title: The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat.
abstract: Naked mole-rats (Heterocephalus glaber) (NMRs) are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs) have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs), and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A), shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process.
authors.affiliation: The Division of Endocrinology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, United States of America.|Department of Chemistry and Bioscience, Aalborg University, Frederik Bajers Vej 7H, DK-9220 Aalborg Oe, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Brohus
authors.affiliation: University of Rochester, Department of Biology, 434 Hutchinson Hall, River Campus, Rochester, New York, 14627, United States of America.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, United Kingdom.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Faulkes
authors.affiliation: Department of Chemistry and Bioscience, Aalborg University, Frederik Bajers Vej 7H, DK-9220 Aalborg Oe, Denmark.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Overgaard
authors.affiliation: The Division of Endocrinology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, United States of America.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D005260:Female; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics*; D008297:Male; D051379:Mice; D019577:Mole Rats; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics*; D051381:Rats; D013002:Somatomedins / Q000235:genetics*; D013045:Species Specificity
chemical_list: D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; D013002:Somatomedins; D011266:Pregnancy-Associated Plasma Protein-A