Aging, Metabolism, and Cancer Development: from Peto's Paradox to the Warburg Effect

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 interindividual 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 cofactors, 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.