mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: A roadmap from energy metabolism to stem cell renewal and aging

Cell Cycle

Volumn 10, Issue 21, 2011, Pages 3658-3677

  Menendez, Javier A ^a,b   Vellon, Luciano ^c   Oliveras Ferraros, Cristina ^a,b   Cufí, Sílvia ^a,b   Vazquez Martin, Alejandro ^a,b  

^a CATALAN INSTITUTE OF ONCOLOGY   (Spain)

^b GIRONA BIOMEDICAL RESEARCH INSTITUTE IDIBGI   (Spain)

^c Fundacion Inbiomed   (Spain)

Author keywords

Aging; Autophagy; iPSCs; Mitochondria; Progeria; Rapamycin; Reprogramming; Senescence

Indexed keywords

ADENOSINE TRIPHOSPHATE; ASCORBIC ACID; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; RAPAMYCIN; REACTIVE OXYGEN METABOLITE; RESVERATROL; TRANSFORMING GROWTH FACTOR BETA; VALPROIC ACID;

AGING; AUTOPHAGY; AUTOPHOSPHORYLATION; BIOENERGY; CAENORHABDITIS ELEGANS; CELL AGING; CELL DIVISION; CELL FUNCTION; CELL POPULATION; DNA DAMAGE; GLYCOLYSIS; HUMAN; MITOCHONDRION; NONHUMAN; NUCLEAR REPROGRAMMING; PLURIPOTENT STEM CELL; REVIEW; SENESCENCE; SIGNAL TRANSDUCTION; SOMATIC CELL;

EID: 80655140600     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.10.21.18128     Document Type: Review

References (213)

1. Takahashi K, Yamanaka S. Induction of pluripotent stem cell from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663-76; PMID:16904174; DOI:10.1016/j.cell.2006.07.024.
2. Hanna JH, Saha K, Jaenisch R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 2010; 143:508-25; PMID:21074044; DOI:10.1016/j.cell.2010.10.008.
3. Ho JC, Zhou T, Lai WH, Huang Y, Chan YC, Li X, et al. Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C. Aging 2011; 3:380-90; PMID:21483033.
4. Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 2009; 23:2134-9; PMID:19696146; DOI:10.1101/gad.1811609.
5. Banito A, Gil J. Induced pluripotent stem cells and senescence: learning the biology to improve the technology. EMBO Rep 2010; 11:353-9; PMID:20379220; DOI:10.1038/embor.2010.47.
6. Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 2008; 26:1269-75; PMID:18849973; DOI:10.1038/nbt.1502.
7. Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 2008; 454:49-55; PMID:18509334; DOI:10.1038/nature07056.
8. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 2008; 454:766-70; PMID:18600261.
9. Shi Y, Desponts C, Do JT, Hahm HS, Scholer HR, Ding S. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 2008; 3:568-74; PMID:18983970; DOI:10.1016/j. stem.2008.10.004.
10. Shi Y, Do JT, Desponts C, Hahm HS, Scholer HR, Ding S. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2008; 2:525-8; PMID:18522845; DOI:10.1016/j.stem.2008.05. 011.
11. Liang G, Taranova O, Xia K, Zhang Y. Butyrate promotes induced pluripotent stem cell generation. J Biol Chem 2010; 285:25516-21; PMID:20554530; DOI:10.1074/jbc.M110.142059.
12. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, et al. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 2009; 460:1145-8; PMID:19668190; DOI:10.1038/nature08285.
13. Yoshida Y, Takahashi K, Okita K, Ichisaka T, Yamanaka S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 2009; 5:237-41; PMID:19716359; DOI:10.1016/j. stem.2009.08.001.
14. Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, et al. Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 2010; 6:71-9; PMID:20036631; DOI:10.1016/j. stem.2009.12.001.
15. Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, et al. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 2009; 460:1149-53; PMID:19668189; DOI:10.1038/nature08287.
16. Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, et al. c-Myc can induce DNA damage, increase reactive oxygen species and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell 2002; 9:1031-44; PMID:12049739; DOI:10.1016/S1097-2765(02)00520-8.
17. Maherali N, Hochedlinger K. Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and c-Myc. Curr Biol 2009; 19:1718-23; DOI:10.1016/j.cub.2009.08.025.
18. Zhou J, Su P, Li D, Tsang S, Duan E, Wang F. High-efficiency induction of neural conversion in human ESCs and human induced pluripotent stem cells with a single chemical inhibitor of transforming growth factor beta superfamily receptors. Stem Cells 2010; 28:1741-50; PMID:20734356; DOI:10.1002/stem.504.
19. Morizane A, Doi D, Kikuchi T, Nishimura K, Takahashi J. Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells. J Neurosci Res 2011; 89:117-26; PMID:21162120; DOI:10.1002/jnr.22547.
20. Li R, Liang J, Ni S, Zhou T, Qing X, Li H, et al. A mesenchymal-to- epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 2010; 7:51-63; PMID:20621050; DOI:10.1016/j.stem.2010.04.014.
21. Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, et al. Functional genomics reveals a BMP-driven mesenchymal-to- epithelialtransition in the initiation of somatic cell reprogramming. Cell Stem Cell 2010; 7:64-77; PMID:20621051; DOI:10.1016/j.stem.2010.04.015.
22. Blum B, Benvenisty N. The tumorigenicity of human embryonic stem cells. Adv Cancer Res 2008; 100:133-58; PMID:18620095; DOI:10.1016/S0065-230X(08)00005- 5.
23. Menendez S, Camus S, Izpisua Belmonte JC. p53: guardian of reprogramming. Cell Cycle 2010; 9:3887-91; PMID:20948296; DOI:10.4161/cc.9.19.13301.
24. Liu L, Rando TA. Manifestations and mechanisms of stem cell aging. J Cell Biol 2011; 193:257-66; PMID:21502357; DOI:10.1083/jcb.201010131.
25. Jones DL, Rando TA. Emerging models and paradigms for stem cell ageing. Nat Cell Biol 2011; 13:506-12; PMID:21540846; DOI:10.1038/ncb0511-506.
26. Espada J, Varela I, Flores I, Ugalde AP, Cadiñanos J, Pendás AM, et al. Nuclear envelope defects cause stem cell dysfunction in premature-aging mice. J Cell Biol 2008; 181:27-35; PMID:18378773; DOI:10.1083/jcb.200801096.
27. Mariño G, Ugalde AP, Fernández AF, Osorio FG, Fueyo A, Freije JM, et al. Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function. Proc Natl Acad Sci USA 2010; 107:16268-73; PMID:20805469; DOI:10.1073/pnas. 1002696107.
28. Ugalde AP, Mariño G, López-Otín C. Rejuvenating somatotropic signaling: a therapeutical opportunity for premature aging? Aging 2010; 2:1017-22; PMID:21212467.
29. Bellantuono I, Sanguinetti G, Keith WN. Progeroid syndromes: models for stem cell aging? Biogerontology 2011; [Epub ahead of print].
30. Chen T, Shen L, Yu J, Wan H, Guo A, Chen J, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 2011; 10:908-11; PMID:21615676; DOI:10.1111/j.1474-9726.2011.00722.x.
31. Easley CA, 4th, Ben-Yehudah A, Redinger CJ, Oliver SL, Varum ST, Eisinger VM, et al. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell Reprogram 2010; 12:263-73; PMID:20698768.
32. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7:38; PMID:19209957; DOI:10.1371/Journal.pbio.1000038.
33. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010; 16:205-13; PMID:20072130; DOI:10.1038/nm.2091.
34. Hoang B, Frost P, Shi Y, Belanger E, Benavides A, Pezeshkpour G, et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood 2010; 116:4560-8; PMID:20686120; DOI:10.1182/blood-2010-05-285726.
35. Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 2009; 8:3831-7; PMID:19901542; DOI:10.4161/cc.8.23.10070.
36. Holz MK, Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 2005; 280:26089-93; PMID:15905173; DOI:10.1074/jbc. M504045200.
37. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010; 1804:433-9.
38. Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 2009; 460:1136-9; PMID:19668188; DOI:10.1038/nature08290.
39. Lamouille S, Derynck R. Cell size and invasion in TGFbeta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 2007; 178:437-51; PMID:17646396; DOI:10.1083/jcb.200611146.
40. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 2011; 71:3246-56; PMID:21430067; DOI:10.1158/0008-5472.CAN-10-4058.
41. Ruiz S, Panopoulos AD, Herrerías A, Bissig KD, Lutz M, Berggren WT, et al. A high proliferation rate is required for cell reprogramming and maintenance of human embryonic stem cell identity. Curr Biol 2011; 21:45-52; PMID:21167714; DOI:10.1016/j. cub.2010.11.049.
42. Prigione A, Adjaye J. Modulation of mitochondrial biogenesis and bioenergetic metabolism upon in vitro and in vivo differentiation of human ES and iPS cells. Int J Dev Biol 2010; 54:1729-41; PMID:21305470; DOI:10.1387/ijdb.103198ap.
43. Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J. The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 2010; 28:721-33; PMID:20201066; DOI:10.1002/stem.404.
44. Blagosklonny MV. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Discov Today 2007; 12:218-24; PMID:17331886; DOI:10.1016/j.drudis.2007.01.004.
45. Blagosklonny MV. Aging, stem cells and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res 2008; 11:801-8; PMID:18729812; DOI:10.1089/rej.2008.0722.
46. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle 2008; 7:3355-61; PMID:18948731; DOI:10.4161/cc.7.21.6919.
47. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle 2009; 8:1888-95; PMID:19471117; DOI:10.4161/cc.8.12.8606.
48. Demidenko ZN, Shtutman M, Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle 2009; 8:1896-900; PMID:19478560; DOI:10.4161/cc.8.12. 8809.
49. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004; 430:686-9; PMID:15254550; DOI:10.1038/nature02789.
50. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006; 5:493-506; PMID:16732220; DOI:10.1038/nrd2060.
51. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444:337-42; PMID:17086191; DOI:10.1038/nature05354.
52. Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 2008; 7:1020-35; PMID:18414053; DOI:10.4161/cc.7.8.5740.
53. Baur JA. Resveratrol, sirtuins and the promise of a DR mimetic. Mech Ageing Dev 2010; 131:261-9; PMID:20219519; DOI:10.1016/j.mad.2010.02.007.
54. Knutson MD, Leeuwenburgh C. Resveratrol and novel potent activators of SIRT1: effects on aging and age-related diseases. Nutr Rev 2008; 66:591-6; PMID:18826454; DOI:10.1111/j.1753-4887.2008.00109.x.
55. Balcerczyk A, Pirola L. Therapeutic potential of activators and inhibitors of sirtuins. Biofactors 2010; 36:383-93; PMID:20848588; DOI:10.1002/biof.112.
56. Demidenko ZN, Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Cell Cycle 2009; 8:1901-4; PMID:19471118; DOI:10.4161/cc.8.12.8810.
57. Demidenko ZN, Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging 2009; 1:1008-16; PMID:20157583.
58. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8:157-68; PMID:18599363; DOI:10.1016/j.cmet.2008.06.011.
59. Sampath P, Pritchard DK, Pabon L, Reinecke H, Schwartz SM, Morris DR, et al. A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation. Cell Stem Cell 2008; 2:448-60; PMID:18462695; DOI:10.1016/j.stem.2008.03.013.
60. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22:159-68; PMID:16603397; DOI:10.1016/j. molcel.2006.03.029.
61. Kapahi P. Protein synthesis and the antagonistic pleiotropy hypothesis of aging. Adv Exp Med Biol 2010; 694:30-7; PMID:20886754; DOI:10.1007/978-1-4419- 7002-2-3.
62. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460:392-5; PMID:19587680.
63. Cox LS, Mattison JA. Increasing longevity through caloric restriction or rapamycin feeding in mammals: common mechanisms for common outcomes? Aging Cell 2009; 8:607-13; PMID:19678809; DOI:10.1111/j.1474-9726.2009.00509.x.
64. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009; 326:140-4; PMID:19797661; DOI:10.1126/science.1177221.
65. Kaeberlein M, Kapahi P. Cell signaling. Aging is RSKy business. Science 2009; 326:55-6; PMID:19797648; DOI:10.1126/science.1181034.
66. Yamanaka S. Elite and stochastic models for induced pluripotent stem cell generation. Nature 2009; 460:49-52; PMID:19571877; DOI:10.1038/nature08180.
67. Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 2009; 462:595-601; PMID:19898493; DOI:10.1038/nature08592.
68. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, et al. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol 2010; 176:2092-7; PMID:20363920; DOI:10.2353/ajpath.2010.091050.
69. Huna A, Salmina K, Jascenko E, Duburs G, Inashkina I, Erenpreisa J. Self-Renewal Signalling in Presenescent Tetraploid IMR90 Cells. J Aging Res 2011; 2011:103253.
70. Kohsaka S, Sasai K, Takahashi K, Akagi T, Tanino M, Kimura T, et al. A population of BJ fibroblasts escaped from Ras-induced senescence susceptible to transformation. Biochem Biophys Res Commun 2011; 410:878-84; PMID:21703241; DOI:10.1016/j. bbrc.2011.06.082.
71. Tapia N, Schöler HR. p53 connects tumorigenesis and reprogramming to pluripotency. J Exp Med 2010; 207:2045-8; PMID:20876313; DOI:10.1084/jem. 20101866.
72. Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, et al. Autophagy mediates the mitotic senescence transition. Genes Dev 2009; 23:798-803; PMID:19279323; DOI:10.1101/gad.519709.
73. Patschan S, Chen J, Polotskaia A, Mendelev N, Cheng J, Patschan D, et al. Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells. Am J Physiol Heart Circ Physiol 2008; 294:1119-29; PMID:18203850; DOI:10.1152/ajpheart.00713.2007.
74. Rehman J. Empowering self-renewal and differentiation: the role of mitochondria in stem cells. J Mol Med (Berl) 2010; 88:981-6; PMID:20809088.
75. Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, et al. Somatic oxidative bioenergetics transitions into pluripotency- dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 2011; 14:264-71; PMID:21803296; DOI:10.1016/j.cmet.2011.06.011.
76. Ingram DK, Anson RM, de Cabo R, Mamczarz J, Zhu M, Mattison J, et al. Development of calorie restriction mimetics as a prolongevity strategy. Ann NY Acad Sci 2004; 1019:412-23; PMID:15247056; DOI:10.1196/annals.1297.074.
77. Dhahbi JM, Mote PL, Fahy GM, Spindler SR. Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 2005; 23:343-50; PMID:16189280; DOI:10.1152/physiolgenomics. 00069.2005.
78. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 2005; 40:685-93; PMID:16125352; DOI:10.1016/j.exger.2005.07.007.
79. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, et al. Calorie restriction mimetics: an emerging research field. Aging Cell 2006; 5:97-108; PMID:16626389; DOI:10.1111/j.1474-9726.2006.00202.x.
80. Spindler SR, Mote PL. Screening candidate longevity therapeutics using gene-expression arrays. Gerontology 2007; 53:306-21; PMID:17570924; DOI:10.1159/000103924.
81. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 2008; 7:2769-73; PMID:18728386; DOI:10.4161/cc.7.17. 6625.
82. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging 2009; 1:281-8; PMID:20157517.
83. Smith DL Jr, Nagy TR, Allison DB. Calorie restriction: what recent results suggest for the future of ageing research. Eur J Clin Invest 2010; 40:440-50; PMID:20534066; DOI:10.1111/j.1365- 2362.2010.02276.x.
84. Mouchiroud L, Molin L, Dallière N, Solari F. Life span extension by resveratrol, rapamycin and metformin: The promise of dietary restriction mimetics for an healthy aging. Biofactors 2010; 36:377-82; PMID:20848587; DOI:10.1002/biof.127.
85. Anisimov VN. Metformin for aging and cancer prevention. Aging 2010; 2:760-74; PMID:21084729.
86. Oliveras-Ferraros C, Vazquez-Martin A, Menendez JA. Pharmacological mimicking of caloric restriction elicits epigenetic reprogramming of differentiated cells to stem-like self-renewal states. Rejuvenation Res 2010; 13:519-26; PMID:21047255; DOI:10.1089/rej.2010.1022.
87. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, et al. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging 2011; 3:148-57; PMID:21386129.
88. Menendez JA, Cufí S, Oliveras-Ferraros C, Vellon L, Joven J, Vazquez-Martin A. Gerosuppressant metformin: less is more. Aging 2011; 3:348-62; PMID:21483040.
89. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66:10269-73; PMID:17062558; DOI:10.1158/0008-5472.CAN-06-1500.
90. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 2007; 67:10804-12; PMID:18006825; DOI:10.1158/0008-5472.CAN-07-2310.
91. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70 S6K1 in human breast carcinoma cells. Cell Cycle 2009; 8:88-96; PMID:19106626; DOI:10.4161/cc.8.1.7499.
92. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 2009; 8:909-15; PMID:19221498; DOI:10.4161/cc.8.6.7933.
93. Vazquez-Martin A, Oliveras-Ferraros C, del Barco S, Martin-Castillo B, Menendez JA. The antidiabetic drug metformin: a pharmaceutical AMPK activator to overcome breast cancer resistance to HER2 inhibitors while decreasing risk of cardiomyopathy. Ann Oncol 2009; 20:592-5; PMID:19153119; DOI:10.1093/annonc/ mdn758.
94. Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Martin-Castillo B, Menendez JA. Metformin and energy metabolism in breast cancer: from insulin physiology to tumour-initiating stem cells. Curr Mol Med 2010; 10:674-91; PMID:20712585; DOI:10.2174/156652410792630625.
95. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66:1500-8; PMID:16452206; DOI:10.1158/0008-5472.CAN-05- 2925.
96. Carracedo A, Baselga J, Pandolfi PP. Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors. Cell Cycle 2008; 7:3805-9; PMID:19098454; DOI:10.4161/cc.7.24.7244.
97. Zakikhani M, Blouin MJ, Piura E, Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 2010; 123:271-9; PMID:20135346; DOI:10.1007/s10549-010- 0763-9.
98. Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 2009; 164:541-51; PMID:19682553; DOI:10.1016/j. neuroscience.2009.08.014.
99. Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 2010; 3:81; PMID:21062993; DOI:10.1126/scisignal.2001017.
100. Bjedov I, Partridge L. A longer and healthier life with TOR downregulation: genetics and drugs. Biochem Soc Trans 2011; 39:460-5; PMID:21428920; DOI:10.1042/BST0390460.
101. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007; 67:6745-52; PMID:17638885; DOI:10.1158/0008-5472.CAN-06-4447.
102. Samari HR, Seglen PO. Inhibition of hepatocytic autophagy by adenosine, aminoimidazole-4-carboxamide riboside and N6-mercaptopurine riboside. Evidence for involvement of amp-activated protein kinase. J Biol Chem 1998; 273:23758-63; PMID:9726984; DOI:10.1074/jbc.273.37.23758.
103. Vucicevic L, Misirkic M, Janjetovic K, Vilimanovich U, Sudar E, Isenovic E, et al. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway. Autophagy 2011; 7:40-50; PMID:20980833; DOI:10.4161/auto.7.1.13883.
104. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 2010; 70:2465-75; PMID:20215500; DOI:10.1158/0008-5472.CAN-09-2782.
105. Sahra IB, Tanti JF, Bost F. The combination of metformin and 2-deoxyglucose inhibits autophagy and induces AMPK dependent apoptosis in prostate cancer cells. Autophagy 2010; 6:670-1; PMID:20559023; DOI:10.4161/auto.6.5.12434.
106. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, et al. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging 2009; 1:961-70; PMID:20157579.
107. Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K, et al. The life spanprolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 2010; 6:186-8; PMID:20023410; DOI:10.4161/auto.6.1.10817.
108. Petrovski G, Das DK. Does autophagy take a front seat in lifespan extension? J Cell Mol Med 2010; 14:2543-51; PMID:21114762; DOI:10.1111/j.1582- 4934.2010.01196.x.
109. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nat Cell Biol 2010; 12:842-6; PMID:20811357; DOI:10.1038/ncb0910-842.
110. Markaki M, Tavernarakis N. The role of autophagy in genetic pathways influencing ageing. Biogerontology 2011; [Epub ahead of print].
111. Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 2010; 31:1424-33; PMID:20530556; DOI:10.1093/carcin/bgq115.
112. Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 2007; 72:29-39; PMID:17395690; DOI:10.1124/mol.106.033167.
113. Shinojima N, Yokoyama T, Kondo Y, Kondo S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 2007; 3:635-7; PMID:17786026.
114. Chen CT, Hsu SH, Wei YH. Upregulation of mitochondrial function and antioxidant defense in the differentiation of stem cells. Biochim Biophys Acta 2010; 1800:257-63.
115. Lonergan T, Brenner C, Bavister B. Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. J Cell Physiol 2006; 208:149-53; PMID:16575916; DOI:10.1002/jcp.20641.
116. Lonergan T, Bavister B, Brenner C. Mitochondria in stem cells. Mitochondrion 2007; 7:289-96; PMID:17588828; DOI:10.1016/j.mito.2007.05.002.
117. Siggins RW, Zhang P, Welsh D, Lecapitaine NJ, Nelson S. Stem cells, phenotypic inversion and differentiation. Int J Clin Exp Med 2008; 1:2-21; PMID:19079683.
118. Parker GC, Acsadi G, Brenner CA. Mitochondria: determinants of stem cell fate? Stem Cells Dev 2009; 18:803-6; PMID:19563264; DOI:10.1089/scd.2009.1806. edi.
119. Facucho-Oliveira JM, St. John JC. The relationship between pluripotency and mitochondrial DNA proliferation during early embryo development and embryonic stem cell differentiation. Stem Cell Rev 2009; 5:140-58; PMID:19521804; DOI:10.1007/s12015-009-9058-0.
120. Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J. The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 2010; 28:721-33; PMID:20201066; DOI:10.1002/stem.404.
121. Armstrong L, Tilgner K, Saretzki G, Atkinson SP, Stojkovic M, Moreno R, et al. Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells 2010; 28:661-73; PMID:20073085; DOI:10.1002/stem.307.
122. Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of ATP-producing pathways. Science 2001; 292:504-7; PMID:11283355; DOI:10.1126/science.1058079.
123. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008; 134:703-7; PMID:18775299; DOI:10.1016/j.cell.2008.08.021.
124. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004; 4:891-9; PMID:15516961; DOI:10.1038/nrc1478.
125. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007; 7:763-77; PMID:17882277; DOI:10.1038/nrc2222.
126. Vousden KH, Ryan KM. p53 and metabolism. Nat Rev Cancer 2009; 9:691-700; PMID:19759539; DOI:10.1038/nrc2715.
127. Cho YM, Kwon S, Pak YK, Seol HW, Choi YM, Park do J, et al. Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochem Biophys Res Commun 2006; 348:1472-8; PMID:16920071; DOI:10.1016/j.bbrc.2006.08.020.
128. Facucho-Oliveira JM, Alderson J, Spikings EC, Egginton S, St. John JC. Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J Cell Sci 2007; 120:4025-34; PMID:17971411; DOI:10.1242/jcs.016972.
129. Folmes CD, Nelson TJ, Martinez-Fernandez A, Arrell DK, Lindor JZ, Dzeja PP, et al. Somatic oxidative bioenergetics transitions into pluripotency- dependent glycolysis to facilitate nuclear reprogramming. Cell Metab 2011; 14:264-71; PMID:21803296; DOI:10.1016/j.cmet.2011.06.011.
130. Panopoulos AD, Izpisua Belmonte JC. Anaerobicizing into pluripotency. Cell Metab 2011; 14:143-4; PMID:21803281; DOI:10.1016/j.cmet.2011.07.003.
131. Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell 2011; 22:165-78; PMID:21119005; DOI:10.1091/mbc.E10-06-0500.
132. Kim JH, Kim HY, Lee YK, Yoon YS, Xu WG, Yoon JK, et al. Involvement of mitophagy in oncogenic K-Ras-induced transformation: Overcoming a cellular energy deficit from glucose deficiency. [Epub ahead of print]. Autophagy 2011; 7; PMID:21738012.
133. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88:593-602; PMID:9054499; DOI:10.1016/S0092-8674(00)81902-9.
134. Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer 2010; 10:51-7; PMID:20029423; DOI:10.1038/nrc2772.
135. Yoon YS, Yoon DS, Lim IK, Yoon SH, Chung HY, Rojo M, et al. Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. J Cell Physiol 2006; 209:468-80; PMID:16883569; DOI:10.1002/jcp.20753.
136. Lee S, Jeong SY, Lim WC, Kim S, Park YY, Sun X, et al. Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence. J Biol Chem 2007; 282:22977-83; PMID:17545159; DOI:10.1074/jbc.M700679200.
137. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27:433-46; PMID:18200046; DOI:10.1038/sj.emboj.7601963.
138. Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006; 281:27643-52; PMID:16847060; DOI:10.1074/jbc.M603536200.
139. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007; 450:736-40; PMID:18046414; DOI:10.1038/nature06322.
140. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426:620; PMID:14668850; DOI:10.1038/426620a.
141. Powers RW, 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 2006; 20:174-84; PMID:16418483; DOI:10.1101/gad.1381406.
142. Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK. The TOR pathway comes of age. Biochim Biophys Acta 2009; 1790:1067-74.
143. Rea S, Johnson TE. A metabolic model for life span determination in Caenorhabditis elegans. Dev Cell 2003; 5:197-203; PMID:12919672; DOI:10.1016/S1534-5807(03)00242-9.
144. Butler JA, Ventura N, Johnson TE, Rea SL. Long-lived mitochondrial (Mit) mutants of Caenorhabditis elegans utilize a novel metabolism. FASEB J 2010; 24:4977-88; PMID:20732954; DOI:10.1096/fj.10-162941.
145. El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted onthe respiratory chain complex I. J Biol Chem 2000; 275:223-8; PMID:10617608; DOI:10.1074/jbc.275.1.223.
146. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1of the mitocondrial respiratory chain. Biochem J 2000; 348:607-14; PMID:10839993; DOI:10.1042/0264-6021:3480607.
147. Detaille D, Guigas B, Leverve X, Wiernsperger N, Devos P. Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function. Biochem Pharmacol 2002; 63:1259-72; PMID:11960602;
148. Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 2004; 53:1052-9; PMID:15047621; DOI:10.2337/diabetes.53.4.1052.
149. Carvalho C, Correia S, Santos MS, Seiça R, Oliveira CR, Moreira PI. Metformin promotes isolated rat liver mitochondria impairment. Mol Cell Biochem 2008; 308:75-83; PMID:17909944; DOI:10.1007/s11010-007-9614-3.
150. Suwa M, Egashira T, Nakano H, Sasaki H, Kumagai S. Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J Appl Physiol 2006; 101:1685-92; PMID:16902066; DOI:10.1152/japplphysiol.00255.2006.
151. Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 2006; 55:120-7; PMID:16380484; DOI:10.2337/diabetes.55.01.06.db05-0943.
152. Mai S, Klinkenberg M, Auburger G, Bereiter-Hahn J, Jendrach M. Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1. J Cell Sci 2010; 123:917-26; PMID:20179104; DOI:10.1242/jcs.059246.
153. Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, et al. Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 2011; 472:221-5; PMID:21346760; DOI:10.1038/nature09879.
154. Zhang J, Lian Q, Zhu G, Zhou F, Sui L, Tan C, et al. A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 2011; 8:31-45; PMID:21185252; DOI:10.1016/j. stem.2010.12.002.
155. Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 2006; 140:2603-24; PMID:16838330; DOI:10.1002/ajmg.a.31346.
156. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 2003; 300:2055; PMID:12702809; DOI:10.1126/science. 1084125.
157. Krishnan V, Chow MZ, Wang Z, Zhang L, Liu B, Liu X, et al. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Acad Sci USA 2011; 108:12325-30; PMID:21746928; DOI:10.1073/pnas.1102789108.
158. Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science 2006; 312:1059-63; PMID:16645051; DOI:10.1126/science.1127168.
159. Scaffidi P, Misteli T. Lamin A-dependent mis-regulation of adult stem cells associated with accelerated ageing. Nat Cell Biol 2008; 10:452-9; PMID:18311132; DOI:10.1038/ncb1708.
160. Niedernhofer LJ, Glorioso JC, Robbins PD. Dedifferentiation rescues senescence of progeria cells but only while pluripotent. Stem Cell Res Ther 2011; 2:28; PMID:21639955; DOI:10.1186/scrt69.
161. Wu SM, Hochedlinger K. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol 2011; 13:497-505; PMID:21540845; DOI:10.1038/ncb0511-497.
162. Lopez-Mejia IC, Vautrot V, De Toledo M, Behm-Ansmant I, Bourgeois CF, Navarro CL, et al. A conserved splicing mechanism of the LMNA gene controls premature aging. Hum Mol Genet 2011; [Epub ahead of print].
163. Cao K, Blair CD, Faddah DA, Kieckhaefer JE, Olive M, Erdos MR, et al. Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J Clin Invest 2011; 121:2833-44; PMID:21670498; DOI:10.1172/JCI43578.
164. Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, et al. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in hutchinson-gilford progeria syndrome cells. Sci Transl Med 2011; 3:89; PMID:21715679; DOI:10.1126/scitranslmed.3002346.
165. Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet 2006; 15:433-42; PMID:16368705; DOI:10.1093/hmg/ddi458.
166. Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W. Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience 2009; 164:541-51; PMID:19682553; DOI:10.1016/j. neuroscience.2009.08.014.
167. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 2007; 131:1149-63; PMID:18083104; DOI:10.1016/j.cell.2007.10.035.
168. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007; 282:24131-45; PMID:17580304; DOI:10.1074/jbc. M702824200.
169. Komatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 2010; 584:1374-8; PMID:20153326; DOI:10.1016/j.febslet.2010.02.017.
170. Burtner CR, Kennedy BK. Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 2010; 11:567-78; PMID:20651707; DOI:10.1038/nrm2944.
171. Mendelsohn AR, Larrick JW. Rapamycin as an antiaging therapeutic? targeting Mammalian target of rapamycin to treat hutchinson-gilford progeria and neurodegenerative diseases. Rejuvenation Res 2011; 14:437-41; PMID:21851176; DOI:10.1089/rej.2011.1238.
172. Blagosklonny MV. Progeria, rapamycin and normal aging: recent breakthrough. Aging 2011; 7:685-91; PMID:21743107.
173. Manju K, Muralikrishna B, Parnaik VK. Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci. J Cell Sci 2006; 119:2704-14; PMID:16772334; DOI:10.1242/jcs.03009.
174. Brenneisen P, Wenk J, Wlaschek M, Krieg T, Scharffetter-Kochanek K. Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA damage-dependent signaling pathway responsible for the ultraviolet B-mediated increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein levels in human dermal fibroblasts. J Biol Chem 2000; 275:4336-44; PMID:10660603; DOI:10.1074/jbc.275.6.4336.
175. Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle 2009; 8:4112-8; PMID:19946210; DOI:10.4161/cc.8.24.10215.
176. Mariño G, Ugalde AP, Salvador-Montoliu N, Varela I, Quirós PM, Cadiñanos J, et al. Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum Mol Genet 2008; 7:2196-211. (Pubitemid 351911988)
177. Mariño G, López-Otín C. Autophagy and aging: new lessons from progeroid mice. Autophagy 2008; 4:807-9; PMID:18612261.
178. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell 2011; 146:682-95; PMID:21884931; DOI:10.1016/j.cell.2011.07.030.
179. Vanhorebeek I, Gunst J, Derde S, Derese I, Boussemaere M, Güiza F, et al. Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients. J Clin Endocrinol Metab 2011; 96:633-45; PMID:21270330; DOI:10.1210/jc.2010-563.
180. Roscic A, Baldo B, Crochemore C, Marcellin D, Paganetti P. Induction of Autophagy with Catalytic mTOR Inhibitors Reduces Huntingtin Aggregates in a Neuronal Cell Model. J Neurochem 2011; [Epub ahead of print]; DOI:10.1111/j.1471-4159.2011.07435.x; PMID:21854390.
181. Bové J, Martínez-Vicente M, Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights. Nat Rev Neurosci 2011; 12:437-52; PMID:21772323; DOI:10.1038/nrn3068.
182. Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8:931-7; PMID:17712358; DOI:10.1038/nrm2245.
183. Cavallini G, Donatia A, Taddei M, Bergamini E. Evidence for selective mitochondrial autophagy and failure in aging. Autophagy 2007; 3:26-7; PMID:16963838.
184. Hands SL, Proud CG, Wyttenbach A. mTOR's role in ageing: protein synthesis or autophagy? Aging 2008; 1:586-97; PMID:20157541.
185. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 2010; 9:3256-76; PMID:20814239; DOI:10.4161/cc.9.16.12553.
186. Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, et al. Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 2010; 9:3506-14; PMID:20818174; DOI:10.4161/cc.9.17. 12731.
187. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, et al. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle 2010; 9:4297-306; PMID:21051947; DOI:10.4161/cc.9.21.13817.
188. Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, et al. Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol Ther 2010; 10:537-42; PMID:20861671; DOI:10.4161/cbt.10.6.13370.
189. Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, et al. Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle 2011; 10:1271-86; PMID:21512313; DOI:10.4161/cc.10.8.15330.
190. Lisanti MP, Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, et al. Accelerated aging in the tumor microenvironment: Connecting aging, inflammation and cancer metabolism with personalized medicine. Cell Cycle 2011; 10:2059-63; PMID:21654190; DOI:10.4161/cc.10.13.16233.
191. Ertl RP, Chen J, Astle CM, Duffy TM, Harrison DE. Effects of dietary restriction on hematopoietic stemcell aging are genetically regulated. Blood 2008; 111:1709-16; PMID:17947508; DOI:10.1182/blood-2007-01-069807.
192. Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009; 2:75; PMID:19934433; DOI:10.1126/scisignal.2000559.
193. Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med 2011; 208:455-67; PMID:21339326; DOI:10.1084/jem.20101145.
194. Watson AS, Mortensen M, Simon AK. Autophagy in the pathogenesis of myelodysplastic síndrome and acute myeloid leukemia. Cell Cycle 2011; 10:1719-25; PMID:21512311; DOI:10.4161/cc.10.11.15673.
195. Mortensen M, Watson AS, Simon AK. Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation. Autophagy 2011; 7:1069-70; PMID:21552009; DOI:10.4161/auto.7.9.15886.
196. Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A, Trotman LC, et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest 2010; 120:681-93; PMID:20197621; DOI:10.1172/JCI40535.
197. Nardella C, Clohessy JG, Alimonti A, Pandolfi PP. Pro-senescence therapy for cancer treatment. Nat Rev Cancer 2011; 11:503-11; PMID:21701512; DOI:10.1038/nrc3057.
198. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M, et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 2008; 10:676-87; PMID:18454141; DOI:10.1038/ncb1730.
199. Morselli E, Tasdemir E, Maiuri MC, Galluzzi L, Kepp O, Criollo A, et al. Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell Cycle 2008; 7:3056-61; PMID:18818522; DOI:10.4161/cc.7.19.6751.
200. Tasdemir E, Maiuri MC, Orhon I, Kepp O, Morselli E, Criollo A, et al. p53 represses autophagy in a cell cycle-dependent fashion. Cell Cycle 2008; 7:3006-11; PMID:18838865; DOI:10.4161/cc.7.19.6702.
201. Martins I, Galluzzi L, Kroemer G. Hormesis, cell death and aging. Aging 2011; 3; [Epub ahead of print]; PMID:21931183.
202. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010; 11:35-46; PMID:20074526; DOI:10.1016/j.cmet.2009. 11.010.
203. Leontieva OV, Gudkov AV, Blagosklonny MV. Weak p53 permits senescence during cell cycle arrest. Cell Cycle 2010; 9:4323-7; PMID:21051933; DOI:10.4161/cc.9.21.13584.
204. Leontieva OV, Blagosklonny MV. DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging 2010; 2:924-35; PMID:21212465.
205. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging 2010; 2:344-52; PMID:20606252.
206. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci USA 2010; 107:9660-4; PMID:20457898; DOI:10.1073/pnas.1002298107.
207. Blagosklonny MV. Increasing healthy lifespan by suppressing aging in our lifetime: preliminary proposal. Cell Cycle 2010; 9:4788-94; PMID:21150328; DOI:10.4161/cc.9.24.14360.
208. Blagosklonny MV. Why human lifespan is rapidly increasing: solving "longevity riddle" with "revealed-slow-aging" hypothesis. Aging 2010; 2:177-82; PMID:20404395.
209. Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives. Aging 2010; 2:265-73; PMID:20519781.
210. Blagosklonny MV. Why the disposable soma theory cannot explain why women live longer and why we age. Aging 2010; 2:884-7; PMID:21191147.
211. -/lowbreast cancer stem-like phenotype. Cell Cycle 2011; 10; [Epub ahead of print].
212. Zhao J, Pei G. Why cell reprogramming is functionally linked to aging? Aging 2011; 3:700; PMID:21937763.
213. Rankin MM, Kushner JA. Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 2009; 58:1365-72; PMID:19265026; DOI:10.2337/db08-1198.