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Aging and Disease    2015, Vol. 6 Issue (1) : 56-75     DOI: 10.14336/AD.2014.0209
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The Intricate Interplay between Mechanisms Underlying Aging and Cancer
Amanda Piano, Vladimir I. Titorenko
Department of Biology, Concordia University, Montreal, Quebec, Canada
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Abstract  

Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.

Keywords aging      cancer      cell cycle      cellular senescence      cell death      cellular signaling     
Corresponding Authors: Vladimir I. Titorenko   
Online First Date: 23 November 2014    Issue Date: 02 February 2015
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Amanda Piano
Vladimir I. Titorenko
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Amanda Piano,Vladimir I. Titorenko. The Intricate Interplay between Mechanisms Underlying Aging and Cancer[J]. Aging and Disease, 2015, 6(1): 56-75.
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http://www.aginganddisease.org/EN/10.14336/AD.2014.0209     OR     http://www.aginganddisease.org/EN/Y2015/V6/I1/56
Figure 1.  The numerous events characteristic of a state of cellular senescence are organized into a multistep cellular senescence program. The advancement of this program through spatially, temporally and mechanistically separable steps is orchestrated by complex circuits integrating several signaling pathways and networks. For additional details, see text. Abbreviations: ASF1a/HIRA, anti-silencing function 1a/Histone Repressor A; ATM/CHK2, the DNA damage response kinases ataxia telangiectasia mutated/checkpoint kinase 2; Bcl-2 (B-cell lymphoma 2), an anti-apoptotic protein; Cdc25, a member of the Rho family of small GTPases; C/EBPβ, a transcriptional factor; CREB, cAMP responsive element binding protein; Csp-3, caspase-3; HMGA, High Mobility Group A proteins; HP1γ, Heterochromatin Protein 1 γ; H3, histone H3; IL-1α, an α isoform of the multifunctional cytokine IL-1; IL-1αR, a juxtaposed receptor of IL-1α; IRAK1, a protein kinase; miR, microRNA; Mn-SOD, manganese superoxide dismutase; mTORC1, mammalian (or mechanistic) target of rapamycin complex 1; NFκB, a transcriptional factor; PKC-δ, a δ isozyme of the protein kinase C; PML, promyelocytic leukemia; PP2A, protein phosphatase 2A; Rac1, a member of the Rho family of small GTPases; ROS, reactive oxygen species; SASP, a senescence-associated secretory phenotype; SAHF, senescence-associated heterochromatic foci; SMS, senescence-messaging secretome.
Figure 2.  Pleiotropic effects of a multistep cellular senescence program on aging and cancer. Multiple mechanisms underlying the advancement of the cellular senescence program through temporally and spatially separable steps impose antagonistically pleiotropic effects on aging and cancer. For additional details, see text. Abbreviations: CXCR-2/IL-8RB, a receptor of the pro-inflammatory cytokine IL-8; IGFBP-7, an insulin-like growth factor binding protein type 7; IGFBP-7, PAI-1, a plasminogen activator inhibitor type 1; SASP, a senescence-associated secretory phenotype; SMS, senescence-messaging secretome.
Affected aspect of cell morphology and functionFeature of senescent cellsObservedCan serve as a hallmark/diagnostic biomarker of senescent cellsReferences
in vitro*in vivo**
Cell size and shapeCell enlargement and acquisition of a flat or spindle-like shape22, 139, 140
Cell cycleCell cycle arrest - which is an essentially irreversible in vivo, but in culture can be reversed by certain genetic manipulations12, 9799, 139,141, 142
LysosomesIncreased size and number of lysosomes140, 143, 145, 146
Many lysosomes become non-functional due to accumulation of lipofuscin-like indigestible molecular aggregates140, 144, 146
Senescence-associated β-galactosidase (SA β-Gal)Elevated activity of SA β-Gal detectable at pH 6 - likely due to a senescence-associated increase in the level of lysosomal β-Gal protein, which exhibits the highest activity at pH 4, but if becomes abundant can also be detected at suboptimal pH 6140, 147, 149151
MitochondriaExcessive proliferation of mitochondria that are elongated, highly interconnected to form an extensive network, and aggregated140, 152, 154, 157
Depolarization of the mitochondrial inner membrane, mitochondrial dysfunction, reduced ATP synthesis in mitochondria, and accumulation of ROS (that are produced mostly in mitochondria)140, 153, 157161
DNA damage fociPermanent establishment of nuclear foci marked with a set of the DNA damage response (DDR) proteins; these stable foci are known as DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), DNA double-strands breaks (DSBs), senescence-associated DNA-damage foci (SDF) and telomere dysfunction-induced foci (TIF)4, 12, 22, 25, 111, 140, 162168
Nuclear bodiesFormation of promyelocytic leukemia nuclear bodies (PML NBs) also known as PML oncogenic domains (PODs); these sub-nuclear organelles concentrate numerous DNA-binding proteins that initiate heterochromatin establishment103, 124, 169171
Heterochrom atic DNA fociPML NBs-instigated formation of senescence-associated heterochromatic foci (SAHF); these foci are enriched in methylated Lys 9 of histone H3 (a heterochromatin marker) and concentrate a set of heterochromatin-associated proteins4, 12, 172177
SASP/SMSSpecific changes in pattern of gene expression at transcriptional level - which result in secretion of a distinct set of interleukins, inflammatory cytokines, chemokines, growth factors, insoluble protein components of the extracellular matrix, extracellular proteases, as well as such non-protein soluble compounds as ROS, nitric oxide and prostaglandin E24, 11, 22, 28, 31, 32, 165
Table 1.  Features of senescent cells that can serve as hallmarks of a state of cellular senescence and/or can be used as diagnostic biomarkers of senescent cells existing in organismal tissues
Affected aspect of cell morphology and functionFeature of senescent cellsObservedCan serve as a hallmark/diagnostic biomarker of senescent cellsReferences
in vitro*in vivo**
Cell morphologyCell multi-nucleation and extensive vacuolization??22, 263
Cell motility and adhesionReduced cell motility; enhanced focal adhesion of cells to the extracellular matrix??140, 264, 265
Cell-cell contactReduced efficacy of cell-cell contacts??86, 140
GlycogenAccumulation of glycogen granules, inactivating phosphorylation of the glycogen synthesis inhibitor GSK3, and activating dephosphorylation of glycogen synthase?140, 143, 266, 267
CytoskeletonReduced cellular level of actin; nuclear accumulation of G-actin, jointly with an active phosphorylated form of the actin depolymerizing factor cofilin?140, 268270
Elevated cellular level of the intermediate filament protein vimentin; elongation, condensation and linearization of the intermediate filaments containing vimentin?140, 271273
Increased number of microtubule organizing center, which nucleates individual microtubules??140, 274
LysosomesEnhanced expression of numerous genes encoding lysosomal enzymes??140, 143, 147, 148
MitochondriaReduced efficacy of mitochondrial fission and the resulting shift of the balance between mitochondrial fission and fusion towards fusion??140, 147, 155, 156
AutophagyReduced efficacy of chaperone-mediated autophagy and non-selective macroautophagy, including mitophagy??114, 115, 125, 275279
NucleusAberrant shape of the nucleus; reduced levels of the lamin A-associated protein LAP2 and several other nuclear proteins?140, 166, 280, 281
ChromosomesChromosomal instability exhibited as polyploidy or aneuploidy?263, 282288
Senescence-associated microRNAs (SA-miRNAs)Expression of numerous SA-miRNAs is altered (either elevated or reduced) in cultured cells undergoing senescence caused by cell exposure to various triggers of either replicative or premature (stress-induced) mode of cellular senescence; many of these SA-miRNAs play essential roles in regulating senescence of cultured cells by targeting the signaling circuitry characteristic of the cellular senescence program; at least one of these SA-miRNAs, miR-22, can induce cellular senescence in vivo??112, 113, 289296
ApoptosisResistance to apoptotic cell death elicited by certain pro-apoptotic stimuli??12, 196202
Table 2.  Features of senescent cells that may or may not serve as hallmarks of a state of cellular senescence and may or may not be used as diagnostic biomarkers of senescent cells existing in organismal tissues
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