|Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging.|
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|PMID: 22394614 Owner: NLM Status: MEDLINE|
|Cell cycle arrest is not yet senescence. When the cell cycle is arrested, an inappropriate growth-promotion converts an arrest into senescence (geroconversion). By inhibiting the growth-promoting mTOR pathway, rapamycin decelerates geroconversion of the arrested cells. And as a striking example, while causing arrest, p53 may decelerate or suppress geroconversion (in some conditions). Here I discuss the meaning of geroconversion and also the terms gerogenes, gerossuppressors, gerosuppressants, gerogenic pathways, gero-promoters, hyperfunction and feedback resistance, regenerative potential, hypertrophy and secondary atrophy, pro-gerogenic and gerogenic cells.|
|Mikhail V Blagosklonny|
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|Type: Journal Article|
|Title: Aging Volume: 4 ISSN: 1945-4589 ISO Abbreviation: Aging (Albany NY) Publication Date: 2012 Mar|
|Created Date: 2012-04-30 Completed Date: 2012-08-21 Revised Date: 2013-06-26|
Medline Journal Info:
|Nlm Unique ID: 101508617 Medline TA: Aging (Albany NY) Country: United States|
|Languages: eng Pagination: 159-65 Citation Subset: IM|
|Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. firstname.lastname@example.org|
|APA/MLA Format Download EndNote Download BibTex|
Cell Aging* / drug effects, genetics
Cell Cycle Checkpoints* / drug effects, genetics
Protein Kinase Inhibitors / pharmacology
Signal Transduction* / drug effects, genetics
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors, genetics, metabolism*
Terminology as Topic
Tumor Suppressor Protein p53 / metabolism
|0/Protein Kinase Inhibitors; 0/Tumor Suppressor Protein p53; 53123-88-9/Sirolimus; EC 126.96.36.199/TOR Serine-Threonine Kinases|
Journal ID (nlm-ta): Aging (Albany NY)
Journal ID (iso-abbrev): Aging (Albany NY)
Journal ID (publisher-id): ImpactJ
Publisher: Impact Journals LLC
Copyright: © 2012 Blagosklonny
Received Day: 17 Month: 2 Year: 2012
Accepted Day: 5 Month: 3 Year: 2012
collection publication date: Month: 3 Year: 2012
Electronic publication date: Day: 5 Month: 3 Year: 2012
Volume: 4 Issue: 3
First Page: 159 Last Page: 165
PubMed Id: 22394614
|Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging|
|Mikhail V. Blagosklonny|
|Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC, L3-312, Buffalo, NY, 14263, USA
|Correspondence: Correspondence to: Mikhail V. Blagosklonny, MD/PhD; email@example.com
A year ago, I wrote a perspective “Cell cycle arrest is not senescence”, intended to clarify a new meaning of cellular senescence . The perspective was not completely understood in part due to its title. The title was missing the word “yet”, which is now included. As discussed in the article, cell cycle arrest is not yet senescence and senescence is not just arrest: senescence can be driven by growth-promoting pathways such as mTOR, when actual growth is impossible. (This mechanism connects cellular senescence, organismal aging and age-related diseases, predicting anti-aging agents [2-6]). In brief, senescence can be caused by growth stimulation, when the cell cycle is arrested [7, 8]. As one hallmark, senescent cells loose proliferative potential (PP) - the potential to resume proliferation. Importantly, inhibitors of mTOR suppress hallmarks of senescence during cell cycle arrest so cells stay quiescent but not senescent [9-13]. Such quiescent cells, with inhibited mTOR, retain PP. Once again, cells may be arrested but retain PP, the ability to restart proliferation, when allowed. In certain conditions, p53 causes arrest but can preserve PP by inhibiting the mTOR pathway [14-16]. However, this phenomenon should not be misunderstood to indicate that “p53 induces proliferation or prevents arrest or keeps cells proliferating” or “arrested cells retain proliferation”; rather, p53 instead regulates proliferative potential. Although we tried to explain what p53 does exactly (causes arrest, while preserving PP) misunderstanding nonetheless ensued. One solution is not to use the term PP altogether, substituting for it the term RP (regenerative potential). In the organism, stem cells and wound-healing cells, while quiescent, are capable to regenerate tissues after cell loss. Unlike non-senescent cells, senescent cells cannot divide in response to cell loss and therefore lose the potential to regenerate tissues. In cell culture, quiescent cells preserve RP. If the cell cycle is blocked, activation of mTOR causes loss of RP . New concepts need new terminology. Instead of squeezing novel meaning into the old terms, here we present new terms for a new meaning of the aging process. And a central term is gerogenic conversion or geroconversion.
Mitogens and growth factors activate growth-promoting pathways, which stimulate (a) growth in size and (b) cell cycle progression. When cells proliferate, an increase in cell mass is balanced by division. Withdrawal of growth factors causes quiescence: the quiescent cell neither grows, nor cycles, and its functions and metabolism are low. In contrast, cell cycle blockage, in the presence of growth-stimulation leads to senescence (Figure 1). Hallmarks of senescence include a large flat morphology, senescence-associated beta-galactosidase (SA-beta-gal) staining, cellular over-activation and hyper-function, feedback signal resistance and loss of RP (that is, the inability to restart proliferation when the cell cycle inhibitor is removed). For example, in one well-studied cellular model, inducible ectopic expression of p21 causes cycle arrest (day 1) and senescence (after 3 days) [18, 19]. At first, the arrested cells are quiescent-like: they are not hypertrophic, and they are SA-beta-gal negative and retain RP. Thus, they can restart proliferation when p21 expression is switched off. After 3 days, however, the cells acquire a senescent morphology and, if p21 is then switched off, the cells cannot restart proliferation or die in mitosis . Importantly, while inhibiting the cell cycle, p21 does not inhibit the mTOR pathway [8-17, 20, 21]. mTOR and perhaps some other growth-promoting pathways convert quiescence (day 1) into senescence (day 3). Inhibition of mTOR by rapamycin decelerates this ‘geroconversion’ [8-17, 20, 21].
Similarly other inhibitors of mTOR also suppress geroconversion [10, 11]. For example, in some cell lines, induction of p53 inhibits mTOR [22-26] and other anabolic pathways [27-32], thus suppressing geroconversion in cells arrested by ectopic p21 . By itself, p53 causes cell cycle arrest but can suppress geroconversion [14-17, 33-35]. In cell culture, cell cycle arrest and geroconversion are initiated simultaneously. In proliferating cultured cells (especially cancer cells) mTOR is activated. Many agents cause cell cycle arrest without inhibiting mTOR (or other growth factor-sensing pathways). Once arrested, such cells are rapidly converted to senescent cells. This is accelerated geroconversion. So it may seem that senescence is “caused” by cell cycle arrest. The above examples, however, suggest that senescence is caused by growth-stimulation when the cell cycle is arrested.
In the organism, most cells are arrested and geroconversion can be slow. When chronically stimulated (but still arrested) they can become senescent. This physiological geroconversion can be imitated in cell culture .
The terms gerogenic conversion and oncogenic transformation sound alike.This is not a coincidence for choosing the term geroconversion. Gerogenic conversion and oncogenic transformation are two sides of the same process.
Activation of growth factor receptors, Ras and Raf family members and members of the MAPK and PI3K/Akt pathways are universal in cancer [36-38]. All these oncogenes activate the mTOR pathway [39-47]. They are gerogenic oncogenes, which drive the geroconversion of arrested cells. Because strong growth-promoting (mitogenic) signals induce cell cycle arrest [48-54], strong mitogenic signaling causes both conditions of senescence: arrest and mTOR/growth signal (Figure 2A). To avoid senescence, cancer cells must disable cell cycle control (Figure 2B) by either loss of p16, p53 and Rb or activation of c-myc, for example [36-38, 48, 55, 56]. In proliferating cells, gerogenic oncogenes render cells malignant and pro-gerogenic (see below). The same gerogenic oncogenes or their analogs accelerate aging and shorten life span in diverse species from worm to mammals. Therefore, these genes can be termed gerogenes . Thus, the mTOR pathway shortens life span, whereas rapamycin extends life span [58-75]. Not coincidentally, Mutations that increase the life span of C. elegans inhibit tumor growth . Finally, metabolic self-destruction, known as chronological senescence in yeast [60, 61, 77] is also stimulated by gerogenes and is inhibited by rapamycin .
Gerosuppressors are genes (and their products) that suppress geroconversion. Gerosuppressors (for example, PTEN, AMPK, sirtuins, TSC2, NF-1 and p53) antagonize the mTOR pathway (see for ref. ). Their inactivation shortens life span in model organisms. Gerosuppressors are also tumor suppressors. So gero-suppressors suppress both geroconversion and cancer.
Gerosuppressants are small molecules (such as rapamycin) that suppress geroconversion. Not co-incidentally, rapamycin also extends life span in diverse species from yeast to mammals. They can, in theory, be used to treat age-related diseases by slowing down aging, thus extending both maximal and healthy lifespan.
Small molecules or drugs that can accelerate or promote geroconversion. One potential candidate is phorbol esters, which can activate mTOR in some cells. Not surprisingly, it is also a tumor-promoter.
Gerogenic signaling pathways promote geroconversion. Whether gerogenic pathways cause or abrogate cell cycle arrest is irrelevant. For example, strong mitogenic/growth signals can induce cell cycle arrest, instead of proliferation [48-54]. Simultaneously, in arrested cells, growth signals cause geroconversion, leading to senescence (Figure 2A). As another example, the effects of p53 on cell cycle and geroconverion can be dissociated .
In proliferating cells, overactivation of the mTOR pathway renders them pro-gerogenic. Cancer cells are proliferating pro-gerogenic cells. When such cells are forcefully arrested, they become senescent. Also, stimulation of mTOR in normal stem cells causes hyper-proliferation, pro-gerogenic conversion and cell exhaustion [79-84], contributing to aging.
Although loss of RP is very useful marker of senescence in cell culture, this marker may not play a key role in age-related pathologies in the organism, because most post-mitotic cells should not be able to restart proliferation anyway. (Notable exceptions are stem, wound-healing and satellite cells). I suggest that active mTOR_in arrested cells is a crucial marker of gerogenic cells and early senescence. Gerogenic (senescent) and quiescent cells can be distinguished by the levels of phosphorylated S6 (pS6), the ribosomal protein that is phosphorylated in response to mTOR activation: high in senescent cells and low in quiescent cells. Levels of pS6 in senescent cells may remain similar to the levels of pS6 in proliferating cells. So senescent/gerogenic cells have many features of proliferating cells. Interestingly, basal (fasting) levels pS6 were elevated in old mice . Gerogenic cells could be defined as arrested cell with activated mTOR. The most physiologically relevant features are hypertrophy, hyperfunction and feedback resistance.
Growth signals during cell cycle arrest lead to an enlarged cell morphology. From theoretical perspective, hypertrophy will eventually be limited by activation of lysosomes/autophagy . This phenomenon may explain the activity of SA-beta-Gal, which is lysosomal enzyme [86-88] and active autophagy despite active mTOR [89, 90].
Due to over-stimulation, senescent cells are hyperfunctional. For example, For example, senescent fibroblasts secrete many cytokines, growth factors and proteases (the hypersecretory senescence-associated secretory phenotype or SASP), senescent osteoclasts resorb bones, smooth muscle cells contract, platelets aggregate, neutrophils generate ROS, neurons charge, endocrine cells produce hormones. Noteworthy, SASP as a marker of senescence [91-99] is an example of hyperfunction.
Hyperfunctions are associated with hypertrophy and hyperplasia. Yet, at the end, cells may fail either to function or to survive, leading to secondary atrophy. When cells fail, conditions become TOR-independent and terminal. This conceals hyperfunction as an initial cause, misleadingly presenting aging as a decline.
You might notice that an accumulation of molecular damage was never mentioned in this article. It was unneeded. Cellular aging and geroconversion is not caused by accumulation of random molecular damage. Although damage accumulates, I suggest that the organism does not live long enough to suffer from this accumulation with one special exception that illuminates the rule . (The weakness of free radical damage theory was discussed in detail [106-114]).
One definition of organismal aging is an increase in the probability of death. Gerogenic cells (due to their hyper-activity and signal-resistance) may slowly cause atherosclerosis, hypertension, insulin-resistance, obesity, cancer, neurodegeneration, age-related macular degeneration, prostate enlargement, menopause, hair loss, osteoporosis, osteoarthritis, benign tumors and skin alterations. These conditions lead to damage -- not molecular damage but organ and system damage. Examples include beta-cell failure , ovarian failure (menopause) , myocardial infarction, stroke, renal failure, broken hips, cancer metastases and so on [6, 117]. These are acute catastrophes, which cause death. I suggest that by suppressing geroconversion, gerosuppressants will prevent diseases and extend healthy life span.
The author of this manuscript has no conflict of interest to declare.
I thank Judith Campisi (Buck Institute for Age Research, Novato, CA, USA) and Manuel Serrano (Spanish National Cancer Research Center, Madrid, Spain) for reading or editing this manuscript and for excellent suggestions.
|Blagosklonny MV. Cell cycle arrest is not senescenceAging (Albany NY)Year: 201139410121297220|
|Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibitionCell CycleYear: 200652087210217012837|
|Blagosklonny MV. An anti-aging drug today: from senescence-promoting genes to anti-aging pillDrug Disc TodayYear: 200712218224|
|Blagosklonny MV. Paradoxes of agingCell CycleYear: 200762997300318156807|
|Blagosklonny MV,Hall MN. Growth and aging: a common molecular mechanismAgingYear: 2009135736220157523|
|Blagosklonny MV. mTOR-driven aging: speeding car without brakesCell CycleYear: 200984055405919923900|
|Blagosklonny MV. Cell senescence and hypermitogenic arrestEMBO RepYear: 2003435836212671679|
|Demidenko ZN,Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blockedCell CycleYear: 200873355336118948731|
|Demidenko ZN,Zubova SG,Bukreeva EI,Pospelov VA,Pospelova TV,Blagosklonny MV. Rapamycin decelerates cellular senescenceCell CycleYear: 200981888189519471117|
|Demidenko ZN,Shtutman M,Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescenceCell CycleYear: 200981896190019478560|
|Demidenko ZN,Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescenceCell CycleYear: 200981901190419471118|
|Demidenko ZN,Blagosklonny MV. Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potentialAging (Albany NY)Year: 200911008101620157583|
|Pospelova TV,Demidenk ZN,Bukreeva EI,Pospelov VA,Gudkov AV,Blagosklonny MV. Pseudo-DNA damage response in senescent cellsCell CycleYear: 200984112411819946210|
|Demidenko ZN,Korotchkina LG,Gudkov AV,Blagosklonny MV. Paradoxical suppression of cellular senescence by p53Proc Natl Acad Sci U S AYear: 20101079660966420457898|
|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 pathwayAging (Albany NY)Year: 2010234435220606252|
|Leontieva O,Gudkov A,Blagosklonny M. Weak p53 permits senescence during cell cycle arrestCell CycleYear: 201094323432721051933|
|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 senescenceAging (Albany NY)Year: 2010292493521212465|
|Chang BD,Xuan Y,Broude EV,Zhu H,Schott B,Fang J,Roninson IB. Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugsOncogeneYear: 1999184808481810490814|
|Chang BD,Broude EV,Fang J,Kalinichenko TV,Abdryashitov R,Poole JC,Roninson IB. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cellsOncogeneYear: 2000192165217010815808|
|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 butyrateCell CycleYear: 201093945395520935470|
|Leontieva OV,Demidenko ZN,Gudkov AV,Blagosklonny MV. Elimination of proliferating cells unmasks the shift from senescence to quiescence caused by rapamycinPLoS OneYear: 20116e2612622022534|
|Stambolic V,MacPherson D,Sas D,Lin Y,Snow B,Jang Y,Benchimol S,Mak TW. Regulation of PTEN transcription by p53Mol CellYear: 2001831732511545734|
|Levine AJ,Feng Z,Mak TW,You H,Jin S. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathwaysGenes DevYear: 20062026727516452501|
|Feng Z,Zhang H,Levine AJ,Jin S. The coordinate regulation of the p53 and mTOR pathways in cellsProc Natl Acad Sci U S AYear: 20051028204820915928081|
|Feng Z,Hu W,de Stanchina E,Teresky AK,Jin S,Lowe S,Levine AJ. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathwaysCancer ResYear: 2007673043305317409411|
|Feng Z,Levine AJ. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 proteinTrends Cell BiolYear: 20102042743420399660|
|Suzuki S,Tanaka T,Poyurovsky MV,Nagano H,Mayama T,Ohkubo S,Lokshin M,Hosokawa H,Nakayama T,Suzuki Y,Sugano S,Sato E,Nagao T,Yokote K,Tatsuno I,Prives C. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen speciesProc Natl Acad Sci U S AYear: 20101077461746620351271|
|Poyurovsky MV,Prives C. P53 and aging: A fresh look at an old paradigmAging (Albany NY)Year: 2010|
|Vousden KH,Ryan KM. p53 and metabolismNat Rev CancerYear: 2009969170019759539|
|Vigneron A,Vousden KH. p53, ROS and senescence in the control of agingAging (Albany NY)Year: 2010247147420729567|
|Madan E,Gogna R,Bhatt M,Pati U,Kuppusamy P,Mahdi AA. Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressorOncotargetYear: 2011294895722248668|
|Zawacka-Pankau J,Grinkevich VV,Hunten S,Nikulenkov F,Gluch A,Li H,Enge M,Kel A,Selivanova G. Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancerJ Biol ChemYear: 2011286416004161521862591|
|Long JS,Ryan KM. p53 and senescence: a little goes a long wayCell CycleYear: 2010940504051|
|Santoro R,Blandino G. p53: The pivot between cell cycle arrest and senescenceCell CycleYear: 201094262426321057199|
|Serrano M. Shifting senescence into quiescence by turning up p53Cell CycleYear: 201094256425720980826|
|Vogelstein B,Kinzler KW. Cancer genes and the pathways they controlNat MedYear: 20041078979915286780|
|Cully M,You H,Levine AJ,Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesisNat Rev CancerYear: 2006618419216453012|
|Hanahan D,Weinberg RA. Hallmarks of cancer: the next generationCellYear: 201114464667421376230|
|Hay N,Sonenberg N. Upstream and downstream of mTORGenes DevYear: 2004181926194515314020|
|Sarbassov dos D,Ali SM,Sabatini DM. Growing roles for the mTOR pathwayCurr Opin Cell BiolYear: 20051759660316226444|
|Inoki K,Corradetti MN,Guan KL. Dysregulation of the TSC-mTOR pathway in human diseaseNat GenetYear: 200537192415624019|
|Wullschleger S,Loewith R,Hall MN. TOR signaling in growth and metabolismCellYear: 200612447148416469695|
|Dann SG,Selvaraj A,Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancerTrends Mol MedYear: 20071325225917452018|
|Dazert E,Hall MN. mTOR signaling in diseaseCurr Opin Cell BiolYear: 2011|
|Zoncu R,Efeyan A,Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageingNat Rev Mol Cell BiolYear: 201012213521157483|
|Conn CS,Qian SB. mTOR signaling in protein homeostasis: less is more?Cell CycleYear: 2011101940194721555915|
|Ma XM,Blenis J. Molecular mechanisms of mTOR-mediated translational controlNat Rev Mol Cell BiolYear: 20091030731819339977|
|Serrano M,Lim AW,McCurrach ME,Beach D,Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK1ACellYear: 1997885936029054499|
|Lloyd AC,Obermuller F,Staddon S,Barth CF,McMahon M,Land H. Cooperating oncogenes converge to regulate cyclin/cdk complexesGenes DevYear: 1997116636779119230|
|Sewing A,Wiseman B,Lloyd AC,Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1Mol Cell BiolYear: 199717558855979271434|
|Woods D,Parry D,Cherwinski H,Bosch E,Lees E,McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1Mol Cell BiolYear: 199717559856119271435|
|Lin AW,Barradas M,Stone JC,van Aelst L,Serrano M,Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signalingGenes DevYear: 199812300830199765203|
|Zhu JY,Woods D,McMahon M,Bishop JM. Senescence of human fibroblasts induced by oncogenic RafGenes DevYear: 199812299730079765202|
|Kerkhoff E,Rapp UR. High-intensity Raf signals convert mitotic cell cycling into cellular growthCancer ResYear: 199858163616409563474|
|Beausejour CM,Krtolica A,Galimi F,Narita M,Lowe SW,Yaswen P,Campisi J. Reversal of human cellular senescence: roles of the p53 and p16 pathwaysEMBO JYear: 2003224212422212912919|
|Hueber AO,Evan GI. Traps to catch unwary oncogenesTrends GenetYear: 1998143643679769732|
|Blagosklonny MV. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-programCell CycleYear: 201093151315620724817|
|Stipp D. A new path to longevitySci AmYear: 2012306323922279832|
|Vellai T,Takacs-Vellai K,Zhang Y,Kovacs AL,Orosz L,Muller F. Genetics: influence of TOR kinase on lifespan in C. elegansNatureYear: 200342662014668850|
|Powers RWr,Kaeberlein M,Caldwell SD,Kennedy BK,Fields S. Extension of chronological life span in yeast by decreased TOR pathway signalingGenes DevYear: 20062017418416418483|
|Kaeberlein M,Powers RWr,Kristan K. Steffen,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 nutrientsScienceYear: 20053101193119616293764|
|Jia K,Chen D,Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life spanDevelopmentYear: 20041313897390615253933|
|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 pathwayCurr BiolYear: 20041488589015186745|
|Hansen M,Taubert S,Crawford D,Libina N,Lee SJ,Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegansAging CellYear: 200769511017266679|
|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 miceNatureYear: 200946039239619587680|
|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 spanScienceYear: 200932614014419797661|
|Moskalev AA,Shaposhnikov MV. Pharmacological Inhibition of Phosphoinositide 3 and TOR Kinases Improves Survival of Drosophila melanogasterRejuvenation ResYear: 20101324624720017609|
|Bjedov I,Toivonen JM,Kerr F,Slack C,Jacobson J,Foley A,Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogasterCell MetabYear: 201011354620074526|
|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 MiceJ Gerontol A Biol Sci Med SciYear: 20116619120120974732|
|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 miceAm J PatholYear: 20101762092209720363920|
|Anisimov VN,Zabezhinski MA,Popovich IG,Piskunova TS,Semenchenko AV,Tyndyk ML,Yurova MN,Blagosklonny MV. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female miceCell CycleYear: 2011104230423622107964|
|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 agingCell MetabYear: 20101145346520519118|
|Blagosklonny MV. Rapamycin and quasi-programmed aging: Four years laterCell CycleYear: 201091859186220436272|
|Bjedov I,Partridge L. A longer and healthier life with TOR down-regulation: genetics and drugsBiochem Soc TransYear: 20113946046521428920|
|Katewa SD,Kapahi P. Role of TOR signaling in aging and related biological processes in Drosophila melanogasterExp GerontolYear: 20114638239021130151|
|Pinkston JM,Garigan D,Hansen M,Kenyon C. Mutations that increase the life span of C. elegans inhibit tumor growthScienceYear: 200631397197516917064|
|Burtner CR,Murakami CJ,Kennedy BK,Kaeberlein M. A molecular mechanism of chronological aging in yeastCell CycleYear: 200981256127019305133|
|Leontieva OV,Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppressionAging (Albany NY)Year: 201131078109122156391|
|Blagosklonny MV. Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cellsRejuvenation ResYear: 20081180180818729812|
|Chen C,Liu Y,Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cellsSci SignalYear: 20092ra7519934433|
|Gan B,Sahin E,Jiang S,Sanchez-Aguilera A,Scott KL,Chin L,Williams DA,Kwiatkowski DJ,DePinho RA. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilizationProc Natl Acad Sci U S AYear: 2008105193841938919052232|
|Gan B,DePinho RA. mTORC1 signaling governs hematopoietic stem cell quiescenceCell CycleYear: 200981003100619270523|
|Castilho RM,Squarize CH,Chodosh LA,Williams BO,Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and agingCell Stem CellYear: 2009527928919733540|
|Wang CY,Kim HH,Hiroi Y,Sawada N,Salomone S,Benjamin LE,Walsh K,Moskowitz MA,Liao JK. Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTORSci SignalYear: 20092ra1119293429|
|Sengupta S,Peterson TR,Laplante M,Oh S,Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageingNatureYear: 20104681100110421179166|
|Kurz DJ,Decary S,Hong Y,Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cellsJ Cell SciYear: 2000113Pt 203613362211017877|
|DeJesus V,Rios I,Davis C,Chen Y,Calhoun D,Zakeri Z,Hubbard K. Induction of apoptosis in human replicative senescent fibroblastsExp Cell ResYear: 2002274929911855860|
|Hampel B,Malisan F,Niederegger H,Testi R,Jansen-Durr P. Differential regulation of apoptotic cell death in senescent human cellsExp GerontolYear: 2004391713172115582287|
|Narita M,Young AR,Arakawa S,Samarajiwa SA,Nakashima T,Yoshida S,Hong S,Berry LS,Reichelt S,Ferreira M,Tavare S,Inoki K,Shimizu S. Spatial coupling of mTOR and autophagy augments secretory phenotypesScienceYear: 201133296697021512002|
|Narita M,Young AR. Autophagy facilitates oncogene-induced senescenceAutophagyYear: 200951046104719652542|
|CoppŽ JP,Patil CK,Rodier F,Sun Y,Mu-oz DP,Goldstein J,Nelson PS,Desprez PY,Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressorPLoS BiolYear: 200862853286819053174|
|Krtolica A,Parrinello S,Lockett S,Desprez PY,Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and agingProc Natl Acad Sci U S AYear: 200198120721207711593017|
|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 secretionNat Cell BiolYear: 20091197397919597488|
|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 secretionJ Cell SciYear: 2011124688121118958|
|Komarova EA,Krivokrysenko V,Wang K,Neznanov N,Chernov MV,Komarov PG,Brennan ML,Golovkina TV,Rokhlin OW,Kuprash DV,Nedospasov SA,Hazen SL,Feinstein E,Gudkov AV. p53 is a suppressor of inflammatory response in miceFaseb JYear: 2005191030103215811878|
|Campisi J,Andersen JK,Kapahi P,Melov S. Cellular senescence: a link between cancer and age-related degenerative disease?Semin Cancer BiolYear: 20112135435921925603|
|Chien Y,Scuoppo C,Wang X,Fang X,Balgley B,Bolden JE,Premsrirut P,Luo W,Chicas A,Lee CS,Kogan SC,Lowe SW. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivityGenes DevYear: 2011252125213621979375|
|Pani G. From growing to secreting: new roles for mTOR in aging cellsCell CycleYear: 2011102450245321720215|
|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 medicineCell CycleYear: 2011102059206321654190|
|Tremblay F,Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cellsJ Biol ChemYear: 2001276380523806011498541|
|Tremblay F,Krebs M,Dombrowski L,Brehm A,Bernroider E,Roth E,Nowotny P,WaldhŠusl W,Marette A,Roden M. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availabilityDiabetesYear: 2005542674268416123357|
|Um SH,Frigerio F,Watanabe M,Picard F,Joaquin M,Sticker M,Fumagalli S,Allegrini PR,Kozma SC,Auwerx J,Thomas G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivityNatureYear: 200443120020515306821|
|Shah OJ,Wang Z,Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficienciesCurr BiolYear: 2004141650165615380067|
|Zhang H,Bajraszewski N,Wu E,Wang H,Moseman AP,Dabora SL,Griffin JD,Kwiatkowski DJ. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTORJ Clin InvestYear: 200711773073817290308|
|Blagosklonny MV. Molecular damage in cancer: an argument for mTOR-driven agingAging (Albany NY)Year: 201131130114122246147|
|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 elegansGenes DevYear: 2008223236324119056880|
|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 damageFree Radic Biol MedYear: 2011511575158221839827|
|Gems D,Doonan R. Antioxidant defense and aging in C. elegans: Is the oxidative damage theory of aging wrong?Cell CycleYear: 200981681168719411855|
|Lapointe J,Hekimi S. When a theory of aging ages badlyCell Mol Life SciYear: 2009671819730800|
|Van Raamsdonk JM,Meng Y,Camp D,Yang W,Jia X,Benard C,Hekimi S. Decreased energy metabolism extends life span in Caenorhabditis elegans without reducing oxidative damageGeneticsYear: 201018555957120382831|
|Speakman JR,Selman C. The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespanBioessaysYear: 20113325525921290398|
|Ristow M,Schmeisser S. Extending life span by increasing oxidative stressFree Radic Biol MedYear: 20115132733621619928|
|Blagosklonny MV. Aging: ROS or TORCell CycleYear: 200873344335418971624|
|Blagosklonny MV. Hormesis does not make sense except in the light of TOR-driven agingAging (Albany NY)Year: 201131051106222166724|
|Blagosklonny MV. Rapamycin-induced glucose intolerance: Hunger or starvation diabetesCell CycleYear: 2011104217422422157190|
|Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspectivesAging (Albany NY)Year: 2010226527320519781|
|Blagosklonny MV. Aging-suppressants: cellular senescence (hyperactivation) and its pharmacologic decelerationCell CycleYear: 200981883188719448395|
Keywords: senescence, geroconversion, gerosuppressants, rapamycin, mTOR.
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