Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Current Osteoporosis Reports
Erschienen in: Current Osteoporosis Reports 2/2019

26.02.2019 | Therapeutics and Medical Management (S Jan de Beur and B Clarke, Section Editors)

Targeting Cell Senescence for the Treatment of Age-Related Bone Loss

verfasst von: Robert J. Pignolo, Rebekah M. Samsonraj, Susan F. Law, Haitao Wang, Abhishek Chandra

Erschienen in: Current Osteoporosis Reports | Ausgabe 2/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose of Review

We review cell senescence in the context of age-related bone loss by broadly discussing aging mechanisms in bone, currently known inducers and markers of senescence, the senescence-associated secretory phenotype (SASP), and the emerging roles of senescence in bone homeostasis and pathology.

Recent Findings

Cellular senescence is a state of irreversible cell cycle arrest induced by insults or stressors including telomere attrition, oxidative stress, DNA damage, oncogene activation, and other intrinsic or extrinsic triggers and there is mounting evidence for the role of senescence in aging bone. Cellular aging also instigates a SASP that exerts detrimental paracrine and likely systemic effects.

Summary

With aging, multiple cell types in the bone microenvironment become senescent, with osteocytes and myeloid cells as primary contributors to the SASP. Targeting undesired senescent cells may be a favorable strategy to promote bone anabolic and anti-resorptive functions in aging bone, with the possibility of improving bone quality and function with normal aging and/or disease.
Literatur
1.
Boros K, Freemont T. Physiology of ageing of the musculoskeletal system. Best Pract Res Clin Rheumatol. 2017;31(2):203–17.CrossRefPubMed
2.
3.
4.
Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res. 2007;22(8):1197–207.CrossRefPubMed
5.
Khosla S. Pathogenesis of age-related bone loss in humans. J Gerontol A Biol Sci Med Sci. 2013;68(10):1226–35.CrossRefPubMed
6.
Khosla S, Pacifici R. Chapter 46 - estrogen deficiency, postmenopausal osteoporosis, and age-related bone loss. In: Marcus R, Feldman D, Dempster DW, Luckey M, Cauley JA, editors. Osteoporosis. Fourth ed. San Diego: Academic Press; 2013. p. 1113–36.
7.
Hay E, Bouaziz W, Funck-Brentano T, Cohen-Solal M. Sclerostin and bone aging: a mini-review. Gerontology. 2016;62(6):618–23.CrossRefPubMed
8.
Girgis CM, Baldock PA, Downes M. Vitamin D, muscle and bone: integrating effects in development, aging and injury. Mol Cell Endocrinol. 2015;410:3–10.CrossRefPubMed
9.
Bianco P, Robey PG. Skeletal stem cells. Development (Cambridge, England). 2015;142(6):1023–7.CrossRef
10.
Guntur AR, Rosen CJ. IGF-1 regulation of key signaling pathways in bone. BoneKEy Rep. 2013;2.
11.
Roberts S, Colombier P, Sowman A, Mennan C, Rölfing JHD, Guicheux J, et al. Ageing in the musculoskeletal system: cellular function and dysfunction throughout life. Acta Orthop. 2016;87(Suppl 363):15–25.CrossRefPubMedPubMedCentral
12.
Chandra A, Rosenzweig A, Pignolo RJ. Osteobiology of aging. In: Pignolo RJ, Ahn J, editors. Fractures in the elderly: a guide to practical management. Cham: Springer International Publishing; 2018. p. 3–37.CrossRef
13.
14.
•• Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, et al. Identification of senescent cells in the bone microenvironment. J Bone Miner Res. 2016;31(11):1920–9 The study provided the first thorough evidence of senescence in bone cells from aged animals and humans. CrossRefPubMed
15.
•• Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med. 2017;23(9):1072–9 This study provided the first detailed evidence that clearance of senescent cells by genetic and pharmacological methods could alleviate age-associated osteoporosis. CrossRefPubMedPubMedCentral
16.
17.
Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.CrossRefPubMed
18.
Lecot P, Alimirah F, Desprez PY, Campisi J, Wiley C. Context-dependent effects of cellular senescence in cancer development. Br J Cancer. 2016;114(11):1180–4.CrossRefPubMedPubMedCentral
19.
Sueblinvong V, Neveu WA, Neujahr DC, Mills ST, Rojas M, Roman J, et al. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury. Adv Biosci Biotechnol (Print). 2014;5(1):19–30.CrossRef
20.
Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–40.CrossRefPubMed
21.
Terzi MY, Izmirli M, Gogebakan B. The cell fate: senescence or quiescence. Mol Biol Rep. 2016;43(11):1213–20.CrossRefPubMed
22.
Marie PJ. Bone cell senescence: mechanisms and perspectives. J Bone Miner Res. 2014;29(6):1311–21.CrossRefPubMed
23.
Mas-Bargues C, Vina-Almunia J, Ingles M, Sanz-Ros J, Gambini J, Ibanez-Cabellos JS, et al. Role of p16(INK4a) and BMI-1 in oxidative stress-induced premature senescence in human dental pulp stem cells. Redox Biol. 2017;12:690–8.CrossRefPubMedPubMedCentral
24.
Mirzayans R, Andrais B, Hansen G, Murray D. Role of p16(INK4A) in replicative senescence and DNA damage-induced premature senescence in p53-deficient human cells. Biochem Res Int. 2012;2012:951574.CrossRefPubMedPubMedCentral
25.
Jin J, Tao J, Gu X, Yu Z, Wang R, Zuo G, et al. P16INK4aDeletion ameliorated renal tubulointerstitial injury in a stress-induced premature senescence model of Bmi-1 deficiency. Sci Rep. 2017;7(1):7502.CrossRefPubMedPubMedCentral
26.
Blazkova H, Krejcikova K, Moudry P, Frisan T, Hodny Z, Bartek J. Bacterial intoxication evokes cellular senescence with persistent DNA damage and cytokine signalling. J Cell Mol Med. 2010;14(1–2):357–67.CrossRefPubMed
27.
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010;6:347.CrossRefPubMedPubMedCentral
28.
Rodier F, Coppé J-P, Patil CK, Hoeijmakers WAM, Muñoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11:973.CrossRefPubMedPubMedCentral
29.
Saeed H, Abdallah BM, Ditzel N, Catala-Lehnen P, Qiu W, Amling M, et al. Telomerase-deficient mice exhibit bone loss owing to defects in osteoblasts and increased osteoclastogenesis by inflammatory microenvironment. J Bone Miner Res. 2011;26(7):1494–505.CrossRefPubMed
30.
Wang H, Chen Q, Lee SH, Choi Y, Johnson FB, Pignolo RJ. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell. 2012;11(4):704–13.CrossRefPubMed
31.
Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, et al. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol. 2002;20(6):592–6.CrossRefPubMed
32.
Yudoh K, Nishioka K. Telomerized presenescent osteoblasts prevent bone mass loss in vivo. Gene Ther. 2004;11(11):909–15.CrossRefPubMed
33.
• Gronthos S, Chen S, Wang CY, Robey PG, Shi S. Telomerase accelerates osteogenesis of bone marrow stromal stem cells by upregulation of CBFA1, osterix, and osteocalcin. J Bone Miner Res. 2003;18(4):716–22 This paper provided evidence that telomerase accelerates osteogenic induction. By transplantation of telomerase-expressing MSCs, the authors reported increased ectopic bone formation accompanied with upregulation of osteogenic genes. CrossRefPubMed
34.
Yudoh K, Matsuno H, Nakazawa F, Katayama R, Kimura T. Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts. J Bone Miner Res. 2001;16(8):1453–64.CrossRefPubMed
35.
•• Pignolo RJ, Suda RK, McMillan EA, Shen J, Lee SH, Choi Y, et al. Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Aging Cell. 2008;7(1):23–31 Using an accelerated aging model of Wrn and Terc deficiencies that resulted in low bone mass phenotype, this paper showed that age-related osteoporosis results from impaired osteoblast differentiation. This paper was also first to demonstrate that MSCs derived from these double mutant mice showed limited in vitro lifespan and impaired osteogenic potential, together supporting that aging of osteoblast precursors due to telomere dysfunction is an important mechanism underlying age-related osteoporosis. CrossRefPubMed
36.
Di Leonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994;8(21):2540–51.CrossRefPubMed
37.
Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell. 2004;14(4):501–13.CrossRefPubMed
38.
d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194–8.CrossRefPubMed
39.
40.
Galbiati A, Beausejour C, d'Adda di Fagagna F. A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell 2017;16(2):422–427.
41.
Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci. 2011;124(Pt 1):68–81.CrossRefPubMed
42.
Munch S, Weidtkamp-Peters S, Klement K, Grigaravicius P, Monajembashi S, Salomoni P, et al. The tumor suppressor PML specifically accumulates at RPA/Rad51-containing DNA damage repair foci but is nonessential for DNA damage-induced fibroblast senescence. Mol Cell Biol. 2014;34(10):1733–46.CrossRefPubMedPubMedCentral
43.
• Kang C, Xu Q, Martin TD, Li MZ, Demaria M, Aron L, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science (New York, NY). 2015;349(6255):aaa5612 This paper was the first to identify that transcription factor GATA4 is both a senescence and SASP regulator. Being stabilized in cells undergoing senescence, GATA4 was also shown to activate the transcription factor NF-κB to initiate the SASP and mediate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). CrossRef
44.
Lee JY, Yu KR, Lee BC, Kang I, Kim JJ, Jung EJ, et al. GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging. Exp Mol Med. 2018;50(5):63.CrossRefPubMedCentral
45.
Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest. 1990;85(3):632–9.CrossRefPubMedPubMedCentral
46.
Baek KH, Oh KW, Lee WY, Lee SS, Kim MK, Kwon HS, et al. Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures. Calcif Tissue Int. 2010;87(3):226–35.CrossRefPubMed
47.
Munro J, Barr NI, Ireland H, Morrison V, Parkinson EK. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp Cell Res. 2004;295(2):525–38.CrossRefPubMed
48.
Ogryzko VV, Hirai TH, Russanova VR, Barbie DA, Howard BH. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol Cell Biol. 1996;16(9):5210–8.CrossRefPubMedPubMedCentral
49.
Wu G, Wang N, Luo Y, Zhang Y, Wang P, Zhu Z, et al. Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells. Tumour Biol. 2017;39(5):1010428317699117.CrossRefPubMed
50.
Ito T, Teo YV, Evans SA, Neretti N, Sedivy JM. Regulation of cellular senescence by Polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 2018;22(13):3480–92.CrossRefPubMedPubMedCentral
51.
52.
Kochetkova EY, Blinova GI, Bystrova OA, Martynova MG, Pospelov VA, Pospelova TV. Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway. Aging (Albany NY). 2017;9(11):2352–75.CrossRef
53.
54.
Malumbres M, Perez De Castro I, Hernandez MI, Jimenez M, Corral T, Pellicer A. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol. 2000;20(8):2915–25.CrossRefPubMedPubMedCentral
55.
Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M. Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology (Baltimore, Md). 2010;52(3):966–74.CrossRef
56.
Luo X, Fu Y, Loza AJ, Murali B, Leahy KM, Ruhland MK, et al. Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep. 2016;14(1):82–92.CrossRefPubMed
57.
Maciel-Baron LA, Morales-Rosales SL, Aquino-Cruz AA, Triana-Martinez F, Galvan-Arzate S, Luna-Lopez A, et al. Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli. Age (Dordr). 2016;38(1):26.CrossRef
58.
Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC, Morton JP, et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 2017;31(2):172–83.CrossRefPubMedPubMedCentral
59.
Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16(5):238–46.CrossRefPubMedPubMedCentral
60.
Greene MA, Loeser RF. Aging-related inflammation in osteoarthritis. Osteoarthr Cartil. 2015;23(11):1966–71.CrossRef
61.
Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536–48.CrossRefPubMedPubMedCentral
62.
Salminen A, Kaarniranta K, Kauppinen A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY). 2012;4(3):166–75.CrossRef
63.
Philipot D, Guérit D, Platano D, Chuchana P, Olivotto E, Espinoza F, et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther. 2014;16(1):R58.CrossRefPubMedPubMedCentral
64.
Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31(6):722–33.CrossRefPubMedPubMedCentral
65.
Jun JI, Lau LF. Cellular senescence controls fibrosis in wound healing. Aging (Albany NY). 2010;2(9):627–31.CrossRef
66.
Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.CrossRefPubMed
67.
Blagosklonny MV. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging (Albany NY). 2012;4(3):159–65.CrossRef
68.
69.
Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008;7(21):3355–61.CrossRefPubMed
70.
Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY). 2016;8(7):1294–315.CrossRef
71.
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114(9):1299–307.CrossRefPubMedPubMedCentral
72.
Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A. 1996;93(24):13742–7.CrossRefPubMedPubMedCentral
73.
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75(4):817–25.CrossRefPubMed
74.
Stein GH, Drullinger LF, Soulard A, Dulic V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 1999;19(3):2109–17.CrossRefPubMedPubMedCentral
75.
Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424–35.CrossRefPubMedPubMedCentral
76.
Mets T, Verdonk G. Variations in the stromal cell population of human bone marrow during aging. Mech Ageing Dev. 1981;15(1):41–9.CrossRefPubMed
77.
Wagner W, Horn P, Castoldi M, Diehlmann A, Bork S, Saffrich R, et al. Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS One. 2008;3(5):e2213.CrossRefPubMedPubMedCentral
78.
Babaei M, Jansen L, Balavarca Y, Sjovall A, Bos A, van de Velde T, et al. Neoadjuvant therapy in rectal cancer patients with clinical stage II to III across European countries: variations and outcomes. Clin Colorectal Cancer. 2017.
79.
Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, et al. Senescent phenotype can be reversed by reduction of caveolin status. J Biol Chem. 2003;278(30):27789–95.CrossRefPubMed
80.
Nishio K, Inoue A, Qiao S, Kondo H, Mimura A. Senescence and cytoskeleton: overproduction of vimentin induces senescent-like morphology in human fibroblasts. Histochem Cell Biol. 2001;116(4):321–7.CrossRefPubMed
81.
Cho KA, Ryu SJ, Oh YS, Park JH, Lee JW, Kim HP, et al. Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem. 2004;279(40):42270–8.CrossRefPubMed
82.
Lipetz J, Cristofalo VJ. Ultrastructural changes accompanying the aging of human diploid cells in culture. J Ultrastruct Res. 1972;39(1):43–56.CrossRefPubMed
83.
De Priester W, Van Manen R, Knook DL. Lysosomal activity in the aging rat liver: II. Morphometry of acid phosphatase positive dense bodies. Mech Ageing Dev. 1984;26(2–3):205–16.CrossRefPubMed
84.
Schmucker DL, Sachs H. Quantifying dense bodies and lipofuscin during aging: a morphologist’s perspective. Arch Gerontol Geriatr. 2002;34(3):249–61.CrossRefPubMed
85.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92(20):9363–7.CrossRefPubMedPubMedCentral
86.
Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009;4(12):1798–806.CrossRefPubMed
87.
Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5(2):187–95.CrossRefPubMed
88.
Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000;113(Pt 20):3613–22.PubMed
89.
Yang NC, Hu ML. The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol. 2005;40(10):813–9.CrossRefPubMed
90.
Cristofalo VJ. SA beta Gal staining: biomarker or delusion. Exp Gerontol. 2005;40(10):836–8.CrossRefPubMed
91.
Hildebrand DG, Lehle S, Borst A, Haferkamp S, Essmann F, Schulze-Osthoff K. alpha-Fucosidase as a novel convenient biomarker for cellular senescence. Cell Cycle. 2013;12(12):1922–7.CrossRefPubMedPubMedCentral
92.
Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18.CrossRefPubMed
93.
Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019–31.CrossRefPubMed
94.
Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6(12):2853–68.CrossRefPubMed
95.
Kim HN, Chang J, Shao L, Han L, Iyer S, Manolagas SC, et al. DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell. 2017;16(4):693–703.CrossRefPubMedPubMedCentral
96.
Piemontese M, Almeida M, Robling AG, Kim HN, Xiong J, Thostenson JD, et al. Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight. 2017;2(17).
97.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMed
98.
Kranjc T, Ostanek B, Marc J. Bone microRNAs and ageing. Curr Pharm Biotechnol. 2017;18(3):210–20.CrossRefPubMed
99.
Okada M, Kim HW, Matsu-ura K, Wang YG, Xu M, Ashraf M. Abrogation of age-induced MicroRNA-195 rejuvenates the senescent mesenchymal stem cells by reactivating telomerase. Stem Cells. 2016;34(1):148–59.CrossRefPubMed
100.
Yoo JK, Kim CH, Jung HY, Lee DR, Kim JK. Discovery and characterization of miRNA during cellular senescence in bone marrow-derived human mesenchymal stem cells. Exp Gerontol. 2014;58:139–45.CrossRefPubMed
101.
He X, Zhang W, Liao L, Fu X, Yu Q, Jin Y. Identification and characterization of microRNAs by high through-put sequencing in mesenchymal stem cells and bone tissue from mice of age-related osteoporosis. PLoS One. 2013;8(8):e71895.CrossRefPubMedPubMedCentral
102.
Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells. 2004;22(5):675–82.CrossRefPubMed
103.
Raz V, Vermolen BJ, Garini Y, Onderwater JJ, Mommaas-Kienhuis MA, Koster AJ, et al. The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells. J Cell Sci. 2008;121(Pt 24):4018–28.CrossRefPubMed
104.
Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988;85(18):6622–6.CrossRefPubMedPubMedCentral
105.
106.
Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–63.CrossRefPubMed
107.
108.
Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007;39(4):457–66.CrossRefPubMed
109.
Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49(2):359–67.CrossRefPubMed
110.
Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;20(4):440–6.CrossRefPubMedPubMedCentral
111.
Weidner CI, Lin Q, Koch CM, Eisele L, Beier F, Ziegler P, et al. Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol. 2014;15(2):R24.CrossRefPubMedPubMedCentral
112.
113.
Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, van Eijk K, et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012;13(10):R97.CrossRefPubMedPubMedCentral
114.
•• Florath I, Butterbach K, Muller H, Bewerunge-Hudler M, Brenner H. Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Hum Mol Genet. 2014;23(5):1186–201 This study provides a thorough description of how an “epigenetic clock” could predict age across individuals in a large epigenome-wide study of 965 individuals. The authors identified 155 significantly age-associated CpG sites mapping to 100 genes and identified over 60 novel age-associated CpG sites with high correlation to age in specific tissues. CrossRefPubMed
115.
Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113(6):703–16.CrossRefPubMed
116.
Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell. 2005;8(1):19–30.CrossRefPubMed
117.
•• Narita M, Narita M, Krizhanovsky V, Nunez S, Chicas A, Hearn SA, et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell. 2006;126(3):503–14 HMGA1 and 2 were identified as proteins that are structural components of SAHFs which stabilize senescence and block proliferation. They modulate transcription involved in the switch between senescence and transformation. CrossRefPubMed
118.
119.
Corpet A, Olbrich T, Gwerder M, Fink D, Stucki M. Dynamics of histone H3.3 deposition in proliferating and senescent cells reveals a DAXX-dependent targeting to PML-NBs important for pericentromeric heterochromatin organization. Cell Cycle. 2014;13(2):249–67.CrossRefPubMed
120.
121.
Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR, et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A. 2006;103(23):8703–8.CrossRefPubMedPubMedCentral
122.
123.
Swanson EC, Manning B, Zhang H, Lawrence JB. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J Cell Biol. 2013;203(6):929–42.CrossRefPubMedPubMedCentral
124.
Swanson EC, Rapkin LM, Bazett-Jones DP, Lawrence JB. Unfolding the story of chromatin organization in senescent cells. Nucleus. 2015;6(4):254–60.CrossRefPubMedPubMedCentral
125.
Pignolo RJ, Martin BG, Horton JH, Kalbach AN, Cristofalo VJ. The pathway of cell senescence: WI-38 cells arrest in late G1 and are unable to traverse the cell cycle from a true G0 state. Exp Gerontol. 1998;33(1–2):67–80.CrossRefPubMed
126.
Bemiller PM, Lee LH. Nucleolar changes in senescing WI-38 cells. Mech Ageing Dev. 1978;8(6):417–27.CrossRefPubMed
127.
•• Lessard F, Igelmann S, Trahan C, Huot G, Saint-Germain E, Mignacca L, et al. Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway. Nat Cell Biol. 2018;20(7):789–99 This study reported how cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. The accumulation of ribosomal protein L29 may serve as a novel senescence biomarker in vivo and in vitro. Further genetic analysis revealed that Rb but not p53 was required for the senescence response to alter ribosome biogenesis. CrossRefPubMed
128.
Donati G, Peddigari S, Mercer CA, Thomas G. 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2-p53 checkpoint. Cell Rep. 2013;4(1):87–98.CrossRefPubMedPubMedCentral
129.
130.
Horn HF, Vousden KH. Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. Oncogene. 2008;27(44):5774–84.CrossRefPubMed
131.
Marechal V, Elenbaas B, Piette J, Nicolas JC, Levine AJ. The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes. Mol Cell Biol. 1994;14(11):7414–20.CrossRefPubMedPubMedCentral
132.
Althubiti M, Lezina L, Carrera S, Jukes-Jones R, Giblett SM, Antonov A, et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis. 2014;5:e1528.CrossRefPubMedPubMedCentral
133.
Odgren PR, MacKay CA, Mason-Savas A, Yang M, Mailhot G, Birnbaum MJ. False-positive beta-galactosidase staining in osteoclasts by endogenous enzyme: studies in neonatal and month-old wild-type mice. Connect Tissue Res. 2006;47(4):229–34.CrossRefPubMed
134.
135.
Parfitt AM. The coupling of bone formation to bone resorption: a critical analysis of the concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone Dis Relat Res. 1982;4(1):1–6.CrossRefPubMed
136.
Biran A, Zada L, Abou Karam P, Vadai E, Roitman L, Ovadya Y, et al. Quantitative identification of senescent cells in aging and disease. Aging Cell. 2017;16(4):661–71.CrossRefPubMedPubMedCentral
137.
138.
Mason DX, Jackson TJ, Lin AW. Molecular signature of oncogenic ras-induced senescence. Oncogene. 2004;23(57):9238–46.CrossRefPubMed
139.
Lau L, David G. Senescence phenotypes induced by Ras in primary cells. Methods Mol Biol. 2017;1534:17–30.CrossRefPubMed
140.
Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science (New York, NY). 2006;311(5765):1257.CrossRef
141.
Chen X, Li M, Yan J, Liu T, Pan G, Yang H, et al. Alcohol induces cellular senescence and impairs osteogenic potential in bone marrow-derived mesenchymal stem cells. Alcohol Alcohol. 2017;52(3):289–97.CrossRefPubMedPubMedCentral
142.
Muthna D, Soukup T, Vavrova J, Mokry J, Cmielova J, Visek B, et al. Irradiation of adult human dental pulp stem cells provokes activation of p53, cell cycle arrest, and senescence but not apoptosis. Stem Cells Dev. 2010;19(12):1855–62.CrossRefPubMed
143.
Sui B, Hu C, Liao L, Chen Y, Zhang X, Fu X, et al. Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis. Sci Rep. 2016;6:30186.CrossRefPubMedPubMedCentral
144.
Kawase M, Tsuda M, Matsuo T. Accelerated bone resorption in senescence-accelerated mouse (SAM-P/6). J Bone Miner Res. 1989;4(3):359–64.CrossRefPubMed
145.
Perkins SL, Gibbons R, Kling S, Kahn AJ. Age-related bone loss in mice is associated with an increased osteoclast progenitor pool. Bone. 1994;15(1):65–72.CrossRefPubMed
146.
Okamoto Y, Takahashi K, Toriyama K, Takeda N, Kitagawa K, Hosokawa M, et al. Femoral peak bone mass and osteoclast number in an animal model of age-related spontaneous osteopenia. Anat Rec. 1995;242(1):21–8.CrossRefPubMed
147.
Bellantuono I, Aldahmash A, Kassem M. Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss. Biochim Biophys Acta. 2009;1792(4):364–70.CrossRefPubMed
148.
Erdmann J, Kogler C, Diel I, Ziegler R, Pfeilschifter J. Age-associated changes in the stimulatory effect of transforming growth factor beta on human osteogenic colony formation. Mech Ageing Dev. 1999;110(1–2):73–85.CrossRefPubMed
149.
Chandra A, Lin T, Young T, Tong W, Ma X, Tseng WJ, et al. Suppression of sclerostin alleviates radiation-induced bone loss by protecting bone-forming cells and their progenitors through distinct mechanisms. J Bone Miner Res. 2017;32(2):360–72.CrossRefPubMed
150.
Li H, Liu P, Xu S, Li Y, Dekker JD, Li B, et al. FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging. J Clin Invest. 2017;127(4):1241–53.CrossRefPubMedPubMedCentral
151.
Abdallah BM, Haack-Sorensen M, Fink T, Kassem M. Inhibition of osteoblast differentiation but not adipocyte differentiation of mesenchymal stem cells by sera obtained from aged females. Bone. 2006;39(1):181–8.CrossRefPubMed
152.
Larsen SA, Kassem M, Rattan SI. Glucose metabolite glyoxal induces senescence in telomerase-immortalized human mesenchymal stem cells. Chem Cent J. 2012;6(1):18.CrossRefPubMedPubMedCentral
153.
154.
Portal-Nunez S, Ardura JA, Lozano D, Bolivar OH, Lopez-Herradon A, Gutierrez-Rojas I, et al. Adverse effects of diabetes mellitus on the skeleton of aging mice. J Gerontol A Biol Sci Med Sci. 2016;71(3):290–9.CrossRefPubMed
155.
Rosso A, Balsamo A, Gambino R, Dentelli P, Falcioni R, Cassader M, et al. p53 mediates the accelerated onset of senescence of endothelial progenitor cells in diabetes. J Biol Chem. 2006;281(7):4339–47.CrossRefPubMed
156.
Oikawa A, Siragusa M, Quaini F, Mangialardi G, Katare RG, Caporali A, et al. Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol. 2010;30(3):498–508.CrossRefPubMed
157.
Carnevale V, Romagnoli E, D'Erasmo L, D'Erasmo E. Bone damage in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2014;24(11):1151–7.CrossRefPubMed
158.
Nilsson AG, Sundh D, Johansson L, Nilsson M, Mellstrom D, Rudang R, et al. Type 2 diabetes mellitus is associated with better bone microarchitecture but lower bone material strength and poorer physical function in elderly women: a population-based study. J Bone Miner Res. 2017;32(5):1062–71.CrossRefPubMed
159.
Karim L, Bouxsein ML. Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone. 2016;82:21–7.CrossRefPubMed
160.
Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol. 2014;2:411–29.CrossRefPubMedPubMedCentral
161.
Sanguineti R, Puddu A, Mach F, Montecucco F, Viviani GL. Advanced glycation end products play adverse proinflammatory activities in osteoporosis. Mediat Inflamm. 2014;2014:975872.CrossRef
162.
163.
Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64(7):2289–98.CrossRefPubMedPubMedCentral
164.
Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, et al. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes. 2006;30(9):1347–55.CrossRef
165.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327–34.CrossRefPubMed
166.
Lau YK, Lee E, Prior HJ, Lix LM, Metge CJ, Leslie WD. Fracture risk in androgen deprivation therapy: a Canadian population based analysis. Can J Urol. 2009;16(6):4908–14.PubMed
167.
Ojeda S, Lloret M, Naranjo A, Deniz F, Chesa N, Dominguez C, et al. Androgen deprivation in prostate cancer and the long-term risk of fracture. Actas Urol Esp. 2017;41(8):491–6.CrossRefPubMed
168.
Salama MN, Eid AA, Hatem A, Swidan AK. Prevalence of erectile dysfunction in Egyptian males with metabolic syndrome. Aging Male. 2018:1–7.
169.
Salvador C, Planas J, Agreda F, Placer J, Trilla E, Lopez MA, et al. Analysis of the lipid profile and atherogenic risk during androgen deprivation therapy in prostate cancer patients. Urol Int. 2013;90(1):41–4.CrossRefPubMed
170.
Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis: the lipid link. Vasc Pharmacol. 2009;51(5–6):303–13.CrossRef
171.
Janowsky JS. Thinking with your gonads: testosterone and cognition. Trends Cogn Sci. 2006;10(2):77–82.CrossRefPubMed
172.
Morote J, Tabernero AJ, Alvarez-Ossorio JL, Ciria JP, Dominguez-Escrig JL, Vazquez F, et al. Cognitive function in patients on androgen suppression: a prospective, multicentric study. Actas Urol Esp. 2018;42(2):114–20.CrossRefPubMed
173.
Smith MR, Saad F, Egerdie B, Sieber PR, Tammela TL, Ke C, et al. Sarcopenia during androgen-deprivation therapy for prostate cancer. J Clin Oncol. 2012;30(26):3271–6.CrossRefPubMedPubMedCentral
174.
Rais M, Wilson RM, Urbanski HF, Messaoudi I. Androgen supplementation improves some but not all aspects of immune senescence in aged male macaques. Geroscience. 2017.
175.
Yialamas MA, Hayes FJ. Androgens and the ageing male and female. Best Pract Res Clin Endocrinol Metab. 2003;17(2):223–36.CrossRefPubMed
176.
177.
Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC. Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. J Clin Invest. 1997;100(7):1755–9.CrossRefPubMedPubMedCentral
178.
Slemenda C, Longcope C, Peacock M, Hui S, Johnston CC. Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women. J Clin Invest. 1996;97(1):14–21.CrossRefPubMedPubMedCentral
179.
Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab. 2006;91(10):3908–15.CrossRefPubMed
180.
Tyagi AM, Srivastava K, Kureel J, Kumar A, Raghuvanshi A, Yadav D, et al. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int. 2012;23(3):1151–61.CrossRefPubMed
181.
Mirochnik Y, Veliceasa D, Williams L, Maxwell K, Yemelyanov A, Budunova I, et al. Androgen receptor drives cellular senescence. PLoS One. 2012;7(3):e31052.CrossRefPubMedPubMedCentral
182.
Saville PD. Changes in bone mass with age and alcoholism. J Bone Joint Surg Am. 1965;47:492–9.CrossRefPubMed
183.
Gaddini GW, Grant KA, Woodall A, Stull C, Maddalozzo GF, Zhang B, et al. Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling. Bone. 2015;71:227–36.CrossRefPubMed
184.
Kristensson H, Lunden A, Nilsson BE. Fracture incidence and diagnostic roentgen in alcoholics. Acta Orthop Scand. 1980;51(2):205–7.CrossRefPubMed
185.
Ferguson JW, Luyk NH, Whitley BD. Mandibular osteomyelitis and pathologic fracture associated with metabolic catabolism induced by 'binge' drinking. Case report. Aust Dent J. 1991;36(5):361–5.CrossRefPubMed
186.
Lee K, Olsen J, Sun J, Chandu A. Alcohol-involved maxillofacial fractures. Aust Dent J. 2017;62(2):180–5.CrossRefPubMed
187.
Angelini F, Pagano F, Bordin A, Picchio V, De Falco E, Chimenti I. Getting old through the blood: circulating molecules in aging and senescence of cardiovascular regenerative cells. Front Cardiovasc Med. 2017;4:62.CrossRefPubMedPubMedCentral
188.
Krall EA, Dawson-Hughes B. Walking is related to bone density and rates of bone loss. Am J Med. 1994;96(1):20–6.CrossRefPubMed
189.
Chen JS, Cameron ID, Cumming RG, Lord SR, March LM, Sambrook PN, et al. Effect of age-related chronic immobility on markers of bone turnover. J Bone Miner Res. 2005;21(2):324–31.CrossRefPubMed
190.
Takata S, Yasui N. Disuse osteoporosis. J Med Investig. 2001;48(3–4):147–56.
191.
Dalsky GP. Weight-bearing exercise training and lumbar bone mineral content in postmenopausal women. Ann Intern Med. 1988;108(6):824.CrossRefPubMed
192.
Wang H, Brennan TA, Russell E, Kim JH, Egan KP, Chen Q, et al. R-Spondin 1 promotes vibration-induced bone formation in mouse models of osteoporosis. J Mol Med (Berl). 2013;91(12):1421–9.CrossRef
193.
Sakai A, Sakata T, Tanaka S, Okazaki R, Kunugita N, Norimura T, et al. Disruption of the p53 gene results in preserved trabecular bone mass and bone formation after mechanical unloading. J Bone Miner Res. 2002;17(1):119–27.CrossRefPubMed
194.
Okazaki R, Sakai A, Ootsuyama A, Sakata T, Nakamura T, Norimura T. Trabecular bone mass and bone formation are preserved after limb immobilisation in p53 null mice. Ann Rheum Dis. 2004;63(4):453–6.CrossRefPubMedPubMedCentral
195.
Amiche MA, Albaum JM, Tadrous M, Pechlivanoglou P, Levesque LE, Adachi JD, et al. Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials. Osteoporos Int. 2016;27(5):1709–18.CrossRefPubMed
196.
Kaji H, Yamauchi M, Chihara K, Sugimoto T. The threshold of bone mineral density for vertebral fracture in female patients with glucocorticoid-induced osteoporosis. Endocr J. 2006;53(1):27–34.CrossRefPubMed
197.
Karcic E, Karcic AA. Osteoporosis and fracture risk prevention in long-term glucocorticoid therapy. Arch Intern Med. 2001;161(14):1780–1.CrossRefPubMed
198.
Yin J, Han L, Cong W. Alpinumisoflavone rescues glucocorticoid-induced apoptosis of osteocytes via suppressing Nox2-dependent ROS generation. Pharmacol Rep. 2018;70(2):270–6.CrossRefPubMed
199.
Basello K, Pacifici F, Capuani B, Pastore D, Lombardo MF, Ferrelli F, et al. Serum- and glucocorticoid-inducible kinase 1 delay the onset of endothelial senescence by directly interacting with human telomerase reverse transcriptase. Rejuvenation Res. 2016;19(1):79–89.CrossRefPubMed
200.
Bose R, Moors M, Tofighi R, Cascante A, Hermanson O, Ceccatelli S. Glucocorticoids induce long-lasting effects in neural stem cells resulting in senescence-related alterations. Cell Death Dis. 2010;1:e92.CrossRefPubMedPubMedCentral
201.
Hodge G, Jersmann H, Tran HB, Holmes M, Reynolds PN, Hodge S. Lymphocyte senescence in COPD is associated with loss of glucocorticoid receptor expression by pro-inflammatory/cytotoxic lymphocytes. Respir Res. 2015;16:2.CrossRefPubMedPubMedCentral
202.
Poulsen RC, Watts AC, Murphy RJ, Snelling SJ, Carr AJ, Hulley PA. Glucocorticoids induce senescence in primary human tenocytes by inhibition of sirtuin 1 and activation of the p53/p21 pathway: in vivo and in vitro evidence. Ann Rheum Dis. 2014;73(7):1405–13.CrossRefPubMed
203.
Cha HH, Cram EJ, Wang EC, Huang AJ, Kasler HG, Firestone GL. Glucocorticoids stimulate p21 gene expression by targeting multiple transcriptional elements within a steroid responsive region of the p21waf1/cip1 promoter in rat hepatoma cells. J Biol Chem. 1998;273(4):1998–2007.CrossRefPubMed
204.
Owen HC, Ahmed SF, Farquharson C. Chondrocyte p21(WAF1/CIP1) expression is increased by dexamethasone but does not contribute to dexamethasone-induced growth retardation in vivo. Calcif Tissue Int. 2009;85(4):326–34.CrossRefPubMed
205.
Leclerc N, Luppen CA, Ho VV, Nagpal S, Hacia JG, Smith E, et al. Gene expression profiling of glucocorticoid-inhibited osteoblasts. J Mol Endocrinol. 2004;33(1):175–93.CrossRefPubMed
206.
Li H, Qian W, Weng X, Wu Z, Li H, Zhuang Q, et al. Glucocorticoid receptor and sequential P53 activation by dexamethasone mediates apoptosis and cell cycle arrest of osteoblastic MC3T3-E1 cells. PLoS One. 2012;7(6):e37030.CrossRefPubMedPubMedCentral
207.
Hurson CJ, Butler JS, Keating DT, Murray DW, Sadlier DM, O'Byrne JM, et al. Gene expression analysis in human osteoblasts exposed to dexamethasone identifies altered developmental pathways as putative drivers of osteoporosis. BMC Musculoskelet Disord. 2007;8:12.CrossRefPubMedPubMedCentral
208.
Ichiyoshi H, Kiyozuka Y, Kishimoto Y, Fukuhara S, Tsubura A. Massive telomere loss and telomerase RNA expression in dexamethasone-induced apoptosis in mouse thymocytes. Exp Mol Pathol. 2003;75(2):178–86.CrossRefPubMed
209.
Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nature medicine. 2018.
210.
Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973–7.CrossRefPubMedPubMedCentral
211.
Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD. Hsp90 inhibitors as senolytic drugs to extend healthy aging. Cell Cycle. 2018.
212.
Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23(6):775–81.CrossRefPubMedPubMedCentral
213.
214.
Ovadya Y, Krizhanovsky V. Senescent cell death brings hopes to life. Cell Cycle. 2017;16(1):9–10.CrossRefPubMed
215.
Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017;9(3):955–63.CrossRef
216.
Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016;15(3):428–35.CrossRefPubMedPubMedCentral
217.
•• Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232–6 This paper provided the first evidence for the beneficial effects of senescent cell clearance on delaying age-related adverse pathologies. CrossRefPubMedPubMedCentral
218.
Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016;22(1):78–83.CrossRefPubMed
219.
Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H. Xu M, et al. EBioMedicine: Fisetin is a senotherapeutic that extends health and lifespan; 2018.
220.
Fuhrmann-Stroissnigg H, Ling YY, Zhao J, McGowan SJ, Zhu Y, Brooks RW, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017;8(1):422.CrossRefPubMedPubMedCentral
221.
Farr J MD, Fraser D, Negley B, Thicke B, Onken J, Pignolo R, Tchkonia T, Kirkland J, Khosla S. Estrogen deficiency and cellular senescence represent independent mechanisms in the pathogenesis of osteoporosis: evidence from studies in mice and humans. American Society for Bone and Mineral Research; Montreal, Canada, 2018.
Metadaten
Titel
Targeting Cell Senescence for the Treatment of Age-Related Bone Loss
verfasst von
Robert J. Pignolo
Rebekah M. Samsonraj
Susan F. Law
Haitao Wang
Abhishek Chandra
Publikationsdatum
26.02.2019
Verlag
Springer US
Erschienen in
Current Osteoporosis Reports / Ausgabe 2/2019
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-019-00504-2

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen. 
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Sind Frauen die fähigeren Ärzte?

30.04.2024 Gendermedizin Nachrichten

Patienten, die von Ärztinnen behandelt werden, dürfen offenbar auf bessere Therapieergebnisse hoffen als Patienten von Ärzten. Besonders gilt das offenbar für weibliche Kranke, wie eine Studie zeigt.

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Arthroskopie kann Knieprothese nicht hinauszögern

25.04.2024 Gonarthrose Nachrichten

Ein arthroskopischer Eingriff bei Kniearthrose macht im Hinblick darauf, ob und wann ein Gelenkersatz fällig wird, offenbar keinen Unterschied.

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise