Overexpression of CYB5R3 and NQO1, Two NAD\u3csup\u3e+\u3c/sup\u3e-Producing Enzymes, Mimics Aspects of Caloric Restriction

Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH‐dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age‐associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH‐dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+/sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan

XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility

Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of ~26 months and a nearly identical maximal life expectancy of ~37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated—weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity—HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure

XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility

Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of ~26 months and a nearly identical maximal life expectancy of ~37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated—weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity—HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure

Perspectives on Risk Perceptions

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72341/1/j.1539-6924.1981.tb01409.x.pd

Measurement of spin–lattice relaxation times and concentrations in systems with chemical exchange using the one-pulse sequence: Breakdown of the Ernst model for partial saturation in NMR spectroscopy

A fundamental problem in Fourier transform NMR spectroscopy is the calculation of observed resonance amplitudes for a repetitively pulsed sample, as first analyzed by Ernst and Anderson in 1966. Applications include determination of spin-lattice relaxation times (T 1 's) by progressive saturation and correction for partial saturation in order to determine the concentrations of the chemical constituents of a spectrum. Accordingly, the Ernst and Anderson formalism has been used in innumerable studies of chemical and, more recently, physiological systems. However, that formalism implicitly assumes that no chemical exchange occurs. Here, we present an analysis of N sites in an arbitrary chemical exchange network, explicitly focusing on the intermediate exchange rate regime in which the spin-lattice relaxation rates and the chemical exchange rates are comparable in magnitude. As a special case of particular importance, detailed results are provided for a system with three sites undergoing mutual exchange. Specific properties of the N-site network are then detailed. We find that (i) the Ernst and Anderson analysis describing the response of a system to repetitive pulsing is inapplicable to systems with chemical exchange and can result in large errors in T 1 and concentration measurements; (ii) T 1 's for systems with arbitrary exchange networks may still be correctly determined from a one-pulse experiment using the Ernst formula, provided that a short interpulse delay time and a large flip angle are used; (iii) chemical concentrations for exchanging systems may be correctly determined from a one-pulse experiment either by using a short interpulse delay time with a large flip angle, as for measuring T 1 's, and correcting for partial saturation by use of the Ernst formula, or directly by using a long interpulse delay time to avoid saturation; (iv) there is a significant signal-to-noise penalty for performing one-pulse experiments under conditions which permit accurate measurements of T 1 's and chemical concentrations. The present results are analogous to but are much more general than those that we have previously derived for systems with two exchanging sites. These considerations have implications for the design and interpretation of one-pulse experiments for all systems exhibiting chemical exchange in the intermediate exchange regime, including virtually all physiologic samples

Analysis of mitochondrial 3D-deformation in cardiomyocytes during active contraction reveals passive structural anisotropy of orthogonal short axes.

The cardiomyocyte cytoskeleton, composed of rigid and elastic elements, maintains the isolated cell in an elongated cylindrical shape with an elliptical cross-section, even during contraction-relaxation cycles. Cardiomyocyte mitochondria are micron-sized, fluid-filled passive spheres distributed throughout the cell in a crystal-like lattice, arranged in pairs sandwiched between the sarcomere contractile machinery, both longitudinally and radially. Their shape represents the extant 3-dimensional (3D) force-balance. We developed a novel method to examine mitochondrial 3D-deformation in response to contraction and relaxation to understand how dynamic forces are balanced inside cardiomyocytes. The variation in transmitted light intensity induced by the periodic lattice of myofilaments alternating with mitochondrial rows can be analyzed by Fourier transformation along a given cardiomyocyte axis to measure mitochondrial deformation along that axis. This technique enables precise detection of changes in dimension of ∼1% in ∼1 µm (long-axis) structures with 8 ms time-resolution. During active contraction (1 Hz stimulation), mitochondria deform along the length- and width-axes of the cell with similar deformation kinetics in both sarcomere and mitochondrial structures. However, significant deformation anisotropy (without hysteresis) was observed between the orthogonal short-axes (i.e., width and depth) of mitochondria during electrical stimulation. The same degree of deformation anisotropy was also found between the myocyte orthogonal short-axes during electrical stimulation. Therefore, the deformation of the mitochondria reflects the overall deformation of the cell, and the apparent stiffness and stress/strain characteristics of the cytoskeleton differ appreciably between the two cardiomyocyte orthogonal short-axes. This method may be applied to obtaining a better understanding of the dynamic force-balance inside cardiomyocytes and of changes in the spatial stiffness characteristics of the cytoskeleton that may accompany aging or pathological conditions

A Novel Extension to Fuzzy Connectivity for Body Composition Analysis: Applications in Thigh, Brain, and Whole Body Tissue Segmentation

###EgeUn###Magnetic resonance imaging (MRI) is the non-invasive modality of choice for body tissue composition analysis due to its excellent soft-tissue contrast and lack of ionizing radiation. However, quantification of body composition requires an accurate segmentation of fat, muscle, and other tissues from MR images, which remains a challenging goal due to the intensity overlap between them. In this study, we propose a fully automated, data-driven image segmentation platform that addresses multiple difficulties in segmenting MR images such as varying inhomogeneity, non-standardness, and noise, while producing a high-quality definition of different tissues. In contrast to most approaches in the literature, we perform segmentation operation by combining three different MRI contrasts and a novel segmentation tool, which takes into account variability in the data. The proposed system, based on a novel affinity definition within the fuzzy connectivity image segmentation family, prevents the need for user intervention and reparametrization of the segmentation algorithms. In order to make the whole system fully automated, we adapt an affinity propagation clustering algorithm to roughly identify tissue regions and image background. We perform a thorough evaluation of the proposed algorithm's individual steps as well as comparison with several approaches from the literature for the main application of muscle/fat separation. Furthermore, whole-body tissue composition and brain tissue delineation were conducted to show the generalization ability of the proposed system. This new automated platform outperforms other state-of-the-art segmentation approaches both in accuracy and efficiency.Intramural Research Program of the National Institute on Aging of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA); Scientific Council of Turkey [TUBITAK-BIDEB 2214/A]This work was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health. The work of I. Irmakci was supported by the Scientific Council of Turkey (TUBITAK-BIDEB 2214/A)