title: Gerometabolites: the pseudohypoxic aging side of cancer oncometabolites.
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.
authors: Metabolism & Cancer Group; Translational Research Laboratory; Catalan Institute of Oncology; Girona, Spain; Molecular Oncology Group; Girona Biomedical Research Institute (IDIBGI); Girona, Spain.
authors: Javier A
authors: JA
authors: Menendez
authors: Computational & Mathematical Biology Research Group; Centre de Recerca Matemàtica (CRM); Barcelona, Spain.
authors: Tomás
authors: T
authors: Alarcón
authors: Unitat de Recerca Biomèdica (URB-CRB); Institut d'Investigació Sanitaria Pere i Virgili (IISPV); Universitat Rovira i Virgili; Reus, Spain.
authors: Jorge
authors: J
authors: Joven
mesh_terms: D000375:Aging / Q000378:metabolism*; D015687:Cell Hypoxia; D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic; D005649:Fumarate Hydratase / Q000235:genetics; D005650:Fumarates / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics; D013386:Succinates / Q000378:metabolism*
chemical_list: D005650:Fumarates; D005977:Glutarates; D051793:Hypoxia-Inducible Factor 1; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D013386:Succinates; D009243:NAD; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; D013385:Succinate Dehydrogenase; D005649:Fumarate Hydratase
keywords: HIF; Myc; Warburg effect; aging; cancer; geroncogenesis; metabolism; oncometabolites; pseudohypoxia