As survival among children treated for cancer continues to improve, more attention is being focussed on the late effects of cancer treatment. In children treated for brain tumours, chronic neurocognitive effects are especially challenging. Deficits in cognitive development have been described most thoroughly among children treated for posterior-fossa tumours, specifically medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumours in children. Most children who have survived brain tumours have required surgical resection and focal or craniospinal radiotherapy (irradiation of the entire subarachnoid volume of the brain and spine), with or without systemic chemotherapy. Historically, intelligence quotient (IQ) scores have provided a benchmark against which to measure changes in cognitive development after treatment. Observed declines in IQ are most likely a result of failure to learn at a rate that is appropriate for the age of the child, rather than from a loss of previously acquired knowledge. The rate of IQ decline is associated with a several risk factors, including younger age at time of treatment, longer time since treatment, female sex, as well as clinical variables such as hydrocephalus, use of radiotherapy and radiotherapy dose, and the volume of the brain that received treatment. Loss of cerebral white matter and failure to develop white matter at a rate appropriate to the developmental stage of the child could partly account for changes in IQ score. Technical advances in radiotherapy hold promise for lowering the frequency of neurocognitive sequelae. Further efforts to limit neurocognitive sequelae have included design of clinical trials to test the effectiveness of cognitive, behavioural, and pharmacological interventions.

Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.

Increasing atmospheric concentrations of methane have led scientists to examine its sources of origin. Ruminant livestock can produce 250 to 500 L of methane per day. This level of production results in estimates of the contribution by cattle to global warming that may occur in the next 50 to 100 yr to be a little less than 2%. Many factors influence methane emissions from cattle and include the following: level of feed intake, type of carbohydrate in the diet, feed processing, addition of lipids or ionophores to the diet, and alterations in the ruminal microflora. Manipulation of these factors can reduce methane emissions from cattle. Many techniques exist to quantify methane emissions from individual or groups of animals. Enclosure techniques are precise but require trained animals and may limit animal movement. Isotopic and nonisotopic tracer techniques may also be used effectively. Prediction equations based on fermentation balance or feed characteristics have been used to estimate methane production. These equations are useful, but the assumptions and conditions that must be met for each equation limit their ability to accurately predict methane production. Methane production from groups of animals can be measured by mass balance, micrometeorological, or tracer methods. These techniques can measure methane emissions from animals in either indoor or outdoor enclosures. Use of these techniques and knowledge of the factors that impact methane production can result in the development of mitigation strategies to reduce methane losses by cattle. Implementation of these strategies should result in enhanced animal productivity and decreased contributions by cattle to the atmospheric methane budget.

We address three problems that limit the use of the atomic force microscope when measuring elastic moduli of soft materials at microscopic scales. The first concerns the use of sharp cantilever tips, which typically induce local strains that far exceed the linear material regime. We show that this problem can be alleviated by using microspheres as probes, and we establish the criteria for their use. The second relates to the common use of the Hertz contact mechanics model, which leads to significant errors when applied to thin samples. We develop novel, simple to use corrections to apply for such cases. Samples that are either bonded or not bonded to a rigid substrate are considered. The third problem concerns the difficulty in establishing when contact occurs on a soft material. We obtain error estimates for the elastic modulus resulting from such uncertainty and discuss the sensitivity of the estimation methods to error in contact point. The theoretical and experimental results are compared to macroscopic measurements on poly(vinyl-alcohol) gels.

Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.

BACKGROUND

Seafood is the predominant source of omega-3 fatty acids, which are essential for optimum neural development. However, in the USA, women are advised to limit their seafood intake during pregnancy to 340 g per week. We used the Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the possible benefits and hazards to a child's development of different levels of maternal seafood intake during pregnancy.

METHODS

11,875 pregnant women completed a food frequency questionnaire assessing seafood consumption at 32 weeks' gestation. Multivariable logistic regression models including 28 potential confounders assessing social disadvantage, perinatal, and dietary items were used to compare developmental, behavioural, and cognitive outcomes of the children from age 6 months to 8 years in women consuming none, some (1-340 g per week), and >340 g per week.

RESULTS

After adjustment, maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ) (no seafood consumption, odds ratio [OR] 1.48, 95% CI 1.16-1.90; some, 1.09, 0.92-1.29; overall trend, p=0.004), compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor, communication, and social development scores. For each outcome measure, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome.

CONCLUSIONS

Maternal seafood consumption of less than 340 g per week in pregnancy did not protect children from adverse outcomes; rather, we recorded beneficial effects on child development with maternal seafood intakes of more than 340 g per week, suggesting that advice to limit seafood consumption could actually be detrimental. These results show that risks from the loss of nutrients were greater than the risks of harm from exposure to trace contaminants in 340 g seafood eaten weekly.

We demonstrate single-molecule fluorescence imaging beyond the optical diffraction limit in 3 dimensions with a wide-field microscope that exhibits a double-helix point spread function (DH-PSF). The DH-PSF design features high and uniform Fisher information and has 2 dominant lobes in the image plane whose angular orientation rotates with the axial (z) position of the emitter. Single fluorescent molecules in a thick polymer sample are localized in single 500-ms acquisitions with 10- to 20-nm precision over a large depth of field (2 microm) by finding the center of the 2 DH-PSF lobes. By using a photoactivatable fluorophore, repeated imaging of sparse subsets with a DH-PSF microscope provides superresolution imaging of high concentrations of molecules in all 3 dimensions. The combination of optical PSF design and digital postprocessing with photoactivatable fluorophores opens up avenues for improving 3D imaging resolution beyond the Rayleigh diffraction limit.

Formerly called IFN-gamma-inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as TH1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-lR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18Rbeta, also a member of the IL-1R family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.

In this paper basic mathematical and physical concepts of the biomagnetic inverse problem are reviewed with some new approaches. The forward problem is discussed for both homogeneous and inhomogeneous media. Geselowitz' formulae and a surface integral equation are presented to handle a piecewise homogeneous conductor. The special cases of a spherically symmetric conductor and a horizontally layered medium are discussed in detail. The non-uniqueness of the solution of the magnetic inverse problem is discussed and the difficulty caused by the contribution of the electric potential to the magnetic field outside the conductor is studied. As practical methods of solving the inverse problem, a weighted least-squares search with confidence limits and the method of minimum norm estimate are discussed.

Brain-derived neurotrophic factor (BDNF), a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor, mediates neuronal survival, differentiation, synaptic plasticity, and neurogenesis. However, BDNF has a poor pharmacokinetic profile that limits its therapeutic potential. Here we report the identification of 7,8-dihydroxyflavone as a bioactive high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signaling. 7,8-Dihydroxyflavone protected wild-type, but not TrkB-deficient, neurons from apoptosis. Administration of 7,8-dihydroxyflavone to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson disease. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases.

Adenosine accumulation during ischemia and inflammation protects tissues from injury. In ischemic tissues adenosine accumulates due to inhibition of adenosine kinase, and in inflamed tissues adenosine is formed from adenine nucleotides that are released from many cells including platelets, mast cells, nerves, and endothelium. Nucleotides are rapidly converted to adenosine by a family of ecto-nucleotidases including CD39 and CD73. Activation of A(1) and possibly A(3) adenosine receptors (ARs) protects heart and other tissues by preconditioning through a pathway including protein kinase C and mitochondrial K(ATP) channels. Activation of A(2A) receptors limits reperfusion injury by inhibiting inflammatory processes in neutrophils, platelets, macrophages and T cells. Adenosine produces proinflammatory responses mediated by receptors that vary among species; A(3) and A(2B) receptors mediate degranulation of rodent and human or canine mast cells, respectively. Novel adenosine receptor subtype-selective ligands have recently been developed. These include MRS1754 (A(2B) blocker), MRS1220 (A(3) blocker), MRE 3008F20 (human A(3) blocker), MRS1523 (rat A(3) blocker), and ATL146e (A(2A) agonist). These new pharmacologic tools will help investigators to sort out how adenosine protects tissues from injury and to identify new therapeutic agents that hold promise for the treatment of inflammatory and ischemic diseases.

Neurogenesis must be properly regulated to ensure that cell production does not exceed the requirements of the growing cerebral cortex, yet our understanding of mechanisms that restrain neuron production remains incomplete. We investigated the function of microglial cells in the developing cerebral cortex of prenatal and postnatal macaques and rats and show that microglia limit the production of cortical neurons by phagocytosing neural precursor cells. We show that microglia selectively colonize the cortical proliferative zones and phagocytose neural precursor cells as neurogenesis nears completion. We found that deactivating microglia in utero with tetracyclines or eliminating microglia from the fetal cerebral cortex with liposomal clodronate significantly increased the number of neural precursor cells, while activating microglia in utero through maternal immune activation significantly decreased the number of neural precursor cells. These data demonstrate that microglia play a fundamental role in regulating the size of the precursor cell pool in the developing cerebral cortex, expanding our understanding of the mechanisms that regulate cortical development. Furthermore, our data suggest that any factor that alters the number or activation state of microglia in utero can profoundly affect neural development and affect behavioral outcomes.

The intestinal epithelium forms a physical barrier to limit access of enteric microbes to the host and contributes to innate host defense by producing effector molecules against luminal microbes. To further define the role of the intestinal epithelium in antimicrobial host defense, we analyzed the expression, regulation, and production of two antimicrobial peptides, human defensins hBD-1 and hBD-2, by human intestinal epithelial cells in vitro and in vivo. The human colon epithelial cell lines HT-29 and Caco-2 constitutively express hBD-1 mRNA and protein but not hBD-2. However, hBD-2 expression is rapidly induced by IL-1alpha stimulation or infection of those cells with enteroinvasive bacteria. Moreover, hBD-2 functions as a NF-kappaB target gene in the intestinal epithelium as blocking NF-kappaB activation inhibits the up-regulated expression of hBD-2 in response to IL-1alpha stimulation or bacterial infection. Caco-2 cells produce two hBD-1 isoforms and a hBD-2 peptide larger in size than previously described hBD-2 isoforms. Paralleling the in vitro findings, human fetal intestinal xenografts constitutively express hBD-1, but not hBD-2, and hBD-2 expression, but not hBD-1, is up-regulated in xenografts infected intraluminally with Salmonella. hBD-1 is expressed by the epithelium of normal human colon and small intestine, with a similar pattern of expression in inflamed colon. In contrast, there is little hBD-2 expression by the epithelium of normal colon, but abundant hBD-2 expression by the epithelium of inflamed colon. hBD-1 and hBD-2 may be integral components of epithelial innate immunity in the intestine, with each occupying a distinct functional niche in intestinal mucosal defense.

The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degradation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the beta-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve beta-cell function and/or survival in the treatment of diabetes.

Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression.

Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.

The purpose of this paper is to point out some limits and inconsistencies in the table of nonprotein respiratory quotient that is universally used. This table, developed by Lusk in 1924, was derived from biochemical and physical data that are now outdated. A new table of nonprotein respiratory quotient, consistent with modern chemical and physical data, is proposed. The revised table is based on (a) the average composition of human triacylglycerol stores, (b) energy potential of fatty acids and glucose, and (c) the volumes occupied by one mole of oxygen or carbon dioxide (which are not ideal gases) under STPD conditions.

Nitrite (NO(2)(-)) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II-IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet.

Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified.

T-regulatory cells (Tregs) are found infiltrating tumors in a vast array of tumor types, and tumor-infiltrating Tregs are often associated with a poor clinical outcome. Tregs are potent immunosuppressive cells of the immune system that promote progression of cancer through their ability to limit antitumor immunity and promote angiogenesis. Here, we discuss the ways in which Tregs suppress the antitumor immune response and elaborate on our recent discovery that Tregs make significant direct contributions to tumor angiogenesis. Further, we highlight several current therapies aimed at eliminating Tregs in cancer patients. Given the multifaceted role of Tregs in cancer, a greater understanding of their functions will ultimately strengthen future therapies.

Current neuroimaging software offer users an incredible opportunity to analyze their data in different ways, with different underlying assumptions. Several sophisticated software packages (e.g., AFNI, BrainVoyager, FSL, FreeSurfer, Nipy, R, SPM) are used to process and analyze large and often diverse (highly multi-dimensional) data. However, this heterogeneous collection of specialized applications creates several issues that hinder replicable, efficient, and optimal use of neuroimaging analysis approaches: (1) No uniform access to neuroimaging analysis software and usage information; (2) No framework for comparative algorithm development and dissemination; (3) Personnel turnover in laboratories often limits methodological continuity and training new personnel takes time; (4) Neuroimaging software packages do not address computational efficiency; and (5) Methods sections in journal articles are inadequate for reproducing results. To address these issues, we present Nipype (Neuroimaging in Python: Pipelines and Interfaces; http://nipy.org/nipype), an open-source, community-developed, software package, and scriptable library. Nipype solves the issues by providing Interfaces to existing neuroimaging software with uniform usage semantics and by facilitating interaction between these packages using Workflows. Nipype provides an environment that encourages interactive exploration of algorithms, eases the design of Workflows within and between packages, allows rapid comparative development of algorithms and reduces the learning curve necessary to use different packages. Nipype supports both local and remote execution on multi-core machines and clusters, without additional scripting. Nipype is Berkeley Software Distribution licensed, allowing anyone unrestricted usage. An open, community-driven development philosophy allows the software to quickly adapt and address the varied needs of the evolving neuroimaging community, especially in the context of increasing demand for reproducible research.

Iron deficiency is one of the leading risk factors for disability and death worldwide, affecting an estimated 2 billion people. Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations consuming monotonous plant-based diets. The high prevalence of iron deficiency in the developing world has substantial health and economic costs, including poor pregnancy outcome, impaired school performance, and decreased productivity. Recent studies have reported how the body regulates iron absorption and metabolism in response to changing iron status by upregulation or downregulation of key intestinal and hepatic proteins. Targeted iron supplementation, iron fortification of foods, or both, can control iron deficiency in populations. Although technical challenges limit the amount of bioavailable iron compounds that can be used in food fortification, studies show that iron fortification can be an effective strategy against nutritional iron deficiency. Specific laboratory measures of iron status should be used to assess the need for fortification and to monitor these interventions. Selective plant breeding and genetic engineering are promising new approaches to improve dietary iron nutritional quality.

The gating kinetics of a Ca2+-activated K+ channel from adult rat muscle plasma membrane are studied in artificial planar bilayers. Analysis of single-channel fluctuations distinguishes two Ca2+- and voltage-dependent processes: (a) short-lived channel closure (less than 1 ms) events appearing in a bursting pattern; (b) opening and closing events ranging from one to several hundred milliseconds in duration. The latter process is studied independently of the first and is denoted as the primary gating mode. At constant voltage, the mean open time of the primary gating mode is a linear function of the [Ca2+], whereas the mean closed time is a linear function of the reciprocal [Ca2+]. In the limits of zero and infinite [Ca2+], the mean open and the mean closed times are, respectively, independent of voltage. These results are predicted by a kinetic scheme consisting of the following reaction steps: (a) binding of Ca2+ to a closed state; (b) channel opening; (c) binding of a second Ca2+ ion. In this scheme, the two Ca2+ binding reactions are voltage dependent, whereas the open-closed transition is voltage independent. The kinetic constant derived for this scheme gives an accurate theoretical fit to the observed equilibrium open-state probability. The results provide evidence for a novel regulatory mechanism for the activity of an ion channel: modulation by voltage of the binding of an agonist molecule, in this case, Ca2+ ion.

The relationships between mitochondrial respiration, reactive oxygen species (ROS), and life span are complex and remain controversial. Inhibition of the target of rapamycin (TOR) signaling pathway extends life span in several model organisms. We show here that deletion of the TOR1 gene extends chronological life span in Saccharomyces cerevisiae, primarily by increasing mitochondrial respiration via enhanced translation of mtDNA-encoded oxidative phosphorylation complex subunits. Unlike previously reported pathways regulating chronological life span, we demonstrate that deletion of TOR1 delays aging independently of the antioxidant gene SOD2. Furthermore, wild-type and tor1 null strains differ in life span only when respiration competent and grown in normoxia in the presence of glucose. We propose that inhibition of TOR signaling causes derepression of respiration during growth in glucose and that the subsequent increase in mitochondrial oxygen consumption limits intracellular oxygen and ROS-mediated damage during glycolytic growth, leading to lower cellular ROS and extension of chronological life span.