A Bartke

..Studies of physiological characteristics and polymorphisms of insulin-related genes in exceptionally long-lived people suggest a role of insulin signaling in the control of human aging...

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..We conclude that dietary soy protein intake can improve plasma and hepatic lipid profiles, reduce fasting glucose, enhance capacity for glucose tolerance, and prolong life, but all of these effects are strongly genotype-dependent...

..Highlights of these recent developments will be briefly discussed in this Review...

..These important novel findings also strengthen the evidence for evolutionary conservation of mechanisms regulating lifespan in worms, insects and mammals...

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..New work on mice with brain-specific or whole-body reductions in insulin receptor substrate 2 (IRS2) (Taguchi et al., 2007) points to a role for insulin/IGF-1 signaling in the central control of mammalian aging...

..These studies also provided novel and still-disputed evidence for involvement of somatotropic axis in the control of aging and life span and in mediating the actions of longevity genes...

..There is considerable evidence to suggest that the genetic and endocrine mechanisms that influence aging and longevity in mice may play a similar role in other mammalian species, including the human...

..Natural decline in GH levels during aging likely contributes to concomitant alterations in body composition and vigor but also may be offering important protection from cancer and other age-associated diseases...

..This last category is of particular interest since genes affected in normal but not GHRKO mice may be related to mechanisms by which DR extends longevity...

..This review summarizes the present understanding of the multifaceted relationship between somatotropic signaling and mammalian aging...

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..The role of GH in the control of human aging continues to be hotly debated, but recent data indicate that reduced somatotropic signaling provides protection from cancer and other age-related diseases and may promote old age survival...

..Although available clinical evidence does not support the use of recombinant GH as an anti-aging therapy, many studies suggest the potential utility of GH and GH secretagogues in the treatment of sarcopenia and frailty...

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..We suspect that IGF-I is important in evolutionarily conserved mechanisms that link life history, including development, reproduction, and aging with availability of energy resources...

..However, activation of signaling molecules downstream from IGF-1 and insulin receptors is reduced in both Klotho and dwarf mice, suggesting common mechanisms of delayed aging...

..These results show that high, persistent levels of circulating endogenous GH induce alterations in neuroendocrine functions related to the hypothalamo-pituitary-gonadal and the hypothalamo-pituitary-adrenal axes...

..Thus, GH and IGF-I influence pituitary and gonadal functions in male mice...

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..These changes are most likely due to the absence of circulating IGF-I. These findings provide evidence that systemic IGF-I plays a major modulatory role in testicular endocrine function...

..Reductions in these parameters may be important to the underlying mechanisms of delayed aging in these animals...

..An important role of IGF-1 and insulin in the control of mammalian longevity is consistent with the well-documented actions of homologous signaling pathways in invertebrates...

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..Taken together, these studies support our previous findings of delayed age-induced cognitive and behavioral decline in GH deficient/resistant mice...

..Animals deficient in GH (dwarf) live longer and exhibit enzyme activities and levels that may combat oxidative stress more efficiently than normal mice and those overexpressing GH...

..In fact, the Ames dwarf mouse may provide a model for studies of delayed mental as well as physical aging...

..In this review, we will describe the key phenotypic characteristics of these animals, the evidence that they exhibit delayed aging, and the mechanisms that are suspected to account for their prolonged longevity...

..001) plasma LH levels. The effect of LHRH on LH secretion was increased (p < 0.001) in dwarf mice pretreated with GH, but this LH response was lower than in normal siblings that received vehicle only.(ABSTRACT TRUNCATED AT 250 WORDS)..

..In Ames dwarf mice, the deficiency of GH and PRL, as well as TSH, is associated with decreased LH-beta and FSH-beta gene expression which may account for the reduction in plasma gonadotropin levels...

..An increase in plasma adiponectin and decrease in plasma IL-6, triglycerides, and cholesterol levels in response to CR may improve insulin sensitivity...

..To examine this possibility, the authors have tested the effects of intratesticular NE injections. This treatment caused decrease of LH-R at 24 h followed by an increase at 72 h.(ABSTRACT TRUNCATED AT 400 WORDS)..

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..The GHRH transgenic mice may be an interesting model to study the regulation of tachykinin stores in the anterior pituitary gland...

..Studies in GH transgenics should allow the identification of mechanisms that mediate the effects of chronic overexposure to GH on reproduction...

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..These results suggest that the decrease in LH secretion in THC- or CBN-treated rats is due to reductions in NE stimulation of LHRH release rather than to changes in LHRH synthesis or pituitary LHRH response...

..These results indicate that GH and T4 treatment has differential impact on insulin signaling during development and adulthood...

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..Yet due to PRL-like activity of hGH, the gonadotropin secretion is altered. Thus, endogenously secreted hGH modulates the hypothalamic-pituitary function of adult female transgenic mice bearing the hGH gene...

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..Thus, it was concluded that inhibitory avoidance performance was not affected by differences of locomotor activity or emotionality, and that the absence of GH signaling may be associated with improved long-term memory in aging mice...

..These results also add to the evidence that targeted disruption of the GH receptor/GH-binding protein gene and CR act via overlapping, but distinct, mechanisms...

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..We conclude that GH resistance and consequent reduction in peripheral IGF-I levels is associated with delay of female puberty, alterations in fetal and placental growth, delay of parturition, and reduced litter size...

..However, whether low Tco per se is related to the increased longevity of the dwarf mice remains an interesting possibility to be investigated...

..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...

..Thus GH and IGF-I promote antioxidant phenotypic changes in the endothelial cells, whereas Ames dwarfism leads to vascular oxidative stress...

..Human placental growth hormone is a highly likely candidate to mediate the insulin resistance of pregnancy...

..Plasma prolactin (PRL) and growth hormone (GH) levels of pituitary-grafted dwarf mice were not changed after TP-1 administration.(ABSTRACT TRUNCATED AT 250 WORDS)..

..Since the genotype of the opaline mink differs from the other mink studied, only in their combination at the pastel (b) and moyle (m) loci, their bb mm genotype could be assumed to be responsible for the increase in testicular steroids...

..These results provide new insights into the roles GH may play in glucose metabolism and perhaps also in adiposity which is a common characteristic of Df/- aged females from this line of mice...

..These results suggest that progesterone may modulate tachykinin stores in the anterior pituitary gland of Siberian hamsters...

..These changes may be related to mechanisms of improving insulin sensitivity and life expectancy...

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..These results indicate that NKA and other tachykinins are present in the pineal gland of the male rat, and they seem to be regulated by gonadal hormones and the innervation originated from the superior cervical ganglia...

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..Therefore, the results observed with the use of some of these antagonists should be interpreted with great caution...

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..These results suggest that the absence of IGF-I secretion delays the normal course of sexual maturation in male GHR-KO mice, indicating that IGF-I plays an important role in the initiation of puberty in male mice...

..We conclude that the remarkable life-span extension of Ames dwarf mice, and the stress resistance of cells from these mice, depends on low levels of GH exposure in juvenile and very young adult mice...

..The results also indicate that CR may increase insulin sensitivity through a different mechanism...

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..However, CR may reduce rather than enhance some of the insulin effects in the highly insulin-sensitive dwarf mice...

..This suggested metabolic change clearly does not affect whole-body insulin action. These findings suggest that whole-animal insulin sensitivity is not regulated through skeletal muscle insulin action...

..The results also show that improved insulin sensitivity in response to CR is not due to increased mRNA expression of the above genes in either normal or GHR-KO animals...

..Insulin sensitivity may be a mechanism and/or a marker of the lifespan extending potential of an intervention...

..Therefore, the concentrations of IGF binding proteins and the ratio of these binding proteins and IGF-I within the body might play a pivotal role in modulating IGF-I effects on the neuroendocrine-gonadal system...

..These parameters also continued to increase with age. Our results indicate that GH resistance alters body composition, bone growth, and bone maintenance during aging in GHR-KO mice...

..In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging...

..Moreover, effects of dwarfism on the expression of the examined genes differed from the effects of CR, thus adding to the evidence that these long-lived mutants are not CR mimetics...

..Although GHR-KO female mice are fertile, they exhibit quantitative deficits in various parameters of reproductive function...

..The results indicate that EOD produces some changes in the insulin and IGF1 signaling pathways, and that these changes are consistent with EOD increasing insulin sensitivity...

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..We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of GH administration...

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..Furthermore, some bioactive compounds in the HIS diet appeared to confound the soy protein-induced beneficial effects...

..Paracrine effects of germ cells on Sertoli cell structure were examined in a mouse model with the W locus (dominant white spotting) mutation in which animals with the W/Wv genotype (referred to as mutants) lack virtually all germ cells...

..These data are the first to show the presence of PRL-R gene expression in various organ systems in fetal mice and suggest that PRL is among several factors necessary to coordinate developmental activities...

..These data suggest that, in addition to GnRH and gonadotropins, GH/IGF-I influences the pituitary and gonadal functions in animals and humans...

..These results add to the growing evidence that cannabinoids can exert direct effects on Sertoli cell function and modulate their responses to physiological stimuli...

..These findings suggest that tachykinins may have a physiological function in the testes as modulators of the functions of the different cell types contained in these organs...

..This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR...

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..This change may be cardioprotective and thus contribute to increased longevity in response to CR. Interestingly, the insulin signaling cascade in the heart of GHRKO mice was unaffected by CR...

..Here we discuss examples of diet/genotype interactions that show a more complex mechanistic view is required and that mild dietary modifications can dramatically change the interpretation of model organism aging studies...

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..Together, these findings suggest that endogenous pituitary GH exerts a feedback action on stomach ghrelin homeostasis and support the hypothesis that a stomach-ghrelin-pituitary GH axis exists...

..We suspect that reduction in relative adiposity may contribute to the previously reported increase in insulin sensitivity of Ames dwarf mice and thus may be a factor in delayed aging and increased longevity of these animals...

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..We are also seeking partial support for the expenses of invited speakers from the United States. ..

..In future studies, we will verify involvement of these mechanisms in the control of normal and delayed aging and examine their potential in designing interventions that prolong health span. ..

..Financial assistance will be provided to those in training to encourage their participation in the meeting. ..

..We are also seeking support for the presenters of the Special Lecture and the Keynote Lecture who will be traveling to Bregenz from the United States. ..