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PubMedDate not supplied

Progress toward a voluntary oral consumption model of alcoholism.

With the goal of obtaining a suitable animal model for voluntary oral consumption of ethanol, the investigators selectively bred lines of alcohol-preferring and alcohol-nonpreferring rats, with preference considered as a function of the concentration of ethanol ingested. Studies with these animals showed that drinking is voluntary and not contingent on caloric restriction; that they will work to obtain ethanol even when food and water are freely available, and in so doing, show psychological or behavioral tolerance; that the amount of ethanol voluntarily consumed approaches their apparent maximum capacity for ethanol elimination. This amount of ethanol was capable of altering brain neurotransmitter content, thus exerting a CNS pharmocologic effect. In addition, the rats will bar-press for intravenous administration of ethanol, and with prolonged, free-choice consumption, ethanol intake increases to as much as 12 g per kg body weight per day without producing behavioral deficits, suggesting the development of tolerance.

Acetaldehyde↗
PubMedDate not supplied

Exogenous and endogenous DNA modifications as monitored by 32P-postlabeling: relationships to cancer and aging.

32P-postlabeling analysis, a highly sensitive method for the detection and measurement of covalent carcinogen-DNA adducts and other DNA modifications, does not require radioactive test substances and, therefore, can be applied to DNA of mammals, including humans exposed to low doses of environmental or occupational genotoxicants. The basic procedure entails the enzymatic incorporation of 32P-label into hydrolysis products of DNA, followed by chromatographic mapping and autoradiography of the 32P-labeled digestion products and quantitative scintillation spectrometry. Microgram amounts of DNA are analyzed: Thus the assay is suited for limited amounts of cells or tissues. Various versions of the assay afford different sensitivities of adduct detection. A single aromatic or bulky/hydrophobic adduct in 10(8)-10(10) nucleotides can be detected and measured (corresponding to 0.3-30 amol adduct/micrograms DNA or 0.1-10 nmol adduct/mol DNA-P). In animal models, the assay has been successfully applied to a variety of mutagenic (genotoxic) as well as nonmutagenic carcinogens. In humans, DNA specimens from cigarette smokers, iron foundry workers, and coke oven workers whose total aromatic adduct levels ranged from 1 adduct in 10(6)-10(8) DNA nucleotides have been examined by 32P-postlabeling. The assay also detects DNA modifications--Indigenous (I)-compounds--that increase with age in untreated animals. I-compound profiles and levels are highly species-, strain-, sex-, and tissue-specific, and also depend on diet composition. Caloric restriction, a highly efficient method for improving resistance to carcinogenesis and extending life span, increased rather than decreased I-compound levels in various tissues of male rats. Nonmutagenic hepatocarcinogens reduced levels of I-compounds in the target organ. Because of the specificity of this effect, reduction of I-compound levels appears to represent a novel biomarker for the action of nonmutagenic carcinogens. DNA from various hepatomas was found largely devoid of I-compounds. The results support a possible antineoplastic and antiaging role of these DNA modifications.

Aging↗
PubMedDate not supplied

Overview of cancer and aging: a mechanistic perspective.

Cancer and aging are approached from the standpoint of damaging agents affecting target cell, local cellular environment, and the organism as a whole. The effects of exogenous agents are represented in a model emphasizing absorption, organismic disposition, and cellular disposition. Endogenous agents are represented similarly. The extent of endogenous damage is illustrated. Factors in the expression of damage as a toxic endpoint are emphasized, with the example of caloric restriction used as an example of environmental modulation of response.

Aging↗
PubMedDate not supplied

Dietary alteration in the rates of cancer and aging.

Both variation of diet and comparative analysis are used to evaluate the effects of nutrition on mortality and cancer. The effects of caloric restriction (CR) are compared in multiple strains raised under similar conditions for a diet developed to assist breeding, and for a standard diet. A standard analysis, using "aging rates," is of limited use for understanding the effects of CR in delaying mortality in certain strains. However, when the effect of the diets on body weight and the known effects on sex-specific P-450 isoenzyme expression are compared, these effects suggest a mechanism for the action of CR. By comparative analysis, the effect of CR on tumor pathology suggests that the same mechanisms responsible for inhibiting reproduction may be responsible for delaying the aging-related increase in incidence of diseases. Based on these data, the adaptive/longevity-related process theory of CR is modified to incorporate aspects of the disposable soma theory of aging, as well as pleiotropism.

Aging↗
PubMedDate not supplied

The uses of intraspecific variation in aging research.

The artificial creation of genetically long-lived populations of several invertebrate species has illustrated how researchers may take advantage of genetic variation within a species to investigate the nature and mechanisms of aging. The advantage of studying intraspecific variation is that populations will be generally similar except for the relevant demographic differences. Also, there are reasons to suspect that genetic mechanisms of aging may differ from mechanisms associated with life extension via environmental manipulations such as caloric restriction. However creating a long-lived mammalian aging model will be expensive and time consuming. An alternative approach is to seek to identify naturally occurring slowly aging populations to contrast mechanistically with a reference population. Ecologists have already noted that demographic alterations of the appropriate type are frequently associated with populations from differing latitudes, differing altitudes, or from islands. Therefore, it is likely that genetically longer- (and shorter)-lived mammal populations of the same species already exist in nature, and could potentially be exploited to inquire into the genetics and mechanisms of aging and longevity. Of particular interest is the indication that some island populations of house mice may exhibit extended longevity compared with laboratory strains.

Aging↗
PubMed1994

Tumor necrosis factor and cachexia: a current perspective.

Anorexia, net proteolysis of skeletal muscle and consumption of body fat are hallmarks of the cachexia syndrome associated with chronic disease states. While inanition contributes to cachexia, this wasting diathesis has little in common with simple starvation. The cachexia syndrome is characterized by progressive weight loss and depletion of lean body mass in excess to that resulting from comparable caloric restriction. Accelerated mobilization and consumption of host protein stores from peripheral tissues occurs to support gluconeogenesis and acute phase protein synthesis [1, 2]. In contrast, simple starvation is associated with a relative sparing of lean tissue with the preferential consumption of fat. While the clinical manifestations of cachexia are readily apparent, identification of the specific mechanisms responsible for the development of cachexia remains an enigma. In recent years, interest has focused on the role that the immune system plays in the development of cachexia. Investigators initially hypothesized that the chronic production of two inflammatory cytokines, tumour necrosis factor alpha (TNF alpha) and/or interleukin-1 (IL-1), could explain the host non-specific responses resulting in cachexia [3-5]. Other pro-inflammatory cytokines, including interleukin-6 (IL-6) [6, 7] and interferon-gamma [8, 9], have been more recently proposed to be involved in this complex process. Although no consensus exists for the exclusive role of any one cytokine in the pathogenesis of cachexia, there is growing acceptance that the progression of cachexia results in part from the inappropriate release of one or more pro-inflammatory cytokines [10, 11]. In the present review, the current role of TNF alpha as a mediator of cachexia is examined.

Cachexia↗
PubMed1991

Treatment of obesity-associated hypertension.

Many obese people are hypertensive either because of obesity-associated hypertension or because the two conditions coexist. Weight loss is recommended for all obese hypertensives as some patients benefit by concomitant reductions of arterial pressure and/or decreased requirements for antihypertensive drugs. Since obesity-associated hypertension cannot be diagnosed as a separate entity, available evidence was reviewed to determine the antihypertensive effectiveness of weight loss and effects of weight loss on antihypertensive drug requirements. Generally speaking, patients with mild hypertension appear to respond better to weight reduction than those with moderate and severe hypertension. However, a substantial percentage of patients with mild hypertension may be unresponsive. Weight loss also seems to have potential for lessening requirements for antihypertensive drug therapy. Beneficial effects for both blood pressure and drug requirements are due to weight loss and not caloric restriction, per se. Mechanisms of the beneficial effects are related to consequences of weight loss and appear to involve decreased cardiac output and blood volume. The issue of salt sensitivity of obesity-associated hypertension is unresolved.

Antihypertensive Agents↗
PubMed2006

Modifications of coronary risk factors.

In addition to the revascularization and glycemic management interventions assigned at random, the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) design includes the uniform control of major coronary artery disease risk factors, including dyslipidemia, hypertension, smoking, central obesity, and sedentary lifestyle. Target levels for risk factors were adjusted throughout the trial to comply with changes in recommended clinical practice guidelines. At present, the goals are low-density lipoprotein cholesterol <2.59 mmol/L (<100 mg/dL) with an optional goal of <1.81 mmol/L (<70 mg/dL); plasma triglyceride level <1.70 mmol/L (<150 mg/dL); blood pressure level <130 mm Hg systolic and <80 mm Hg diastolic; and smoking cessation treatment for all active smokers. Algorithms were developed for the pharmacologic management of dyslipidemia and hypertension. Dietary prescriptions for the management of glycemia, plasma lipid profiles, and blood pressure levels were adapted from existing clinical practice guidelines. Patients with a body mass index >25 were prescribed moderate caloric restriction; after the trial was under way, a lifestyle weight-management program was instituted. All patients were formally prescribed both endurance and resistance/flexibility exercises, individually adapted to their level of disability and fitness. Pedometers were distributed as a biofeedback strategy. Strategies to achieve the goals for risk factors were designed by BARI 2D working groups (lipid, cardiovascular and hypertension, and nonpharmacologic intervention) and the ongoing implementation of the strategies is monitored by lipid, hypertension, and lifestyle intervention management centers.

Algorithms↗
PubMed2004

Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations.

Given the myriad of age-related changes and the many proposed mechanistic theories of ageing, a major problem in gerontology is distinguishing causes from effects. This review aims to identify and evaluate those mechanisms which have gathered experimental support in favour of seeing them as a cause rather than an effect of ageing. Recent results related to energy metabolism and ageing, the free radical and the DNA damage theories of ageing are reviewed and their predictions evaluated through a systems biology rationale. Crucial in this approach are genetic manipulations in animal models that enable researchers to discriminate causes from effects of ageing and focus on the causal structure of human ageing. Based on a system-level interpretation, the GH/IGF-1 axis appears the most likely explanation for caloric restriction and a possible causal mechanism of human ageing. Although much work remains to fully understand the human ageing process, there is little evidence that free radicals are a causal factor in mammalian ageing, though they may be involved in signalling pathways related to ageing. On the other hand, studying how the DNA machinery affects ageing appears a promising avenue for disclosing the human ageing process.

Aged↗
PubMed2004

The role of ubiquinone in Caenorhabditis elegans longevity.

Aging is an irreversible physiological process that affects all living organisms. Different mutations in the insulin signaling pathway and caloric restriction have been shown to retard aging in Caenorhabditis elegans. In addition, mutations or RNAi silencing of components of the respiratory chain results in the modification of adult life span. Another class of genes that affect life span in C. elegans is the clock (clk) genes. Particularly interesting is clk-1, which encodes an enzyme required for ubiquinone (coenzyme Q, CoQ) biosynthesis. Down-regulation by RNAi silencing of the genes required for ubiquinone biosynthesis also extends life span in C. elegans, and CoQ supplied in the diet also affects nematode longevity in both clk-1 and wild-type strains. Although there are many aspects that can be considered in aging, we focus this review on the role of CoQ in the longevity of C. elegans. We will review the current information about the biosynthesis of CoQ and its dietary supplementation related to the extension of life span. We will also analyze the function of CoQ in the electron transport chain and reactive oxygen species production in the context of aging. We hypothesize that the role of CoQ on longevity of C. elegans supports the oxidative damage theory of aging.

Animals↗
PubMed2026

Decoding SUMOylation as a metabolic stress sensor in aging and age-related disorders: Mechanisms, tissue specificity and therapeutic potential.

SUMOylation is a reversible post-translational modification increasingly recognized for its role in coordinating cellular responses to metabolic stress during aging. Emerging evidence indicates that it functions beyond a conventional modification, representing an adaptive stress&#x2011;responsive regulatory network that integrates metabolic, oxidative, inflammatory, and proteotoxic signals. Rather than acting on isolated pathways, this network finely tunes mitochondrial function, proteostasis, genome maintenance, immune balance, and epigenetic regulation. Accumulating evidence indicates that SUMO-dependent regulation exhibits remarkable tissue specificity, supporting mitochondrial adaptation and contractile integrity in skeletal muscle, shaping lipid and glucose metabolism in the liver, modulating proteotoxic stress and neuronal resilience in the brain, and contributing to immune cell differentiation and chronic low-grade inflammation during aging. In this review, we summarize current mechanistic insights into SUMO signaling across aging-relevant tissues, with particular emphasis on its functional interplay with other post-translational modifications, including ubiquitination and acetylation. We discuss how SUMOylation operates as a shared regulatory layer while enabling context-dependent outcomes that underlie diverse aging phenotypes and age-related disorders. Finally, we evaluate emerging translational approaches-ranging from pharmacological modulation of SUMO enzymes to lifestyle interventions such as caloric restriction and exercise-that highlight both the opportunities and challenges of targeting SUMO-regulated stress responses in aging. Together, this synthesis provides a framework for understanding how SUMOylation links metabolic stress to tissue-specific aging trajectories and therapeutic potential.

Aging↗
PubMed2004

Soluble thrombomodulin and vascular adhesion molecule-1 are associated to leptin plasma levels in obese women.

Recent studies have suggested that leptin, a plasma protein secreted by adipocytes, may play a role in artherothrombosis. In this study, we tested the hypothesis that leptin contributes to in vivo endothelial dysfunction in obese subjects. A cross-sectional comparison of plasma leptin, soluble thrombomodulin (sTM) and soluble vascular adhesion molecule-1 (VCAM-1) was carried out in 35 obese women (age 48+/-13) selected with a body mass index (BMI) > or =30kg/m(2) and 25 normal weight women (age 50+/-11, BMI < 25). An additional study was conducted to determine the short-term effects of weight loss induced by caloric restriction. Plasma levels of leptin, sTM and sVCAM-1 were measured before and after weight loss. Obese women had higher levels of leptin (35+/-22 versus 22+/-19, P<0.01), sTM (4.8+/-1.8 versus 1.9+/-1.5, P<0.001) and sVCAM-1 (726+/-109 versus 583+/-50, P<0.001) than non-obese women. sTM and sVCAM-1 concentrations had a positive correlation with BMI (sTM, r=0.70, P<0.001; sVCAM-1, r=0.60, P<0.001), waist circumference (sTM, r=0.66, P<0.001; sVCAM-1, r=0.37, P<0.01) and leptin levels (sTM, r=0.53, P<0.001; sVCAM-1, r=0.42, P<0.005). At multiple regression analysis leptin predicted sTM and sVCAM-1 independently of obesity measures and other covariates. Twenty-nine obese patients who completed the program of weight reduction showed a significant decrease in leptin, sTM, and sVCAM-1 levels. The magnitude of decrease of sTM and sVCAM-1 was related to the magnitude of reduction in leptin levels. Therefore, our results show that obesity is associated with enhanced levels of atherosclerosis markers. These abnormalities are related to abdominal obesity possibly mediated by leptin levels, and are reversible with weight loss.

Arteriosclerosis↗
PubMed2004

Expression of connective tissue growth factor, a biomarker in senescence of human diploid fibroblasts, is up-regulated by a transforming growth factor-beta-mediated signaling pathway.

Molecular changes associated with cellular senescence in human diploid fibroblasts (HDF), IMR-90, were analyzed by two-dimensional differential proteome analysis. A high percentage of replicative senescent cells were positive for senescence-associated beta-galactosidase activity, and displayed elevated levels of p21 and p53 proteins. Comparison of early population doubling level (PDL) versus replicative senescent cells among the 1000 spots resolved on gels revealed that the signal intensities of six spots were increased fivefold, whereas those of four spots were decreased. Proteome analysis data demonstrated that connective tissue growth factor (CTGF) is an age-associated protein. Up-regulation of CTGF expression in senescent cells was further confirmed by Western blotting and RT-PCR. We postulate that CTGF expression is controlled, in part, by transforming growth factor-beta (TGF-beta), in view of the high levels of TGF-beta isoforms as well as type I and II receptors detected only in late PDL of HDF cells. To verify this hypothesis, we stimulated early PDL cells with TGF-beta1 as well as stress inducing agents such as hydrogen peroxide. As expected, CTGF expression and Smad protein phosphorylation were dramatically increased up to observed levels in normal replicative senescent cells. In vivo experiments disclosed that CTGF, pSmad, and p53 were constitutively expressed at basal levels in up to 18-month-old rat liver, and expression was significantly up-regulated in 24-month-old rat tissue. However, expression patterns were not altered at all periods examined in livers of caloric-restricted rats. In view of both in vitro and in vivo data, we propose that the TGF-beta/Smad pathway functions in the induction of CTGF, a novel biomarker protein of cellular senescence in human fibroblasts.

Animals↗
PubMed2005

FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression.

Sirtuin 1 (SirT1), an NAD-dependent deacetylase that is important for promoting longevity during caloric restriction, can deacetylate and enhance the function of forkhead box transcription factors, O subfamily (FoxO). We examined the effect of SirT1 on the regulation of insulin-like growth factor-binding protein 1 (IGFBP-1), a known target of FoxO proteins that is increased in fasting. Co-transfection with a SirT1 expression vector dose-dependently stimulated IGFBP-1 promoter activity and a heterologous reporter gene construct containing three FoxO-binding sites linked to a minimal promoter. This effect is mimicked by 20muM resveratrol, a potent SirT1 activator, and immunoprecipitation and Western blotting confirm that SirT1 and FoxO1 interact in cells. Interestingly, mutation of FoxO-binding sites in the IGFBP-1 promoter reduces, but does not completely disrupt, the stimulatory effect of SirT1 on promoter activity. We found that overexpression of SirT1 is accompanied by enhanced mitogen-activated protein kinase (MAPK) activation. Treatment of SirT1-cotransfected cells with PD98059, which inhibits MAPK activation, decreased IGFBP-1 promoter activity by approximately 50%, in a FoxO-binding site-independent manner, and disrupts the residual effect of SirT1. These results indicate that SirT1 stimulates IGFBP-1 promoter activity through FoxO-dependent and -independent mechanisms, and provides the first evidence that activation of MAPK contributes to effects of SirT1 on gene expression.

Base Sequence↗
PubMed2004

The role of insulin and insulin-like growth factor-I in mammalian ageing.

Research with invertebrates over the past 10 years has suggested that alterations in insulin and/or insulin-like growth factor I (IGF-I) signalling result in increased lifespan and retard ageing. In this chapter, we describe the current research in mammalian systems with respect to the role of insulin or IGF-I in ageing. Using rodent models of caloric restriction and genetic mouse models, e.g. the Ames and Snell dwarf mice, fat-specific insulin receptor knockout mice (FIRKO) and mice that are heterozygous for the IGF-I receptor (Igf1r+/-), investigators have shown that a reduction in plasma levels of insulin and/or IGF-I or reductions in insulin/IGF-I signalling appear to be correlated with increased longevity and retarded ageing.

Aging↗
PubMed2005

Programming of the endocrine pancreas by the early nutritional environment.

A substantial body of evidence now suggests that poor intrauterine milieu elicited by maternal nutritional disturbance or placental insufficiency may programme susceptibility in the foetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. Further data showing the developmental programming of the metabolic syndrome are now available thanks to animal studies in which the foetal environment has been manipulated. This review examines the developmental programming of glucose intolerance by disturbed intrauterine metabolic condition in rats. It focuses on the alteration of the endocrine pancreas at birth. Long-term consequences, deterioration of glucose tolerance and even transgenerational effects are reported. Maternal protein, caloric restriction and diabetes during gestation/lactation lead to altered beta-cell mass. This review also tempts to identify cellular and molecular mechanisms involved in this process.

Animals↗
PubMed2005

Plasma tryptophan during weight restoration in patients with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a mental disorder characterized by low weight and concerns about body shape and weight. Disturbance in serotonin function has been described as central to the psychobiology of this disorder. Plasma tryptophan (TRP), the essential amino acid needed for serotonin production, is known to be low following acute caloric restriction but has not been measured during the course of refeeding. METHODS: Plasma TRP and other large neutral amino acids (LNAA) levels were measured in 26 female patients with AN and 15 control subjects. Patient levels were measured at admission for inpatient treatment, after 1 week of treatment, and upon weight restoration to weight > or =90% ideal body weight (IBW). For 17 patients, an additional assessment was made when weight reached 80% IBW. Plasma levels were obtained on one occasion from healthy control subjects. RESULTS: Plasma TRP and TRP/LNAA ratio increased significantly during refeeding process. Plasma TRP in patients was 46.88 nmol/mL (SD = 19.59) on admission and 55.54 nmol/L/mL (SD = 8.1) at normal weight, p < .05. The ratio of TRP to LNAA was .11 (SD = .03) on admission and .13 (SD = .02) at normal weight, p < .05. Plasma TRP is significantly lower in low-weight patients than in healthy control subjects (TRP = 53.73 [SD = 8.21]), but there was no significant difference between control subjects and normal-weight patients. CONCLUSIONS: Plasma TRP normalizes during the course of refeeding, supporting the hypothesis that serotonin function is disturbed in patients with anorexia nervosa.

Adult↗
PubMed2005

The plasticity of aging: insights from long-lived mutants.

Mutations in genes affecting endocrine signaling, stress responses, metabolism, and telomeres can all increase the life spans of model organisms. These mutations have revealed evolutionarily conserved pathways for aging, some of which appear to extend life span in response to sensory cues, caloric restriction, or stress. Many mutations affecting longevity pathways delay age-related disease, and the molecular analysis of these pathways is leading to a mechanistic understanding of how these two processes--aging and disease susceptibility--are linked.

Animals↗