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Aging and disease    2017, Vol. 8 Issue (3) : 314-333     DOI: 10.14336/AD.2016.1101
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Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases
Cao Yiwei, Wang Rui-Hong*
Faculty of Health Science, University of Macau, Macau, China
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Accumulating epidemiological studies have implicated a strong link between age associated metabolic diseases and cancer, though direct and irrefutable evidence is missing. In this review, we discuss the connection between Warburg effects and tumorigenesis, as well as adaptive responses to environment such as circadian rhythms on molecular pathways involved in metabolism. We also review the central role of the sirtuin family of proteins in physiological modulation of cellular processes and age-associated metabolic diseases. We also provide a macroscopic view of how the circadian rhythm affects metabolism and may be involved in cell metabolism reprogramming and cancer pathogenesis. The aberrations in metabolism and the circadian system may lead to age-associated diseases directly or through intermediates. These intermediates may be either mutated or reprogrammed, thus becoming responsible for chromatin modification and oncogene transcription. Integration of circadian rhythm and metabolic reprogramming in the holistic understanding of metabolic diseases and cancer may provide additional insights into human diseases.

Keywords Age-associated diseases      circadian rhythm      metabolic reprogramming      sirtuin      tumorigenesis      Warburg effect     
Corresponding Authors: Wang Rui-Hong   
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These authors contributed equally to the work.

Issue Date: 01 June 2017
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Cao Yiwei
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Cao Yiwei,Wang Rui-Hong. Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases[J]. Aging and disease, 2017, 8(3): 314-333.
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Metabolic diseaseCancer riskCountry/PopulationReference
HyperglycemiaRenal cell and liver cancer in men; Endometrial and pancreatic cancers in women are increasedEurope; Taiwan[161, 162]
DiabetesColon, liver, pancreatic, endometrial and kidney, esophagus, rectum (F), stomach (F), thyroid (F), brain (F), lung (F), bladder, biliary tract and ovary cancer risks are increasedSweden; Netherlands; Australia; African Americans; Native Hawaiians, Japanese Americans; Taiwan, Italy; USA; Japan; Hong Kong; Netherlands; Canada[161-175]
Metabolic syndromeColorectal neoplasm; Prostate cancer; liver cancer risks are increasedTaiwan; Canada; England[177-179]
ObesityEsophageal, thyroid, liver, biliary tract, colorectal, ovary, gastric, breast, prostate, lung cancer risks are increasedUSA; Europe; Japan; African American; Australia; Italy[180-185]
Metformin useReduced breast, prostate, colorectal cancer risk and mortality, increased survival with gastric cancerCanada; USA; Denmark; Taiwan; Korea[186-191]
Table 1  The recent epidemiological studies relating metabolic disease and cancer risk.
Figure 1.  The metabolic cycle gates cell cycle entry

On the left is the metabolic cycle with two phases, glycolysis and respiration; different colors of circular icon represent either suppressors (blue) or oncogenes in tumorigenesis (orange); on the right is the cell cycle, in which the regulatory relationship of mediators between these two cycles have been illustrated.

Fig 2.  Enhanced anabolic PI3K/Akt pathway in a cancer cell

PI3K/Akt/mTOR pathways are involved in 1. Glycolysis; 2. Cell growth; 3. Cell cycle; 4. Cell survival.

Figure 3.  Regulation of PKM2 and its function in the nucleus.
Lysine demethylase (LSD1)Overexpressed in hepatocellular carcinomaGlycolytic activity; Decreases mitochondrial metabolism genesMethylate histone H3 at Lysine 4 in the promoter region[192]
miR-122 microRNABreast cancer-secretedRegulating the glycolytic enzyme PKM; Glucose uptakeRegulates glucose consumption in distant organs, including brain and lungs, and increases the incidence of metastasis[92]
miR-290 miRNAsPromotes pluripotency in PSCsUp-regulates glycolytic enzymes Pkm2 and Ldha, stimulates glycolysismiR-290 targets Mbd2, a reader for methylated CpGs, unregulated Myc[193]
MnSOD-deficient miceSkin carcinogenesisIncreased aerobic glycolysisIncreased uncoupling proteins (UCPs); p53[194]
Fructose-1,6-bisphosphatase (FBP1)FBP1 was suppressed in kidney tumoursFBP1 controls cell proliferation, glycolysis and the pentose phosphate pathwayInhibits nuclear HIF function via direct interaction with the HIF inhibitory domain[73]
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (pFKFB3)Colon carcinomaGlycolytic enzyme
Induced by insulin
Regulates autophagy; increases cyclin-dependent kinase (Cdk)-1, Cdc25C, and cyclin D3; decreased the expression of the cell cycle inhibitor p27[142]
[195] [76] [77]
Type I transmembrane protein (MUC)Pancreatic adenocarcinomaEnhances glycolytic activity; enhances in vivo glucose uptakeMUC1 facilitates and stabilizes recruitment of HIF-1α and p300 on glycolytic gene promoters in a hypoxia-dependent manner[74]
ENO1 (alpha-enolase)Pancreatic cancerGlycolytic enzymeAlternative splicing form of ENO1, transcriptionally represses MYC[75]
Table 2  Non-metabolic functions of glycolytic factors
Figure 4.  The transcriptional and post-translational loop of circadian systems
Figure 5.  Proposed mechanism relating metabolic disease and cancer
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