Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging
نویسندگان
چکیده
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.
منابع مشابه
Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging
The correlation of physiological sensitivity to insulin ( vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the mo...
متن کاملInteraction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging [version 2; referees: 2 approved]
The correlation of physiological sensitivity to insulin ( glycemic vis-à-vis regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The gene-disrupted growth hormone receptor/ binding protein (GHR-KO) mouse is the mo...
متن کاملInflammatory and Glutamatergic Homeostasis Are Involved in Successful Aging.
Whole body studies using long-lived growth hormone receptor gene disrupted or knock out (GHR-KO) mice report global GH resistance, increased insulin sensitivity, reduced insulin-like growth factor 1 (IGF-1), and cognitive retention in old-age, however, little is known about the neurobiological status of these mice. The aim of this study was to determine if glutamatergic and inflammatory markers...
متن کاملPuberty is delayed in male growth hormone receptor gene-disrupted mice.
The role of insulin-like growth factor-I (IGF-I) in the initiation of puberty and testicular function is poorly understood. Growth hormone (GH) receptor (R) gene-disrupted mice or GHR gene "knockouts" (GHR-KO) are GH resistant and IGF-I deficient. To assess whether the age of sexual maturation is affected by the absence of IGF-I, various parameters of sexual development including testicular and...
متن کاملEffects of caloric restriction and growth hormone resistance on the expression level of peroxisome proliferator-activated receptors superfamily in liver of normal and long-lived growth hormone receptor/binding protein knockout mice.
Growth hormone receptor/binding protein knockout (GHR-KO) mice live approximately 40% longer than their normal siblings do. These mice have dramatically reduced plasma levels of insulin-like growth factor 1 (IGF1) and enhanced insulin sensitivity. We examined the expression level of peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors family genes in the livers of normal...
متن کامل