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.     

A mechanism of extreme growth and reliable signaling in sexually selected ornaments and weapons

Many male animals wield ornaments or weapons of exaggerated proportions. We propose that increased cellular sensitivity to signaling through the insulin/insulin-like growth factor (IGF) pathway may be responsible for the extreme growth of these structures. We document how rhinoceros beetle horns, a sexually selected weapon, are more sensitive to nutrition and more responsive to perturbation of the insulin/IGF pathway than other body structures. We then illustrate how enhanced sensitivity to insulin/IGF signaling in a growing ornament or weapon would cause heightened condition sensitivity and increased variability in expression among individuals--critical properties of reliable signals of male quality. The possibility that reliable signaling arises as a by-product of the growth mechanism may explain why trait exaggeration has evolved so many different times in the context of sexual selection.     

Regulation of C. elegans life-span by insulinlike signaling in the nervous system

An insulinlike signaling pathway controls Caenorhabditis elegans aging, metabolism, and development. Mutations in the daf-2 insulin receptor-like gene or the downstream age-1 phosphoinositide 3-kinase gene extend adult life-span by two- to threefold. To identify tissues where this pathway regulates aging and metabolism, we restored daf-2 pathway signaling to only neurons, muscle, or intestine. Insulinlike signaling in neurons alone was sufficient to specify wild-type life-span, but muscle or intestinal signaling was not. However, restoring daf-2 pathway signaling to muscle rescued metabolic defects, thus decoupling regulation of life-span and metabolism. These findings point to the nervous system as a central regulator of animal longevity.     

缢蛏IGFALS基因的表达特征及IGF系统对生长的调控作用

类胰岛素生长因子(insulin-like growth factor,IGF)信号通路在机体的发育、繁殖以及生长等过程中起着重要的调控作用。类胰岛素生长因子酸不稳定亚基(IGF acid-labile subunit,IGFALS)是IGF系统中的重要一员,可通过延长IGF的半衰期参与IGF信号通路的调控。本研究首次在缢蛏转录组数据库中筛选鉴定了两个IGFALS基因,包含完整的开放阅读框,分别命名为IGFALSa和IGFALSb。IGFALSa基因的cDNA序列为4809 bp,编码996个氨基酸;IGFALSb基因的cDNA序列为1925 bp,编码546个氨基酸。在缢蛏不同发育期的表达分析中发现,IGFALSa和IGFALSb在幼虫的前期发育阶段均只有少量表达,而随着幼虫的发育,其表达量逐渐上升;组织表达分析表明,IGFALSa在外套膜和性腺中高表达,IGFALSb则在水管中高表达。利用不同质量浓度胰岛素短期刺激缢蛏稚贝,当质量浓度为10 mg/L时,两个IGFALS基因表达量均显著上调,其下游基因IRS、PDK1、MPKP1的表达量也显著上调;进一步利用10 mg/L胰岛素长期喂养缢蛏稚贝,结果显示其壳长和壳宽的日生长率均显著提升。     

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.     

鲮胰岛素样生长因子Ⅰ(IGF-Ⅰ)cDNA的分子克隆和序列分析

采用逆转录-聚合酶链式反应（RT-PCR）方法，从鲮肝脏总RNA中扩增出胰岛素样生长因子-I（IGF-I）基因，克隆至质粒PUGm-T。测定该基因序列，推导其编码的蛋白质序列。克隆的鲮IGF-IcDNA编码序列包括信号肽、B、C、A、D和E6个区域，共161个氨基酸残基。与鲤IGF-I比较，信号肽由44个氨基酸残基组成比鲤少17个，成熟肽核苷酸序列和氨基酸序列的同源性分别为95.2%和100%,E区域分析结果表明，克隆的鲮IGF-I序列属于IGF-I Ea-2亚型。     

鲮胰岛素样生长因子Ⅰ(IGF-Ⅰ)cDNA的分子克隆和序列分析

采用逆转录-聚合酶链式反应（RT-PCR）方法，从鲮肝脏总RNA中扩增出胰岛素样生长因子-I（IGF-I）基因，克隆至质粒PUGm-T。测定该基因序列，推导其编码的蛋白质序列。克隆的鲮IGF-IcDNA编码序列包括信号肽、B、C、A、D和E6个区域，共161个氨基酸残基。与鲤IGF-I比较，信号肽由44个氨基酸残基组成比鲤少17个，成熟肽核苷酸序列和氨基酸序列的同源性分别为95.2%和100%,E区域分析结果表明，克隆的鲮IGF-I序列属于IGF-I Ea-2亚型。     

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.     

Comment on "Brain IRS2 signaling coordinates life span and nutrient homeostasis"

Taguchi et al. (Reports, 20 July 2007, p. 369) reported that mice heterozygous for a null mutation in insulin receptor substrate-2 (Irs2) display a 17% increase in median life span. However, using the same mouse model, we find no evidence for life-span extension and suggest that the findings of Taguchi et al. were due to atypical life-span profiles in their study animals.     

Autophagy genes are essential for dauer development and life-span extension in C. elegans

Both dauer formation (a stage of developmental arrest) and adult life-span in Caenorhabditis elegans are negatively regulated by insulin-like signaling, but little is known about cellular pathways that mediate these processes. Autophagy, through the sequestration and delivery of cargo to the lysosomes, is the major route for degrading long-lived proteins and cytoplasmic organelles in eukaryotic cells. Using nematodes with a loss-of-function mutation in the insulin-like signaling pathway, we show that bec-1, the C. elegans ortholog of the yeast and mammalian autophagy gene APG6/VPS30/beclin1, is essential for normal dauer morphogenesis and life-span extension. Dauer formation is associated with increased autophagy and also requires C. elegans orthologs of the yeast autophagy genes APG1, APG7, APG8, and AUT10. Thus, autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans.     

The endocrine regulation of aging by insulin-like signals

Reduced signaling of insulin-like peptides increases the life-span of nematodes, flies, and rodents. In the nematode and the fly, secondary hormones downstream of insulin-like signaling appear to regulate aging. In mammals, the order in which the hormones act is unresolved because insulin, insulin-like growth factor-1, growth hormone, and thyroid hormones are interdependent. In all species examined to date, endocrine manipulations can slow aging without concurrent costs in reproduction, but with inevitable increases in stress resistance. Despite the similarities among mammals and invertebrates in insulin-like peptides and their signal cascade, more research is needed to determine whether these signals control aging in the same way in all the species by the same mechanism.     

亚硝酸钠对果蝇寿命影响及Vc拮抗作用研究

以黑腹果蝇(Drosophila melanogaster)为试验材料,探讨了亚硝酸钠对果蝇寿命的影响及维生素C(Vc)的拮抗作用.结果表明:培养基中添加亚硝酸钠可以显著缩短果蝇的平均寿命,添加30、120和480 mg/mL亚硝酸钠处理组的雌果蝇平均寿命分别减少17.60%、44.47%和68.52%,雄性果蝇分别减...     

不同品种鸭胚胎期骨骼肌成肌细胞GHR和IGF 1 mRNA表达差异分析

为探讨生长激素受体（growth hormone receptor,GHR）和胰岛素样生长因子 1（Insulin like growth factor 1,IGF 1）在不同品种鸭胚胎期骨骼肌成肌细胞中的表达差异。选择生长速度不同的金定鸭和高邮鸭为试验动物,采用实时荧光定量PCR方法检测鸭13,15,17,19,21和23胚龄时胸肌和腿肌成肌细胞GHR,IGF 1 mRNA的表达情况,并进行了品种间比较。结果发现：13胚龄时,高邮鸭胸肌和腿肌成肌细胞IGF 1的表达均显著高于金定鸭（P<0.05）;17胚龄是两个品种鸭GHR和IGF 1共同的表达高峰期;17胚龄之后,鸭胸肌和腿肌成肌细胞GHR和IGF 1表达均显著降低。在19,21胚龄时,高邮鸭胸肌成肌细胞2个基因的表达均显著高于金定鸭（P<0.05）,而腿肌成肌细胞GHR和IGF 1表达在品种间无显著差异（P>0.05）。鸭胚胸肌和腿肌成肌细胞GHR和IGF 1表达呈现极显著的正线性相关（P<0.01）。提示：GHR和IGF 1的表达谱及各自在品种间的变化规律基本一致;鸭胚骨骼肌成肌细胞GHR和IGF 1 mRNA表达有组织特异性,二者之间可能存在正调控的作用机制。     

亚硝酸钠对果蝇寿命及SOD和MDA的影响

以果蝇(Drosophila melanogaster)为试验动物,探讨亚硝酸钠对果蝇寿命、超氧化物岐化酶(SOD)活性及丙二醛(MDA)含量的影响.结果表明:培养基中添加亚硝酸钠能显著缩短果蝇平均寿命,其中30//L、120g/L和480g/L组雌果蝇平均寿命与对照组相比分别缩短了12.53、31.49、48.79d...     

顶坛花椒花粉活力及其对Zn的响应研究

用TTC法测定了顶坛花椒花粉的活力和寿命,用拟合二次方程(Quadratic)、分析建立曲线估计模块(Curve estimation)的方法分析了顶坛花椒花粉活力和寿命对微量元素Zn的响应。研究结果表明:在3~8年和生长在海拔600 m左右的顶坛花椒花粉具有较强活力,散粉后花粉的最长寿命为6 d。当ZnSO4浓度为0.08%时,各年龄级的顶坛花椒花粉活力达到最大值;ZnSO4浓度为0.06%时,Zn可以促使不同海拔的顶坛花椒花粉活力达到最大值;当ZnSO4浓度为0.09%时,顶坛花椒花粉寿命可以从散粉后6 d延长到7 d。因此,当ZnSO4浓度为0.06%~0.09%,顶坛花椒花粉活力和花粉寿命均能大幅度提高。     

Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.