Does anti-aging equal anti-microbial?

Aging is the dominant risk factor for human disease in developed countries. Could it be that a wide variety of disease states all have their origins in a common mechanism? Major signaling pathways that determine the rate of aging, such as the insulin/insulin-like growth factor 1 (IGF-1) pathway, might give clues to the nature of this major disease risk factor. It has now been shown that insulin/IGF-1 signaling influences Caenorhabditis elegans resistance to bacteria in such a way that long-lived worms are stress-resistant and slow to succumb to infection. Perhaps enhanced innate immunity is a feature of genetically determined longevity.     

C. elegans gives the dirt on aging

The worm Caenorhabditis elegans has become a popular model organism for the study of mechanisms involved in aging. The C. elegans life span is controlled by several pathways that have been extensively characterized at the molecular level. These include pathways that regulate metabolism and development (namely, the insulin/IGF-1 pathway), nutrition, mitochondrial activity, and reproduction. Presentations at a recent C. elegans conference add to the growing body of knowledge about the genetic networks that control the complex process of aging and suggest new avenues for further investigations.     

Oxygen? No thanks, I'm on a diet

In yeast and worms, mutations that extend longevity appear to simulate starvation conditions. The daf-2 pathway in worms plays a major role in life-span extension and in entry into the starvation-resistant and low-metabolism dauer phase. In a recent study published in Science Express on 13 June 2002, researchers screened for Caenorhabditis elegans mutants that survive in a low-oxygen environment and identified a number of daf-2 mutants that are resistant to hypoxia. The implications of these results are discussed in this Perspective.     

Murine models of life span extension

Mice are excellent experimental models for genetic research and are being used to investigate the genetic component of organismal aging. Several mutant mice are known to possess defects in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) neurohormonal pathway and exhibit dwarfism together with extended life span. Their phenotypes resemble those of mice subjected to caloric restriction. Targeted mutations that affect components of this pathway, including the GH receptor, p66Shc, and the IGF-1 receptor (IGF-1R), also extend life span; mutations that affect IGF-1R or downstream components of the pathway decouple longevity effects from dwarfism. These effects on life span may result from an increased capacity to resist oxidative damage.     

Insulin-like growth factor 1 receptor polymorphism rs2229765 and circulating interleukin-6 level affect male longevity in a population-based prospective study (Treviso Longeva--TRELONG)

Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based "Treviso Longeva"--TRELONG Study from Italy (n = 668, age range 70-105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose-response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females.     

Inside insulin signaling, communication is key to long life

In a recent Nature paper, Tatar and colleagues show that inhibition of insulin/insulin-like growth factor (IGF) signaling specifically in the adipose tissue of Drosophila melanogaster retards organismal aging, increases resistance to oxidative stress, augments lipid deposition, and restricts insulin signaling in peripheral tissues by a cell-non-autonomous mechanism. Consistent with recent work in the worm, these results suggest that insulin/IGF signaling itself may mediate communication among various tissues to influence organismal longevity.     

Gene expression of insulin receptor,insulin-like growth factor increases and insulin-like growth factor-binding protein-3 reduces with increase in prostate size in benign prostatic hyperplasia

Introduction: Although the role of insulin in the development of benign prostatic hyperplasia (BPH) is well established, there are no studies regarding alteration in the gene expression of components of insulin-signaling pathway and their association with prostate size in BPH. Hence, the study was designed to analyze the gene and protein expression of insulin receptor and its related components in patients with BPH.

Materials and methods: Twenty-seven BPH patients aged between 55 and 75 years were recruited in the study and prostatic tissues were obtained after transurethral resection of the prostate. Gene expression levels of Insulin receptor (IR), insulin receptor substrate (IRS), insulin-like growth factor (IGF) and insulin-like growth factor-binding protein-3 (IGFBP-3) were assessed by q-PCR.

Results: Insulin receptor (IR-A and B) and insulin-like growth factors (IGF-1 and IGF-2) gene expression were significantly increased and IGFBP-3 gene expression was reduced in BPH patients with larger prostate size. Also, serum insulin was significantly increased and IGFBP-3 was significantly reduced in patients with larger prostate size.

Conclusion: Increased expression of IR-A, B and IGF-1, 2 genes and reduced IGFBP-3 gene expression was associated with larger prostate size in BPH.     

Growth hormone in anti-aging medicine: a critical review

Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based “Treviso Longeva”? TRELONG Study from Italy (n?=?668, age range 70–105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose–response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females.     

Interfering with longevity

Several recent studies have highlighted how RNA interference has advanced aging-related research in Caenorhabditis elegans. Two new genome-wide RNAi-based screens together identified more than 100 new candidate longevity genes. RNAi has also greatly facilitated the functional validation of several large-scale gene expression profiling studies. Furthermore, RNAi is flexible and can be administered at different times throughout life; this feature has been exploited to analyze the temporal requirement of genes in life-span determination.     

Regulation of aging by germline stem cells

The author discusses a recent paper published in Science (see Arantes-Oliveira) that shows that germline stem cells in the worm Caenorhabditis elegans send a signal to a steroid hormone receptor and a forkhead-family member to stimulate reproduction and shorten longevity. The author compares the new results to previous findings in the fruit fly and discusses possible mechanisms behind the inverse relationship between reproduction and life-span extension.     

Is Akt the mastermind behind age-related heart disease?

Over the past several years, the insulin/insulin-like growth factor (IGF) signaling pathway has become a central figure in the study of organismal aging. Mutations in components of this pathway have led to enhanced longevity in several organisms, but it is still not clear whether and how this pathway contributes to human aging and aging-related diseases. In a new study, Miyauchi and colleagues propose that Akt, a member of the phosphatidylinositol 3-kinase family and a downstream component of the insulin/IGF pathway, plays a central role in the life span of endothelial cells. These findings implicate the insulin/IGF pathway in the development and progression of cardiovascular disease.     

Linking development and aging

Evolutionary theory predicts that the different life stages of organisms are coordinated to achieve maximal reproductive output. Moreover, aging can be seen as an evolutionary side effect of this selective process that applies to many living organisms. Hence, genetic, developmental, and physiological mechanisms resulting from this selection are expected to be conserved in diverse lineages. The insulin/insulin-like growth factor signaling (INS) pathway appears to be such a mechanism that regulates life span and reproduction in a variety of model organisms. Here I argue that the experimental tools of environmental manipulation and gene by environment interaction should be used more often both during the experimental organism's development and its adult life. This approach will help us to fully understand the functions of longevity-determining pathways and will determine the life stages during which these pathways exert their effects on adult life. These points are raised because of a recent Aging Cell publication by Tu and Tatar, in which the larval food environment was manipulated to determine the effects on adult reproduction, life span, aging, and INS. The results of this study are a promise of the usefulness of this approach for understanding the aging process.     

Genes, culture, and aging flies--what the lab can and cannot tell us about natural genetic variation for senescence

Model organisms cultured in the lab provide a powerful way to explore basic biological processes. However, lab culture can select for high early fecundity and dramatically shorten the life-span of lab organisms. Studies that use these short-lived organisms to identify aging-related genes might identify genes that simply restore the organism's original life-span. These results might not be fully relevant to wild populations. Experiments that reduce selection for shorter life-span or seek genes in naturally long-lived cohorts should lead to a more accurate understanding of aging.     

How good are quantitative complementation tests?

Several recent studies have used quantitative complementation tests to identify relatively short chromosome regions that contain genes that influence life span and to screen for candidate life-span genes in flies. The methodology and logic of quantitative complementation tests are described. Arguments are presented that suggest that these tests may be misleading because there is a substantial, but unknown, likelihood of false positive results. The arguments are supported by the published results of quantitative complementation tests.     

血管生成素通过ERK信号通路促进HeLa细胞的增殖

目的通过细胞外信号调节激酶（extracellularregulatedproteinkinases,ERK）通路及NF-xB信号途径探讨血管生成素（angiogenin,Ang）对HeLa细胞的促增殖及抗凋亡作用机制。方法用不同浓度的重组人Ang刺激HeLa细胞,MTr法分析Ang对HeLa细胞的促增殖作用,蛋白质印迹实验检测ERK信号通路相关分子的表达情况。U0126抑制ERK信号通路,检测Ang诱导的ERKl／2的磷酸化及c—myc的表达情况,同时检测Ang对细胞增殖的影响。敲低Ang的表达,检测细胞的凋亡情况。双荧光素酶报告基因检测Ang对NF-KB报告基因的激活。蛋白水平检测Ang刺激的HeLa细胞后,NF—KB通路相关分子的表达。结果Ang能促进HeLa细胞增殖,ERKl／2的磷酸化水平及c—myc的表达随重组人Ang浓度的升高而增加。U0126能抑制Ang诱导的ERKI／2的磷酸化、c—myc的上调及细胞的增殖。Ang的低表达促进HeLa细胞的凋亡,但不影响NF-KB报告基因的激活及NF—KB通路上相关分子的表达。结论Ang能够促进HeLa细胞增殖,并通过活化ERK通路促进细胞的增殖,但其抑凋亡作用与NF-KB通路无关。     

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25?mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while β-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment.

The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and β-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain.

In conclusion, the present study demonstrates that 25?mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.     

Toward a better understanding of Klotho

klotho mutant mice were originally described as a short-lived mouse model with premature aging-like disorders. The klotho gene responsible for these phenotypes encodes a type I membrane protein with a considerable similarity to beta-glycosidase. klotho is predominantly expressed in tissues functioning in the regulation of calcium homeostasis. Suggested functions of Klotho are (i) a fundamental regulator of calcium homeostasis, namely, a cofactor for the fibroblast growth factor (FGF) receptor 1c in FGF23 signaling and a regulator of parathyroid hormone secretion; (ii) a hormone that interferes with the intracellular signaling of insulin and insulin-like growth factor-1; and (iii) a beta-glucuronidase that activates the transient receptor potential ion channel TRPV5 by trimming its sugar moiety. How can we reconcile these pleiotropic functions of Klotho? Is there any common mechanism? Further in vivo studies, and biochemical as well as physiological analyses, are required for a better understanding of the molecular aspects of Klotho.     

Not wisely but too well: aging as a cost of neuroendocrine activity

Progressive decline of some neuroendocrine signaling systems has long been assumed to cause age-related physiological impairments and limit life span. However, hypophysectomy--removal of the pituitary gland--can delay many aspects of the aging process, and recent genetic studies have confirmed that reducing the secretion of pituitary hormones can increase the life span of laboratory organisms. Most strikingly, reducing activity of the insulin/insulin-like growth factor-1 signaling system substantially increases life span. Conversely, activity of the reproductive system or activation of stress responses can curtail life span. Because caloric restriction also reduces the activity of several neuroendocrine systems while increasing life span, it now appears that the aging process is driven, at least in part, by neuroendocrine activity rather than by its decline with age.