Research Article: Aging, Metabolism, and Cancer Development: from Peto’s Paradox to the Warburg Effect

Date Published: October 1, 2017

Publisher: JKL International LLC

Author(s): Tia R. Tidwell, Kjetil Søreide, Hanne R. Hagland.


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.

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Aging is defined as a physiological decline that leads to the loss of major organ function, ultimately leading to death. The question remains as to what is the cause of aging as, from an evolutionary perspective, an organism would benefit most from extended reproductive ability and lifespan. A possible answer is that aging is but a side effect of life progression and not a programmed occurrence. Supporting this is the fact that rates of aging are not fixed; for example, lower body temperatures tend to result in extended lifespan [4], possibly due to metabolic adaptations. Considering the environmental effects on rates of aging, it has become increasingly relevant in aging research to differentiate between physiological age and chronological age [5]. It is possible for two humans of identical or similar years of life, or even same genetic background as with monozygotic twins, to have very divergent states of health and lifespans [6]. The last decade of scientific research has dramatically improved our understanding of the aging process and that it is closely regulated by key metabolic proteins such as mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and insulin/insulin growth factor (IGF) [7, 8], which are associated with age-related metabolic syndrome [9] and common to those found dysregulated in cancer [10]. The long-term causative effect of aging and how this relates to increased cancer risk therefore seems to be linked through metabolic control.

Mitochondria are remnants of an aerobic prokaryote that brought the selective advantage of using respiration for higher yield energy production to a cell dependent on rudimentary substrate fermentation. The endosymbiotic event that occurred some two billion years ago is thought to only have happened once to give rise to all advanced lifeforms known today.

Life is a physical system that maintains structure and avoids decay by feeding on negative entropy through metabolism [35]. Changes in metabolites and substrate availability are reflected in the energy output of the whole cell system in the form of the ATP and adenosine monophosphate (AMP) ratio, or other reducing equivalents such as nicotinamide adenine dinucleotide (NAD+) vs NADH, which are detected by energy sensing mechanisms. Maintaining a constant ATP level within the cell is crucial, to the extent that all cells maintain a ∆G’ATP of approximately -56 kJ/mol [36], and any disruption of this energy balance will compromise cell function and viability [37].

Aging and cancer involve many of the same cellular pathways in their progression, suggesting they are closely related in pathology. However, instead of following this lead, there is an ongoing pursuit to define cancers based on largely their mutational patterns. Meanwhile, the heterogenous gene expression pattern found in nearly all cancers begs the question of how critical each individual nuclear gene mutation is in the progression of the disease. Several theories exist to explain carcinogenesis, with the most prevalent being the mutation-centric theory stating that somatic nuclear mutations acquired over time eventually leads to a cancerous transition. Yet, this theory alone is unable to explain why a discrepancy exists between high cancer incidence in small, short-lived animals (i.e. few cells and less mutational events) compared to a low cancer incidence in larger, long-lived animals (i.e. many cells and more mutational events) (visualized in Fig. 1). This observation was named “Peto’s paradox” after the epidemiologist Sir Richard Peto [2]. It highlights the discrepancy that if cancers are initiated by a series of somatic mutations acquired over time and cell number, then organisms with larger body size (more cells) and longer lifespans (more cell divisions) should have a cancer risk that is orders of magnitude greater than organisms of smaller size and shorter lifespan. Thus, in theory, humans should have a higher cancer incidence than mice. However, this is not confirmed in nature, as mice have a higher risk of cancer in their relatively short lifespan (about 4 years) [59], when compared to humans. The mutation-centric theory is established on a belief that there is a linear increase in mutations during cell division as we age. This is in contradiction to data that shows that a substantial portion of somatic mutations (up to 50%) accumulate early in life before full body maturation [1] and seem to slow when stem cells convert from body building to body maintenance [60]. A further challenge with mutagenesis models is the assumption that any mutation can affect cellular fitness, which is not supported by evolutionary theory. From an evolutionary perspective, only mutations that enhance cellular fitness above others in relation to the growth environment will be advantageous [61]. Thus, both mutations and the tissue microenvironment play a role in cell growth. Early-acquired mutations may stay latent and not provide a growth advantage to cells until the tissue microenvironment changes in aging organisms, further enhancing the relationship between aging and cancer risk. This was recently shown by using a computational stochastic model integrating real data on age dependent dynamics of hematopoietic stem cell division. The model demonstrated that previously acquired mutations only became advantageous in an aging microenvironment according to non-cell-autonomous mechanisms [11]. Identification of the most prevalent mutations in cancer and their clear link to metabolic regulations [62] therefore confers that they may be providing the cells with a selective advantage for growth in a changing microenvironment.

Direct signals from mitochondria in the form of substrates, ROS, and other intermediates can affect cellular physiology via genetic and epigenetic mechanisms, and form the foundation for cancer development. The interplay between these metabolic changes, aging, and cancer development is illustrated in Figure 2. In support of the age-associated risk of cancer, 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 OXPHOS as the dominant energy generator of the cell. Substrate-level phosphorylation can compensate gradually for minor OXPHOS damages accumulated over time. Consequently, expansion of mtDNA mutations affecting ATP production can happen gradually [63] or by asymmetric segregation of cellular content during cell division [12]. This compensatory effect by the continued adaptation by substrate-level phosphorylation for energy production (i.e. 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, such as lactate from glycolysis, and succinate, alanine, and aspartate from glutamine or amino acid fermentation [64], that can regulate gene expression epigenetically.

The influence of metabolism on overall life span is still controversial. However, there must be an evolutionary trade-off to lower metabolic rates in larger animals to avoid cellular harm and increase life span. A possible answer is “somatic maintenance” [74], where the investment in gene repair will increase or decrease to maximize reproductive success in a changing environment. Therefore, lifespans of animals have evolved to maintain fitness and invest in somatic maintenance until reproduction is most likely to be achieved. This explains why most wild animals do not develop cancer, as they do not survive beyond reproductive age in the wild. Humans are the only species that have developed technological advances and designed their living environment to extend their lifespan far beyond reproductive age, thus exposing themselves to a variety of diseases associated with old age. This also holds true for animals kept in captivity, which live beyond their normal lifespan in the wild, and do develop cancer [75, 76].

Deregulation and loss of homeostasis is a driver of damage and dysfunction frequently encountered in aging and cancer, affecting all functions of the cell. Normal systemic operation requires the proper flexibility and functioning of gene and protein expression to respond adequately to intracellular and extracellular signals. This flexibility is made possible by epigenetic control over how the primary DNA sequence is expressed. Besides changes in bioenergetics and creation of cellular building blocks, metabolism can affect function through control of gene expression. Much of the enzymatic maintenance of epigenetic patterns occurs through information provided by metabolic substrates and metabolites, signaling when to grow and trigger transcription based on nutrient availability. The crucial role they hold in the support of cancer growth has been proven in elegant experiments in which enucleated normal cells were fused with nuclei from tumor cells to form cybrids. These cybrid cells did not form malignant cells, whereas tumor cells infused with normal cytoplasm had their tumorigenic potential in mice reduced from 92% to 51% [98]. The important feature of their study was that the non-transformed and transformed cells all originated from a cloned progenitor cell with a common nuclear and cytoplasmic background. When the experiments were conducted, the authors did not identify the nature of the observed effects, but with experimental results from a more recent study focusing on the role of mitochondria in this situation [99], it is highly likely that substrates and intermediates of metabolism could drive this effect via epigenetic regulation. These experiments and the increasing data showing that most of the common mutations found in cancers are related to changes in metabolism [62], demonstrate that there is more than just gene mutations driving cancer and aging. Compounds directly essential to the function of epigenetic enzymes are produced during metabolism, such as S-adenosylmethionine (SAM) and alpha-ketoglutarate (α-KG), nicotinamide adenine dinucleotide (NAD) and acetyl coenzyme-A (acetyl-CoA), and uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). ATP is also vital for proper function but not rate limiting for these enzymatic reactions due to its relative abundance [100].

Cellular dysfunction and stress are recurring themes presented in this review for their likely role in accelerating aging and induction of cancer. This is largely due to increased metabolic activity, abnormal metabolism through diet or genetic/epigenetic modification, and inhibition of healthy cellular maintenance. These conditions are all capable of improvement through lifestyles changes.

Further investigation into the differentiating genetic or metabolic factors between species is a key to understanding the source of neoplasms and the mechanisms nature has adapted to fight them. With the explanations given here and even the outliers of Peto’s paradox, a need to explain cancer formation using only the multi-stage mutational model lessens. The refitting of the model with respect to cell size and volume, differential tissue behavior, and the presence of long-living organisms with no cancer at all could have a unifying relationship within cell metabolism. Larger cells, less proliferating tissues, and long-living organisms all have slow metabolism and consequently slower cell growth. Upon analysis, carcinogenesis may be driven by a forced change in metabolism that is not tolerated by an organism or tissue and its adapted mechanisms.




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