Answering the ultimate question "What is the proximal cause of aging?"

Aging

Volumn 4, Issue 12, 2012, Pages 861-877

  Blagosklonny, Mikhail V ^a  

^a ROSWELL PARK CANCER INSTITUTE   (United States)

Author keywords

Cancer; Development; Growth; MTOR; Rapamycin; Senescence; Stroke; TOR

Indexed keywords

EID: 84874801912     PISSN: 19454589     EISSN: None     Source Type: Journal    
DOI: 10.18632/aging.100525     Document Type: Review

References (227)

1. Kirkwood TB. Understanding the odd science of aging. Cell. 2005; 120: 437-447.
2. Kirkwood T. Why women live longer. Stress alone does not explain the longevity gap. Sci Am. 2010; 303: 34-35.
3. Zimniak P. What is the proximal cause of aging? Front Genet. 2012; 3: 189.
4. Blagosklonny MV. Paradoxes of aging. Cell Cycle. 2007; 6: 2997-3003.
5. Blagosklonny MV. Why the disposable soma theory cannot explain why women live longer and why we age. Aging (Albany NY). 2010; 2: 884-887.
6. Blagosklonny MV. Aging: ROS or TOR. Cell Cycle. 2008; 7: 3344-3354.
7. Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, Matscheski A, Vanfleteren JR, Gems D. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev. 2008; 22: 3236-3241.
8. Gems D, Doonan R. Antioxidant defense and aging in C. elegans: Is the oxidative damage theory of aging wrong? Cell Cycle. 2009; 8: 1681-1687.
9. Perez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, Richardson A. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell. 2009; 8: 73-75.
10. Pani G. P66SHC and ageing: ROS and TOR? Aging (Albany NY). 2010; 2: 514-518.
11. Cabreiro F, Ackerman D, Doonan R, Araiz C, Back P, Papp D, Braeckman BP, Gems D. Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic Biol Med. 2011; 51: 1575-1582.
12. Lapointe J, Hekimi S. When a theory of aging ages badly. Cell Mol Life Sci. 2009; 67: 1-8.
13. Van Raamsdonk JM, Hekimi S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 2009; 5: e1000361.
14. Speakman JR, Selman C. The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan. Bioessays. 2011; 33: 255-259.
15. Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med. 2011; 51: 327-336.
16. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008; 7: 3355-3361.
17. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009; 8: 1888-1895.
18. 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: 1896-1900.
19. Demidenko ZN, Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential. Aging (Albany NY). 2009; 1: 1008-1016.
20. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci U S A. 2010; 107: 9660-9664.
21. Leontieva OV, Natarajan V, Demidenko ZN, Burdelya LG, Gudkov AV, Blagosklonny MV. Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Proc Natl Acad Sci U S A. 2012; 109: 13314-13318.
22. Leontieva OV, Demidenko ZN, Gudkov AV, Blagosklonny MV. Elimination of proliferating cells unmasks the shift from senescence to quiescence caused by rapamycin. PLoS One. 2011; 6: e26126.
23. Schug TT. mTOR favors senescence over quiescence in p53- arrested cells. Aging (Albany NY). 2010; 2: 327-328.
24. Galluzzi L, Kepp O, Kroemer G. TP53 and MTOR crosstalk to regulate cellular senescence. Aging (Albany NY). 2010; 2: 535-537.
25. Romanov VS, Abramova MV, Svetlikova SB, Bykova TV, Zubova SG, Aksenov ND, Fornace AJ, Jr., Pospelova TV, Pospelov VA. p21(Waf1) is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate. Cell Cycle. 2010; 9: 3945-3955.
26. Kolesnichenko M, Hong L, Liao R, Vogt PK, Sun P. Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence. Cell Cycle. 2012; 11: 2391-2401.
27. Pospelova TV, Leontieva OV, Bykova TV, Zubova SG, Pospelov VA, Blagosklonny MV. Suppression of replicative senescence by rapamycin in rodent embryonic cells. Cell Cycle. 2012; 11: 2402-2407.
28. 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 (Albany NY). 2010; 2: 924-935.
29. Leontieva O, Gudkov A, Blagosklonny M. Weak p53 permits senescence during cell cycle arrest. Cell Cycle. 2010; 9: 4323-4327.
30. Dulic V. Be quiet and you'll keep young: does mTOR underlie p53 action in protecting against senescence by favoring quiescence? Aging (Albany NY). 2011; 3: 3-4.
31. Maki CG. Decision-making by p53 and mTOR. Aging (Albany NY). 2010; 2: 324-326.
32. Wesierska-Gadek J. mTOR and its link to the picture of Dorian Gray - re-activation of mTOR promotes aging. Aging (Albany NY). 2010; 2: 892-893.
33. Serrano M. Shifting senescence into quiescence by turning up p53. Cell Cycle. 2010; 9. 4256-4257.
34. Lane DP, Verma C, Fang CC. The p53 inducing drug dosage may determine quiescence or senescence. Aging (Albany NY). 2010; 2: 748.
35. Blagosklonny MV. Cell cycle arrest is not senescence. Aging (Albany NY). 2011; 3: 94-101.
36. 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: 159-165.
37. Stipp D. A new path to longevity. Sci Am. 2012; 306: 32-39.
38. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004; 14: 885-890.
39. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development. 2004; 131: 3897-3906.
40. Kaeberlein M, Powers RWr, K.K. S, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science. 2005; 310: 1193-1196.
41. Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ. Remarkable longevity and stress resistance of nematode PI3Knull mutants. Aging Cell. 2008; 7: 13-22.
42. Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK. The TOR pathway comes of age. Biochim Biophys Acta. 2009; 1790: 1067-1074.
43. Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D., Robinson, IC, Thornton JM, Gems D, Partridge L, Withers DJ. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 2008; 22: 807-818.
44. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009; 326: 140-144.
45. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, Kockel L. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab. 2010; 11: 453-465.
46. Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E, Karin M. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science. 2010; 327: 1223-1228.
47. Katewa SD, Kapahi P. Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp Gerontol. 2011; 46: 382-390.
48. Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012; 61: 1315-1322.
49. de Magalhaes JP. A role for Ras signaling in modulating mammalian aging by the GH/IGF1 axis. Aging (Albany NY). 2011; 3: 336-337.
50. Partridge L, Alic N, Bjedov I, Piper MD. Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. Exp Gerontol. 2011; 46: 376-381.
51. Demidenko ZN. Rapamycin for life: a step to immortality. Cell Cycle. 2011; 10: 4206.
52. Passtoors WM, Beekman M, Deelen J, van der Breggen R, Maier AB, Guigas B, Derhovanessian E, van Heemst D, de Craen AJ, Gunn DA, Pawelec G, Slagboom PE. Gene expression analysis of mTOR pathway: association with human longevity. Aging Cell. 2012.
53. Haselton A, Sharmin E, Schrader J, Sah M, Poon P, Fridell YW. Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance. Cell Cycle. 2010; 9: 3063-3071.
54. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006; 5: 2087-2102.
55. Tsang CK, Qi H, Liu LF, Zheng XFS. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Disc Today. 2007; 12: 112-124.
56. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSCmTOR pathway in human disease. Nat Genet. 2005; 37: 19-24.
57. Chen WQ, Zhong L, Zhang L, Ji XP, Zhang M, Zhao YX, Zhang C, Zhang Y. Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels. Br J Pharmacol. 2009; 156: 941-951.
58. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY); 2009. 1: 281-288.
59. Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. Am J Pathol. 2012; 181: 1142-1146.
60. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011.
61. Zhao C, Vollrath D. mTOR pathway activation in age-related retinal disease. Aging (Albany NY). 2011; 3: 346-347.
62. Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle. 2011; 10: 3447-3451.
63. Lu MK, Gong XG, Guan KL. mTOR in podocyte function: is rapamycin good for diabetic nephropathy? Cell Cycle. 2011; 10: 3415-3416.
64. Williamson DL. Normalizing a hyperactive mTOR initiates muscle growth during obesity. Aging (Albany NY). 2011; 3: 83-84.
65. Majumder S, Caccamo A, Medina DX, Benavides AD, Javors MA, Kraig E, Strong R, Richardson A, Oddo S. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell. 2012; 11: 326-335.
66. Blagosklonny MV. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Cell Cycle. 2010; 9: 3151-3156.
67. Blagosklonny MV, Hall MN. Growth and aging: a common molecular mechanism. Aging (Albany NY). 2009; 1: 357-362.
68. Pani G. From growing to secreting: new roles for mTOR in aging cells. Cell Cycle. 2011; 10: 2450-2453.
69. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6: 2853-2868.
70. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescenceassociated secretory phenotype. Embo J. 2011; 30: 1536-1548.
71. Laberge RM, Zhou L, Sarantos MR, Rodier F, Freund A, de Keizer PL, Liu S, Demaria M, Cong YS, Kapahi P, Desprez PY, Hughes RE, Campisi J. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell. 2012; 11: 569-578.
72. Neilsen PM, Noll JE, Suetani RJ, Schulz RB, Al-Ejeh F, Evdokiou A, Lane DP, Callen DF. Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a proinvasive secretome. Oncotarget. 2011; 2: 1203-1217.
73. de Keizer PL, Laberge RM, Campisi J. p53: Pro-aging or prolongevity? Aging (Albany NY). 2010; 2: 377-379.
74. Blagosklonny MV. Cell senescence and hypermitogenic arrest. EMBO Rep. 2003; 4: 358-362.
75. Caruso C, Lio D, Cavallone L, Franceschi C. Aging, longevity, inflammation, and cancer. Ann N Y Acad Sci. 2004; 1028: 1-13.
76. Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottaviani E, Franceschi C. Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Curr Pharm Des. 2006; 12: 161-3171.
77. Lisanti MP, Martinez-Outschoorn UE, Pavlides S, Whitaker- Menezes D, Pestell RG, Howell A, Sotgia F. Accelerated aging in the tumor microenvironment: connecting aging, inflammation and cancer metabolism with personalized medicine. Cell Cycle. 2011; 10: 2059-2063.
78. Lisanti MP, Martinez-Outschoorn UE, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs "fertilizer". Cell Cycle. 2011; 10: 2440-2449.
79. Ye J, Keller JN. Regulation of energy metabolism by inflammation: a feedback response in obesity and calorie restriction. Aging (Albany NY). 2010; 2: 361-368.
80. Weiss EP, Villareal DT, Fontana L, Han DH, Holloszy JO. Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. Aging (Albany NY). 2011; 3: 533-542.
81. Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B. How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Aging Cell. 2004; 3: 169-176.
82. Wanner SP, Garami A, Pakai E, Oliveira DL, Gavva NR, Coimbra CC, Romanovsky AA. Aging reverses the role of the transient receptor potential vanilloid-1 channel in systemic inflammation from anti-inflammatory to proinflammatory. Cell Cycle. 2012; 11: 343-349.
83. Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet. 2001; 358: 472-473.
84. Gadalla SM, Cawthon R, Giri N, Alter BP, Savage SA. Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes. Aging (Albany NY). 2010; 2: 867-874.
85. Njajou OT, Hsueh WC, Blackburn EH, Newman AB, Wu SH, Li R, Simonsick EM, Harris TM, Cummings SR, Cawthon RM. Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. J Gerontol A Biol Sci Med Sci. 2009; 64: 860-864.
86. Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004; 101: 17312-17315.
87. Epel ES, Merkin SS, Cawthon R, Blackburn EH, Adler NE, Pletcher MJ, Seeman TE. The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging (Albany NY). 2009; 1: 81-88.
88. Gramatges MM, Bertuch AA. Measuring relative telomere length: is tissue an issue? Aging (Albany NY). 2010; 2: 756-757.
89. Jemielity S, Kimura M, Parker KM, Parker JD, Cao X, Aviv A, Keller L. Short telomeres in short-lived males: what are the molecular and evolutionary causes? Aging Cell. 2007; 6: 225-233.
90. Bekaert S, De Meyer T, Rietzschel ER, De Buyzere ML, De Bacquer D, Langlois M, Segers P, Cooman L, Van Damme P, Cassiman P, Van Criekinge W, Verdonck P, De Backer GG, Gillebert TC, Van Oostveldt P. Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease. Aging Cell. 2007; 6: 639-647.
91. Kuhlow D, Florian S, von Figura G, Weimer S, Schulz N, Petzke KJ, Zarse K, Pfeiffer AF, Rudolph KL, Ristow M. Telomerase deficiency impairs glucose metabolism and insulin secretion. Aging (Albany NY). 2010; 2: 650-658.
92. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, Cummings JL, Effros RB. Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol Aging. 2003; 24: 77-84.
93. Ishikawa N, Nakamura K, Izumiyama-Shimomura N, Aida J, Ishii A, Goto M, Ishikawa Y, Asaka R, Matsuura M, Hatamochi A, Kuroiwa M, Takubo K. Accelerated in vivo epidermal telomere loss in Werner syndrome. Aging (Albany NY). 2011; 3: 417-429.
94. Gems DH, de la Guardia YI. Alternative Perspectives on Aging in C. elegans: Reactive Oxygen Species or Hyperfunction? Antioxid Redox Signal. 2012.
95. Gems D, Partridge L. Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. Annu Rev Physiol. 2012.
96. Blagosklonny MV. Rapamycin and quasi-programmed aging: Four years later. Cell Cycle. 2010; 9: 1859-1862.
97. Blagosklonny MV. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Disc Today. 2007; 12: 218-224.
98. Pan KZ, Palter JE, Rogers AN, Olsen A, Chen D, Lithgow GJ, Kapahi P. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell. 2007; 6: 111-119.
99. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell. 2007; 6: 95-110.
100. Mehta R, Chandler-Brown D, Ramos FJ, Shamieh LS, Kaeberlein M. Regulation of mRNA translation as a conserved mechanism of longevity control. Adv Exp Med Biol. 2010; 694: 14-29.
101. Blagosklonny MV. NCI's provocative questions on cancer: some answers to ignite discussion. Oncotarget. 2011; 2: 1352-1367.
102. Powe DG, Voss MJ, Zanker KS, Habashy HO, Green AR, Ellis IO, Entschladen F. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010; 1: 628-638.
103. Pasquier E, Ciccolini J, Carre M, Giacometti S, Fanciullino R, Pouchy C, Montero MP, Serdjebi C, Kavallaris M, Andre N. Propranolol potentiates the anti-angiogenic effects and antitumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget. 2011; 2: 797-809.
104. Huang CC, Chan WL, Chen YC, Chen TJ, Lin SJ, Chen JW, Leu HB. Angiotensin II receptor blockers and risk of cancer in patients with systemic hypertension. Am J Cardiol. 2011; 107: 1028-1033.
105. Shen XZ, Bernstein KE. The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis. Cell Cycle. 2011; 10: 1363-1369.
106. Sadoshima J, Izumo S. Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. Circ Res. 1995; 77: 1040-1052.
107. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY). 2010; 2: 760-774.
108. Demidenko ZN. Chronological lifespan in stationary culture: from yeast to human cells. Aging (Albany NY). 2011; 3: 1041-1042.
109. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY). 2011; 3: 148-157.
110. Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA. Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle. 2010; 9: 188-197.
111. Gosmanova EO, Canada RB, Mangold TA, Rawls WN, Wall BM. Effect of metformin-containing antidiabetic regimens on allcause mortality in veterans with type 2 diabetes mellitus. Am J Med Sci. 2008; 336: 241-247.
112. Menendez JA, Cufi S, Oliveras-Ferraros C, Vellon L, Joven J, Vazquez-Martin A. Gerosuppressant metformin: less is more. Aging (Albany NY). 2011; 3: 348-362.
113. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandezr E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogenous mice. Nature. 2009; 460: 392-396.
114. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2011; 66: 191-201.
115. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle. 2011; 10: 4230-4236.
116. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010; 176: 2092-2097.
117. Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, Woodward MA, Miller RA. Rapamycin slows aging in mice. Aging Cell. 2012; 11: 675-682.
118. Khanna A, Kapahi P. Rapamycin: killing two birds with one stone. Aging (Albany NY). 2011; 3: 1043-1044.
119. Longo VD, Fontana L. Intermittent supplementation with rapamycin as a dietary restriction mimetic. Aging (Albany NY). 2011; 3: 1039-1040.
120. Blagosklonny MV. Increasing healthy lifespan by suppressing aging in our lifetime: Preliminary proposal. Cell Cycle. 2010; 9: 4788-4794.
121. Blagosklonny MV. How to save Medicare: the anti-aging remedy. Aging (Albany NY). 2012; 4: 547-552.
122. Blagosklonny MV. Molecular damage in cancer: an argument for mTOR-driven aging. Aging (Albany NY). 2011; 3: 1130-1141.
123. Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle. 2009; 8: 4112-4118.
124. Leontieva OV, Lenzo F, Demidenko ZN, Blagosklonny MV. Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells. Cell Cycle. 2012; 11: 4642-4649.
125. Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, Coppe JP, Campeau E, Beausejour CM, Kim SH, Davalos AR, Campisi J. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci. 2011; 124: 68-81.
126. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009; 11: 973-979.
127. Blagosklonny MV. mTOR-driven aging: speeding car without brakes. Cell Cycle. 2009; 8: 4055-4059.
128. Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives. Aging (Albany NY). 2010; 2: 265-273.
129. Blagosklonny MV. Rapamycin-induced glucose intolerance: Hunger or starvation diabetes. Cell Cycle. 2011; 10: 4217-4224.
130. Blandino-Rosano M, Chen AY, Scheys JO, Alejandro EU, Gould AP, Taranukha T, Elghazi L, Cras-Meneur C, Bernal- Mizrachi E. mTORC1 signaling and regulation of pancreatic betacell mass. Cell Cycle. 2012; 11.
131. Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet. 2002; 3: 165-175.
132. Bishop NA, Guarente L. Two neurons mediate dietrestriction- induced longevity in C. elegans. Nature. 2007; 447: 545-549.
133. Krakauer T, Buckley M, Issaq HJ, Fox SD. Rapamycin Protects Mice from Staphylococcal Enterotoxin B-Induced Toxic Shock and Blocks Cytokine Release In vitro and In Vivo. Antimicrob Agents Chemother. 2010.
134. Weiss G, Skurnick JH, Goldsmith LT, Santoro NF, Park SJ. Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA. 2004; 292: 2991-2996.
135. Prior JC. Ovarian aging and the perimenopausal transition: the paradox of endogenous ovarian hyperstimulation. Endocrine. 2005; 26: 297-300.
136. Horiuchi S. Postmenopausal acceleration of age-related mortality increase. J Gerontol A Biol Sci Med Sci. 1997; 52: B78-92.
137. Heys KR, Cram SL, Truscott RJ. Massive increase in the stiffness of the human lens nucleus with age: the basis for presbyopia? Mol Vis. 2004; 10: 956-963.
138. Truscott RJ. Presbyopia. Emerging from a blur towards an understanding of the molecular basis for this most common eye condition. Exp Eye Res. 2009; 88: 241-247.
139. Wendt M, Croft MA, McDonald J, Kaufman PL, Glasser A. Lens diameter and thickness as a function of age and pharmacologically stimulated accommodation in rhesus monkeys. Exp Eye Res. 2008; 86: 746-752.
140. Rosen AM, Denham DB, Fernandez V, Borja D, Ho A, Manns F, Parel JM, Augusteyn RC. In vitro dimensions and curvatures of human lenses. Vision Res. 2006; 46: 1002-1009.
141. McGinty SJ, Truscott RJ. Presbyopia: the first stage of nuclear cataract? Ophthalmic Res. 2006; 38: 137-148.
142. Blagosklonny MV. Program-like aging and mitochondria: instead of random damage by free radicals. J Cell Biochem. 2007; 102: 1389-1399.
143. Michno K, van de Hoef D, Wu H, Boulianne GL. Modeling age-related diseases in Drosophila: can this fly? Curr Top Dev Biol. 2005; 71: 199-223.
144. Nelson B, Nishimura S, Kanuka H, Kuranaga E, Inoue M, Hori G, Nakahara H, Miura M. Isolation of gene sets affected specifically by polyglutamine expression: implication of the TOR signaling pathway in neurodegeneration. Cell Death Differ. 2005; 12: 1115-1123.
145. Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol. 2006; 16: 230-241.
146. Chaudhuri A, Bowling K, Funderburk C, Lawal H, Inamdar A, Wang Z, O'Donnell JM. Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J Neurosci. 2007; 27: 2457-2467.
147. Birse RT, Choi J, Reardon K, Rodriguez J, Graham S, Diop S, Ocorr K, Bodmer R, Oldham S. High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metab. 2010; 12: 533-544.
148. Wessells R, Fitzgerald E, Piazza N, Ocorr K, Morley S, Davies C, Lim HY, Elmen L, Hayes M, Oldham S, Bodmer R. d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila. Aging Cell. 2009; 8: 542-552.
149. Teleman AA, Ratzenbock I, Oldham S. Drosophila: a model for understanding obesity and diabetic complications. Exp Clin Endocrinol Diabetes. 2012; 120: 184-185.
150. Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, Bodmer R, Oldham SM. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 2006; 4: 133-142.
151. Broughton SJ, Piper MD, Ikeya T, Bass TM, Jacobson J, Driege Y, Martinez P, Hafen E, Withers DJ, Leevers SJ, Partridge L. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci U S A. 2005; 102: 3105-3110.
152. Oldham S. Obesity and nutrient sensing TOR pathway in flies and vertebrates: Functional conservation of genetic mechanisms. Trends Endocrinol Metab. 2011; 22: 45-52.
153. Diop SB, Bodmer R. Drosophila as a model to study the genetic mechanisms of obesity-associated heart dysfunction. J Cell Mol Med. 2012; 16: 966-971.
154. Morris SN, Coogan C, Chamseddin K, Fernandez-Kim SO, Kolli S, Keller JN, Bauer JH. Development of diet-induced insulin resistance in adult Drosophila melanogaster. Biochim Biophys Acta. 2012; 1822: 1230-1237.
155. Haselton AT, Fridell YW. Adult Drosophila melanogaster as a model for the study of glucose homeostasis. Aging (Albany NY). 2010; 2: 523-526.
156. Musselman LP, Fink JL, Narzinski K, Ramachandran PV, Hathiramani SS, Cagan RL, Baranski TJ. A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis Model Mech. 2011; 4: 842-849.
157. Luong N, Davies CR, Wessells RJ, Graham SM, King MT, Veech R, Bodmer R, Oldham SM. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 2006; 4: 133-142.
158. Biteau B, Karpac J, Hwangbo D, Jasper H. Regulation of Drosophila lifespan by JNK signaling. Exp Gerontol. 2011; 46: 349-354.
159. Jasper H, Kennedy BK. Niche science: the aging stem cell. Cell Cycle. 2012; 11: 2959-2960.
160. Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H. Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet. 2010; 6: e1001159.
161. Biteau B, Hochmuth CE, Jasper H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell. 2008; 3: 442-455.
162. Moskalev A, Shaposhnikov M. Pharmacological inhibition of NF-kappaB prolongs lifespan of Drosophila melanogaster. Aging (Albany NY). 2011; 3: 391-394.
163. Brignull HR, Morley JF, Garcia SM, Morimoto RI. Modeling polyglutamine pathogenesis in C. elegans. Methods Enzymol. 2006; 412: 256-282.
164. Vosseller K. O-GlcNAc and aging: C. elegans as a genetic model to test O-GlcNAc roles in type II diabetic insulin resistance. Aging (Albany NY). 2010; 2: 749-751.
165. Rahman MM, Stuchlick O, El-Karim EG, Stuart R, Kipreos ET, Wells L. Intracellular protein glycosylation modulates insulin mediated lifespan in C.elegans. Aging (Albany NY). 2010; 2: 678-690.
166. Williams TW, Dumas KJ, Hu PJ. EAK proteins: novel conserved regulators of C. elegans lifespan. Aging (Albany NY). 2010; 2: 742-747.
167. Zhou KI, Pincus Z, Slack FJ. Longevity and stress in Caenorhabditis elegans. Aging (Albany NY). 2011; 3: 733-753.
168. Solari F. CeKlotho opens a new road for investigation in worm aging. Aging (Albany NY). 2010; 2: 539-540.
169. Shmookler Reis RJ, Xu L, Lee H, Chae M, Thaden JJ, Bharill P, Tazearslan C, Siegel E, Alla R, Zimniak P, Ayyadevara S. Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants. Aging (Albany NY). 2011; 3: 125-147.
170. Hulbert AJ. Longevity, lipids and C. elegans. Aging (Albany NY). 2011; 3: 81-82.
171. Chateau MT, Araiz C, Descamps S, Galas S. Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. Aging (Albany NY). 2010; 2: 567-581.
172. Rongo C. Epidermal growth factor and aging: a signaling molecule reveals a new eye opening function. Aging (Albany NY). 2011; 3: 896-905.
173. Alavez S, Lithgow GJ. Pharmacological maintenance of protein homeostasis could postpone age-related disease. Aging Cell. 2012; 11: 187-191.
174. Lithgow GJ. Does anti-aging equal anti-microbial? Sci Aging Knowledge Environ. 2003; 2003: PE16.
175. Briaud I, Dickson LM, Lingohr MK, McCuaig JF, Lawrence JC, Rhodes CJ. Insulin receptor substrate-2 proteasomal degradation mediated by a mammalian target of rapamycin (mTOR)-induced negative feedback down-regulates protein kinase B-mediated signaling pathway in beta-cells. J Biol Chem. 2005; 280: 2282-2293.
176. Elghazi L, Balcazar N, Blandino-Rosano M, Cras-Meneur C, Fatrai S, Gould AP, Chi MM, Moley KH, Bernal-Mizrachi E. Decreased IRS signaling impairs beta-cell cycle progression and survival in transgenic mice overexpressing S6K in beta-cells. Diabetes. 2010; 59: 2390-2399.
177. Rachdi L, Balcazar N, Osorio-Duque F, Elghazi L, Weiss A, Gould A, Chang-Chen KJ, Gambello MJ, Bernal-Mizrachi E. Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1- dependent manner. Proc Natl Acad Sci U S A. 2008; 105: 9250-9255.
178. Shigeyama Y, Kobayashi T, Kido Y, Hashimoto N, Asahara S, Matsuda T, Takeda A, Inoue T, Shibutani Y, Koyanagi M, Uchida T, Inoue M, Hino O, Kasuga M, Noda T. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol. 2008; 28: 2971-2979.
179. Bonda DJ, Evans TA, Santocanale C, Llosa JC, Vina J, Bajic VP, Castellani RJ, Siedlak SL, Perry G, Smith MA, Lee HG. Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease. Aging (Albany NY). 2009; 1: 382-388.
180. Frade JM. Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones. J Cell Sci. 2000; 113 (Pt 7): 1139-1148.
181. Song B, Davis K, Liu XS, Lee HG, Smith M, Liu X. Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer's disease. Aging (Albany NY). 2011; 3: 846-851.
182. Frade JM, Lopez-Sanchez N. A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75 (NTR). Cell Cycle. 2010; 9: 1934-1941.
183. Futatsugi A, Utreras E, Rudrabhatla P, Jaffe H, Pant HC, Kulkarni AB. Cyclin-dependent kinase 5 regulates E2F transcription factor through phosphorylation of Rb protein in neurons. Cell Cycle. 2012; 11: 1603-1610.
184. Stanga S, Lanni C, Govoni S, Uberti D, D'Orazi G, Racchi M. Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link? Aging (Albany NY). 2010; 2: 545-554.
185. Gan B, DePinho RA. mTORC1 signaling governs hematopoietic stem cell quiescence. Cell Cycle. 2009; 8: 1003-1006.
186. Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell. 2009; 5: 279-289.
187. Ratajczak MZ, Shin DM, Ratajczak J, Kucia M, Bartke A. A novel insight into aging: are there pluripotent very small embryonic-like stem cells (VSELs) in adult tissues overtime depleted in an Igf-1-dependent manner? Aging (Albany NY). 2010; 2: 875-883.
188. Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du C, Tang W, HŠmŠlŠinen T, Peng SL, Lan ZJ, Cooney AJ, Huhtaniemi I, Liu K. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science. 2008; 319: 611-613.
189. Reddy P, Adhikari D, Zheng W, Liang S, Hamalainen T, Tohonen V, Ogawa W, Noda T, Volarevic S, Huhtaniemi I, Liu K. PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles. Hum Mol Genet. 2009; 18: 2813-2824.
190. Adhikari D, Liu K. mTOR signaling in the control of activation of primordial follicles. Cell Cycle. 2010; 9: 1673-1674.
191. Adhikari D, Flohr G, Gorre N, Shen Y, Yang H, Lundin E, Lan Z, Gambello MJ, Liu K. Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles. Mol Hum Reprod. 2009; 15: 765-770.
192. Blagosklonny MV. Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res. 2008; 11: 801-808.
193. Leontieva OV, Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging (Albany NY). 2011; 3: 1078-1091.
194. Fabrizio P, Wei M. Conserved role of medium acidification in chronological senescence of yeast and mammalian cells. Aging (Albany NY). 2011; 3: 1127-1129.
195. Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, Schmitt I, Wullner U, Evert BO, O'Kane CJ, Rubinsztein DC. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet. 2006; 15: 433-442.
196. Williams A, Jahreiss L, Sarkar S, Saiki S, Menzies FM, Ravikumar B, Rubinsztein DC. Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications. Curr Top Dev Biol. 2006; 76: 89-101.
197. Sarkar S, Rubinsztein DC. Huntington's disease: degradation of mutant huntingtin by autophagy. Febs J. 2008; 275: 4263-4270.
198. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinpathies. Cell Death Differ. 2009; 16: 46-56.
199. Menzies FM, Rubinsztein DC. Broadening the therapeutic scope for rapamycin treatment. Autophagy. 2010; 6: 286-287.
200. Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, Collins FS. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med. 2011; 3: 89ra58.
201. Kharas MG, Okabe R, Ganis JJ, Gozo M, Khandan T, Paktinat M, Gilliland DG, Gritsman K. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood. 2010; 115: 1406-1415.
202. Hay N. Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta. 2011; 1813: 1965-1970.
203. Ghosh HS, McBurney M, Robbins PD. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One. 2010; 5: e9199.
204. Blagosklonny MV. Linking calorie restriction to longevity through sirtuins and autophagy: any role for TOR. Cell Death Dis. 2010; 1: e12.
205. Sheaffer KL, Updike DL, Mango SE. The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr Biol. 2008; 18: 1355-1364.
206. Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell. 2010; 18: 592-604.
207. Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A. 2005; 102: 4494-4499.
208. Balasubramanian P, Longo VD. Linking Klotho, Nrf2, MAP kinases and aging. Aging (Albany NY). 2010; 2: 632-633.
209. Belgardt BF, Mauer J, Bruning JC. Novel roles for JNK1 in metabolism. Aging (Albany NY). 2010; 2: 621-626.
210. Spencer NF, Poynter ME, Im SY, Daynes RA. Constitutive activation of NF-kappa B in an animal model of aging. Int Immunol. 1997; 9: 1581-1588.
211. Vaughan S, Jat PS. Deciphering the role of nuclear factorkappaB in cellular senescence. Aging (Albany NY). 2011; 3: 913-919.
212. Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, Reay DP, Nasto LA, St Croix CM, Usas A, Vo N, Huard J, Clemens PR, Stolz DB, Guttridge DC, Watkins SC, Garinis GA et al. NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest. 122: 2601-2612.
213. Dreesen O, Stewart CL. Accelerated aging syndromes, are they relevant to normal human aging? Aging (Albany NY). 2011; 3: 889-895.
214. Blagosklonny MV. Hormesis does not make sense except in the light of TOR-driven aging. Aging (Albany NY). 2011; 3: 1051-1062.
215. Schmidt-Kittler O, Zhu J, Yang J, Liu G, Hendricks W, Lengauer C, Gabelli SB, Kinzler KW, Vogelstein B, Huso DL, Zhou S. PI3Kalpha inhibitors that inhibit metastasis. Oncotarget. 2010; 1: 339-348.
216. Weber GL, Parat MO, Binder ZA, Gallia GL, Riggins GJ. Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells. Oncotarget. 2011; 2: 833-849.
217. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441: 424-430.
218. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007; 12: 9-22.
219. Gruppuso PA, Boylan JM, Sanders JA. The physiology and pathophysiology of rapamycin resistance: implications for cancer. Cell Cycle. 2011; 10: 1050-1058.
220. Bhatia B, Nahle Z, Kenney AM. Double trouble: when sonic hedgehog signaling meets TSC inactivation. Cell Cycle. 2010; 9: 456-459.
221. Adams JR, Schachter NF, Liu JC, Zacksenhaus E, Egan SE. Elevated PI3K signaling drives multiple breast cancer subtypes. Oncotarget. 2011; 2: 435-447.
222. Garrett JT, Chakrabarty A, Arteaga CL. Will PI3K pathway inhibitors be effective as single agents in patients with cancer? Oncotarget. 2011; 2: 1314-1321.
223. Sokolosky ML, Stadelman KM, Chappell WH, Abrams SL, Martelli AM, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, Steelman LS, McCubrey JA. Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget. 2011; 2: 538-550.
224. Green AS, Chapuis N, Lacombe C, Mayeux P, Bouscary D, Tamburini J. LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology. Cell Cycle. 2011; 10: 2115-2120.
225. Hart JR, Vogt PK. Phosphorylation of AKT: a mutational analysis. Oncotarget. 2011; 2: 467-476.
226. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, Basecke J, Stivala F, Donia M, Fagone P, Malaponte G, Mazzarino MC, Nicoletti F, Libra M, Maksimovic-Ivanic D, Mijatovic S et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget. 2011; 2: 135-164.
227. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov. 2011; 10: 868-880.