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Abstract
Oncometabolites are defined as small-molecule components (or enantiomers) of normal metabolism whose accumulation causes signaling dysregulation to establish a milieu that initiates carcinogenesis. In a similar manner, we propose the term “gerometabolites” to refer to small-molecule components of normal metabolism whose depletion causes signaling dysregulation to establish a milieu that drives aging. In an investigation of the pathogenic activities of the currently recognized oncometabolites R(-)-2-hydroxyglutarate (2-HG), fumarate, and succinate, which accumulate due to mutations in isocitrate dehydrogenases (IDH), fumarate hydratase (FH), and succinate dehydrogenase (SDH), respectively, we illustrate the fact that metabolic pseudohypoxia, the accumulation of hypoxia-inducible factor (HIFα) under normoxic conditions, and the subsequent Warburg-like reprogramming that shifts glucose metabolism from the oxidative pathway to aerobic glycolysis are the same mechanisms through which the decline of the “gerometabolite” nicotinamide adenine dinucleotide (NAD)+ reversibly disrupts nuclear–mitochondrial communication and contributes to the decline in mitochondrial function with age. From an evolutionary perspective, it is reasonable to view NAD+-driven mitochondrial homeostasis as a conserved response to changes in energy supplies and oxygen levels. Similarly, the natural ability of 2-HG to significantly alter epigenetics might reflect an evolutionarily ancient role of certain metabolites to signal for elevated glutamine/glutamate metabolism and/or oxygen deficiency. However, when chronically altered, these responses become conserved causes of aging and cancer. Because HIFα-driven pseudohypoxia might drive the overproduction of 2-HG, the intriguing possibility exists that the decline of gerometabolites such as NAD+ could promote the chronic accumulation of oncometabolites in normal cells during aging. If the sole activation of a Warburg-like metabolic reprogramming in normal tissues might be able to significantly increase the endogenous production of bona fide etiological determinants in cancer, such as oncometabolites, this undesirable trade-off between mitochondrial dysfunction and activation of oncometabolites production might then pave the way for the epigenetic initiation of carcinogenesis in a strictly metabolic-dependent manner. Perhaps it is time to definitely adopt the view that aging and aging diseases including cancer are governed by a pivotal regulatory role of metabolic reprogramming in cell fate decisions.
