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.
Highlights
Aging can be described as the inevitable process of gradual decreases in physiological and biochemical functions, which are prominent in single cells as well as in whole organisms, and with death as the ultimate outcome
We carried out a bioinformatic analysis for identifying components of the insulin-like growth factors (IGFs) system in the NMR that could potentially underlie its longevity and improved aging process
Because the cysteines are crucial for IGF binding proteins (IGFBPs) structure and because the other genome sequence (Accession: AHKG00000000) does not contain this variation, we suggest that this database variation is most likely due to sequencing errors
Summary
Aging can be described as the inevitable process of gradual decreases in physiological and biochemical functions, which are prominent in single cells as well as in whole organisms, and with death as the ultimate outcome. Humans age slower than predicted, based on the common correlation between body mass and maximum lifespan For this reason naturally long-lived animal models may be more suitable for delineating mechanisms of aging pertinent to humans [5, 6]. A promising species that meets this criteria is the longest living rodent known, the naked mole-rat (Heterocephalus glaber) (NMR) which lives 5- to 10-times longer than predicted for their body mass of a mouse [2, 7]. It shows negligible senescence and is resistant to certain damaging effects associated with aging, including oxidative stress [2]. We chose to investigate the insulin-like growth factor (IGF) system
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