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Biomedical subjects

Nir Barzilai

Publications and source records attributed to Nir Barzilai.

At least 19 recordsLinked to original sources
PubMed2006

Lipoprotein genotype and conserved pathway for exceptional longevity in humans.

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians (n = 213), their offspring (n = 216), and an age-matched Ashkenazi control group (n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the -641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) (p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the -641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable -641C homozygote (p < 0.0001). Homozygosity for the APOC3 -641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans.

Aged↗
PubMed2005

The insulin/IGF-1 signaling in mammals and its relevance to human longevity.

Hormones, like insulin and insulin-like growth factor 1 (IGF-1), are thought to be deeply involved with longevity. Lower species have been the source for most of our current knowledge on the role of the insulin/IGF-1 signaling in modulating lifespan. This hormonal system may have originated from a very early common ancestor and is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like flies, nematodes and mammalians. Disruption of the insulin/IGF-1 receptor in nematodes and flies increases lifespan significantly. With evolution, mammals developed two well characterized hormonal systems: insulin and growth hormone (GH)/IGF-1, with different metabolic and developmental functions. Abnormalities in the insulin signaling pathway generate age-related diseases and increased mortality, whereas the GH/IGF-1 axis could potentially modulate longevity in many species. In this review we briefly describe the lifespan regulatory role of the insulin/IGF-1 signaling of nematodes, flies and rodent models and compare it with the human equivalent.

Animals↗
PubMed2005

Central resistance to the inhibitory effects of leptin on stimulated insulin secretion with aging.

Aging is associated with resistance to the effects of leptin on food intake and energy homeostasis. We examined if old rats were resistant to the effects of leptin on glucose stimulated insulin secretion. When leptin was infused intravenously (0.5 microg/kg/min) under hyperglycemic clamp conditions (11 mM) in young (n=5) and old rats (n=10, 5 ad libitum fed and five with surgical removal of visceral fat), glucose stimulated insulin secretion was significantly decreased by 44% in the young rats, but not in old rats (31.8+/-2.8 to 17.9+/-1.0 versus 33.7+/-1.4 versus 31.0+/-1.7 and 24.7+/-1.6 versus 21.0+/-2.8 in young versus old versus old VF- respectively, p<0.01). To identify if the resistance to leptin is secondary to impaired transport across the blood brain barrier (BBB), we infused leptin into the third ventricle (intra-cerebro ventricular, ICV). ICV infusion of leptin elicited a partial effect on glucose stimulated insulin secretion in the old (25.7+/-2.5 to 15.4+/-2.4 versus 24.4+/-2.4 to 19.0+/-2.0 in young versus old, respectively) suggesting that part of the leptin resistance was beyond the BBB. Resistance to the effects of leptin on insulin secretion in aging may protect against the onset of diabetes in old subjects.

Age Factors↗
PubMed2005

Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity.

We previously identified a functional variant of KLOTHO, termed KL-VS, that is associated with human aging and early-onset occult coronary artery disease. Here, we determine whether the KL-VS allele influences cardiovascular disease risk factors, cardiovascular events, and ultimately, mortality. A total of 525 Ashkenazi Jews composed of 216 probands (age > or =95 years) and 309 unrelated individuals (ages 51 to 94) were genotyped for the KL-VS allele. In concordance with our previous data in Czech individuals (age > or =79; P<0.01), a heterozygous advantage for longevity was observed for individuals > or =79 years of age (P<0.004). Combined analysis indicates a 1.57-fold (95% CI, 1.23 to 1.98) increased odds ratio (OR) for 5-year survival in two independent populations (P<0.0002). Cardiovascular disease risk factors were assessed through multivariate regression analysis, demonstrating that high-density lipoprotein cholesterol (HDL-C; P<0.05) and systolic blood pressure (SBP; P<0.008) are associated with KL-VS genotype. History of vascular events was analyzed using logistic regression, indicating that after adjustment for traditional risk factors, heterozygous individuals were at significantly lower risk for stroke than wild-type individuals (OR, 5.88; 95% CI, 1.18 to 29.41), whereas homozygous KL-VS individuals had the highest risk (OR, 30.65; 95% CI, 2.55 to 368.00). Similarly, prospective analysis of mortality in probands using Cox regression indicates that wild-type individuals have a 2.15-fold (95% CI, 1.18 to 3.91) and homozygous KL-VS individuals a 4.49-fold (95% CI, 1.35 to 14.97) increase in relative risk for mortality after adjusting for potential confounders. Thus, cross-sectional and prospective studies confirm a genetic model in which the KL-VS allele confers a heterozygous advantage in conjunction with a marked homozygous disadvantage for HDL-C levels, SBP, stroke, and longevity.

Aged↗
PubMed2005

Inflammatory peptides derived from adipose tissue.

The low-grade inflammation seen with aging is noted particularly in subjects with the metabolic syndrome of aging. Insulin resistance, obesity/abdominal obesity, and risks for many age-related diseases characterize this common syndrome. It is becoming clear that this increased adipose tissue is not simply a reservoir for excess nutrients, but rather an active and dynamic organ capable of expressing several cytokines and other fat-derived peptides (FDP). Some, but not all, FDP may have a role in development of the metabolic syndrome but there is no evidence that these FDP are causing inflammation directly. We suggest that high levels of inflammatory peptides are markers for obesity/abdominal obesity seen with aging, but some may not necessarily have a causative role in the development of inflammation.

Editorial↗
PubMed2005

The voyage to healthy longevity: from experimental models to the ultimate goal.

Understanding mechanisms underlying longevity, and endeavor towards the specific goals of alleviating frailty in old age, require a comprehensive approach that considers the various theoretical and experimental approaches, as well as compiling the data on humans. This logistic has underlined the program of the conference, and is reflected in the present special issue. Considerable volume of data now point to distinct genes that are associated with exceptional longevity in humans, as reflected from the articles in this volume. However, this symposium also highlighted non-genetic effects, including physical, mental and social activities, and elucidate the relevant underlying mechanisms. The symposium focused on understanding the basis of human longevity coupled to extended health-span and function into old age.

Aged↗
PubMed2005

Biological evidence for inheritance of exceptional longevity.

Subjects with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. In a case control study, we aim to determine phenotype and genotype of exceptional longevity in a genetically homogenous population (Ashkenazi Jews), and their offspring, while an age-matched control group of Ashkenazi Jews was used as control groups. We demonstrated that exceptional longevity and healthy aging in humans is an inherited phenotype across three generations. Moreover, we demonstrated that subjects with exceptional longevity and their offspring have significantly larger high-density lipoprotein (HDL) levels and particle sizes and low-density lipoprotein (LDL) levels that reflect on their health and cognitive function performance. This phenotype have led us to study candidate genes involved in lipoprotein metabolism, and to the implication of homozygosity for the 405 valine (V) allele of cholesteryl ester transfer protein (CETP). A markedly higher frequency of a functional CETP variant that led to increased particle sizes of HDL and LDL and thus a better health performance is the first example of a phenotype and an associated genotype in humans with exceptional longevity. Hopefully, this line of research will lead us to establish which genotype is necessary (although not necessary sufficient) for a prolonged disease-free aging.

Age Factors↗
PubMed2005

Differential responses of visceral and subcutaneous fat depots to nutrients.

Increased visceral adiposity is a pivotal component of the metabolic syndrome. Differential gene expression patterns of fat-derived peptides (FDPs) in visceral fat and subcutaneous fat have been characterized in the fasting state. Here we examined whether delivery of nutrients differentially affects the expression of FDPs in visceral fat versus subcutaneous fat (in the fed state). We increased the rate of glucose flux into adipose tissue of normal rats (n = 16) by hyperglycemia or hyperinsulinemia using the clamp technique. Glucose uptake was associated with increased expression of FDPs, including resistin ( approximately 5-fold), adiponectin ( approximately 2-fold), leptin ( approximately 15-fold), plasminogen activating inhibitor-1 ( approximately 10-fold), and angiotensinogen ( approximately 4-fold) in visceral fat, but markedly less in subcutaneous fat. Cytokine expression derived mainly from vascular/stromal/macrophage components of adipose tissue was less dramatically increased. Infusion of glucosamine amplified the results obtained by increasing glucose uptake into adipose tissue, suggesting that flux through the hexosamine biosynthetic pathway may serve as a mechanism for "nutrient sensing." Nutrient-dependent expression of FDPs in visceral fat was also associated with increased plasma levels of several FDPs. Because a biologic sensing pathway can dynamically couple daily food intake to abnormal plasma levels of important FDPs, we challenge the practice of obtaining plasma levels after fasting to assess risk factors for metabolic syndrome.

Adipose Tissue↗
PubMed2004

The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species.

Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mm to cells differentiated at 25 mm glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mm glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by co-infusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.

3T3-L1 Cells↗
PubMed2004

Einstein's Institute for Aging Research: collaborative and programmatic approaches in the search for successful aging.

While aging research has been progressing rapidly recently, the involvement of multiple organs and systems in the aging process has hampered a comprehensive assessment of some of aging's basic features. In response to this problem, the Institute for Aging Research at Einstein did not emerge out of the traditional geriatric programs, but through enhanced collaborations between basic and clinical scientists who had successful careers in the research of a specific organ or system. The strength of the Center derives from three specific programs focused on a specific area of aging research. The programs focus on the Biology of Aging, Genetics of Aging and the Aging Brain. Each programmatic area is characterized by collaboration between basic and clinical scientists. In addition to addressing the traditional questions about the mechanisms of involution, the programs also examine the mechanisms for exceptional and healthy longevity. The mechanisms favoring longevity are being examined in models of caloric restriction (biological nutrient sensing pathways), in human centenarians (longevity genes), and in longitudinal studies identifying humans who maintain excellent cognitive function (protection from Alzheimer's). Each programmatic area is enhanced by common research core laboratory and by the creation of a scientific training program for new investigators. In addition to the investigators involved in the program project, the Institute for Aging Research includes other investigators with funded aging research who participate in journal clubs, seminars, and in specific collaborations. We suggest that this Institute serve as a model that gerontologists at other institutions should consider as they evaluate opportunities for collaborative, multi-disciplinary approaches to enhance aging research.

Academies and Institutes↗
PubMed2004

The paradox of the insulin/IGF-1 signaling pathway in longevity.

Ageing may be controlled by a genetic-hormonal system that may have originated from a very early common ancestor. One of the pathways that has been implicated in ageing is the insulin/insulin-like growth factor (IGF-1) signaling, which is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like flies, nematodes, and mammalians. While disruption of the insulin/IGF-1 receptor in nematodes and flies increases lifespan significantly, mammals with genetic or acquired defects in insulin signaling pathway are at risk for age-related diseases and increased mortality. This contradiction can be explained by the acquisition of more complicated metabolic pathways in mammalians over evolution. Mammals have insulin/IGF-1 receptors in many organs, but their functions are opposite if they are located in the central nervous system or in the periphery; whereas lower species have insulin/IGF-1 receptors signaling mainly through the nervous system. Furthermore, mammalians have different and very specific receptors for insulin and IGF-1, with distinct pathways and diverse functions. Striking evidence suggests that decreased IGF-1 levels and signaling during early development, but not the insulin signaling may modulate longevity in many species. Thus, paradoxical outcomes follow the decrease of insulin and/or IGF-1 signal pathway in invertebrates and in mammals, prolonging life in the former and shortening it in the latter. In this review we focus on the downstream cascade of events in the insulin and IGF-1 signaling to identify specific pathways that are relevant to human longevity.

Animals↗
PubMed2004

Clinical phenotype of families with longevity.

OBJECTIVES: To determine whether offspring of centenarians acquired protection from age-related diseases. DESIGN: Case-control study. SETTING: The study was part of the Longevity Genes Project at Albert Einstein College of Medicine. PARTICIPANTS: Centenarians (n=145), offspring of centenarians (n=180), and spouses of the offspring of centenarians (n=75) as a control group. Two additional groups served as controls: age-matched Ashkenazi Jews, and an age-matched control group from the Third National Health and Nutrition Examination Survey. MEASUREMENTS: Self-reported family history of longevity; prevalence of hypertension, diabetes mellitus, heart attacks, and strokes; and objective measurements of body mass index and fat mass. RESULTS: Parents of centenarians (born in approximately 1870) had a markedly greater ( approximately sevenfold) "risk" for longevity (reaching ages 90-99), supporting the notion that genetics contributed to longevity in these families. The offspring of long-lived parents had significantly lower prevalence of hypertension (by 23%), diabetes mellitus (by 50%), heart attacks (by 60%), and strokes (no events reported) than several age-matched control groups. CONCLUSION: Offspring of centenarians may inherit significantly better health. The authors suggest that a cohort of these subjects and their spouses is ideal to study the phenotype and genotype of longevity and its interaction with the environment.

Aged↗
PubMed2004

Hepatic insulin resistance precedes the development of diabetes in a model of intrauterine growth retardation.

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We developed an IUGR model in rats whereby at age 3-6 months the animals develop a diabetes that is associated with insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed at age 8 weeks, before the onset of obesity and diabetes. Basal hepatic glucose production (HGP) was significantly higher in IUGR than in control rats (14.6 +/- 0.4 vs. 12.3 +/- 0.3 mg. kg(-1). min(-1); P < 0.05). Insulin suppression of HGP was blunted in IUGR versus control rats (10.4 +/- 0.6 vs. 6.5 +/- 1.0 mg. kg(-1). min(-1); P < 0.01); however, rates of glucose uptake and glycogenolysis were similar between the two groups. Insulin-stimulated insulin receptor substrate 2 and Akt-2 phosphorylation were significantly blunted in IUGR rats. PEPCK and glucose-6-phosphatase mRNA levels were increased at least threefold in liver of IUGR compared with control rats. These studies suggest that an aberrant intrauterine milieu permanently impairs insulin signaling in the liver so that gluconeogenesis is augmented in the IUGR rat. These processes occur early in life, before the onset of hyperglycemia, and indicate that uteroplacental insufficiency causes a primary defect in gene expression and hepatic metabolism that leads to the eventual development of overt hyperglycemia.

Animals↗
PubMed2004

Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action.

While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes.

Aged↗
PubMed2003

Unique lipoprotein phenotype and genotype associated with exceptional longevity.

CONTEXT: Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. OBJECTIVE: To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. DESIGN, SETTING, AND PARTICIPANTS: In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n = 216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n = 258) and participants from the Framingham Offspring Study (n = 589) were accepted as control groups. MAIN OUTCOME MEASURES: Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. RESULTS: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P =.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P =.001 and P =.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. CONCLUSIONS: Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.

Aged↗
PubMed2003

Physiologic effect of leptin on insulin secretion is mediated mainly through central mechanisms.

Leptin has been shown to decrease glucose-stimulated insulin secretion in both in vivo and in vitro studies. As some of the effects of leptin have been elicited through both peripheral and central mechanisms, we assessed whether leptin modulates insulin secretion also through the central nervous system. We infused leptin or saline through implanted intracerebro-ventricular (ICV) catheters to chronically catheterized, conscious rats (n=15), 2 h after initiation of hyperglycemic (approximately 11 mM) clamp. On ICV administration of leptin, there was a gradual and progressive decrease in plasma insulin levels by 52% with 30 ng (P<0.005) and by 28% with 20 ng (P<0.05) of leptin compared with ICV saline. The effect of 20 ng leptin ICV was replicated by intravenous (IV) leptin infusion that achieved physiological leptin levels of approximately 17 ng/ml (n=5). When the melanocortin (MC) pathway was blocked with a nonselective MC-3/4 antagonist SHU 9119 administered ICV, and either saline or leptin (n=12) was infused IV, intravenous leptin failed to produce a decrease in glucose-stimulated insulin levels. We conclude that leptin decreases insulin levels by a predominantly central mechanism, probably via the melanocortin receptors; and peripheral leptin receptors on the beta-cells do not play a major role. The physiological features of this response suggest a possible role for leptin in the evolution of diabetes in overweight individuals.

Animals↗
PubMed2003

Surgical removal of visceral adipose tissue: effects on insulin action.

Many studies have demonstrated that excess of visceral fat has deleterious effects on insulin action. Mainly, it has been shown to be associated with a decrease in hepatic and peripheral insulin sensitivity, which results in a clinical condition also known as insulin resistance. This report describes a novel experimental method that we employed in order to analyze the particular effects of visceral fat on insulin activity. By extracting visceral fat we were able to distinguish the specific role that it plays in insulin action, and to analyze its effects on the gene expression of a variety of fat-derived peptides, which may be considered to be (at least partially) mediators in the development of the metabolic syndrome and possibly diabetes mellitus.

Adipose Tissue↗