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Aging and Disease    2014, Vol. 5 Issue (4) : 263-273     DOI: 10.14336/AD.2014.0500263
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mTOR Signaling from Cellular Senescence to Organismal Aging
Shaohua Xu2, Ying Cai1, Yuehua Wei1, 2, *
1No.3 People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
2Gladstone Institute of Cardiovascular Disease, University of California San Francisco, San Francisco, CA94102, USA
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Abstract  

The TOR (target of rapamycin) pathway has been convincingly shown to promote aging in various model organisms. In mice, inhibiting mTOR (mammalian TOR) by rapamycin treatment later in life can significantly extend lifespan and mitigate multiple age-related diseases. However, the underlying mechanisms are poorly understood. Cellular senescence is strongly correlated to organismal aging therefore providing an attractive model to examine the mechanisms by which mTOR inhibition contributes to longevity and delaying the onset of related diseases. In this review, we examine the connections between mTOR and cellular senescence and discuss how understanding cellular senescence on the aspect of mTOR signaling may help to fully appreciate its role in the organismal aging. We also highlight the opposing roles of senescence in various human diseases and discuss the caveats in interpreting the emerging experimental data.

Keywords senescence      aging      mTOR      rapamycin      age-related disease     
Corresponding Authors: Yuehua Wei   
Issue Date: 04 November 2014
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Shaohua Xu
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Shaohua Xu,Ying Cai,Yuehua Wei. mTOR Signaling from Cellular Senescence to Organismal Aging[J]. Aging and Disease, 2014, 5(4): 263-273.
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http://www.aginganddisease.org/EN/10.14336/AD.2014.0500263     OR     http://www.aginganddisease.org/EN/Y2014/V5/I4/263
Figure 1.  An overview of cellular senescence. (A) A variety of stimuli, such as oncogene expression, PTEN loss of function, DNA damage and telomere attrition can lead to cellular senescence. The establishment of cellular senescence requires the activation of at least one of the two largely independent pathways involving the well-known tumor suppressors p53/p21 and p16/pRb. (B) Senescent cells secrete a plethora of cytokines, chemokines, growth factors and proteases, termed SASP, which is thought to contribute to the organismal aging. (C) SA-β-gal activity is a marker for cellular senescence. Images show the SA-β-gal staining pattern of pre-senescent and replicative senescent primary human fibroblast (IMR90).
ModelDescriptionSenescence inducing methodsEffect of rapamycinRef.
HT1080-p21Human fibrasarcomaIPTG-induced p21 expressionReduce SA-β-gal activity[30]
HT1080-p21Human fibrasarcomaIPTG-induced p21 expressionRe-enter cell cycle when inducing agents are removed. Remain large size[50]
HT1080-p16Human fibrasarcomaIPTG-induced p16 expressionPreserve the proliferative capacity[50]
ERasRodent fibroblastSodium butyrate-induced p21Marginal decrease in SA-β-gal, no change in morphology, yet prevent the loss of proliferative potential[50]
WI-38Human primary lung fibroblastDNA damage by DoxorubicinPartially prevented senescent phenotype[30]
ARPE-19human retinal pigment epithelial cellH2O2Reduce SA-β-gal activity, did not change flat morphology, prevent the permanent loss of proliferation[50]
BJHuman skin fibroblastsContinuous passageSuppress IL-8 and p21 but not SA-β-gal activity and flattened morphology in senescent cells[52]
BJHuman skin fibroblastsContinuous passageTreatment of pre-senescent cells delay SA-β-gal, no change in cell morphology[52]
BJHuman skin fibroblastsRAS overexpressionHigher proliferation rate and less SA-β-gal[52]
MEFsMouse embryonic cellsContinuous passagePartially suppress senescent marker. Cells adapt to rapmycin, not useful for long term treatment.[53]
REFsRat embryonic cellsContinuous passageReverse SA-β-gal and DNA damage marker H2AX and 53BP1[53]
Wnt1 transgenic miceDoxycycline-inducible K5rtTA/tet-Wnt1 micePersistent activation of Wnt1Partially suppressed disappearance of the epidermal stem cell compartment and subsequent hair loss[54]
Table 1.  Targeting mTOR to delay cellular senescence
Figure 2.  Emerging role of mTOR in cellular senescence and organismal aging. (A) mTOR integrates different signaling pathways to cellular senescence. mTOR regulates cellular senescence through modulation of mitochondrial metabolism, autophagy and protein translation. (B) mTOR homologs in many model organisms promote organismal aging through poorly characterized mechanisms.
Figure 3.  Opposing roles of cellular senescence in disease. Cellular senescence on the one hand can cause chronic inflammation, decrease stem cell renewal ability and promote progerial syndrome, but on the other hand serves to inhibit cancerous transformation and enhance tissue repair. The role of cellular senescence in disease, especially age-related disease awaits further investigation.
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