DhHP-6延长秀丽线虫寿命的作用机制

考察次血红素六肽(DhHP-6)对秀丽线虫寿命的影响及其与DAF-16(abnormal dauer -formation-16)的关系. [JP2]实验结果表明: DhHP-6给药可提高野生秀丽线虫的平均寿命约20%, 未影响DAF-16表达缺失型秀丽线虫的平均寿命; DhHP-6可促进DAF-16入核, 启动下游基因表达; DhHP-6给药可增强DAF-16的转录活性, 提高sod-3表达量, 降低线虫体内的自由基含量.     

IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice

Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.     

Resveratrol improves health and survival of mice on a high-calorie diet

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.     

Growth restoration of insulin-deficient diabetic rats by recombinant human insulin-like growth factor I

Insulin-like growth factor I (IGF-I) and insulin stem from a common precursor, are structural homologues, act through similar receptors and elicit insulin-like and growth-promoting effects in vitro and in vivo. Serum IGF-I levels are controlled by growth hormone, insulin and nutrition. Insulin-deficient growth-arrested diabetic animals have reduced serum IGF-I levels which are restored towards normal by insulin but not by growth-hormone treatment. Here we show that normal growth of diabetic rate is restored by infusion of recombinant human (rh)IGF-I without normalization of the blood sugar level and that insulin acts via an increase of IGF-I synthesis on growth of diabetic rats. We describe a new mechanism of endocrine control of growth in which IGF-I is the major stimulator at the cellular level. Growth hormone and insulin act mainly by modulating the hepatic synthesis of IGF-I.     

Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila

Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.     

Localization of insulin-like growth factor genes to human chromosomes 11 and 12

The insulin-like growth factors IGF-I and IGF-II are required for growth and development. Both are single-chain proteins (of 70 and 67 amino acids respectively) derived from precursors by proteolytic processing. IGF-I may be particularly important in promoting normal stature and IGF-II may be a fetal growth hormone. The IGF proteins are probably synthesized by many normal tissues and by some tumours. The secretion of growth factors by tumours and tumour-derived cell lines suggests that they may act as autocrine regulators of cell proliferation. Because of the possible role of these proteins in growth disorders and cancer, and their sequence homology with insulin, we have determined their chromosomal localization. Using somatic cell hybrids and cloned cDNA probes for these proteins, we have assigned the genes for IGF-I and IGF-II to human chromosomes 12 and 11, respectively. We present evidence that the IGF-II gene is located on the short arm of chromosome 11 with a ras proto-oncogene and the insulin structural gene, and also suggest the existence of a fragment length polymorphism using the IGF-I probe.     

The sirtuin SIRT6 regulates lifespan in male mice

The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

薄荷提取物对提高秀丽线虫应激抵抗能力的影响

以秀丽线虫为模型， 研究药食同源植物薄荷提取物对其应激抵抗能力的影响， 并以紫外辐射为应激条件， 进一步研究薄荷提取物抵抗紫外辐射的作用机制.  结果表明： 薄荷提取物可明显提高线虫抵抗紫外辐射、 绿脓杆菌感染、 35 ℃热应激和胡桃醌氧化的应激能力； 薄荷提取物可明显降低紫外辐射后线虫体内活性氧（ROS）水平、提高超氧化物歧化酶（SOD）活性，并可通过胰岛素/IGF-1样信号通路发挥作用，  提高通路下游转录因子sod-3,hsp-12.6,hsp-16.1和hsp-16.49的mRNA水平表达量以及转录因子daf-16的细胞核定位数量;  薄荷提取物可提高线虫的运动能力和吞咽能力， 但不影响其寿命和生育能力.     

Human chromosomal mapping of genes for insulin-like growth factors I and II and epidermal growth factor

Many of the actions previously attributed to pituitary-derived growth hormone are mediated by polypeptide growth factors. These include the insulin-like growth factors I and II (IGF-I and IGF-II), which are members of the insulin family of proteins. We report here the chromosomal mapping of the human genes for IGF-I and IGF-II. IGF-II maps to the short arm of chromosome 11, which also contains the gene for insulin and the proto-oncogene c-Ha-ras1 (ref. 9). IGF-I maps to chromosome 12, which is evolutionarily related to chromosome 11 and carries the gene for the proto-oncogene c-Ki-ras2 (refs 10,44). We have also localized the human gene for an unrelated polypeptide hormone, epidermal growth factor, to chromosome 4q, in the same region as another specialized growth factor, T-cell growth factor. We speculate that these map assignments reflect the existence of gene families involved in growth control.