, R.; Losonczy, G.; Sonntag, W.E.; Ungvari, Z.; Csiszar, A. Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J. Gerontol. A Biol. Sci. Med. Sci., 2012, 67(8), 821-829.
[http://dx.doi.org/10.1093/gerona/glr229] [PMID: 22219515]

Ciechanover, A. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Cell Death Differ., 2005, 12(9), 1178-1190.
[http://dx.doi.org/10.1038/sj.cdd.4401692] [PMID: 16094394]

Gelino, S.; Hansen, M. 2012.

Brunk, U.T.; Terman, A. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur. J. Biochem., 2002, 269(8), 1996-2002.
[http://dx.doi.org/10.1046/j.1432-1033.2002.02869.x] [PMID: 11985575]

Carrard, G.; Bulteau, A-L.; Petropoulos, I.; Friguet, B. Impairment of proteasome structure and function in aging. Int. J. Biochem. Cell Biol., 2002, 34(11), 1461-1474.
[http://dx.doi.org/10.1016/S1357-2725(02)00085-7] [PMID: 12200039]

Rubinsztein, D.C.; Mariño, G.; Kroemer, G. Autophagy and aging. Cell, 2011, 146(5), 682-695.
[http://dx.doi.org/10.1016/j.cell.2011.07.030] [PMID: 21884931]

Mizushima, N.; Levine, B. Autophagy in Human Diseases. N. Engl. J. Med., 2020, 383(16), 1564-1576.
[http://dx.doi.org/10.1056/NEJMra2022774] [PMID: 33053285]

Wolfe, D.M.; Lee, J-H.; Kumar, A.; Lee, S.; Orenstein, S.J.; Nixon, R.A. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur. J. Neurosci., 2013, 37(12), 1949-1961.
[http://dx.doi.org/10.1111/ejn.12169] [PMID: 23773064]

Cuervo, A.M.; Macian, F. Autophagy and the immune function in aging. Curr. Opin. Immunol., 2014, 29, 97-104.
[http://dx.doi.org/10.1016/j.coi.2014.05.006] [PMID: 24929664]

Shi, C-S.; Shenderov, K.; Huang, N-N.; Kabat, J.; Abu-Asab, M.; Fitzgerald, K.A.; Sher, A.; Kehrl, J.H. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol., 2012, 13(3), 255-263.
[http://dx.doi.org/10.1038/ni.2215] [PMID: 22286270]

Zhong, Z.; Umemura, A.; Sanchez-Lopez, E.; Liang, S.; Shalapour, S.; Wong, J.; He, F.; Boassa, D.; Perkins, G.; Ali, S.R.; McGeough, M.D.; Ellisman, M.H.; Seki, E.; Gustafsson, A.B.; Hoffman, H.M.; Diaz-Meco, M.T.; Moscat, J.; Karin, M. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell, 2016, 164(5), 896-910.
[http://dx.doi.org/10.1016/j.cell.2015.12.057] [PMID: 26919428]

Blagosklonny, M.V. Linking calorie restriction to longevity through sirtuins and autophagy: any role for TOR. Cell Death Dis., 2010, 1, e12.
[http://dx.doi.org/10.1038/cddis.2009.17] [PMID: 21364614]

Blagosklonny, M.V. Rapamycin extends life- and health span because it slows aging. Aging (Albany NY), 2013, 5(8), 592-598.
[http://dx.doi.org/10.18632/aging.100591] [PMID: 23934728]

Zoncu, R.; Efeyan, A.; Sabatini, D.M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol., 2011, 12(1), 21-35.
[http://dx.doi.org/10.1038/nrm3025] [PMID: 21157483]

Fogarty, S.; Hardie, D.G. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim. Biophys. Acta, 2010, 1804(3), 581-591.
[http://dx.doi.org/10.1016/j.bbapap.2009.09.012] [PMID: 19778642]

Guma, M.; Wang, Y.; Viollet, B.; Liu-Bryan, R. AMPK Activation by A-769662 controls IL-6 expression in inflammatory arthritis. PLoS One, 2015, 10(10), e0140452.
[http://dx.doi.org/10.1371/journal.pone.0140452] [PMID: 26474486]

Glossmann, H.H.; Lutz, O.M.D. Metformin and aging: a review. Gerontology, 2019, 65(6), 581-590.
[http://dx.doi.org/10.1159/000502257] [PMID: 31522175]

Vaiserman, A.M.; Marotta, F. Longevity-promoting pharmaceuticals: is it a time for implementation? Trends Pharmacol. Sci., 2016, 37(5), 331-333.
[http://dx.doi.org/10.1016/j.tips.2016.02.003] [PMID: 27113007]

Yan, Z.; Lira, V.A.; Greene, N.P. Exercise training-induced regulation of mitochondrial quality. Exerc. Sport Sci. Rev., 2012, 40(3), 159-164.
[http://dx.doi.org/10.1097/JES.0b013e3182575599] [PMID: 22732425]

Ferreira-Marques, M.; Aveleira, C.A.; Carmo-Silva, S.; Botelho, M.; Pereira de Almeida, L.; Cavadas, C. Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation. Aging (Albany NY), 2016, 8(7), 1470-1484.
[http://dx.doi.org/10.18632/aging.100996] [PMID: 27441412]

Durik, M.; Kavousi, M.; van der Pluijm, I.; Isaacs, A.; Cheng, C.; Verdonk, K.; Loot, A.E.; Oeseburg, H.; Bhaggoe, U.M.; Leijten, F.; van Veghel, R.; de Vries, R.; Rudez, G.; Brandt, R.; Ridwan, Y.R.; van Deel, E.D.; de Boer, M.; Tempel, D.; Fleming, I.; Mitchell, G.F.; Verwoert, G.C.; Tarasov, K.V.; Uitterlinden, A.G.; Hofman, A.; Duckers, H.J.; van Duijn, C.M.; Oostra, B.A.; Witteman, J.C.M.; Duncker, D.J.; Danser, A.H.; Hoeijmakers, J.H.; Roks, A.J.M. Nucleotide excision DNA repair is associated with age-related vascular dysfunction. Circulation, 2012, 126(4), 468-478.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.104380] [PMID: 22705887]

Matsumoto, T.; Baker, D.J.; d’Uscio, L.V.; Mozammel, G.; Katusic, Z.S.; van Deursen, J.M. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke, 2007, 38(3), 1050-1056.
[http://dx.doi.org/10.1161/01.STR.0000257967.86132.01] [PMID: 17272762]

Morgan, R.G.; Ives, S.J.; Walker, A.E.; Cawthon, R.M.; Andtbacka, R.H.I.; Noyes, D.; Lesniewski, L.A.; Richardson, R.S.; Donato, A.J. Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping. J. Hypertens., 2014, 32(6), 1293-1299.
[http://dx.doi.org/10.1097/HJH.0000000000000157] [PMID: 24686009]

Martinet, W.; Knaapen, M.W.M.; De Meyer, G.R.Y.; Herman, A.G.; Kockx, M.M. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation, 2002, 106(8), 927-932.
[http://dx.doi.org/10.1161/01.CIR.0000026393.47805.21] [PMID: 12186795]

Gray, K.; Kumar, S.; Figg, N.; Harrison, J.; Baker, L.; Mercer, J.; Littlewood, T.; Bennett, M. Effects of DNA damage in smooth muscle cells in atherosclerosis. Circ. Res., 2015, 116(5), 816-826.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.304921] [PMID: 25524056]

Ungvari, Z.; Kaley, G.; de Cabo, R.; Sonntag, W.E.; Csiszar, A. Mechanisms of vascular aging: new perspectives. J. Gerontol. A Biol. Sci. Med. Sci., 2010, 65(10), 1028-1041.
[http://dx.doi.org/10.1093/gerona/glq113] [PMID: 20576649]

Asai, K.; Kudej, R.K.; Shen, Y.T.; Yang, G.P.; Takagi, G.; Kudej, A.B.; Geng, Y.J.; Sato, N.; Nazareno, J.B.; Vatner, D.E.; Natividad, F.; Bishop, S.P.; Vatner, S.F. Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler. Thromb. Vasc. Biol., 2000, 20(6), 1493-1499.
[http://dx.doi.org/10.1161/01.ATV.20.6.1493] [PMID: 10845863]

Meng, L.; Jin, W.; Wang, X. RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality. Proc. Natl. Acad. Sci. USA, 2015, 112(35), 11007-11012.
[http://dx.doi.org/10.1073/pnas.1514730112] [PMID: 26283397]

Deepa, S.S.; Unnikrishnan, A.; Matyi, S.; Hadad, N.; Richardson, A. Necroptosis increases with age and is reduced by dietary restriction. Aging Cell, 2018, 17(4), e12770.
[http://dx.doi.org/10.1111/acel.12770] [PMID: 29696779]

Wang, Q.; Liu, Z.; Ren, J.; Morgan, S.; Assa, C.; Liu, B. Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation. Circ. Res., 2015, 116(4), 600-611.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.304899] [PMID: 25563840]

Spinetti, G.; Wang, M.; Monticone, R.; Zhang, J.; Zhao, D.; Lakatta, E.G. Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function. Arterioscler. Thromb. Vasc. Biol., 2004, 24(8), 1397-1402.
[http://dx.doi.org/10.1161/01.ATV.0000134529.65173.08] [PMID: 15178559]

Wang, M.; Takagi, G.; Asai, K.; Resuello, R.G.; Natividad, F.F.; Vatner, D.E.; Vatner, S.F.; Lakatta, E.G. Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension, 2003, 41(6), 1308-1316.
[http://dx.doi.org/10.1161/01.HYP.0000073843.56046.45] [PMID: 12743015]

Wang, M.; Zhang, J.; Spinetti, G.; Jiang, L-Q.; Monticone, R.; Zhao, D.; Cheng, L.; Krawczyk, M.; Talan, M.; Pintus, G.; Lakatta, E.G.; Angiotensin, I.I. Angiotensin II activates matrix metalloproteinase type II and mimics age-associated carotid arterial remodeling in young rats. Am. J. Pathol., 2005, 167(5), 1429-1442.
[http://dx.doi.org/10.1016/S0002-9440(10)61229-1] [PMID: 16251426]

Basso, N.; Cini, R.; Pietrelli, A.; Ferder, L.; Terragno, N.A.; Inserra, F. Protective effect of long-term angiotensin II inhibition. Am. J. Physiol. Heart Circ. Physiol., 2007, 293(3), H1351-H1358.
[http://dx.doi.org/10.1152/ajpheart.00393.2007] [PMID: 17557916]

de Cavanagh, E.M.V.; Inserra, F.; Ferder, L.; Angiotensin, I.I. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am. J. Physiol. Heart Circ. Physiol., 2015, 309(1), H15-H44.
[http://dx.doi.org/10.1152/ajpheart.00459.2014] [PMID: 25934099]

Benigni, A.; Corna, D.; Zoja, C.; Sonzogni, A.; Latini, R.; Salio, M.; Conti, S.; Rottoli, D.; Longaretti, L.; Cassis, P.; Morigi, M.; Coffman, T.M.; Remuzzi, G. Disruption of the Ang II type 1 receptor promotes longevity in mice. J. Clin. Invest., 2009, 119(3), 524-530.
[http://dx.doi.org/10.1172/JCI36703] [PMID: 19197138]

Siasos, G.; Tsigkou, V.; Kosmopoulos, M.; Theodosiadis, D.; Simantiris, S.; Tagkou, N.M.; Tsimpiktsioglou, A.; Stampouloglou, P.K.; Oikonomou, E.; Mourouzis, K.; Philippou, A.; Vavuranakis, M.; Stefanadis, C.; Tousoulis, D.; Papavassiliou, A.G. Mitochondria and cardiovascular diseases-from pathophysiology to treatment. Ann. Transl. Med., 2018, 6(12), 256.
[http://dx.doi.org/10.21037/atm.2018.06.21] [PMID: 30069458]

Toth, P.; Tarantini, S.; Springo, Z.; Tucsek, Z.; Gautam, T.; Giles, C.B.; Wren, J.D.; Koller, A.; Sonntag, W.E.; Csiszar, A.; Ungvari, Z. Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell, 2015, 14(3), 400-408.
[http://dx.doi.org/10.1111/acel.12315] [PMID: 25677910]

Kumar, S.; Dietrich, N.; Kornfeld, K. Angiotensin converting enzyme (ACE) inhibitor extends Caenorhabditis elegans life Span. PLoS Genet., 2016, 12(2), e1005866.
[http://dx.doi.org/10.1371/journal.pgen.1005866] [PMID: 26918946]

Woll, P.S.; Morris, J.K.; Painschab, M.S.; Marcus, R.K.; Kohn, A.D.; Biechele, T.L.; Moon, R.T.; Kaufman, D.S. Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells. Blood, 2008, 111(1), 122-131.
[http://dx.doi.org/10.1182/blood-2007-04-084186] [PMID: 17875805]

Cheng, C.W.; Yeh, J.C.; Fan, T-P.; Smith, S.K.; Charnock-Jones, D.S. Wnt5a-mediated non-canonical Wnt signalling regulates human endothelial cell proliferation and migration. Biochem. Biophys. Res. Commun., 2008, 365(2), 285-290.
[http://dx.doi.org/10.1016/j.bbrc.2007.10.166] [PMID: 17986384]

Brigstock, D.R. Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61). Angiogenesis, 2002, 5(3), 153-165.
[http://dx.doi.org/10.1023/A:1023823803510] [PMID: 12831056]

Li, F.; Chong, Z.Z.; Maiese, K. Winding through the WNT pathway during cellular development and demise. Histol. Histopathol., 2006, 21(1), 103-124.
[PMID: 16267791]

Kang, J-Q.; Chong, Z.Z.; Maiese, K. Critical role for Akt1 in the modulation of apoptotic phosphatidylserine exposure and microglial activation. Mol. Pharmacol., 2003, 64(3), 557-569.
[http://dx.doi.org/10.1124/mol.64.3.557] [PMID: 12920191]

Chong, Z.Z.; Kang, J-Q.; Maiese, K. AKT1 drives endothelial cell membrane asymmetry and microglial activation through Bcl-xL and caspase 1, 3, and 9. Exp. Cell Res., 2004, 296(2), 196-207.
[http://dx.doi.org/10.1016/j.yexcr.2004.01.021] [PMID: 15149850]

Chong, Z.Z.; Li, F.; Maiese, K. The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection. Int. J. Mol. Med., 2007, 19(2), 263-272.
[PMID: 17203200]

Li, F.; Chong, Z.Z.; Maiese, K. Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3beta, beta-catenin, and nuclear factor-kappaB. Curr. Neurovasc. Res., 2006, 3(3), 187-201.
[http://dx.doi.org/10.2174/156720206778018758] [PMID: 16918383]

Li, F.; Chong, Z.Z.; Maiese, K. Vital elements of the Wnt-Frizzled signaling pathway in the nervous system. Curr. Neurovasc. Res., 2005, 2(4), 331-340.
[http://dx.doi.org/10.2174/156720205774322557] [PMID: 16181124]

Mallat, M.; Marín-Teva, J.L.; Chéret, C. Phagocytosis in the developing CNS: more than clearing the corpses. Curr. Opin. Neurobiol., 2005, 15(1), 101-107.
[http://dx.doi.org/10.1016/j.conb.2005.01.006] [PMID: 15721751]

Dringen, R. Oxidative and antioxidative potential of brain microglial cells. Antioxid. Redox Signal., 2005, 7(9-10), 1223-1233.
[http://dx.doi.org/10.1089/ars.2005.7.1223] [PMID: 16115027]

Sankarapandi, S.; Zweier, J.L.; Mukherjee, G.; Quinn, M.T.; Huso, D.L. Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway. Arch. Biochem. Biophys., 1998, 353(2), 312-321.
[http://dx.doi.org/10.1006/abbi.1998.0658] [PMID: 9606965]

Lobov, I.B.; Rao, S.; Carroll, T.J.; Vallance, J.E.; Ito, M.; Ondr, J.K.; Kurup, S.; Glass, D.A.; Patel, M.S.; Shu, W.; Morrisey, E.E.; McMahon, A.P.; Karsenty, G.; Lang, R.A. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature, 2005, 437(7057), 417-421.
[http://dx.doi.org/10.1038/nature03928] [PMID: 16163358]

Chong, Z.Z.; Li, F.; Maiese, K. Cellular demise and inflammatory microglial activation during beta-amyloid toxicity are governed by Wnt1 and canonical signaling pathways. Cell. Signal., 2007, 19(6), 1150-1162.
[http://dx.doi.org/10.1016/j.cellsig.2006.12.009] [PMID: 17289346]

Ungvari, Z.; Labinskyy, N.; Mukhopadhyay, P.; Pinto, J.T.; Bagi, Z.; Ballabh, P.; Zhang, C.; Pacher, P.; Csiszar, A. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am. J. Physiol. Heart Circ. Physiol., 2009, 297(5), H1876-H1881.
[http://dx.doi.org/10.1152/ajpheart.00375.2009] [PMID: 19749157]

Csiszar, A.; Labinskyy, N.; Pinto, J.T.; Ballabh, P.; Zhang, H.; Losonczy, G.; Pearson, K.; de Cabo, R.; Pacher, P.; Zhang, C.; Ungvari, Z. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am. J. Physiol. Heart Circ. Physiol., 2009, 297(1), H13-H20.
[http://dx.doi.org/10.1152/ajpheart.00368.2009] [PMID: 19429820]

Lee, I.H.; Cao, L.; Mostoslavsky, R.; Lombard, D.B.; Liu, J.; Bruns, N.E.; Tsokos, M.; Alt, F.W.; Finkel, T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. USA, 2008, 105(9), 3374-3379.
[http://dx.doi.org/10.1073/pnas.0712145105] [PMID: 18296641]

de Picciotto, N.E.; Gano, L.B.; Johnson, L.C.; Martens, C.R.; Sindler, A.L.; Mills, K.F.; Imai, S.; Seals, D.R. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell, 2016, 15(3), 522-530.
[http://dx.doi.org/10.1111/acel.12461] [PMID: 26970090]

Donato, A.J.; Magerko, K.A.; Lawson, B.R.; Durrant, J.R.; Lesniewski, L.A.; Seals, D.R. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J. Physiol., 2011, 589(Pt 18), 4545-4554.
[http://dx.doi.org/10.1113/jphysiol.2011.211219] [PMID: 21746786]

Fry, J.L.; Al Sayah, L.; Weisbrod, R.M.; Van Roy, I.; Weng, X.; Cohen, R.A.; Bachschmid, M.M.; Seta, F. Vascular smooth muscle sirtuin-1 protects against diet-induced aortic stiffness. Hypertension, 2016, 68(3), 775-784.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07622] [PMID: 27432859]

Chen, Y.X.; Zhang, M.; Cai, Y.; Zhao, Q.; Dai, W. The Sirt1 activator SRT1720 attenuates angiotensin II-induced atherosclerosis in apoE⁻/⁻ mice through inhibiting vascular inflammatory response. Biochem. Biophys. Res. Commun., 2015, 465(4), 732-738.
[http://dx.doi.org/10.1016/j.bbrc.2015.08.066] [PMID: 26296466]

Baur, J.A.; Ungvari, Z.; Minor, R.K.; Le Couteur, D.G.; de Cabo, R. Are sirtuins viable targets for improving healthspan and lifespan? Nat. Rev. Drug Discov., 2012, 11(6), 443-461.
[http://dx.doi.org/10.1038/nrd3738] [PMID: 22653216]

Gorenne, I.; Kumar, S.; Gray, K.; Figg, N.; Yu, H.; Mercer, J.; Bennett, M. Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation, 2013, 127(3), 386-396.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.124404] [PMID: 23224247]

Xu, S.; Yin, M.; Koroleva, M.; Mastrangelo, M.A.; Zhang, W.; Bai, P.; Little, P.J.; Jin, Z.G. SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. Aging (Albany NY), 2016, 8(5), 1064-1082.
[http://dx.doi.org/10.18632/aging.100975] [PMID: 27249230]

Cardus, A.; Uryga, A.K.; Walters, G.; Erusalimsky, J.D. SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence. Cardiovasc. Res., 2013, 97(3), 571-579.
[http://dx.doi.org/10.1093/cvr/cvs352] [PMID: 23201774]

Das, D.K.; Maulik, N. Resveratrol in cardioprotection: a therapeutic promise of alternative medicine. Mol. Interv., 2006, 6(1), 36-47.
[http://dx.doi.org/10.1124/mi.6.1.7] [PMID: 16507749]

Stivala, L.A.; Savio, M.; Carafoli, F.; Perucca, P.; Bianchi, L.; Maga, G.; Forti, L.; Pagnoni, U.M.; Albini, A.; Prosperi, E.; Vannini, V. Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J. Biol. Chem., 2001, 276(25), 22586-22594.
[http://dx.doi.org/10.1074/jbc.M101846200] [PMID: 11316812]

Yoshino, J.; Mills, K.F.; Yoon, M.J.; Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab., 2011, 14(4), 528-536.
[http://dx.doi.org/10.1016/j.cmet.2011.08.014] [PMID: 21982712]

Johnson, S.C.; Sangesland, M.; Kaeberlein, M.; Rabinovitch, P.S. Modulating mTOR in aging and health. Interdiscip. Top. Gerontol., 2015, 40, 107-127.
[http://dx.doi.org/10.1159/000364974] [PMID: 25341517]

Caccamo, A.; Majumder, S.; Richardson, A.; Strong, R.; Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J. Biol. Chem., 2010, 285(17), 13107-13120.
[http://dx.doi.org/10.1074/jbc.M110.100420] [PMID: 20178983]

Lin, A-L.; Zheng, W.; Halloran, J.J.; Burbank, R.R.; Hussong, S.A.; Hart, M.J.; Javors, M.; Shih, Y-Y.I.; Muir, E.; Solano Fonseca, R.; Strong, R.; Richardson, A.G.; Lechleiter, J.D.; Fox, P.T.; Galvan, V. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J. Cereb. Blood Flow Metab., 2013, 33(9), 1412-1421.
[http://dx.doi.org/10.1038/jcbfm.2013.82] [PMID: 23801246]

Wang, C-Y.; Kim, H-H.; Hiroi, Y.; Sawada, N.; Salomone, S.; Benjamin, L.E.; Walsh, K.; Moskowitz, M.A.; Liao, J.K. Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci. Signal., 2009, 2(62), ra11.
[http://dx.doi.org/10.1126/scisignal.2000143] [PMID: 19293429]

Yepuri, G.; Velagapudi, S.; Xiong, Y.; Rajapakse, A.G.; Montani, J-P.; Ming, X-F.; Yang, Z. Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging. Aging Cell, 2012, 11(6), 1005-1016.
[http://dx.doi.org/10.1111/acel.12001] [PMID: 22928666]

Lesniewski, L.A.; Seals, D.R.; Walker, A.E.; Henson, G.D.; Blimline, M.W.; Trott, D.W.; Bosshardt, G.C.; LaRocca, T.J.; Lawson, B.R.; Zigler, M.C.; Donato, A.J. Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell, 2017, 16(1), 17-26.
[http://dx.doi.org/10.1111/acel.12524] [PMID: 27660040]

Jahrling, J.B.; Lin, A-L.; DeRosa, N.; Hussong, S.A.; Van Skike, C.E.; Girotti, M.; Javors, M.; Zhao, Q.; Maslin, L.A.; Asmis, R.; Galvan, V. mTOR drives cerebral blood flow and memory deficits in LDLR^-/- mice modeling atherosclerosis and vascular cognitive impairment. J. Cereb. Blood Flow Metab., 2018, 38(1), 58-74.
[http://dx.doi.org/10.1177/0271678X17705973] [PMID: 28511572]

Zhang, W.; Khatibi, N.H.; Yamaguchi-Okada, M.; Yan, J.; Chen, C.; Hu, Q.; Meng, H.; Han, H.; Liu, S.; Zhou, C. Mammalian target of rapamycin (mTOR) inhibition reduces cerebral vasospasm following a subarachnoid hemorrhage injury in canines. Exp. Neurol., 2012, 233(2), 799-806.
[http://dx.doi.org/10.1016/j.expneurol.2011.11.046] [PMID: 22177999]

Fletcher, L.; Evans, T.M.; Watts, L.T.; Jimenez, D.F.; Digicaylioglu, M. Rapamycin treatment improves neuron viability in an in vitro model of stroke. PLoS One, 2013, 8(7), e68281.
[http://dx.doi.org/10.1371/journal.pone.0068281] [PMID: 23861877]

Yin, L.; Ye, S.; Chen, Z.; Zeng, Y. Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice. Int. J. Neurosci., 2012, 122(12), 748-756.
[http://dx.doi.org/10.3109/00207454.2012.721827] [PMID: 22901235]

Hattori, Y.; Suzuki, K.; Hattori, S.; Kasai, K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension, 2006, 47(6), 1183-1188.
[http://dx.doi.org/10.1161/01.HYP.0000221429.94591.72] [PMID: 16636195]

Hardie, D.G.; Hawley, S.A.; Scott, J.W. AMP-activated protein kinase-development of the energy sensor concept. J. Physiol., 2006, 574(Pt 1), 7-15.
[http://dx.doi.org/10.1113/jphysiol.2006.108944] [PMID: 16644800]

Lesniewski, L.A.; Zigler, M.C.; Durrant, J.R.; Donato, A.J.; Seals, D.R. Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism. Mech. Ageing Dev., 2012, 133(5), 368-371.
[http://dx.doi.org/10.1016/j.mad.2012.03.011] [PMID: 22484146]

Pu, Y.; Zhang, H.; Wang, P.; Zhao, Y.; Li, Q.; Wei, X.; Cui, Y.; Sun, J.; Shang, Q.; Liu, D.; Zhu, Z. Dietary curcumin ameliorates aging-related cerebrovascular dysfunction through the AMPK/uncoupling protein 2 pathway. Cell. Physiol. Biochem., 2013, 32(5), 1167-1177.
[http://dx.doi.org/10.1159/000354516] [PMID: 24335167]

Chen, Z.P.; Mitchelhill, K.I.; Michell, B.J.; Stapleton, D.; Rodriguez-Crespo, I.; Witters, L.A.; Power, D.A.; Ortiz de Montellano, P.R.; Kemp, B.E. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett., 1999, 443(3), 285-289.
[http://dx.doi.org/10.1016/S0014-5793(98)01705-0] [PMID: 10025949]

Chen, Z.; Peng, I-C.; Sun, W.; Su, M-I.; Hsu, P-H.; Fu, Y.; Zhu, Y.; DeFea, K.; Pan, S.; Tsai, M-D.; Shyy, J.Y-J. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ. Res., 2009, 104(4), 496-505.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.187567] [PMID: 19131647]

Levine, Y.C.; Li, G.K.; Michel, T. Agonist-modulated regulation of AMP-activated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK -> Rac1 -> Akt -> endothelial nitric-oxide synthase pathway. J. Biol. Chem., 2007, 282(28), 20351-20364.
[http://dx.doi.org/10.1074/jbc.M702182200] [PMID: 17519230]