title: Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging.
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.
authors.affiliation: Department of Internal Medicine, Southern Illinois University-School of Medicine, Springfield, IL, 62794, USA.
authors.forename: Oge
authors.initials: O
authors.lastname: Arum
authors.forename: Ravneet K
authors.initials: RK
authors.lastname: Boparai
authors.forename: Jamal K
authors.initials: JK
authors.lastname: Saleh
authors.forename: Feiya
authors.initials: F
authors.lastname: Wang
authors.forename: Angela L
authors.initials: AL
authors.lastname: Dirks
authors.forename: Jeremy G
authors.initials: JG
authors.lastname: Turner
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Liu
authors.forename: Romesh K
authors.initials: RK
authors.lastname: Khardori
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D005260:Female; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011986:Receptors, Somatotropin / Q000378:metabolism*
chemical_list: D007328:Insulin; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I
keywords: (neuro)endocrinology of senescence; endocrinology and metabolism; growth hormone hormonal signaling; insulin sensitivity; longevity regulation