Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction

Department of Internal Medicine-Geriatrics Research, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2006; 103(20):7901-5. DOI: 10.1073/pnas.0600161103
Source: PubMed


Reduced intake of nutrients [calorie restriction (CR)] extends longevity in organisms ranging from yeast to mammals. Mutations affecting somatotropic, insulin, or homologous signaling pathways can increase life span in worms, flies, and mice, and there is considerable evidence that reduced secretion of insulin-like growth factor I and insulin are among the mechanisms that mediate the effects of CR on aging and longevity in mammals. In the present study, mice with targeted disruption of the growth hormone (GH) receptor [GH receptor/GH-binding protein knockout (GHRKO) mice] and their normal siblings were fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age. In normal females and males, CR produced the expected increases in overall, average, median, and maximal life span. Longevity of normal mice subjected to CR resembles that of GHRKO animals fed AL. In sharp contrast to its effects in normal mice, CR failed to increase overall, median, or average life span in GHRKO mice and increased maximal life span only in females. In a separate group of animals, CR for 1 year improved insulin sensitivity in normal mice but failed to further enhance the remarkable insulin sensitivity in GHRKO mutants. These data imply that somatotropic signaling is critically important not only in the control of aging and longevity under conditions of unlimited food supply but also in mediating the effects of CR on life span. The present findings also support the notion that enhanced sensitivity to insulin plays a prominent role in the actions of CR and GH resistance on longevity.

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Available from: Khalid A Al-Regaiey, Oct 19, 2015
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    • "Mutations in mammalian genes that downregulate IIS increase longevity , such as in the case of dwarf mice, which harbor mutations in the pituitary growth hormone (GH) receptor, involved in regulating IGF-I release from the liver (reviewed in [14]). This lifespan extension effect has been linked to that induced by CR, with partially overlapping mechanisms [71]. Similar to TOR, IIS activates the downstream effector S6K, which plays a key role in the regulation of aging in worms and mammals [17]. "
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    ABSTRACT: Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on healthspan and lifespan. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1847(11). DOI:10.1016/j.bbabio.2015.05.005 · 4.66 Impact Factor
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    • "Insulin sensitivity is important in senescence of GHR-KO mice, O. Arum et al. transgene, as well as enhanced second-phase GSIS in the control mice (Guo et al., 2005). All experiments henceforth were performed in females for two reasons: (i) the normalizing effects of the RIP::IGF-1 transgene on insulin sensitivity were more robust in female GHR-KO mice, and (ii) GHR-KO stock male littermate controls are insensitive to a common dosage of insulin (0.75 USPU per kg BW) during insulin tolerance testing (Bonkowski et al., 2006; Arum et al., 2009, data not shown), thusly confounding any assessments of the effects of the RIP:: IGF-1 transgene on them (as we do not desire to investigate the slowaging-associated effects of inducing insulin resistance, merely those consequent to normalizing insulin sensitivity). Once again, the RIP::IGF-1 transgene had no effect on body weight trajectories (Fig. S4), and the same was true for absolute and relative organ weights of multiple organs listed previously (data not shown). "
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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.
    Aging cell 09/2014; 13(6). DOI:10.1111/acel.12262 · 6.34 Impact Factor
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    • "In humans, insulin resistance accompanied by compensatory dysinsulinemia has been implicated as a risk factor for a range of age-related diseases (Ford et al., 2002). In support of this, the prolonged existence and improved multiple features of delayed aging have been described in mice, rats, and other mammals, in which insulin sensitivity is enhanced by genetic mutations or calorie restriction (Bonkowski et al., 2006). The current study showed that the serum insulin level was significantly higher in the vehicle-treated old rats than young rats, whereas the oral administration of Kangen-karyu in old rats produced a slight decrease in the serum glucose level with a significant decrease in the serum insulin levels. "
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    ABSTRACT: This study examined whether Kangen-karyu and its crude drug, Salviae Miltiorrhizae Radix, have a reno-protective effect on the age-related oxidative stress and inflammatory response through the phosphoinositide 3-kinase (PI3K)/Akt or mitogen-activated protein kinase (MAPK) pathways in aged rats. Kangen-karyu or Salviae Miltiorrhizae Radix (20 mg/kg body weight/day) was administered orally to old groups of rats for 16 days, and their effects were compared with the vehicle-treated old and young rats. The administration of Kangen-karyu caused a slight decrease in the serum glucose level and a significant decrease in the serum insulin level in the old rats. The increased levels of serum renal functional parameter (urea-nitrogen) and oxidative parameter were significantly reduced by both Kangen-karyu and Salviae Miltiorrhizae Radix. The old rats exhibited a dysregulation of the protein expression related to insulin resistance, oxidative stress, and inflammation in the kidneys, but Kangen-karyu administration significantly reduced the expression of the inflammatory proteins through the PI3K/Akt pathway. On the other hand, the Salviae Miltiorrhizae Radix-treated old rats showed a decrease in the inflammatory cytokines through the MAPK pathway. These results provide important evidence that Kangen-karyu and Salviae Miltiorrhizae Radix have a pleiotropic effect on the PI3K/Akt and MAPK pathways, showing renoprotective effects against the development of inflammation in old rats. This study provides scientific evidence that Kangen-karyu and Salviae Miltiorrhizae Radix improve the inflammatory responses via the PI3K/Akt or MAPK pathways in the kidney of old rats.
    The American Journal of Chinese Medicine 07/2014; 42(4):987-1005. DOI:10.1142/S0192415X14500621 · 2.76 Impact Factor
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