Specific suppression of insulin sensitivity in growth hormone receptor gene‐disrupted (GHR‐KO) mice attenuates phenotypic features of slow aging |
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Authors: | Oge Arum Feiya Wang Angela L. Dirks Jeremy G. Turner John J. Kopchick Jun‐Li Liu Romesh K. Khardori Andrzej Bartke |
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Affiliation: | 1. Department of Internal Medicine, Southern Illinois University‐School of Medicine, , Springfield, IL, 62794 USA;2. Division of ENT‐Otolaryngology, Department of Surgery, Southern Illinois University‐School of Medicine, , Springfield, IL, 62794 USA;3. Edison Biotechnology Institute and Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, , Athens, OH, 45701 USA;4. Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, , Montreal, QC, H3A 1A1 Canada;5. Division of Endocrinology & Metabolism, Department of Internal Medicine, Eastern Virginia Medical School, , Norfolk, VA, 23507 USA |
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Abstract: | In addition to their extended lifespans, slow‐aging growth hormone receptor/binding protein gene‐disrupted (knockout) (GHR‐KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR‐KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β‐cells by expressing Igf‐1 under the rat insulin promoter 1 (RIP::IGF‐1). The RIP::IGF‐1 transgene increased circulating insulin content in GHR‐KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non‐β‐cell cell types. Multiple (nonsurvivorship) longevity‐associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR‐KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated. |
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Keywords: | endocrinology and metabolism growth hormone hormonal signaling insulin sensitivity longevity regulation (neuro)endocrinology of senescence |
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