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Rejuvenating immunity: “anti-aging drug today” eight years later

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Oncotarget. 2015; 6:19405-19412. doi: 10.18632/oncotarget.3740

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Mikhail V. Blagosklonny _

Abstract

Mikhail V. Blagosklonny1

1 Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

Correspondence to:

Mikhail V. Blagosklonny, email:

Keywords: mTOR, TOR, gerosuppression, rapalogs, lifespan, longevity, diseases

Received: February 16, 2015 Accepted: March 28, 2015 Published: March 31, 2015

Abstract

The 2014 year ended with celebration: Everolimus, a rapamycin analog, was shown to improve immunity in old humans, heralding ‘a turning point’ in research and new era in human quest for immortality. Yet, this turning point was predicted a decade ago. But what will cause human death, when aging will be abolished?


Mikhail V. Blagosklonny.html

“Defining ageing as a disease and then trying to cure it is unscientific and misguided.” [1]

Introduction

Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented.

Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR (Target of Rapamycin). TOR-centric model predicts that rapamycin (and other rapalogs) can be used in humans to treat aging and prevent diseases [2]. In proper doses and schedules, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans [2, 3].

This theory was ridiculed by opponents and anonymous peer-reviewers. Yet, it was predicted in 2008 that “five years from now, current opponents will take the TOR-centric model for granted” [4]. And this prediction has been fulfilled.

Rapamycin today

The study that Evirolimus (RAD001), a rapamycin analog, improves immunity in aging humans [5] made sensational headlines:

“Novartis Working on ‘Fountain of Youth’ Drug”. “Researchers could be closing in on a “fountain of youth” drug that can delay the effects of aging and improve the health of older adults”.

As summarized by Nir Barzilai, “it sets the stage for using this drug to target aging, to improve everything about aging. That’s really going to be, for us, a turning point in research, and we are very excited.” http://www.medicaldaily.com/anti-aging-drug-works-first-steps-toward-boosting-immune-system-delaying-aging-315592

Rapamycin yesterday

In 2006, it was concluded that “ Sirolimus or Rapamune, which is known in the basic science as rapamycin, is already approved for clinical use, available and can be used immediately. In addition to cancer, cardiovascular diseases, autoimmunity, and metabolic disorders, all diseases of aging from osteoporosis to Alzheimer’s may be treated with rapamycin. Finally, rapamycin will be most useful as an anti-aging drug to slow down senescence and to prevent diseases.” [2]

And further, “Rapamycin is safe enough to be administrated daily to transplant patients for several years. Actually, rapamycin is so safe that its pharmacokinetics have been studied in healthy volunteers”. “Figuratively, it [rapamycin] transforms immunity from aged-type to infant-type”. In simple words, rapamycin rejuvenates the immunity. Thus, “rapamycin eliminates hyper-immunity rather than suppresses immunity” [2].

“Anti-aging drug today” [3] was actually published yesterday: “Rapamycin is a non-toxic, well-tolerated drug that is suitable for everyday oral administration. Preclinical and clinical data indicate that rapamycin is a promising drug for age-related diseases and seems to have anti-tumor, bone-sparing and calorie-restriction-mimicking ‘side-effects’.” [3]. As recently reviewed, in proper doses, lifespan-extending agents including rapamycin posses certain immunostimulatory activities [6].

By 2010, many predictions of the TOR-centric model have been tested and confirmed [7]. In 2010, one prediction remained: “rapamycin will become the cornerstone of anti-aging therapy in our life time.” [7]. Until December 2014, all gerontological papers on rapamycin stated that current rapalogs are just proof of principle and will not be used due to side effects. Even further, use of anti-aging drugs in our lifetime was called science fiction. For unclear reasons, scientists emphasized that rapamacin and other current rapalogs will not be used in aging humans due to imaginary side effects.

Triumph of mTOR-centric model

The hyperfunctional theory predicts calorie-restriction-mimicking ‘side-effects’ of rapalogs. For example, rapamycin increases lipolysis, thus imitating fasting [3]. And in some conditions, rapamycin may cause “starvation diabetes”, a benevolent insulin-resistance and glucose intolerance. “Starvation or Hunger Diabetes” was well known during famine and prolonged fasting [8]. Rapamycin, as calorie-restriction-mimetic, can cause starvation-like symptoms in certain conditions. This benevolent rapamycin-induced state prevents complications of true type II diabetes [9, 10]. In certain strains of mice, rapamycin causes some symptoms of starvation-like insulin-resistance, erroneously viewed as real diabetes [11]. These metabolic alterations are reversible [12, 13]. MTOR-centric model predicts that this reversible insulin resistance is benevolent and is associated with increased longevity because longevity is promoted not via increased insulin sensitivity, but instead via decreased mTOR pathway signaling [9].

Initially, mTOR-centic model was ignored. As announced by Lamming et al, “A growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans.” [14] Now however the same opponent re-invented mTOR-centric model (without appropriate reference), suggesting that “longevity is promoted not via increased insulin sensitivity, but instead via decreased PI3K/Akt/mTOR pathway signaling” [15]. As it was predicted in 2008 [4], opponents indeed take mTOR-centric model for granted. This is the ultimate triumph of the TOR-centric (hyperfunction) theory of aging.

TOR-centric model

Evolutionary theory predicts that growth-promoting pathways are antagonistically pleiotropic [16]. In other words, growth-promoting signaling is essential during development and may be harmful later in life. In particular, the nutrient-sensing mTOR pathway is essential for growth and development. In adults, its excessive activity leads to pathology (aging) [17-20]. Aging is an unintended, harmful continuation of developmental growth. It is a quasi -program (not a program), a shadow of development. More on that was discussed previously [16, 21-27].

Three sources for the TOR-centric model

1. Genetics of longevity

The work in model organisms revealed numerous genes whose inactivation extends life span [3, 28-57]. Some gerogenes encode the TOR pathway. Yet, is the TOR pathway central or just one of the numerous pathways? Independent work on cellular senescence answers this question.

2. Cellular senescence

In 2003 it was proposed that activation of growth-promoting pathways should cause senescence, when the cell cycle is blocked [58]. In fact, mTOR converts reversible cell cycle arrest to cellular senescence (geroconversion) [59-61]. Rapamycin partially suppresses geroconversion [62-76]. All gerogenic pathways converge on the mTOR pathway: upstream and downstream [77-83]. Typically, oncogenes are gerogenes, whereas tumor suppressors are gerosuppressors [59, 84-87]. Gerogenes and gerosuppressors constitute the mTOR network. This network is identical to gerogenic pathways identified in model organisms [3].

3. Diseases

Completely independently, mTOR pathway was revealed in the studies of human diseases: Parkinson and Alzheimer, cancer and benign tumors, cardiac fibrosis and atherosclerosis, renal hypertrophy and diabetic complications [19, 88-97]. And while gerontologists thought that rapamycin causes cancer, numerous studies by nephrologists and transplantologists showed that rapamycin prevents cancer in humans [86, 98-103]. Most studies were performed by scientists, working in narrow clinical fields [104-106]. Only taken together, these studies illuminate the role of mTOR in all age-related diseases. These age-related diseases are direct causes of death in aging. No one dies from aging per se.

Michael Hall, who discovered TOR and named it after rapamycin [107], remarkably envisioned in 2005 that “inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders” [93]. This generalization, combined with discoveries in model organisms and cellular senescence, was taken a step further [2]. mTOR-driven hyperfubnction leads to alterations of homeostasis, diseases and death. Examples of systemic hyperfuctions include hypertension, hyper-insulinemia and organ hypertrophy.

How will people die, when aging will be abolished: post-aging syndrome

Currently, humans and animals (in protected environment) die from age-related diseases, which are manifestation of aging. By slowing aging, rapamycin and calorie restriction can delay age-related diseases including cancer [108-125]. They extend life span. Yet, the causes of death seem to be the same. Or not? Why is this important?

Consider an analogy. 300 years ago in London, 75% of people died from external causes (infections, trauma, starvation) before they reached the age of 26. [22]. So only a few died from mTOR-driven aging. Only when most external causes have been eliminated, people now die from mTOR-driven age-related diseases. Similarly, if TOR-driven aging would be eliminated by a rational combination of anti-aging drugs, even then we still would not be immortal. There will be new, currently unknown causes of death. I call this post-aging syndrome. We do not know what it is. But we know that accumulation of molecular damage or telomere shortening (as examples) eventually would cause post-aging syndrome [2].

Why do we not recognize symptoms of post-aging syndrome?

Even in the ancient world, when most people died from “external causes”, symptoms of mTOR-driven aging were well known. In contrast, we do not know symptoms of post-aging syndrome. Aging is quasi-programmed and is not accidental. Although its rate varies among individuals, the chances to outlive aging and to die from post-aging syndrome are very low. Still, we may identify these symptoms in humans over 110 years old and especially in animals treated with rapamycin (and other anti-aging modalities). Inhibition of mTOR may extend life span, thus revealing post-aging syndrome.

How will we know that we observe post-aging syndrome? There are potential criteria: Animals and humans die from either unknown diseases, unusual variants of known-disease and rare diseases. Or at least, the range of age-related diseases is dramatically changed.

As discussed in 2006, causes of post-aging syndrome may include accumulation of random molecular damage, telomere shortening, selfish mitochondria and so on. As also discussed, when people die from post-aging syndrome, then anti-oxidants may help, in theory of course [2].

Conclusion

Criticizing the TOR-centric hyperfunction theory of aging, an opponent wrote: “The advent of the hyperfunction theory of aging has been compared to the replacement of the geocentric with the heliocentric worldview. Within this rather grand conceptual framework, I may be seen as an old-timer who desperately tries to salvage a doomed theory by piling up epicycles. Perhaps so – time will tell.” [126].

Time told unexpectedly fast. While gerontologists were studying free radicals and anti-oxidants, the TOR-centric (hyperfunction) theory revealed anti-aging drugs such as rapamycin and metformin. There are several potential anti-aging drugs in clinical use [127, 128]. Combining drugs and modalities, selecting doses and schedules in clinical trial will ensure the maximal lifespan extension [27, 129].

Simultaneously, medical progress improves aging-tolerance [129, 130]. Aging tolerance is the ability to survive despite aging [130]. For example, bypass surgery allows patients with coronary disease to live, despite aging-associated atherosclerosis.

Gerontologists do not need to catch the train that has already departed. No need to study rapamycin, which already entered the clinic. This is now a merely medical task. Gerontologists may continue to study free radicals and accumulation of random molecular damage as a potential cause of post-aging syndrome (not aging). It is important to study post-aging syndrome, to be ready to fight it, when medical progress with rapamycin will allow us to reach post-aging age: perhaps 50 years from now.

References

1. Rattan SIS. Anti-ageing strategies: prevention or therapy. EMBO Rep. 2005; 6: S25-29.

2. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006; 5: 2087-2102.

3. Blagosklonny MV. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Disc Today. 2007; 12: 218-224.

4. Blagosklonny MV. Aging: ROS or TOR. Cell Cycle. 2008; 7: 3344-3354.

5. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 6: 268ra179.

6. Bravo-San Pedro JM, Senovilla L. Immunostimulatory activity of lifespan-extending agents. Aging (Albany NY). 2013; 5: 793-801.

7. Blagosklonny MV. Rapamycin and quasi-programmed aging: Four years later. Cell Cycle. 2010; 9: 1859-1862.

8. Blagosklonny MV. Rapamycin-induced glucose intolerance: Hunger or starvation diabetes. Cell Cycle. 2011; 10: 4217-4224.

9. Blagosklonny MV. Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Aging (Albany NY). 2012; 4: 350-358.

10. Blagosklonny MV. TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis. 2013; 4: e964.

11. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012; 335: 1638-1643.

12. Liu Y, Diaz V, Fernandez E, Strong R, Ye L, Baur JA, Lamming DW, Richardson A, Salmon AB. Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging (Albany NY). 2014; 6: 742-754.

13. Fang Y, Bartke A. Prolonged rapamycin treatment led to beneficial metabolic switch. Aging (Albany NY). 2013; 5: 328-329.

14. Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013; 123: 980-989.

15. Lamming DW. Diminished mTOR signaling: a common mode of action for endocrine longevity factors. Springerplus. 3: 735.

16. Blagosklonny MV. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Cell Cycle. 2010; 9: 3151-3156.

17. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY). 2009; 1: 281-288.

18. Blagosklonny MV. mTOR-driven aging: speeding car without brakes. Cell Cycle. 2009; 8: 4055-4059.

19. Blagosklonny MV. Prospective treatment of age-related diseases by slowing down aging. Am J Pathol. 2012; 181: 1142-1146.

20. Blagosklonny MV. Answering the ultimate question “what is the proximal cause of aging?” Aging (Albany NY). 2012; 4: 861-877.

21. Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives. Aging (Albany NY). 2010; 2: 265-273.

22. Blagosklonny MV. Why human lifespan is rapidly increasing: solving “longevity riddle” with “revealed-slow-aging” hypothesis. Aging (Albany NY). 2010; 2: 177-182.

23. Blagosklonny MV. Big mice die young but large animals live longer. Aging (Albany NY). 2013; 5:227-233.

24. Blagosklonny MV. M(o)TOR of aging: MTOR as a universal molecular hypothalamus. Aging (Albany NY). 2013; 5: 490-494.

25. Blagosklonny MV. MTOR-driven quasi-programmed aging as a disposable soma theory: blind watchmaker vs. intelligent designer. Cell Cycle. 2013; 12: 1842-1847.

26. Blagosklonny MV. Aging is not programmed: Genetic pseudo-program is a shadow of developmental growth. Cell Cycle. 2013; 12: 3736-3742.

27. Blagosklonny MV. Increasing healthy lifespan by suppressing aging in our lifetime: Preliminary proposal. Cell Cycle. 2010; 9: 4788-4794.

28. Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 1997; 278: 1319-1322.

29. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993: 366: 461-464.

30. Berman JR, Kenyon C. Germ-Cell Loss Extends C. elegans Life Span through Regulation of DAF-16 by kri-1 and Lipophilic-Hormone Signaling. Cell. 2006.

31. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell. 2005; 120: 449-460.

32. Masse I, Molin L, Billaud M, Solari F. Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF-18. Dev Biol. 2005; 286: 91-101.

33. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003; 426: 620.

34. 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.

35. 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.

36. Powers RWr, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006; 20: 174-184.

37. 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, J.R., Carmignac, D., Robinson, I.C., Thornton, J.M., Gems, D., Partridge, L., Withers, D.J. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 2008; 22: 807-818.

38. 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.

39. 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.

40. Moskalev AA, Shaposhnikov MV. Pharmacological Inhibition of Phosphoinositide 3 and TOR Kinases Improves Survival of Drosophila melanogaster. Rejuvenation Res. 2010; 13: 246-247.

41. Bjedov I, Partridge L. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans. 2011; 39: 460-465.

42. Katewa SD, Kapahi P. Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp Gerontol. 2011; 46: 382-390.

43. Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK. The TOR pathway comes of age. Biochim Biophys Acta. 2009; 1790: 1067-1074.

44. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003; 421: 182-187.

45. 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.

46. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 2012; 15: 713-724.

47. 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. 2013; 12: 24-31.

48. Selman C, Partridge L, Withers DJ. Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS One. 2011; 6: e16144.

49. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013; 493: 338-345.

50. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, Fergusson MM, Rovira, II, Allen M, Springer DA, Lago CU, Zhang S, Dubois W, Ward T, Decabo R, Gavrilova O et al. Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression. Cell Rep. 2013; 4: 913-920.

51. Leontieva OV, Novototskaya LR, Paszkiewicz GM, Komarova EA, Gudkov AV, Blagosklonny MV. Dysregulation of the mTOR pathway in p53-deficient mice. Cancer Biol Ther. 2013; 14: 1182-1188.

52. Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ. Remarkable longevity and stress resistance of nematode PI3K-null mutants. Aging Cell. 2008; 7: 13-22.

53. Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV. BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging (Albany NY). 2014; 6: 48-57.

54. 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.

55. Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet. 2002; 3: 165-175.

56. Gems DH, de la Guardia YI. Alternative Perspectives on Aging in C. elegans: Reactive Oxygen Species or Hyperfunction? Antioxid Redox Signal. 2013; 19: 321-329.

57. Gems D, Partridge L. Genetics of Longevity in Model Organisms: Debates and Paradigm Shifts. Annu Rev Physiol. 2013; 75: 621-644.

58. Blagosklonny MV. Cell senescence and hypermitogenic arrest. EMBO Rep. 2003; 4: 358-362.

59. 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.

60. Blagosklonny MV. Geroconversion: irreversible step to cellular senescence. Cell Cycle. 2014: 13; 3628-3635.

61. Sousa-Victor P, Gutarra S, Garcia-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, Jardi M, Ballestar E, Gonzalez S, Serrano AL, Perdiguero E, Munoz-Canoves P. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014; 506: 316-321.

62. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008; 7: 3355-3361.

63. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009; 8: 1888-1895.

64. 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 (Albany NY). 2010; 2: 344-352.

65. 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.

66. Leontieva OV, Demidenko ZN, Blagosklonny MV. S6K in geroconversion. Cell Cycle. 2013; 12: 3249-3252.

67. Leontieva OV, Blagosklonny MV. CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle. 2013; 12: 3063-3069.

68. 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.

69. 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.

70. 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.

71. Hinojosa CA, Mgbemena V, Van Roekel S, Austad SN, Miller RA, Bose S, Orihuela CJ. Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Exp Gerontol. 2012; 47: 958-965.

72. Cho S, Hwang ES. Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol Cells. 2012; 33: 597-604.

73. Serrano M. Dissecting the role of mTOR complexes in cellular senescence. Cell Cycle. 2012; 11: 2231-2232.

74. Dulic V. Senescence regulation by mTOR. Methods Mol Biol. 2013; 965: 15-35.

75. Iglesias-Bartolome R, Patel V, Cotrim A, Leelahavanichkul K, Molinolo AA, Mitchell JB, Gutkind JS. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell. 2012; 11: 401-414.

76. Luo Y, Li L, Zou P, Wang J, Shao L, Zhou D, Liu L. Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence. Transplantation. 2014; 97: 20-29.

77. 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.

78. 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.

79. Leontieva OV, Demidenko ZN, Blagosklonny MV. Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program. Proc Natl Acad Sci U S A. 2014; 111: 8832-8837.

80. Leontieva OV, Lenzo F, Demidenko ZN, Blagosklonny MV. Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells. Cell Cycle. 2012; 11: 4642 - 4649.

81. Leontieva OV, Demidenk ZN, Blagosklonny MV. MEK drives cyclin D1 hyperelevation during geroconversion. Cell Deth Diff. 2013; 20: 1241-1249.

82. Zhao H, Halicka HD, Li J, Darzynkiewicz Z. Berberine suppresses gero-conversion from cell cycle arrest to senescence. Aging (Albany NY). 2013; 5: 623-636.

83. 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.

84. Blagosklonny MV. Molecular damage in cancer: an argument for mTOR-driven aging. Aging (Albany NY). 2011; 3: 1130-1141.

85. Blagosklonny MV. Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression? Aging (Albany NY). 2012; 4: 450-455.

86. Blagosklonny MV. Rapalogs in cancer prevention: Anti-aging or anticancer? Cancer Biol Ther. 2012; 13: 1349-1354.

87. Blagosklonny MV. Selective anti-cancer agents as anti-aging drugs. Cancer Biol Ther. 2013; 14.

88. Pakala R, Stabile E, Jang GJ, Clavijo L, Waksman R. Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J Cardiovasc Pharmacol. 2005; 46: 481-486.

89. Neef M, Ledermann M, Saegesser H, Schneider V, Reichen J. Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol. 2006; 45: 786-796.

90. Kolosova NG, Muraleva NA, Zhdankina AA, Stefanova NA, Fursova AZ, Blagosklonny MV. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Am J Pathol. 2012; 181: 472-477.

91. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005; 37: 19-24.

92. Tee AR, Blenis J. mTOR, translational control and human disease. Semin Cell Dev Biol. 2005; 16: 29-37.

93. Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005; 17: 158-166.

94. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006; 124: 471-484.

95. Cornu M, Albert V, Hall MN. mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev. 2013; 33C:55-66.

96. 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.

97. Zheng XF. Chemoprevention of age-related macular regeneration (AMD) with rapamycin. Aging (Albany NY). 2012; 4: 375-376.

98. Campistol JM, Eris J, Oberbauer R, Friend P, Hutchison B, Morales JM, Claesson K, Stallone G, Russ G, Rostaing L, Kreis H, Burke JT, Brault Y, Scarola JA, Neylan JF. Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation. J Am Soc Nephrol. 2006; 17: 581-589.

99. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004; 18: 446-449.

100. Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005; 80: 883-889.

101. Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, Broeders N, del Marmol V, Chatelet V, Dompmartin A, Kessler M, Serra AL, Hofbauer GF, Pouteil-Noble C, Campistol JM, Kanitakis J et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012; 367: 329-339.

102. Blagosklonny MV. Prevention of cancer by inhibiting aging. Cancer Biol Ther. 2008; 7: 1520-1524.

103. Blagosklonny MV. Immunosuppressants in cancer prevention and therapy. Oncoimmunology. 2013; 2: e26961.

104. Paoletti E, Cannella G. Regression of left ventricular hypertrophy in kidney transplant recipients: the potential role for inhibition of mammalian target of rapamycin. Transplant Proc. 2010; 42: S41-43.

105. Bonegio RG, Fuhro R, Wang Z, Valeri CR, Andry C, Salant DJ, Lieberthal W. Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy. J Am Soc Nephrol. 2005; 16: 2063-2072.

106. Chollet P, Abrial C, Tacca O, Mouret-Reynier MA, Leheurteur M, Durando X, Cure H. Mammalian target of rapamycin inhibitors in combination with letrozole in breast cancer. Clin Breast Cancer. 2006; 7: 336-338.

107. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991; 253: 905-909.

108. 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.

109. 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.

110. 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.

111. 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.

112. 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.

113. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:468-477.

114. Anisimov VN. Multifaceted aging and rapamycin. Aging (Albany NY). 2013; 5: 487.

115. Ye L, Widlund AL, Sims CA, Lamming DW, Guan Y, Davis JG, Sabatini DM, Harrison DE, Vang O, Baur JA. Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging (Albany NY). 2013; 5: 539-550.

116. Kondratov RV, Kondratova AA. Rapamycin in preventive (very low) doses. Aging (Albany NY). 2014; 6: 158-159.

117. Emran S, Yang M, He X, Zandveld J, Piper MD. Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration. Aging (Albany NY). 2014; 6: 390-398.

118. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, Palmiter RD, Rabinovitch PS, Morgan PG et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013; 342: 1524-1528.

119. Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, Schreiber KH, MacKay VL, An EH, Strong R, Ladiges WC, Rabinovitch PS, Kaeberlein M, Kennedy BK. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med. 2012; 4: 144ra103.

120. Liu Y, Huang Y, Wang Z, Li X, Louie A, Wei G, Mao JH. Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development. Aging (Albany NY). 2013; 5: 111-119.

121. Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD. Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. Aging (Albany NY). 2013; 5: 100-110.

122. Popovich IG, Anisimov VN, Zabezhinski MA, Semenchenko AV, Tyndyk ML, Yurova MN, Blagosklonny MV. Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin. Cancer Biol Ther. 2014; 15: 586-592.

123. Komarova EA, Antoch MP, Novototskaya LR, Chernova OB, Paszkiewicz G, Leontieva OV, Blagosklonny MV, Gudkov AV. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/- mice. Aging (Albany NY). 2012; 4: 709-714.

124. Leontieva OV, Paszkiewicz GM, Blagosklonny MV. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging Cell. 2014; 13: 616-622.

125. Donehower LA. Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency. Aging (Albany NY). 2012; 4: 660-661.

126. Zimniak P. What is the proximal cause of aging? Front Genet. 2012; 3: 189.

127. Blagosklonny MV. Common drugs and treatments for cancer and age-related diseases: revitalizing answers to NCI’s provocative questions. Oncotarget. 2012; 3: 1711-1724.

128. Blagosklonny MV. Koschei the immortal and anti-aging drugs. Cell Death Disease. 2014;5:e1552.

129. Blagosklonny MV. How to save Medicare: the anti-aging remedy. Aging (Albany NY). 2012; 4: 547-552.

130. Blagosklonny MV. Hormesis does not make sense except in the light of TOR-driven aging. Aging (Albany NY). 2011; 3: 1051-1062.

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