Résultat complémentaire 1 : Des souris C57Bl/6 sont soumises pendant 1 semaine à une constriction
de l’aorte transverse (TAC). Les souris Sham sont soumises à une thoracotomie sans TAC. Après 1 semaine de TAC, les cardiomyocytes sont isolés et l’expression génique est évaluée par RT-PCR. Les résultats sont exprimés en expression relative moyenne ± SEM vs le groupe Sham. Test statistique : t- test *P<0.05, **P<0.01 vs sham. n=6 souris par groupe.
C d k n 2 a ( p 1 6 ) 0 1 2 3 ** C d k n 1 a ( p 2 1 ) 0 1 2 3 4 * C d k n 2 b ( p 1 5 ) 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 P r o m 2 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 ns P a h 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 ns K c n k 1 0 . 0 0 . 5 1 . 0 1 . 5 ns E d n 3 0 2 4 6 8 ** G d f 1 5 0 1 2 3 4 * T g f 2 0 1 2 3 4 *
Sham TAC Sham TAC Sham TAC
Sham TAC Sham TAC Sham TAC
Sham TAC Sham TAC Sham TAC
R e la ti v e m R N A e x p re s s io n (2 ^ -ΔΔ CT ) R e la ti v e m R N A e x p re s s io n (2 ^ -ΔΔ CT ) R e la ti v e m R N A e x p re s s io n (2 ^ -ΔΔ CT ) Cdkn2a (p16) Cdkn2b (p15) Cdnk1a (p21) Prom2 Kcnk1 Pah Edn3 Gdf15 Tgfb2
175
Résultat complémentaire 2 : (A) Image représentative de la Prominin-2 (rouge, anticorps anti
prominin-2 Abcam Ab74997) et du cil primaire (vert, anticorps anti tubuline α-acétylée Sigma T6793) au sein de cellules H9c2 traitées avec de la doxorubicine 100nM (doxorubicine) ou de l’eau distillée (control) pendant 96 heures. Les noyaux sont marqués au DAPI (bleu). La flèche indique la présence de la prominin-2. Acquisition confocale par microscope à fluorescence, barre d’échelle = 10μm. (B) Quantification du nombre de cellules exprimant la protéine Prom2 à la base des cils primaires. Les résultats sont exprimés en % moyen de cellules ± SEM. Test statistique : t-test **P<0.05 vs control. n=3 expériences. B A Co ntr ol Do xo rub icin e 0 1 0 2 0 3 0 4 0 % C il ia + P r o m 2 ** B
176
Bibliographie
Acosta, J.C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J.P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990.
Adnot, S., Amsellem, V., Boyer, L., Marcos, E., Saker, M., Houssaini, A., Kebe, K., Dagouassat, M., Lipskaia, L., and Boczkowski, J. (2015). Telomere Dysfunction and Cell Senescence in Chronic Lung Diseases: Therapeutic Potential. Pharmacol. Ther. 153, 125–134.
Ahmad, T., Sundar, I.K., Lerner, C.A., Gerloff, J., Tormos, A.M., Yao, H., and Rahman, I. (2015). Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J. 29, 2912–2929.
Ahmed, N., Mandel, R., and Fain, M.J. (2007). Frailty: An Emerging Geriatric Syndrome. Am. J. Med. 120, 748– 753.
Aird, K.M., and Zhang, R. (2013). Detection of senescence-associated heterochromatin foci (SAHF). Methods Mol. Biol. Clifton NJ 965, 185–196.
Alper, G., Sözmen, E.Y., Kanit, L., Mentes, G., Ersöz, B., and Kutay, F.Z. (1998). Age-related alterations in superoxide dismutase and catalase activities in rat brain. Turk. J. Med. Sci. 28, 491–494.
Althubiti, M., Lezina, L., Carrera, S., Jukes-Jones, R., Giblett, S.M., Antonov, A., Barlev, N., Saldanha, G.S., Pritchard, C.A., Cain, K., et al. (2014). Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis. 5, e1528.
Amaral, J.D., Xavier, J.M., Steer, C.J., and Rodrigues, C.M. (2010). The Role of p53 in Apoptosis. Discov. Med. 9, 145–152.
Andujar, P., Courbon, D., Bizard, E., Marcos, E., Adnot, S., Boyer, L., Demoly, P., Jarvis, D., Neukirch, C., Pin, I., et al. (2017). Smoking, telomere length and lung function decline: a longitudinal population-based study. Thorax thoraxjnl-2017-210294.
Anton, S.D., Karabetian, C., Heekin, K., and Leeuwenburgh, C. (2013). Caloric Restriction to Moderate Senescence: Mechanisms and Clinical Utility. Curr. Transl. Geriatr. Exp. Gerontol. Rep. 2, 239–246.
Anversa, P., Palackal, T., Sonnenblick, E.H., Olivetti, G., Meggs, L.G., and Capasso, J.M. (1990). Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ. Res. 67, 871–885.
Atadja, P., Wong, H., Garkavtsev, I., Veillette, C., and Riabowol, K. (1995). Increased activity of p53 in senescing fibroblasts. Proc. Natl. Acad. Sci. U. S. A. 92, 8348–8352.
Atlas, S.A. (2007). The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J. Manag. Care Pharm. JMCP 13, 9–20.
van Attikum, H., and Gasser, S.M. (2009). Crosstalk between histone modifications during the DNA damage response. Trends Cell Biol. 19, 207–217.
Avery, S.V. (2011). Molecular targets of oxidative stress. Biochem. J. 434, 201–210.
Baar, M.P., Brandt, R.M.C., Putavet, D.A., Klein, J.D.D., Derks, K.W.J., Bourgeois, B.R.M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D.A., et al. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 169, 132–147.e16.
Bae, N.S., and Baumann, P. (2007). A RAP1/TRF2 Complex Inhibits Nonhomologous End-Joining at Human Telomeric DNA Ends. Mol. Cell 26, 323–334.
Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., and van Deursen, J.M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236.
177
Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., A. Saltness, R., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., et al. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189.
Bakkenist, C.J., and Kastan, M.B. (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506.
Baraibar, M.A., and Friguet, B. (2013). Oxidative proteome modifications target specific cellular pathways during oxidative stress, cellular senescence and aging. Exp. Gerontol. 48, 620–625.
Baraibar, M.A., Liu, L., Ahmed, E.K., and Friguet, B. (2012). Protein Oxidative Damage at the Crossroads of Cellular Senescence, Aging, and Age-Related Diseases.
Baraibar, M.A., Hyzewicz, J., Rogowska-Wrzesinska, A., Bulteau, A.-L., Prip-Buus, C., Butler-Browne, G., and Friguet, B. (2016). Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes. Aging 8, 3375–3389.
Barascu, A., Chalony, C.L., Pennarun, G., Genet, D., Imam, N., Lopez, B., and Bertrand, P. (2012). Oxidative stress induces an ATM‐ independent senescence pathway through p38 MAPK‐ mediated lamin B1 accumulation. EMBO J. 31, 1080–1094.
Barilari, M., Bonfils, G., Treins, C., Koka, V., De Villeneuve, D., Fabrega, S., and Pende, M. (2017). ZRF1 is a novel S6 kinase substrate that drives the senescence programme. EMBO J. 36, 736–750.
Basso, N., Cini, R., Pietrelli, A., Ferder, L., Terragno, N.A., and Inserra, F. (2007). Protective effect of long-term angiotensin II inhibition. Am. J. Physiol. Heart Circ. Physiol. 293, H1351-1358.
Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J., and Lukas, J. (2005). Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. J. Cell Biol. 170, 201–211. Beltrami, A.P., Barlucchi, L., Torella, D., Baker, M., Limana, F., Chimenti, S., Kasahara, H., Rota, M., Musso, E., Urbanek, K., et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776.
Benson, E.K., Lee, S.W., and Aaronson, S.A. (2010). Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J Cell Sci 123, 2605–2612.
Berbari, N.F., O’Connor, A.K., Haycraft, C.J., and Yoder, B.K. (2009). The Primary Cilium as a Complex Signaling Center. Curr. Biol. CB 19, R526.
Berger, N.A., Savvides, P., Koroukian, S.M., Kahana, E.F., Deimling, G.T., Rose, J.H., Bowman, K.F., and Miller, R.H. (2006). Cancer in the Elderly. Trans. Am. Clin. Climatol. Assoc. 117, 147–156.
Bergmann, O., Bhardwaj, R.D., Bernard, S., Zdunek, S., Barnabé-Heider, F., Walsh, S., Zupicich, J., Alkass, K., Buchholz, B.A., Druid, H., et al. (2009). Evidence for cardiomyocyte renewal in humans. Science 324, 98–102. Bernadotte, A., Mikhelson, V.M., and Spivak, I.M. (2016). Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging 8, 3–11.
Bernardes de Jesus, B., and Blasco, M.A. (2012). Assessing Cell and Organ Senescence Biomarkers. Circ. Res. 111, 97–109.
Bers, D.M. (2008). Calcium Cycling and Signaling in Cardiac Myocytes. Annu. Rev. Physiol. 70, 23–49.
Bhatia, R.S., Tu, J.V., Lee, D.S., Austin, P.C., Fang, J., Haouzi, A., Gong, Y., and Liu, P.P. (2006). Outcome of heart failure with preserved ejection fraction in a population-based study. N. Engl. J. Med. 355, 260–269.
Bielak-Zmijewska, A., Wnuk, M., Przybylska, D., Grabowska, W., Lewinska, A., Alster, O., Korwek, Z., Cmoch, A., Myszka, A., Pikula, S., et al. (2014). A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta. Biogerontology 15, 47–64. Biernacka, A., and Frangogiannis, N.G. (2011). Aging and Cardiac Fibrosis. Aging Dis. 2, 158–173.
178
Birch, J., Anderson, R.K., Correia-Melo, C., Jurk, D., Hewitt, G., Marques, F.M., Green, N.J., Moisey, E., Birrell, M.A., Belvisi, M.G., et al. (2015). DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 309, L1124-1137.
Bishop, N.A., Lu, T., and Yankner, B.A. (2010). Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535.
Blackburn, E.H. (1991). Structure and function of telomeres. Nature 350, 569–573.
Bode-Böger, S.M., Scalera, F., and Martens-Lobenhoffer, J. (2005). Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc. Med. Lond. Engl. 10 Suppl 1, S65-71.
Bodnar, A.G., Ouellette, M., Frolkis, M., Holt, S.E., Chiu, C.-P., Morin, G.B., Harley, C.B., Shay, J.W., Lichtsteiner, S., and Wright, W.E. (1998). Extension of Life-Span by Introduction of Telomerase into Normal Human Cells. Science 279, 349–352.
Bracken, A.P., Kleine-Kohlbrecher, D., Dietrich, N., Pasini, D., Gargiulo, G., Beekman, C., Theilgaard-Mönch, K., Minucci, S., Porse, B.T., Marine, J.-C., et al. (2007). The Polycomb group proteins bind throughout the INK4A- ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530.
Brady, C.A., Jiang, D., Mello, S.S., Johnson, T.M., Jarvis, L.A., Kozak, M.M., Kenzelmann Broz, D., Basak, S., Park, E.J., McLaughlin, M.E., et al. (2011). Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145, 571–583.
Bratic, A., and Larsson, N.-G. (2013). The role of mitochondria in aging. J. Clin. Invest. 123, 951–957.
Buist, A.S., McBurnie, M.A., Vollmer, W.M., Gillespie, S., Burney, P., Mannino, D.M., Menezes, A.M., Sullivan, S.D., Lee, T.A., Weiss, K.B., et al. (2007). International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. The Lancet 370, 741–750.
Bupha-Intr, T., Haizlip, K.M., and Janssen, P.M.L. (2012). Role of Endothelin in the Induction of Cardiac Hypertrophy In Vitro. PLOS ONE 7, e43179.
Burd, C.E., Sorrentino, J.A., Clark, K.S., Darr, D.B., Krishnamurthy, J., Deal, A.M., Bardeesy, N., Castrillon, D.H., Beach, D.H., and Sharpless, N.E. (2013). Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a- Luciferase Model. Cell 152, 340–351.
Calado, R.T., and Young, N.S. (2008). Telomere maintenance and human bone marrow failure. Blood 111, 4446–4455.
Caliò, A., Zamò, A., Ponzoni, M., Zanolin, M.E., Ferreri, A.J.M., Pedron, S., Montagna, L., Parolini, C., Fraifeld, V.E., Wolfson, M., et al. (2015). Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 21, 5164–5172.
Campisi, J., and d’Adda di Fagagna, F. (2007). Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740.
Carnes, C.A., Geisbuhler, T.P., and Reiser, P.J. (2004). Age-dependent changes in contraction and regional myocardial myosin heavy chain isoform expression in rats. J. Appl. Physiol. 97, 446–453.
Carroll, B., Nelson, G., Rabanal-Ruiz, Y., Kucheryavenko, O., Dunhill-Turner, N.A., Chesterman, C.C., Zahari, Q., Zhang, T., Conduit, S.E., Mitchell, C.A., et al. (2017). Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing. J Cell Biol jcb.201610113.
Ceylan-Isik, A.F., Dong, M., Zhang, Y., Dong, F., Turdi, S., Nair, S., Yanagisawa, M., and Ren, J. (2013). Cardiomyocyte-Specific Deletion of Endothelin Receptor A Rescues Ageing-Associated Cardiac Hypertrophy and Contractile Dysfunction: Role of Autophagy. Basic Res. Cardiol. 108, 335.
Chaudhary, K.R., El-Sikhry, H., and Seubert, J.M. (2011). Mitochondria and the aging heart. J. Geriatr. Cardiol. JGC 8, 159–167.
Chen, J.-H., Hales, C.N., and Ozanne, S.E. (2007). DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. 35, 7417–7428.
179
Chen, X., Mao, G., and Leng, S.X. (2014). Frailty syndrome: an overview. Clin. Interv. Aging 9, 433–441.
Chen, X., Li, M., Yan, J., Liu, T., Pan, G., Yang, H., Pei, M., and He, F. (2017). Alcohol Induces Cellular Senescence and Impairs Osteogenic Potential in Bone Marrow-Derived Mesenchymal Stem Cells. Alcohol Alcohol. Oxf. Oxfs. 52, 289–297.
Cheng, T.-H., Shih, N.-L., Chen, C.-H., Lin, H., Liu, J.-C., Chao, H.-H., Liou, J.-Y., Chen, Y.-L., Tsai, H.-W., Chen, Y.- S., et al. (2005). Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced beta-myosin heavy chain gene expression and cardiomyocyte hypertrophy. J. Biomed. Sci. 12, 123–133.
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J.E., Premsrirut, P., Luo, W., Chicas, A., Lee, C.S., et al. (2011). Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125–2136.
Childs, B.G., Baker, D.J., Kirkland, J.L., Campisi, J., and Deursen, J.M. van (2014). Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 15, 1139–1153.
Childs, B.G., Durik, M., Baker, D.J., and van Deursen, J.M. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435.
Childs, B.G., Gluscevic, M., Baker, D.J., Laberge, R.-M., Marquess, D., Dananberg, J., and van Deursen, J.M. (2017). Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735.
Chimenti, C., Kajstura, J., Torella, D., Urbanek, K., Heleniak, H., Colussi, C., Meglio, F.D., Nadal-Ginard, B., Frustaci, A., Leri, A., et al. (2003). Senescence and Death of Primitive Cells and Myocytes Lead to Premature Cardiac Aging and Heart Failure. Circ. Res. 93, 604–613.
Chipuk, J.E., Kuwana, T., Bouchier-Hayes, L., Droin, N.M., Newmeyer, D.D., Schuler, M., and Green, D.R. (2004). Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis. Science 303, 1010–1014.
Choi, Y.-H., Kurtz, A., and Stamm, C. (2010). Mesenchymal Stem Cells for Cardiac Cell Therapy. Hum. Gene Ther. 22, 3–17.
Chondrogianni, N., Stratford, F.L.L., Trougakos, I.P., Friguet, B., Rivett, A.J., and Gonos, E.S. (2003). Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. J. Biol. Chem. 278, 28026–28037.
Christou, D.D., and Seals, D.R. (2008). Decreased maximal heart rate with aging is related to reduced β- adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate. J. Appl. Physiol. 105, 24–29.
Cleland, J.G.F., Tendera, M., Adamus, J., Freemantle, N., Polonski, L., Taylor, J., and PEP-CHF Investigators (2006). The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur. Heart J. 27, 2338– 2345.
Clement, C.A., Ajbro, K.D., Koefoed, K., Vestergaard, M.L., Veland, I.R., Henriques de Jesus, M.P.R., Pedersen, L.B., Benmerah, A., Andersen, C.Y., Larsen, L.A., et al. (2013). TGF-β Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium. Cell Rep. 3, 1806–1814.
Cocco, T., Pacelli, C., Sgobbo, P., and Villani, G. (2009). Control of OXPHOS efficiency by complex I in brain mitochondria. Neurobiol. Aging 30, 622–629.
Collado, M., Blasco, M.A., and Serrano, M. (2007). Cellular Senescence in Cancer and Aging. Cell 130, 223–233. Coppé, J.-P., Patil, C.K., Rodier, F., Sun, Y., Muñoz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.-Y., and Campisi, J. (2008). Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLOS Biol. 6, e301.
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., and Campisi, J. (2010). The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. 5, 99–118.
180
Coppé, J.-P., Rodier, F., Patil, C.K., Freund, A., Desprez, P.-Y., and Campisi, J. (2011). Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype. J. Biol. Chem. 286, 36396–36403.
Correia-Melo, C., and Passos, J.F. (2015). Mitochondria: Are they causal players in cellular senescence? Biochim. Biophys. Acta 1847, 1373–1379.
Correia‐ Melo, C., Marques, F.D., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B.M., Miwa, S., Birch, J., Merz, A., et al. (2016). Mitochondria are required for pro‐ ageing features of the senescent phenotype. EMBO J. 35, 724–742.
Cotter, G., Metzkor, E., Kaluski, E., Faigenberg, Z., Miller, R., Simovitz, A., Shaham, O., Marghitay, D., Koren, M., Blatt, A., et al. (1998). Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. The Lancet 351, 389– 393.
Cristofalo, V.J. (2005). SA β Gal staining: Biomarker or delusion. Exp. Gerontol. 40, 836–838.
Crowley, S.D., Gurley, S.B., Herrera, M.J., Ruiz, P., Griffiths, R., Kumar, A.P., Kim, H.-S., Smithies, O., Le, T.H., and Coffman, T.M. (2006). Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc. Natl. Acad. Sci. U. S. A. 103, 17985–17990.
Cruz-Jentoft, A.J., Baeyens, J.P., Bauer, J.M., Boirie, Y., Cederholm, T., Landi, F., Martin, F.C., Michel, J.-P., Rolland, Y., Schneider, S.M., et al. (2010). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39, 412–423.
Cruz-Jentoft, A.J., Landi, F., Schneider, S.M., Zúñiga, C., Arai, H., Boirie, Y., Chen, L.-K., Fielding, R.A., Martin, F.C., Michel, J.-P., et al. (2014). Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing 43, 748–759.
Csepe, T.A., Kalyanasundaram, A., Hansen, B.J., Zhao, J., and Fedorov, V.V. (2015). Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction. Front. Physiol. 6.
Cypen, J., Ahmad, T., Testani, J.M., and DeVore, A.D. (2017). Novel Biomarkers for the Risk Stratification of Heart Failure with Preserved Ejection Fraction. Curr. Heart Fail. Rep. 14, 434–443.
Dai, D.-F., Santana, L.F., Vermulst, M., Tomazela, D.M., Emond, M.J., MacCoss, M.J., Gollahon, K., Martin, G.M., Loeb, L.A., Ladiges, W.C., et al. (2009). Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119, 2789–2797.
Dai, D.-F., Chen, T., Wanagat, J., Laflamme, M., Marcinek, D.J., Emond, M.J., Ngo, C.P., Prolla, T.A., and Rabinovitch, P.S. (2010). Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9, 536–544.
Dai, D.-F., Johnson, S.C., Villarin, J.J., Chin, M.T., Nieves-Cintrón, M., Chen, T., Marcinek, D.J., Dorn, G.W., Kang, Y.J., Prolla, T.A., et al. (2011). Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ. Res. 108, 837–846.
Dai, D.-F., Chen, T., Johnson, S.C., Szeto, H., and Rabinovitch, P.S. (2012). Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease. Antioxid. Redox Signal. 16, 1492–1526.
Dalle Pezze, P., Nelson, G., Otten, E.G., Korolchuk, V.I., Kirkwood, T.B.L., von Zglinicki, T., and Shanley, D.P. (2014). Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions. PLoS Comput. Biol. 10, e1003728.
Damy, T., Guellich, A., Vermes, E., Deswarte, G., and Hittinger, L. (2007). Physiologie et physiopathologie du système rénine-angiotensine-aldostérone. Mt Cardio 3, 257–262.
Davalli, P., Mitic, T., Caporali, A., Lauriola, A., and D’Arca, D. (2016). ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases. Oxid. Med. Cell. Longev. 2016.
181
Deas, E., Wood, N.W., and Plun-Favreau, H. (2011). Mitophagy and Parkinson’s disease: the PINK1-parkin link. Biochim. Biophys. Acta 1813, 623–633.
Dechat, T., Pfleghaar, K., Sengupta, K., Shimi, T., Shumaker, D.K., Solimando, L., and Goldman, R.D. (2008). Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev. 22, 832–853.
Dehay, C., and Kennedy, H. (2007). Cell-cycle control and cortical development. Nat. Rev. Neurosci. 8, 438– 450.
Demaria, M., Ohtani, N., Youssef, S.A., Rodier, F., Toussaint, W., Mitchell, J.R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M.E.T., et al. (2014). An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA. Dev. Cell 31, 722–733.
Demidenko, Z.N., and Blagosklonny, M.V. (2008). Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle 7, 3355–3361.
Deng, C., Zhang, P., Wade Harper, J., Elledge, S.J., and Leder, P. (1995). Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684.
Di Leonardo, A., Linke, S.P., Clarkin, K., and Wahl, G.M. (1994). DNA damage triggers a prolonged p53- dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8, 2540–2551. Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Nuciforo, P.G., Bensimon, A., et al. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642.
Di Mitri, D., and Alimonti, A. (2016). Non-Cell-Autonomous Regulation of Cellular Senescence in Cancer. Trends Cell Biol. 26, 215–226.
Dierick, J.F., Pascal, T., Chainiaux, F., Eliaers, F., Remacle, J., Larsen, P.M., Roepstorff, P., and Toussaint, O. (2000). Transcriptome and proteome analysis in human senescent fibroblasts and fibroblasts undergoing premature senescence induced by repeated sublethal stresses. Ann. N. Y. Acad. Sci. 908, 302–305.
Dierick, J.-F., Eliaers, F., Remacle, J., Raes, M., Fey, S.J., Larsen, P.M., and Toussaint, O. (2002). Stress-induced premature senescence and replicative senescence are different phenotypes, proteomic evidence. Biochem. Pharmacol. 64, 1011–1017.
Dimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., and Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. 92, 9363–9367.
Dobaczewski, M., Chen, W., and Frangogiannis, N.G. (2011). Transforming growth factor (TGF)-β signaling in cardiac remodeling. J. Mol. Cell. Cardiol. 51, 600–606.
Doherty, T.J. (2003). Invited Review: Aging and sarcopenia. J. Appl. Physiol. 95, 1717–1727.
Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery, C.A., Butel, J.S., and Bradley, A. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221.
Duan, J., Duan, J., Zhang, Z., and Tong, T. (2005). Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening. Int. J. Biochem. Cell Biol. 37, 1407–1420.
Dulic, V. (2013). Senescence regulation by mTOR. Methods Mol. Biol. Clifton NJ 965, 15–35.
Edelmann, F., Wachter, R., Schmidt, A.G., Kraigher-Krainer, E., Colantonio, C., Kamke, W., Duvinage, A., Stahrenberg, R., Durstewitz, K., Löffler, M., et al. (2013). Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA 309, 781–791.
182
Efeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L.T., and Serrano, M. (2007). Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin. Cancer Res. 67, 7350–7357.
Eghbali, M., Eghbali, M., Robinson, T.F., Seifter, S., and Blumenfeld, O.O. (1989). Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc. Res. 23, 723–729.
El’darov, C.M., Vays, V.B., Vangeli, I.M., Kolosova, N.G., and Bakeeva, L.E. (2015). Morphometric Examination of Mitochondrial Ultrastructure in Aging Cardiomyocytes. Biochem. Biokhimiia 80, 604–609.
Ellis, R.E., Yuan, J.Y., and Horvitz, H.R. (1991). Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698.
Elzi, D.J., Lai, Y., Song, M., Hakala, K., Weintraub, S.T., and Shiio, Y. (2012). Plasminogen activator inhibitor 1 - insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence. Proc. Natl. Acad. Sci. 109, 12052–12057.
Ensrud, K.E., Ewing, S.K., Cawthon, P.M., Fink, H.A., Taylor, B.C., Cauley, J.A., Dam, T.-T., Marshall, L.M., Orwoll, E.S., Cummings, S.R., et al. (2009). A comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men. J. Am. Geriatr. Soc. 57, 492–498.
Esler, M., Kaye, D., Thompson, J., Jennings, G., Cox, H., Turner, A., Lambert, G., and Seals, D. (1995). Effects of aging on epinephrine secretion and regional release of epinephrine from the human heart. J. Clin. Endocrinol. Metab. 80, 435–442.
Evangelou, K., Lougiakis, N., Rizou, S.V., Kotsinas, A., Kletsas, D., Muñoz‐ Espín, D., Kastrinakis, N.G., Pouli, N., Marakos, P., Townsend, P., et al. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell 16, 192–197.
Fagagna, F. d’Adda di, Reaper, P.M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N.P., and Jackson, S.P. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198.
d’Adda di Fagagna, F. (2008). Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512–522.
Falck, J., Coates, J., and Jackson, S.P. (2005). Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611.
Fearnley, C.J., Roderick, H.L., and Bootman, M.D. (2011). Calcium Signaling in Cardiac Myocytes. Cold Spring Harb. Perspect. Biol. 3.
Feng, X.H., Lin, X., and Derynck, R. (2000). Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta. EMBO J. 19, 5178–5193.
Feridooni, H.A., Dibb, K.M., and Howlett, S.E. (2015). How cardiomyocyte excitation, calcium release and contraction become altered with age. J. Mol. Cell. Cardiol. 83, 62–72.
Ferrara, N., Komici, K., Corbi, G., Pagano, G., Furgi, G., Rengo, C., Femminella, G.D., Leosco, D., and Bonaduce, D. (2014). β-adrenergic receptor responsiveness in aging heart and clinical implications. Front. Physiol. 4. Ferrucci, L., Giallauria, F., and Guralnik, J.M. (2008). Epidemiology of Aging. Radiol. Clin. North Am. 46, 643–v. Fielder, E., von Zglinicki, T., and Jurk, D. (2017). The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State? J. Alzheimers Dis. Preprint, 1–25.
Finkel, T. (2011). Signal transduction by reactive oxygen species. J. Cell Biol. 194, 7–15.
Flor, A.C., and Kron, S.J. (2016). Lipid-derived reactive aldehydes link oxidative stress to cell senescence. Cell Death Dis. 7, e2366.
Fragoso, C.A.V. (2016). Epidemiology of Chronic Obstructive Pulmonary Disease (COPD) in Aging Populations. COPD J. Chronic Obstr. Pulm. Dis. 13, 125–129.
183
Freund, A., Laberge, R.-M., Demaria, M., and Campisi, J. (2012). Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075.
Fried, L.P., Tangen, C.M., Walston, J., Newman, A.B., Hirsch, C., Gottdiener, J., Seeman, T., Tracy, R., Kop, W.J., Burke, G., et al. (2001). Frailty in older adults: evidence for a phenotype. J. Gerontol. A. Biol. Sci. Med. Sci. 56, M146–M157.
Fumagalli, M., Rossiello, F., Mondello, C., and d’Adda di Fagagna, F. (2014). Stable Cellular Senescence Is Associated with Persistent DDR Activation. PLoS ONE 9.
Fyhrquist, F., Saijonmaa, O., and Strandberg, T. (2013). The roles of senescence and telomere shortening in cardiovascular disease. Nat. Rev. Cardiol. 10, 274–283.
Gabay, C., and Kushner, I. (1999). Acute-Phase Proteins and Other Systemic Responses to Inflammation. N. Engl. J. Med. 340, 448–454.
Gallage, S., and Gil, J. (2014). Primary cilia and senescence: a sensitive issue. Cell Cycle Georget. Tex 13, 2653– 2654.
García-Cao, I., García-Cao, M., Martín-Caballero, J., Criado, L.M., Klatt, P., Flores, J.M., Weill, J.-C., Blasco, M.A.,