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Aging and Disease    2017, Vol. 8 Issue (5) : 662-676     DOI: 10.14336/AD.2017.0713
Review |
Aging, Metabolism, and Cancer Development: from Peto’s Paradox to the Warburg Effect
Tia R. Tidwell1,2,Kjetil Søreide2,3,4,Hanne R. Hagland1,2,*
1Department of Mathematics and Natural Sciences, Centre for Organelle Research, University of Stavanger, Stavanger, Norway
2Gastrointestinal Translational Research Unit, Molecular Laboratory, Hillevaåg, Stavanger University Hospital, Stavanger, Norway
3Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
4Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Medical advances made over the last century have increased our lifespan, but age-related diseases are a fundamental health burden worldwide. Aging is therefore a major risk factor for cardiovascular disease, cancer, diabetes, obesity, and neurodegenerative diseases, all increasing in prevalence. However, huge inter-individual variations in aging and disease risk exist, which cannot be explained by chronological age, but rather physiological age decline initiated even at young age due to lifestyle. At the heart of this lies the metabolic system and how this is regulated in each individual. Metabolic turnover of food to energy leads to accumulation of co-factors, byproducts, and certain proteins, which all influence gene expression through epigenetic regulation. How these epigenetic markers accumulate over time is now being investigated as the possible link between aging and many diseases, such as cancer. The relationship between metabolism and cancer was described as early as the late 1950s by Dr. Otto Warburg, before the identification of DNA and much earlier than our knowledge of epigenetics. However, when the stepwise gene mutation theory of cancer was presented, Warburg’s theories garnered little attention. Only in the last decade, with epigenetic discoveries, have Warburg’s data on the metabolic shift in cancers been brought back to life. The stepwise gene mutation theory fails to explain why large animals with more cells, do not have a greater cancer incidence than humans, known as Peto’s paradox. The resurgence of research into the Warburg effect has given us insight to what may explain Peto’s paradox. In this review, we discuss these connections and how age-related changes in metabolism are tightly linked to cancer development, which is further affected by lifestyle choices modulating the risk of aging and cancer through epigenetic control.

Keywords Cancer      aging      mitochondria      metabolism      Warburg effect      Peto’s paradox      epigenetics     
Corresponding Authors: Hanne R. Hagland   
Just Accepted Date: 14 July 2017   Issue Date: 27 September 2017
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Tia R. Tidwell
Kjetil Søreide
Hanne R. Hagland
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Tia R. Tidwell,Kjetil Søreide,Hanne R. Hagland. Aging, Metabolism, and Cancer Development: from Peto’s Paradox to the Warburg Effect[J]. A&D, 2017, 8(5): 662-676.
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Figure 1.  As animals age, there is an accumulation of dysfunction

This affects the mitochondria to a great extent and a higher metabolic rate provides further amplification, reflected by the slope in this line. Once the dysfunction passes a threshold and the cell can no longer compensate, a cancerous transition may occur. The difference in resting metabolic rate (RMR) and their relative cancer development can be seen between large and small animals, with large animals having a low RMR and late or nonexistent cancer development. While RMR may not increase in larger individuals within species, metabolic stress accumulates at a faster rate and the individual can reach the dysfunctional threshold at an earlier timepoint, as exemplified here by the obese human figure having a shifted cancer risk.

Figure 2.  Tumors rarely occur following acute injury to cellular respiration and considerable time is required for non-oxidative energy metabolism (i.e. glycolysis, TCA cycle via substrate-level phosphorylation) to replace oxidative phosphorylation (OXPHOS) as the dominant energy generator of the cell

As minor OXPHOS damages accumulated over time, the cell uses substrate-level phosphorylation to compensate gradually for the energy debt. This compensatory effect, by increasing the uptake of glucose and glutamine to be broken down for ATP production, is a well-known hallmark of cancer called “the Warburg effect”. Cells that undergo a Warburg transition and switch their metabolism to glycolysis and glutaminolysis produce increased levels of substrates that can have many downstream effects. Only glucose metabolism is highlighted here, with the solid arrows denoting the increased reliance on glycolysis and production of lactate, and dotted arrows denoting decreased activity in the remainder of the pathway. This translates to lowered production of acetyl-coenzyme-A (acetyl-CoA) from pyruvate, activity of the TCA cycle, and production of precursors necessary to carry out OXPHOS. Also, mutations of key TCA cycle enzymes commonly found in cancer are shown, such as isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH), as well as substrates accumulated due to their alterations. Abbreviations: ECM, extracellular matrix; IGF, insulin growth factor; SAM, s-adenosylmethionine; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; ATP, adenosine triphosphate; AMPK, AMP-activated protein kinase.

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