Ageing and Cancer: Breaking the Dont Put All Eggs in One basket and Natural Self-organisation, and their Potential Reprogramming viaModulation of Mi-2/NuRD, mTOR Kinase and Metabolism

Yue Zhang^*

Research Center, CHUM, Notre Dame Hospital, Montreal, Canada

Keywords: Mi-2/NuRD, mTOR, Cell metabolism, Ageing, Cancer reprogramming

Introduction

Ageing and cancer share some common biology [1]. Genomewide examinations show that overlapping genes between them can be classified into functional categories and pathways, e.g., cell cycle regulation, metabolic processes, DNA damage response, apoptosis, the P53 signalling and chemokine signalling pathway, and the immune/inflammatory response [2]. Currently, both the cause-effects “mutation” theory of cancer and the free radical theory of ageing are under question [3-5]. The former has difficulty explaining how cancers arise, and why conventional chemotherapy succeeds or fails [6]. Similarly, the idea that the macromolecular damage from toxic reactive oxygen species is the cause of ageing now faces challenges from evidences regarding the rival mTOR-centric model [3,7,8]. Oxidative stress has some signatures in cardiovascular ageing [9], but clinical trials with various combinations of antioxidants have failed to obtain the expected results [10]. Thus, novel concepts regarding the mechanisms of ageing and cancer are welcome [11]. Cancer was proposed to be viewed as a programmed, evolutionarily conserved lifeform, encouraging different thinking around its treatment [12].

As other experts previously proposed, I consider, that carcinogenesis is the speciation based on ageing host with maternal effects and beyond the host in figure 1. Breaking the rule of “Don’t put all eggs in one basket”, particularly the “sharing” interaction and diseased multicellularity, may cause ageing and cancer; the reprogramming of ageing and cancer is feasible via modulation of master regulators in ageing and cancer, such as Mi-2/NuRD, mTOR kinase and cell metabolism.

Figure 1: “Don’t put all eggs in one basket” in life forms. Life forms (particularly multicellular one) experience normal development embryo and young stages via soma-germline distinction, sufficient asymmetry cell division to reach adult and have fertilization to produce sufficient progeny. The reduction of fertility requirement and rise of mutations are along with the ensuing aging process. At the same time, the release of restraints of Mi-2/NuRD, dysregulation of mTOR signalling and related cell metabolism eventually make organisms to initiate a new possible speciation and thus generate a host-dependent quasi-species like cancer and even a rare hostindependent new life species, i.e., contagious cancer in devil and dog. Hereby, we assumed that cancer is in general obeying rule of “Don’t put all eggs in one basket” with its cancer stem cell and differentiated tumour cells.
AD: Alzheimer’s disease.
OA: Osteoarthritis.
HD: Huntington’s disease
PD: Parkinson’s disease.

Are ageing and cancer inevitable and/or reversible?

Mature cells can be reprogrammed to become pluripotent–the discovery for which Dr. Yamanaka and Dr. Gurdon won the 2012 Nobel Prize in medicine. The Waddington’s epigenetic landscape hypothesis has gained popularity in induced Pluripotent Stem Cells (iPSc) [13,14] and the Self-organisation Map (SOM) program embedded cell attractors studies in cancer research, for example tumor heterogeneity [15,16]. Reprogramming could be significant for our understanding carcinogenesis and ageing, and it theoretically suggests that reversals of ageing/cancer might be possible.

Weissmann’s germ-soma distinction hypothesis [17] includes the ageing-fertility trade-off concept [18-20] along with the proposal of “Nothing makes sense in biology except in the light of evolution” [21]. We postulate that life systems are spatiotemporally struggling for survival and broadly-defined immortality. Spatially, systems may try to occupy as much room as possible by producing more progeny and more cell growth and proliferation; temporally, they strive for as long a lifespan as possible. “Don’t put all eggs in one basket” means diversifying the options. While pursuing the long-term survival or immortality, the gonad or germline cells can emit the signal, an organism could thus need sacrifice its cell growth, cell proliferation or lifespan, this eventually makes ageing and cancer inevitable [22,23].

Two cell attractor theories have been recently updated: the GRNSOM cell attractors theory [24,25] with an emphasis on the high dimensional nonlinear systems and of self-organized behavior; on the contrast, the “metabolism-first” Independent Attractors (IA) theory [26,27] which emphasizes interactions between active gene products (mainly proteins) and independence of the genomic sequence are descended from a pre-cellular state from which life originated. As IA model is based on the cell as an open system, the attractor acts as the interface between the cell and environment. Environmental stressors can serve to trigger attractor and therefore phenotypic transitions. Based on these, and taking into account various levels of self-organization, such as individuals, population, we have described the CRS-related GRN-SOM cell attractor hypothesis to understand diseased multicellularity-induced carcinogenesis [28-31]. Clinically, epigenetic reprogramming may reverse some cancers through targeting the components of Mi-2/NuRD with histone deacetylase (HDAC) 1 or Dnmt1/2 inhibitors [32].

~3.8 billion years ago (BYA), there would come earliest chemical evidence of life. Many principles of chemistry and physics including self organisation system (SO) (i.e., complex systems are capable of adapting themselves completely at each instant to the results of their analysis of external conditions and previous performance) can be applied on life systems, which evolved from chemical and physical world. I argue that, similarly, cancer comes from its host, owning many traits of host, but likely as intermediate or new specie since we may consider cancer as a “jump from the sinking ship (host)” as a different life form [33,34] (Figure 1). The ageing of the host is here surmised to provide the resources for and the possibility of carcinogenesis [35] and thus speciation. If it could be the case, we can definitely find out the different systems governing the host and cancer and targeting the cancer and leave the host healthy [36]. Besides, the cancer “avalanche” can be triggered by a minor event with little significance of its own. However, due to ageing and environmental stresses, at one time point, a few cells reside in a sub-critical state and ripe for collapse and restructuring, so paradigm shift. After the catastrophe, the system (somatic cells) moves itself into a cancer “stem-like” states, such new sub-critical state with proliferation descends to cancerous state (Figure 1). The sequential multi-stable states happen essentially among a random process, and thus exist on the edge of chaos. The studies of self-organized oscillations and chaos have already provided some novel insights [37-39]. This notion is compatible with the GRN-SOM cancer attractors theory [24,40] and the CRS-linked GRN-SOM cell attractor hypothesis [31,41]. Alongside ageing/cancer, the whole life system could be arbitrarily defined as “survival “with its progeny’s continuity (Figure 1). However, as a life system is one dissipative system [27,42], an interruption in external energy ( i.e. the price) could logically delay system failures during ageing/cancer processes. According to Huang, “Nothing in evolution makes sense except in the light of (systems) biology,” implying the whole system rather than single gene is being critical for complex diseases [43]. Through systematic epigenetic modulation of the genome GRN, human cell and tissue reprogramming engineering could deal with the inevitability of ageing/cancer [44].

The origin of modern life and the rise of mitochondria

There are many different angles from which to look into the basis for reversing ageing/cancer. Although the details much remain to explore, Mi-2/NRD likely orchestrates asymmetry cell division, “sharing” interaction, chaotic and oscillatory gene expressions, sex, stemness, tumor heterogeneity, ageing damage heterogeneity [45-47]. The factors, which are under the regulation of Mi-2/NuRD or other CRS, ensure the robustness of multi-cellularity among the cell communities [41].

Alongside epigenesis, such as Mi-2/NuRD linked-processes, the mitochondria also contribute to ageing/cancer. Many factors associated with mitochondria are longevity/ageing genes, particularly mTOR (or TOR) [11,48,49]. Since the IA has a “metabolism-first” notion embedded [26] and emphasizes the significance of environmental cues and proteins, we extend our CRS-GRN cell attractor concept to the interplay of Mi-2/NuRD with mTOR and cell metabolism in that mTOR is an environmental sensor, and a master regulator for the translation process and also for recycling and refolding the protein aggregates through autophagy. Besides, the metabolism itself can probably get involved the chemical network, information flow and interaction. The cause-effects “mutation theory” says nothing about the metabolic derangements common to virtually all cancers [6]. Here, we consider a focus on their “sharing” interaction (rather than keeping all in their own hands) with fittest comparative advantages during major evolutionary transitions.

First, the origin of modern life might have evolved via “sharing” [50] ~3 billion years ago (BYA). That is, a group of archaic life elements such as archaic cells, which individually differed in their comparative advantages and capacity for replication and metabolism [51] may have collaborated and fought to survive better than single units in the harsh environment. They may have cross-fed not only genetically but also metabolically without competition-possibly a global mega-organism [52]. It is not individuals but the community of those that “share” that survives and evolves. It was the communal ancestor of modern life [50]. Coincided with the appearance of oxygen in the atmosphere, around 2.9 BYA [52], the mega-organism has broken apart as three. In modern cells, the fine system need for such functional “sharing” network, possibly including Mi-2/NuRD [31]. Interestingly, the MEP- 1, an interactor of Mi-2/NuRD, controls gene expression via the 3’ untranslated region (3 UTR) in the worm Caenorhabditis elegans [53], which may be similar to archaic microRNA repression [54] in predated RNA system in “proto-cells” in “RNA world” theory.

Another result of “sharing” is multi-cellularity, characterized by cell labor division and communication in an extra-cellular matrix ~0.9 BYA [27]. Some “altruistic” cells undergo programmed cell death to benefit the whole multi-cellular organism [31,55]. Further, mitochondria function as power stations for the cell, which is vital for evolutionary innovations and nucleus development. Endosymbiosis generated the mitochondria and restructured the distribution of DNA in relation to the bioenergetic membranes. This leads to a vast expansion in the number of genes expressed. This quantum leap in genomic capacity relied on mitochondrial power and paved the way to multi-cellular life [56]. Disruption of the “sharing” interaction, we could say, less chance keep the beneficial traits to cells, and in modern cells and organisms, loss of multicellularity may lead to cancer, and epigenetic therapeutic reprogramming needs to reverse this abnormality [31,57,58]. We stop here and keep from descending to further hypothesis. Loss of communication through the extra-cellular matrix or a link between LMNA and Mi-2/NuRD could cause premature ageing [59] and cancer [60,61]. While we treated cultured primary osteoarthritis chondrocyte cells with rapamycin, an inhibitor of mTOR signalling, cells dramatically reduced touching branches; so mTOR signalling could promote cell-cell communications and/ or cell growth alone (Zhang Y, unpublished observation). I speculate that the return to normal sharing connection may help the reversals of ageing and cancer. It is tempting to test whether a block of component of Mi-2/NuRD, mTOR signalling or metabolism in germline alone can affect the aging and to see what will happen with interruptions in somatic cells alone and/or in combination [62]. I am wondering if any surprise could be there. Keep in mind, some genes are not easy to manage since many mitochondria related genes have maternal effects and aging-related features, they will otherwise provide significant insights to ageing and cancer, which is out of scope of this article.

Mi-2/NuRD, mTOR and metabolism in ageing and cancer

Paradoxically, it is exciting to demonstrate that mutations in metabolic enzymes may be carcinogenic while the somatic “mutation” theory is under question. Mutations in several TriCarboxylic Acid (TCA) cycle enzymes are linked to human cancer: Succinate Dehydrogenase (SDH) is linked to hereditary paragangliomas [63], Fumarate Hydratase (FH) is linked to skin leiomyomas and renal cancer [64] and isocitrate dehydrogenase (IDH) 2 and IDH1 are linked to gliomas and acute myeloid leukemia [65-67], driving R-2-hydroxyglutarate synthesis [68]. The conditional knock-in mice for IDH1 mutations show more reprogrammed early hematopoietic progenitors [66,67]. Epigenetic programming via the Tet2 DNA methylase is involved in their activity [68]. The metabolic products of mutant SDH, FH and IDHs can inhibit the activity of a class of α-ketoglutarate-dependent enzymes and may lead to alterations in DNA methylation linked to the histone demethylases. Further, mutant SDH, FH, and IDH1 may induce pseudohypoxia [69,70]. MBD3/NuRD may regulate many target genes in embryonic stem cells, and MBD3 association with its in vivo targets requires 5-methylcytosine hydroxylase Tet1 and MBD3 to bind preferentially to hydroxymethylated DNA relative to methylated DNA. We may postulate that induced pseudohypoxia could reverse cells to “archaic” cell attractors, similar to single cell state [23,31,71,72].

Fuel signals from cell metabolism are crucial for the activities of the Mi-2/NuRDs in normal health, ageing and cancer. For instance, the energy of ATP is essential for remodeling the Mi-2/NuRD, and is generally provided through the glucose-pyruvate axis and the TCA cycle. Cell metabolism also ensures that cells have a reservoir for acetyl- CoA, which is important for balancing Histone Acetyl Transferase (HAT) and HDAC [73]. Moreover, the oncogenic activation of Myc promotes glutamine utilization. Furthermore, c-myc regulate glucose metabolism and stimulate the Warburg effect [74]. The LMNA1-linked NuRD may be a key modulator of these ageing-associated chromatin defects [75]. Other than LMNA1, in many contexts, Mi-2/NuRD will be transiently recruited by different TFs [46,76].

In C. elegans, fumaryl acetoacetate hydrolase, which catalyzes tyrosine metabolism and causes fumarate to cycle into the TCA cycle, is required for a normal lifespan [77] and has a role in protein aggregation in connection with heat-shock factor 1 (HSF1), the master regulator of the heat-shock response for environmental stress cues [78]. The enhanced HSF1 expression was associated with poor cancer prognosis in human through several processes, including metabolism and translation. HSP genes are integral to this program, e.g. uniquely regulated hsp70 via HSF1/NuRD [79]. Basically, HSF1 rewires the transcriptome in tumorigenesis. Furthermore, our assays have related HSF1 regulation of the promoter activity of one of the important ATP transporters, the multi-drug resistance gene 1 (mdr1) (Zhang Y, Supplementary Figure 1), expanding its activity to drug resistance. Moreover, over-expression of HSF1 can promote longevity in C. elegans [80]. Further, HSF1 is essential for protecting cells from the proteindamaging stress associated with misfolded proteins, partly through autophagy [81]. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter of Hsp70 by maintaining HSF1 in a deacetylated DNA-binding competent state [82]. Besides, mTOR may phosphotate HSF1 [83]. Lastly, those genes are also longevity genes, and those mitochondrial genes have maternal effects.

In normal cells, glutamine is used for the synthesis of amino acids and nitrogen for de novo nucleotide formation. Cancer cells, in contrast, secrete glutamine-derived nitrogen as waste [74]. The cellular uptake of L-glutamine activates mTOR. Certain tumor cell lines do not need it. L-glutamine flux regulates mTOR translation and autophagy [84]. Glutamine is a key factor that influences the axis of mTOR-linked autophagy. Autophagy generally promotes longevity in C. elegans [85] and mammalian cancer survival [86]. A network of 3M can be seen in figure 2.

Figure 2: Networks and reprogramming of 3M (Mi-2/NuRD, mTOR and metabolism) in ageing and cancer. A. The network of 3M in ageing and cancer. In addition, those in purple highlight the fields with some of author’s publications. B. The concerted activities of Mi-2/NuRD, mTOR and metabolism in cellular reprogramming.

Concerted activities of Mi-2/NuRD and mTOR in reprogramming

Mi-2/NuRD can be recruited by many transcription factors for reprogramming [46,76] in different contexts. For example, Zfp281 mediates Nanog auto-repression through recruitment of the Mi-2/ NuRD and inhibits somatic cell reprogramming [87]. It is well known that HDAC inhibitors can significantly enhance the efficiency of cellular reprogramming [88]. Vitamin C has been shown to enhance reprogramming significantly [89]. Additionally, treatment with an inhibitor of DNA methylation, such as 5-aza-2’-deoxycytidine, increases the efficiency of iPS reprogramming [90]. The major activities of mTOR include control of cell growth, cell proliferation and autophagy-related pathways. Dual targeting of mTORC1/C2 complexes enhances HDAC inhibitor-mediated anti-tumor efficacy in primary Hepato Cellular Carcinoma (HCC) in vitro and in vivo [91]. Some well-characterized mTOR inhibitors and autophagy activators (e.g. PP242, rapamycin and resveratrol) notably improve the speed and efficiency of reprogramming of iPSCs [92]. Cao et al. [93] have recently confirmed that the mTOR inhibitor rapamycin can efficiently prevent the accelerated geroconversion of human cells that is induced by progerin LMNA accumulation [94]. Similarly, [95] shows that mice deficient in LMNA had enhanced mTOR complex 1 signalling specifically in tissues linked to pathology. The reversal of elevated mTORC1 signalling by rapamycin enhances survival and improved the defective autophagic-mediated degradation in LMNA (-/-) mice. The use of rapamycin-like mTORC1 inhibitors (e.g., temsirolimus) activates autophagy and ameliorates cardiomyopathy caused by lamin A mutation [96].

Because mTOR signalling is up-regulated in HCCs, one recent study [97] showed that the two mTOR inhibitors (RAD001 and BEZ235) had synergistic effects on the inhibition of the proliferation of HCC cells. A large number of genes reverted to normal liver tissue expression in mice treated with both drugs. Also, the down-regulation of autophagy genes is seen in tumors in comparison with in the normal liver. On the other hand, LMNA mutations can affect the adipocyte differentiation pathway acting upstream to SREBP1 and PPARg [98,99]. In fact, cells harboring mutations in these genes accumulate an immature form of lamin A that can stably interact with a transcription factor SREBP1 involved in adipocyte differentiation [100]. Oltipraz regulation of the AMPK-S6K1 pathway also affects Liver X Receptor (LXR) activity and LXRα-induced lipogenesis, leading to the identification of AMPK and S6K1 as attractive targets for intervention of steatosis in the liver [101]. Activation of AMPK following oltipraz treatment resulted in decreased phosphorylation and inactivation of S6K1, a subsequent decrease in phosphorylation of LXRα by S6K1[101], decreased binding of ligand-bound LXRα to the LXRE upstream of sterol regulatory element-binding protein-1 (SREBP-1), and ultimate inactivation of SREBP-1 expression. DAF-12, one homolog of liver x receptor in the nematode C. elegans is one critical factor in ageing and regulates a connected network of genes to ensure robust developmental decisions [102]. The reduction in SREBP-1 expression contributes to reduced lipogenesis, fat accumulation, and hepatic steatosis [101]. The result is consistent with the previous observation that the induction of acetyl- CoA carboxylase (ACC) and fatty acid synthase (FAS) in the fatty liver patients is associated with SREBP-1 [103,104]. Hepatic fibrosis and/or carcinogenesis can be caused by a gain-of-toxic function with accumulation of the mutant Alpha1-Antitrypsin Z (ATZ) variant inside cells. The autophagy enhancing drug Carbamazepine (CBZ) decreased the hepatic load of ATZ and hepatic fibrosis in a mouse model of AT deficiency-associated liver disease [105].

Inhibition of Mi-2/NuRD for HDAC or knock-down of RBBPP48/46 facilitate direct conversion, for instance, the direct conversion of C. elegans germ cells into specific neuron types [106]. Broadly to say, the metabolism chemical network is also one kind of neuron network. Interestingly, LIN-1/ETS, an interactor of Mi-2/NuRD in C. elegans [107] has its role in Ras and Hox cancer-related signalling pathways. In mammals, three ETS TFs- reprogrammed amniotic fluid cells could treat vascular diseases. Finally, the histone demethylases Jhdm1a/1b are key effectors of somatic cell reprogramming downstream of vitamin C [89]. In general, we hypothesize that, alongside the dysregulated Mi-2/NuRD, mTOR signalling and cell metabolism, the sequential multi-stable states toward cancerous states happen essentially among a random process, the diverse reprogramming causes the tumour heterogeneity due to accidentally forced expression of TFs and thus those resulting reprogramming or the like.

Reversals of aging and cancer, and application of GRN-SOM cell attractors in cancer

Reversal cases of aging and cancer appear. Just name a few: for example, implanting young stem cells has rejuvenated ageing stem cells in the treatment of progeria, which is a disease that causes abnormally accelerated ageing and a deficiency of Lamina A [31,41,59,108]. The researchers injected stem-like or progenitor cells into progeriatric mice. Some transplant recipients had robust health and a lifespan up to 2-3-fold of the controls [109]. Another case using mice has shown that modifying telomerase activity can rejuvenate the tissue and organs [110]. Recently, a stem cell-based approach to ageing-related cartilage damage repair has been published [111].

Another significance of GRN-SOM attractor’s theory is to make prognosis. Gene Expression Dynamic Inspector (GEDI) patterns may be promisingly developed for identifying the onset and progression of cancer and ageing [24,25,41,48,112] (Figure 3). I made systematic analysis of cell-division mechanism with GEDI, strikingly, they have a consistently similar pattern when deficiency in either component in this mechanism (Zhang Y, in preparation). Therefore, I speculate, like weather forecasts, simple genome-wide expression patterns like GEDIs can be predictive, for example, predicting that the cancer “weather” will be “stormy”, “cloudy” or “sunny”. They are like impressionist paintings of a landscape, giving an overall image when viewed as a whole rather than capturing the fine details of paint chemicals. For sure, what is largely unknown to us is the genius from the painters and the beyond. However, further studies need to refine and identify the distinct patterns for different stages for clinical use. For some cancers, this might even involve running a PCR array with miRNAs and using the resulting data as a proxy for GRN, since the medusa-like pattern of GRN has been revealed in cancer subtypes, with particular miRNAs as dominators [113].

Figure 3: Reprogramming of cancer cells in mTOR-regulated epigenetic landscape. Representative GEDI maps of stem-like attractors, progenitor/intermediate attractors and differentiation attractors. B. (Left panel) An illustration of hierarchy within an epigenetic landscape for a single transition pathway from stem cell (top) to final cell type (bottom). (Right panel) Deregulation and modification of the epigenetic landscape as a consequence of defective mTOR caused dysregulated epigenetic landscape. However, the Mi-2/NuRD and metabolism may join the activities of mTOR.

Conclusion

References

1. Finkel T, Serrano M, Blasco MA (2007) The common biology of cancer and ageing. Nature 448: 767-774.
2. Wang X (2012) Microarray analysis of ageing-related signatures and their expression in tumors based on a computational biology approach. Genomics, proteomics & bioinformatics 10: 136-141.
3. Lapointe J, Hekimi S (2010) When a theory of aging ages badly. Cellular and molecular life sciences. Cell Mol Life Sci 67: 1-8.
4. Parr E (2012) The default state of the cell: quiescence or proliferation? Bioessays 34: 36-37.
5. Moore A (2012) Cancer: escape route from a "doomed" host? Bioessays 34: 2.
6. Vincent MD (2011) Cancer: beyond speciation. Advances in Cancer Research 112: 283-350.
7. Hekimi S, Lapointe J, Wen Y (2011) Taking a "good" look at free radicals in the aging process. Trends Cell Biol 21: 569-576.
8. Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010) Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci 65: 1028-1041.
9. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, et al. (2008) Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA 300: 2123-2133.
10. Ming XF, Montani JP, Yang Z (2012) Perspectives of Targeting mTORC1-S6K1 in Cardiovascular Aging. Frontiers in physiology 3:5.
11. Vincent M (2012) Cancer: a de-repression of a default survival program common to all cells?: a life-history perspective on the nature of cancer. Bioessays 34: 72-82.
12. Yamanaka S (2009) Elite and stochastic models for induced pluripotent stem cell generation. Nature 460: 49-52.
13. Huang S (2009) Reprogramming cell fates: reconciling rarity with robustness. Bioessays 31: 546-560.
14. Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12: 323-334.
15. Huang S (2012) The molecular and mathematical basis of Waddington's epigenetic landscape: a framework for post-Darwinian biology? BioEssays 34: 149-157.
16. Hughes SE, Evason K, Xiong C, Kornfeld K (2007) Genetic and pharmacological factors that influence reproductive aging in nematodes. PLoS genetics 3: e25.
17. Zhang Y, Calderwood, SK, Moriguchi H (2011) Visualization of Archaic Cancer Attractors and Chromatin Regulators Connecting to Ageing, Robustness and Cellular Reprogramming. Nova Publishers.
18. Lane N (2011) Mitonuclear match: optimizing fitness and fertility over generations drives ageing within generations. Bioessays 33: 860-869.
19. Dobzhansky T (1964) Biology, Molecular and Organismic. Am Zool 4: 443-452.
20. Huang S (2011) On the intrinsic inevitability of cancer: from foetal to fatal attraction. Semin Cancer Biol 21: 183-199.
21. Moore A (2012) TOR: The ancient link between cancer and ageing? Could ageing and cancer be unified by TOR via the 'compromise' struck between soma and germline at the dawn of multicellular life? Bioessays 34: 443-444.
22. Huang S, Ernberg I, Kauffman S (2009) Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective. Semin Cell Devl Biol 20: 869-876.
23. Huang S, Eichler G, Bar-Yam Y, Ingber DE (2005) Cell fates as high-dimensional attractor states of a complex gene regulatory network. Phys Rev Lett 94: 128701.
24. Baverstock K (2011) A comparison of two cell regulatory models entailing high dimensional attractors representing phenotype. Prog Biophys Mol Biol 106: 443-449.
25. Baverstock K (2012) Life as physics and chemistry: A system view of biology. Prog Biophys Mol Biol.
26. Sugimoto K, Gordon SP, Meyerowitz EM (2011) Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation? Trends Cell Biol 21: 212-218.
27. Moriguchi H, Chung RT, Mihara M, Sato C (2010) The generation of human induced pluripotent stem (iPS) cells from liver progenitor cells by only small molecules and the risk for malignant transformations of the cells. ACSC 2: 5-9.
28. Davies PCW (2012) The epigenome and top-down causation. Interface focus 2: 42-48.
29. Zhang Y, Moriguchi H (2011) Chromatin remodeling system, cancer stem-like attractors, and cellular reprogramming. Cellular and molecular life sciences 68: 3557-3571.
30. Tsai HC, Baylin SB (2011) Cancer epigenetics: linking basic biology to clinical medicine. Cell research 21: 502-517.
31. Duesberg P, Mandrioli D, McCormack A, Nicholson JM (2011) Is carcinogenesis a form of speciation? Cell Cycle 10: 2100-2114.
32. Vincent MD (2010) The animal within: carcinogenesis and the clonal evolution of cancer cells are speciation events sensu stricto. Evolution International journal of organic evolution 64: 1173-1183.
33. Gladyshev VN (2012) On the cause of aging and control of lifespan: heterogeneity leads to inevitable damage accumulation, causing aging; control of damage composition and rate of accumulation define lifespan. Bioessays 34: 925-929.
34. Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, et al. (2012) The requirement for cyclin d function in tumor maintenance. Cancer cell 22: 438-451.
35. Chang HH, Hemberg M, Barahona M, Ingber DE, Huang S (2008) Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453: 544-547.
36. Brock A, Chang H, Huang S (2009) Non-genetic heterogeneity--a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet 10: 336-342 .
37. Furusawa C, Kaneko K (2012) A dynamical-systems view of stem cell biology. Science 338: 215-217.
38. Huang S (2012) Tumor progression: Chance and necessity in Darwinian and Lamarckian somatic (mutationless) evolution. Prog Biophys Mol Biol 110: 69-86.
39. Zhang Y (2011) New Concepts of Germline Gene-reactivated Cancer. Human Genet Embryol.
40. Huang S (2010) Cell lineage determination in state space: a systems view brings flexibility to dogmatic canonical rules. PLoS biol 8: 1000380.
41. Wigle D, Jurisica I (2007) Cancer as a system failure. Cancer informatics 5: 10-18 .
42. Mali P, Cheng L (2012) Concise review: Human cell engineering: cellular reprogramming and genome editing. Stem cells 30: 75-81.
43. Lai AY, Wade PA (2011) Cancer biology and NuRD: a multifaceted chromatin remodelling complex. Nat Rev Cancer 11: 588-596.
44. Zhang Y, Yinghua L (2011) The expanding Mi-2/NuRD complexes: a schematic glance. Proteomics insights 3: 79-109.
45. Unhavaithaya Y, Shin TH, Miliaras N, Lee J, Oyama T, et al. (2002) MEP-1 and a homolog of the NURD complex component Mi-2 act together to maintain germline-soma distinctions in C. elegans. Cell 111: 991-1002.
46. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, et al. (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426: 620.
47. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, et al. (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460: 392-395.
48. Woese C (1998) The universal ancestor. Proceedings of the National Academy of Sciences of the United States of America 95: 6854-6859.
49. Caetano-Anolles G, Caetano-Anolles D (2003) An evolutionarily structured universe of protein architecture. Genome research 13: 1563-1571.
50. Kim KM, Caetano-Anolles G (2011) The proteomic complexity and rise of the primordial ancestor of diversified life. BMC evolutionary biology 11: 140.
51. Belfiore M, Mathies LD, Pugnale P, Moulder G, Barstead R, et al. (2002) The MEP-1 zinc-finger protein acts with MOG DEAH box proteins to control gene expression via the fem-3 3' untranslated region in Caenorhabditis elegans. Rna 8: 725-739.
52. Ruvkun G (2006) Clarifications on miRNA and cancer. Science 311: 36-37.
53. Miller SM (2010) Volvox, Chlamydomonas, and the evolution of multicellularity. Nature Education 3: 65.
54. Lane N, Martin W (2010) The energetics of genome complexity. Nature 467: 929-934.
55. Wang S, Deepak K, Lo PK, Chandrashekaran V, Duan X, et al. (2012) Enrichment and Selective Targeting of Cancer Stem Cells in Colorectal Cancer Cell Lines. Human Genet Embryol 1: S2-006 .
56. Zhang Y (2012) New Frontiers of Aging Reversal and Aging-Related Diseases Reprogramming. Med Advancements in Genet Eng 1: e101.
57. Meshorer E, Gruenbaum Y (2009) NURD keeps chromatin young. Nat Cell Biol 11: 1176-1177.
58. Karotki AV, Baverstock K (2012) What mechanisms/processes underlie radiation-induced genomic instability? Cell Mol Life Sci 69: 3351-3360.
59. Huang S, Ingber DE (2005) Cell tension, matrix mechanics, and cancer development. Cancer Cell 8: 175-176.
60. Arantes-Oliveira N, Berman JR, Kenyon C (2003) Healthy animals with extreme longevity. Science 302: 611.
61. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, et al. (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287: 848-851.
62. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, et al. (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30: 406-410.
63. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, et al. (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 465: 966.
64. Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, et al. (2012) D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 26: 2038-2049.
65. Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, et al. (2012) IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488: 656-659.
66. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18: 553-567.
67. Haigis MC, Deng CX, Finley LW, Kim HS, Gius D (2012) SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res 72: 2468-2472.
68. Bayley JP, Devilee P (2010) Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Curr Opin Genet Dev 20: 324-329.
69. Davies PC, Lineweaver CH (2011) Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Phys Biol 8: 015001.
70. Davies PCW, Demetrius L, Tuszynski JA (2011) Cancer as a dynamical phase transition. T Bio Medical Mod 8: 30.
71. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11-20.
72. Dang CV (2009) MYC, microRNAs and glutamine addiction in cancers. Cell Cycle 8: 3243-3245.
73. Pegoraro G, Kubben N, Wickert U, Gohler H, Hoffmann K, et al. (2009) Ageing-related chromatin defects through loss of the NURD complex. Nat Cell Biol 11: 1261-1267.
74. Ng PM, Lufkin T (2011) Embryonic stem cells: protein interaction networks. Biomol Concepts. 2: 13-25.
75. Fisher AL, Page KE, Lithgow GJ, Nash L (2008) The Caenorhabditis elegans K10C2.4 gene encodes a member of the fumarylacetoacetate hydrolase family: a Caenorhabditis elegans model of type I tyrosinemia. J Biol Chem 283: 9127-9135.
76. Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, et al. (2012) HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers. Cell 150: 549-562.
77. Khaleque MA, Bharti A, Gong J, Gray PJ, Sachdev V, et al. (2008) Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1. Oncogene 27:1886-1893.
78. Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300(5622): 1142-1145.
79. Zhang Y, Calderwood SK (2011) Autophagy, protein aggregation and hyperthermia: a mini-review. International journal of hyperthermia: the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 27: 409-414.
80. Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI (2009) Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323: 1063-1066.
81. Chou SD, Prince T, Gong J, Calderwood SK (2012) mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS one 7: e39679.
82. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, et al. (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136: 521-534.
83. Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, et al. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301:1387-1391 .
84. Yang S, Wang X, Contino G, Liesa M, Sahin E, et al. (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25: 717-29.
85. Fidalgo M, Faiola F, Pereira CF, Ding J, Saunders A, et al. (2012) Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming. Proc Natl Acad Sci U S A 109:16202-16207.
86. Kretsovali A, Hadjimichael C, Charmpilas N (2012) Histone deacetylase inhibitors in cell pluripotency, differentiation, and reprogramming. Stem cells Int 2012:184154.
87. Wang T, Chen K, Zeng X, Yang J, Wu Y, et al. (2011) The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9: 575-587.
88. 90. Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, et al. (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454: 49-55.
89. Shao H, Gao C, Tang H, Zhang H, Roberts LR, Hylander BL, et al. (2012) Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol 56: 176-183.
90. Menendez JA, Vellon L, Oliveras-Ferraros C, Cufi S, Vazquez-Martin A (2011) mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle 10: 3658-3577.
91. Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, et al. (2011) Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med 3: 89ra58.
92. Graziotto JJ, Cao K, Collins FS, Krainc D (2012) Rapamycin activates autophagy in Hutchinson-Gilford progeria syndrome: implications for normal aging and age-dependent neurodegenerative disorders. Autophagy 8: 147-51.
93. Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, et al. (2012) Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C-Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival. Sci Transl Med 4: 144ra03.
94. Choi JC, Muchir A, Wu W, Iwata S, Homma S, et al. (2012) Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin a/c gene mutation. Sci Transl Med 4: 144ra02.
95. Thomas HE, Mercer CA, Carnevalli LS, Park J, Andersen JB, et al. (2012) mTOR Inhibitors Synergize on Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma. Sci Transl Med 4: 139ra84.
96. Agarwal AK, Garg A (2006) Genetic basis of lipodystrophies and management of metabolic complications. Annu Rev Med 57: 297-311.
97. Capanni C, Mattioli E, Columbaro M, Lucarelli E, Parnaik VK, et al. (2005) Altered pre-lamin A processing is a common mechanism leading to lipodystrophy. Hum Mol Genet 14:1489-1502.
98. Maraldi NM, Capanni C, Lattanzi G, Camozzi D, Facchini A, et al. (2008) SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies. Adv Enzyme Regul 48:209-223.
99. Hwahng SH, Ki SH, Bae EJ, Kim HE, Kim SG (2004) Role of adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway in repression of liver X receptor-alpha-dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones. Hepatology 49: 1913-1925.
100. Hochbaum D, Zhang Y, Stuckenholz C, Labhart P, Alexiadis V, et al. (2011) DAF-12 regulates a connected network of genes to ensure robust developmental decisions. PLoS Genet 7: e1002179.
101. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, et al. (2007) The nuclear receptor LXR is a glucose sensor. Nature 445: 219-223.
102. Higuchi N, Kato M, Shundo Y, Tajiri H, Tanaka M, et al. (2008) Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol Res 38: 1122-1129.
103. Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, et al. (2010) An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329: 229-232.
104. Tursun B, Patel T, Kratsios P, Hobert O ( 2011) Direct conversion of C. elegans germ cells into specific neuron types. Science 331: 304-308.
105. Guerry F, Marti CO, Zhang Y, Moroni PS, Jaquiery E, et al. (2007) The Mi-2 nucleosome-remodeling protein LET-418 is targeted via LIN-1/ETS to the promoter of lin-39/Hox during vulval development in C. elegans. Dev Biol 306: 469-479.
106. Zhang Y (2011) Biology of the Mi-2/NuRD Complex in SLAC (Stemness, Longevity/Ageing, and Cancer). Gene Regul Syst Bio 5: 1-26.
107. Lavasani M, Robinson AR, Lu A, Song M, Feduska JM, et al. (2012) Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nature Com 3: 608.
108. Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, et al. (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469: 102-106.
109. Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, et al. (2012) A Stem Cell-Based Approach to Cartilage Repair. Science 336: 717-721.
110. Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, et al. (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470: 359-365.
111. Guo Y, Feng Y, Trivedi NS, Huang S (2011) Medusa structure of the gene regulatory network: dominance of transcription factors in cancer subtype classification. Experimental biology and medicine 236: 628-636.