Cells with DNA damage undergo apoptosis or cellular senescence if the damage cannot be repaired. Recent studies highlight that cellular senescence plays a major role in aging. However, age-associated diseases, including emphysema and neurodegenerative disorders, are caused by apoptosis of lung alveolar epithelial cells and neurons, respectively. Therefore, enhanced apoptosis also promotes aging and shortens the life span depending on the cell type. Recently, we reported that ku70−/−bax−/− and ku70−/−bax+/− mice showed significantly extended life span in comparison with ku70−/−bax+/+ mice. Ku70 is essential for non-homologous end joining pathway for DNA double strand break repair, and Bax plays an important role in apoptosis. Our study suggests that Bax-induced apoptosis has a significant impact on shortening the life span of ku70−/− mice, which are defective in one of DNA repair pathways. The lung alveolar space gradually enlarges during aging, both in mouse and human, and this age-dependent change results in the decrease of respiration capacity during aging that can lead to emphysema in more severe cases. We found that emphysema occurred in ku70−/− mice at the age of three-months old, and that Bax deficiency was able to suppress it. These results suggest that Bax-mediated apoptosis induces emphysema in ku70−/− mice. We also found that the number of cells, including bronchiolar epithelial cells and type 2 alveolar epithelial cells, shows a higher DNA double strand break damage response in ku70 KO mouse lung than in wild type. Recent studies suggest that non-homologous end joining activity decreases with increased age in mouse and rat model. Together, we hypothesize that the decline of Ku70-dependent DNA repair activity in lung alveolar epithelial cells is one of the causes of age-dependent decline of lung function resulting from excess Bax-mediated apoptosis of lung alveolar epithelial cells (and their progenitor cells).
KorsmeyerSJ. BCL-2 gene family and the regulation of programmed cell death. Cancer Res1999; 59(7 Suppl): 1693s–700s.
2.
DanialNNKorsmeyerSJ. Cell death: critical control points. Cell2004; 116: 205–19.
3.
WolterKGHsuYTSmithCLNechushtanAXiXGYouleRJ. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol1997; 139: 1281–92.
4.
DownsJAJacksonSP. A means to a DNA end: the many roles of Ku. Nat Rev Mol Cell Biol2004; 5: 367–78.
5.
GomezJAGamaVYoshidaTSunWHayesPLeskovK. Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides. Biochem Soc Transac2007; 35(Pt 4): 797–801.
6.
LiYYokotaTGamaVYoshidaTGomezJAIshikawaK. Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation. Cell Death Differ2007; 14: 2058–67.
7.
GamaVGomezJAMayoLDJacksonMWDanielpourDSongK. Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization. Cell Death Differ2009; 16: 758–69.
8.
CohenHYLavuSBittermanKJHekkingBImahiyeroboTAMillerC. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell2004; 13: 627–38.
9.
CohenHYMillerCBittermanKJWallNRHekkingBKesslerB. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science2004; 305: 390–2.
10.
SubramanianCOpipariAWJrBianXCastleVPKwokRP. Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A2005; 102: 4842–7.
11.
PlescaDMazumderSGamaVMatsuyamaSAlmasanA. A C-terminal fragment of cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron. J Biol Chem2008; 283: 30796–803.
12.
IijimaKMuranakaCKobayashiJSakamotoSKomatsuKMatsuuraS. NBS1 regulates a novel apoptotic pathway through Bax activation. DNA Repair (Amst)2008; 7: 1705–16.
13.
AnekondaTSAdamusG. Resveratrol prevents antibody-induced apoptotic death of retinal cells through upregulation of Sirt1 and Ku70. BMC Res Notes2008; 1: 122–122.
14.
PucciSPaolaMFabiolaSDavidBALuigiSG. Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression. Cell Cycle2009; 8: 473–81.
15.
SundaresanNRSamantSAPillaiVBRajamohanSBGuptaMP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol2008; 28: 6384–401.
16.
TrougakosIPLourdaMAntonelouMHKletsasDGorgoulisVGPapassideriIS. Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex. Clin Cancer Res2009; 15: 48–59.
17.
YamaguchiHWoodsNTPilusoLGLeeHHChenJBhallaKN. p53 acetylation is crucial for its transcription-independent proapoptotic functions. J Biol Chem2009; 284: 11171–83.
18.
VishnudasVKMillerJB. Ku70 regulates Bax-mediated pathogenesis in laminin-alpha2-deficient human muscle cells and mouse models of congenital muscular dystrophy. Hum Mol Genet2009; 18: 4467–77.
19.
ZouHVolonteDGalbiatiF. Interaction of caveolin-1 with Ku70 inhibits Bax-mediated apoptosis. PloS One2012; 7: e39379–e39379.
20.
LiJJGuQHLiMYangHPCaoLMHuCP. Role of Ku70 and Bax in epigallocatechin-3-gallate-induced apoptosis of A549 cells in vivo. Oncol Lett2013; 5: 101–6.
21.
KimSHKimDHanJSJeongCSChungBSKangCD. Ku autoantigen affects the susceptibility to anticancer drugs. Cancer research1999; 59: 4012–7.
22.
YoshidaTTomiokaINagaharaTHolystTSawadaMHayesP. Bax-inhibiting peptide derived from mouse and rat Ku70. Biochem Biophys Res Commun2004; 321: 961–6.
23.
TanakaKKobayashiNGutierrezASRivas-CarrilloJDNavarro-AlvarezNChenY. Prolonged survival of mice with acute liver failure with transplantation of monkey hepatocytes cultured with an antiapoptotic pentapeptide V5. Transplantation2006; 81: 427–37.
24.
ChenYNYamadaHMaoWMatsuyamaSAiharaMAraieM. Hypoxia-induced retinal ganglion cell death and the neuroprotective effects of beta-adrenergic antagonists. Brain Res2007; 1148: 28–37.
25.
SotoPSmithLC. BH4 peptide derived from Bcl-xL and Bax-inhibitor peptide suppresses apoptotic mitochondrial changes in heat stressed bovine oocytes. Mol Reprod Dev2009; 76: 637–46.
26.
DumitruRGamaVFaganBMBowerJJSwahariVPevnyLH. Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis. Molecular Cell2012; 46: 573–83.
27.
QinQPatilKSharmaSC. The role of Bax-inhibiting peptide in retinal ganglion cell apoptosis after optic nerve transection. Neurosci Lett2004; 372: 17–21.
28.
WangXHanWDuXZhuCCarlssonYMallardC. Neuroprotective effect of Bax-inhibiting peptide on neonatal brain injury. Stroke2010; 41: 2050–5.
29.
HanBWangQCuiGShenXZhuZ. Post-treatment of Bax-inhibiting peptide reduces neuronal death and behavioral deficits following global cerebral ischemia. Neurochem Int2011; 58: 224–33.
30.
KudoWLeeHPSmithMAZhuXMatsuyamaSLeeHG. Inhibition of Bax protects neuronal cells from oligomeric abeta neurotoxicity. Cell Death Dis2012; 3: e309–e309.
31.
LiHVogelHHolcombVBGuYHastyP. Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer. Mol Cell Biol2007; 27: 8205–14.
32.
NgoJMatsuyamaMKimCPoventud-FuentesIBatesASiedlakSL. Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases. Cell Death Dis2015; 6: e1706–e1706.
33.
VerbekenEKCauberghsMMertensIClementJLauwerynsJMVan de WoestijneKP. The senile lung. Comparison with normal and emphysematous lungs. 2. Functional aspects. Chest1992; 101: 800–9.
34.
VerbekenEKCauberghsMMertensIClementJLauwerynsJMVan de WoestijneKP. The senile lung. Comparison with normal and emphysematous lungs. 1. Structural aspects. Chest1992; 101: 793–9.
35.
MacNeeW. Aging, inflammation, and emphysema. Am J Respir Crit Care Med2011; 184: 1327–9.
ChoudhuryARJuZDjojosubrotoMWSchienkeALechelASchaetzleinS. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet2007; 39: 99–105.
41.
MaslovAYGanapathiSWesterhofMQuispe-TintayaWWhiteRRVan HoutenB. DNA damage in normally and prematurely aged mice. Aging Cell2013; 12: 467–77.
42.
PeeperDS. Ageing: old cells under attack. Nature2011; 479: 186–7.
43.
ZhaoBBensonEKQiaoRWangXKimSManfrediJJ. Cellular senescence and organismal ageing in the absence of p21(CIP1/WAF1) in ku80(-/-) mice. EMBO Rep2009; 10: 71–8.
44.
BakerDJWijshakeTTchkoniaTLeBrasseurNKChildsBGvan de SluisB. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature2011; 479: 232–6.
45.
KoikeMKoikeA. The Ku70-binding site of Ku80 is required for the stabilization of Ku70 in the cytoplasm, for the nuclear translocation of Ku80, and for Ku80-dependent DNA repair. Exp Cell Res2005; 305: 266–76.
46.
SperkaTWangJRudolphKL. DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol2012; 13: 579–90.
47.
GuYSekiguchiJGaoYDikkesPFrankKFergusonD. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Proc Natl Acad Sci U S A2000; 97: 2668–73.
48.
VoelkelNFGomez-ArroyoJMizunoS. COPD/emphysema: the vascular story. Pulm Circ2011; 1: 320–6.
49.
VoelkelNFGomez-ArroyoJAbbateABogaardHJNicollsMR. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J2012; 40: 1555–65.
50.
KasaharaYTuderRMTaraseviciene-StewartLLe CrasTDAbmanSHirthPK. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest2000; 106: 1311–9.
PerezGIJurisicovaAWiseLLipinaTKanisekMBechardA. Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice. Proc Natl Acad Sci U S A2007; 104: 5229–34.
53.
ChapmanJRTaylorMRBoultonSJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell2012; 47: 497–510.
54.
RackleyCRStrippBR. Building and maintaining the epithelium of the lung. J Clin Invest2012; 122: 2724–30.
55.
BarkauskasCECronceMJRackleyCRBowieEJKeeneDRStrippBR. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest2013; 123: 3025–36.
56.
DesaiTJBrownfieldDGKrasnowMA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature2014; 507: 190–4.
57.
LeeJEHeoJIParkSHKimJHKhoYJKangHJ. Calorie restriction (CR) reduces age-dependent decline of non-homologous end joining (NHEJ) activity in rat tissues. Exp Gerontol2011; 46: 891–6.
58.
ZahnJMPoosalaSOwenABIngramDKLustigACarterA. AGEMAP: a gene expression database for aging in mice. PLoS Genet2007; 3: e201–e201.
59.
YaoHSundarIKGorbunovaVRahmanI. P21-PARP-1 pathway is involved in cigarette smoke-induced lung DNA damage and cellular senescence. PloS One2013; 8: e80007–e80007.
