Extended longevity in mice lacking the insulin receptor in adipose tissue

Caloric restriction has been shown to increase longevity in organisms ranging from yeast to mammals. In some organisms, this has been associated with a decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore these associations with enhanced longevity, we studied mice with a fat-specific insulin receptor knockout (FIRKO). These animals have reduced fat mass and are protected against age-related obesity and its subsequent metabolic abnormalities, although their food intake is normal. Both male and female FIRKO mice were found to have an increase in mean life-span of approximately 134 days (18%), with parallel increases in median and maximum life-spans. Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling.     

Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein

The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.     

Neuropeptides and peptide hormones in Anopheles gambiae

The African malaria mosquito, Anopheles gambiae, is specialized for rapid completion of development and reproduction. A vertebrate blood meal is required for egg production, and multiple feedings subsequently allow transmission of malaria parasites, Plasmodium spp. Regulatory peptides from 35 genes annotated from the A. gambiae genome likely coordinate these and other physiological processes. Plasmodium parasites may affect actions of newly identified insulin-like peptides, which coordinate growth and reproduction of its vector, A. gambiae, as in Drosophila melanogaster, Caenorhabditis elegans, and mammals. This genomic information provides a basis to expand understanding of hematophagy and pathogen transmission in this mosquito.     

Structure of the receptor for insulin-like growth factor II: the puzzle amplified

The insulin-like growth factor II (IGF-II) is a polypeptide hormone with structural homologies to insulin and insulin-like growth factor I (IGF-I). In contrast to these other hormones, the in vivo function of IGF-II is not known. Although IGF-II can stimulate a broad range of biological responses in isolated cells, these responses have usually been found to be mediated by the insulin and IGF-I receptors. Recently, the receptor for IGF-II was found to also be the receptor for mannose-6-phosphate. Since this latter receptor has been implicated in targeting of lysosomal enzymes, the question is now raised of whether the same protein can also mediate metabolic responses to IGF-II.     

Evolutionary medicine: from dwarf model systems to healthy centenarians?

Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.     

Suppression of aging in mice by the hormone Klotho

A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals.     

Timing requirements for insulin/IGF-1 signaling in C. elegans

The insulin/IGF-1 (where IGF-1 is insulin-like growth factor-1) signaling pathway influences longevity, reproduction, and diapause in many organisms. Because of the fundamental importance of this system in animal physiology, we asked when during the animal's life it is required to regulate these different processes. We find that in Caenorhabditis elegans, the pathway acts during adulthood, to relatively advanced ages, to influence aging. In contrast, it regulates diapause during development. In addition, the pathway controls longevity and reproduction independently of one another. Together our findings show that life-span regulation can be dissociated temporally from phenotypes that might seem to decrease the quality of life.     

Signaling pathways for PC12 cell differentiation: making the right connections

A key issue in signal transduction is how signaling pathways common to many systems-so-called canonical signaling cassettes-integrate signals from molecules having a wide spectrum of activities, such as hormones and neurotrophins, to deliver distinct biological outcomes. The neuroendocrine cell line PC12, derived from rat pheochromocytoma, provides an example of how one canonical signaling cassette-the Raf --> mitogen-activated protein kinase kinase (MEK) --> extracellular signal-regulated kinase (ERK) pathway-can promote distinct outcomes, which in this case include neuritogenesis, gene induction, and proliferation. Two growth hormones, epidermal growth factor (EGF) and nerve growth factor (NGF), use the same pathway to cause PC12 proliferation and differentiation, respectively. In addition, pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotransmitter that also causes differentiation, uses the same canonical cassette as NGF but in a different way. The Connections Map for PC12 Cell Differentiation brings into focus the complex array of specific cellular responses that rely on canonical signal transduction systems.     

抗菌肽的研究进展及在农业中的应用

具有广谱高效杀菌活性的小分子多肽类物质———抗菌肽,是机体非特异性免疫系统的重要组成部分。据研究表明,抗菌肽对细菌、部分真菌、原虫、病毒、肿瘤细胞都具有杀伤作用。从目前国内外在抗菌肽研究热点着手,分析阐述了抗菌肽的分类、作用机理、抗菌肽基因工程,及抗菌肽在农业中的应用,并展望了利用植物生物反应器生产抗菌肽的可能性及应用前景。     

小肽转运载体(PepT1)及其活性的调控

近来发现蛋白质的消化产物在动物肠道内有相当一部分是以小肽的形式吸收和利用。克隆和分析两个结构相似的小肽转运载体 (Pep T1和 Pep T2 )揭示了哺乳动物和禽类的小肽转运机制。这些小肽转运载体识别二肽和三肽 ,其活性受日粮蛋白质水平和各种激素的调控。目前对人、猪、鸡、大鼠、小鼠、兔子、绵羊等的 Pep T1的基因结构和蛋白质结构已有了系统的认识。就其生理特性、分布、基因和蛋白质的结构和日粮及各种因子对其活性调控等进行综述     

An activating mutation of AKT2 and human hypoglycemia

Pathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules or by inborn errors of metabolism impairing liver glucose production. We studied three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and in one case in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. Thus, systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.     

胰岛素样生长因子Ⅰ

胰岛素样生长因子 I(IGF-I)分子量约7000道尔顿,IGF-I 结合蛋白对 IGF-I具有保护和调节作用.卵泡颗粒细胞 IGF-I 的分泌受促性腺激素、雌二醇、卵泡大小、各种生长因子及颗粒细胞自身的调节.在卵泡,IGF-I 刺激卵泡颗粒细胞的代谢、增生、分化,甾体激素的生成及受体的诱导,并对膜-间质细胞具有旁分泌作用.     

Amphibian pituitary growth hormone and prolactin: immunochemical relatedness to rat growth hormone

Growth hormone and prolactin were electrophoretically isolated from amphibian pituitaries and then were tested in a radioimmunoassay with labeled rat growth hormone and antiserum to the same hormone. This isolation and purification of the hormones increased the steepness of the slopes of competitive inhibition in this system when compared to those of crude extracts. Both hormones from most species tested showed high immunochemical cross-reactivity, indicating that amphibian growth hormone and prolactin are structurally related to rat growth hormone.     

甘肃境内国家重点保护兽类的分布规律

对甘肃省境内国家重点保护兽类的分布规律进行了分析，结果表明：陇南山地、祁连山地和河西走廊是国家重点保护兽类的集中分布区；陇南山地属动物地理成分的过渡带，东洋界占50．0％，古北界占35．0％，广布种占15.0％，以森林灌丛动物为主：祁连山地的兽类均为古北界成分，以森林灌丛动物为主；河西走廊兽类均为古北界成分，以荒漠、高山裸岩动物群为主。     

Cellular senescence in aging primates

The aging of organisms is characterized by a gradual functional decline of all organ systems. Mammalian somatic cells in culture display a limited proliferative life span, at the end of which they undergo an irreversible cell cycle arrest known as replicative senescence. Whether cellular senescence contributes to organismal aging has been controversial. We investigated telomere dysfunction, a recently discovered biomarker of cellular senescence, and found that the number of senescent fibroblasts increases exponentially in the skin of aging baboons, reaching >15% of all cells in very old individuals. In addition, the same cells contain activated ataxia-telangiectasia mutated kinase and heterochromatinized nuclei, confirming their senescent status.     

Amino-terminal amino Acid sequence of the silkworm prothoracicotropic hormone: homology with insulin

Three molecular forms of prothoracicotropic hormone were isolated from the head of the adult silkworm, Bombyx mori, and the amino acid sequence of 19 amino acid residues in the amino terminus of these prothoracicotropic hormones was determined. These residues exhibit significant homology with insulin and insulin-like growth factors.     

Brain IRS2 signaling coordinates life span and nutrient homeostasis

Reduced insulin-like signaling extends the life span of Caenorhabditis elegans and Drosophila. Here, we show that, in mice, less insulin receptor substrate-2 (Irs2) signaling throughout the body or just in the brain extended life span up to 18%. At 22 months of age, brain-specific Irs2 knockout mice were overweight, hyperinsulinemic, and glucose intolerant; however, compared with control mice, they were more active and displayed greater glucose oxidation, and during meals they displayed stable superoxide dismutase-2 concentrations in the hypothalamus. Thus, less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice.     

Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase

A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.