Identification of longevity-associated genes in long-lived Snell and Ames dwarf mice

Abstract Recent landmark molecular genetic studies have identified an evolutionarily conserved insulin/IGF-1 signal transduction pathway that regulates lifespan. In C. elegans, Drosophila, and rodents, attenuated insulin/IGF-1 signaling appears to regulate lifespan and enhance resistance to environmental stress. The Ames (Prop1 df/df ) and Snell (Pit1 dw/dw ) hypopituitary dwarf mice with growth hormone (GH), thyroidstimulating hormone (TSH), and prolactin deficiencies live 40-60% longer than control mice. Both mutants are resistant to multiple forms of environmental stress in vitro. Taken collectively, these genetic models indicate that diminished insulin/IGF-l signaling may play a central role in the determination of mammalian lifespan by conferring resistance to exogenous and endogenous stressors. These pleiotropic endocrine pathways control diverse programs of gene expression that appear to orchestrate the development of a biological phenotype that promotes longevity. With the ability to investigate thousands of genes simultaneously, several microarray surveys have identified potential longevity assurance genes and provided information on the mechanism(s) by which the dwarf genotypes (dw/dw) and (df/df), and caloric restriction may lead to longevity. We propose that a comparison of specific changes in gene expression shared between Snell and Ames dwarf mice may provide a deeper understanding of the transcriptional mechanisms of longevity determination. Furthermore, we propose that a comparison of the physiological consequences of the Pit1dw and Prop1df mutations may reveal transcriptional profiles similar to those reported for the C. elegans and Drosophila mutants. In this study we have identified classes of genes whose expression is similarly affected in both Snell and Ames dwarf mice. Our comparative microarray data suggest that specific detoxification enzymes of the P 450 (CYP) family as well as oxidative and steroid metabolism may play a key role in longevity assurance of the Snell and Ames dwarf mouse mutants. We propose that the altered expression of these genes defines a biochemical phenotype which may promote longevity in Snell and Ames dwarf mice

Effective Estimation and Computer Control of Minimum Tumour Temperature During Conductive Interstitial Hyperthermia

The goal of heat therapy in the treatment of malignant disease is to raise the temperature of all neoplastic tissue to a cytotoxic temperature for a predetermined period of time. This seemingly simple task has proved difficult in-vivo, in part because of nonuniform power absorption and in part because of nonhomogeneous and time varying tumour blood flow. We have addressed this difficulty first by utilizing the conceptually simple technique of conductive interstitial hyperthermia, in which the tumour is warmed by multiple, electrically heated catheters, and second by implementing on-line conu·ol of minimum tumour temperatures near each catheter, estimated on the basis of the steadystate ratio of catheter power to catheter temperature rise. This report presents an analysis of the accuracy, precision, and stability of the on-line minimum temperature estimation/conu·ol technique for 22 patients who received 31 separate courses of conductive interstitial hyperthermia for the treatment of malignant brain tumours, and in whom temperature was monitored independently by 12 to 16 independent sensors per patient. In all patients, the technique was found to accurately and precisely estimate and control the local minimum temperatures. Comparison of measured and estimated temperatures revealed a mean difference of 0.0 ±0.4 °C for those sensors within 1.0 mm of the expected location for minimum temperatures. This technique, therefore, offers an attractive method for controlling hyperthermia therapy -- even in the presence of time varying local blood flow

Accuracy and precision of computer-simulated tissue temperatures in individual human intracranial tumours treated with interstitial hyperthermia

Accurate knowledge of tissue temperature is necessary for effective delivery of clinical hyperthermia in the treatment of malignant tumours. This report compares computer-predicted versus measured intratumoral temperatures in 11 human subjects with intracranial tumours, treated with a conceptually simple \u27conductive\u27 interstitial hyperthermia system. Interstitial hyperthermia was achieved by the use of parallel arrays of implanted, electrically heated catheters. The tissue was warmed by thermal conduction and blood convection. Simulation of intratumoral temperatures was achieved by solving a modified bioheat transfer equation on a digital computer using a finite difference method. Comparison of intratumoral temperatures from simulations and measured values differed by about ± 0.75 oC. Further analysis of computed temperature distributions between catheters revealed a rapidly computable relationship between the local minimum tumour temperature and nearby catheter power and temperature that accounts for effects of varying blood flow. These findings suggest that \u27on-line\u27 prediction and control of local minimum tumour temperatures are feasible with the conductive interstitial technique

Evidence of changes in regional blood perfusion in human intracranial tumours during conductive interstitial hyperthermia

Human intracranial tumours were treated using local heat therapy produced by surgically implanted catheters containing local resistive heating elements. Changes in local tumor blood flow were assessed indirectly from an algorithm based on the bioheat transfer equation. The algorithm used the ratio of catheter power to catheter temperature rise to estimate regional blood perfusion. Local heat therapy produced consistent reductions in local apparent perfusion. Changes in apparent regional perfusion occurred in intriguing patterns that gave clues to possible vascular events of therapeutic significance

On the re-acceleration of bunched beams

We examine the re-acceleration of a bunched beam through a linear induction accelerator (LIA) cavity, with attention to the energy lost through coupling to the TM modes of the structure. We find that the energy lost at 1 kA peak current is a small fraction of the boost which the LIA is designed to impart. We discuss implications for a Relativistic Klystron or Free Electron Laser (FEL) version of the Two-Beam Accelerator (TBA). 18 refs., 5 figs., 1 tab

Electron transport in TiO2 probed by THz time-domain spectroscopy

Euan Hendry, F. Wang, J. Shan, T. F. Heinz, and Mischa Bonn, Physical Review B, Vol. 69, article 081101 (2004). "Copyright © 2004 by the American Physical Society."Electron transport in crystalline TiO2 (rutile phase) is investigated by frequency-dependent conductivity measurements using THz time-domain spectroscopy. Transport is limited by electron-phonon coupling, resulting in a strongly temperature-dependent electron-optical phonon scattering rate, with significant anisotropy in the scattering process. The experimental findings can be described by Feynman polaron theory within the intermediate coupling regime and allow for a determination of electron mobility

Design and evaluation of closed-loop feedback control of minimum temperatures in human intracranial tumors treated with interstitial hyperthermia

The dynamic nature of blood flow during hyperthermia therapy has made the control of minimum tumor temperature a difficult task. This paper presents initial studies of a novel approach to closed-loop control of local minimum tissue temperatures utilizing a newly developed estimation algorithm for use with conductive interstitial heating systems. The local minimum tumor temperature is explicitly estimated from the power required to maintain each member of an array of electrically heated catheters at a known temperature, in conjunction with a new bioheat equation-based algorithm to predict the ‘droop’ or fractional decline in tissue temperature between heated catheters. A closed loop controller utilizes the estimated minimum temperature near each catheter as a feedback parameter, which reflects variations in local blood flow. In response the controller alters delivered power to each catheter to compensate for changes in blood flow. The validity and stability of this estimation/control scheme were tested in computer simulations and in closed-loop control of nine patient treatments. The average estimation error from patient data analysis of 21 sites at which temperature was independently measured (three per patient) was 0.0 oC, with a standard deviation of 0.8 oC. These results suggest that estimation of local minimum temperature and feedback control of power delivery can be employed effectively during conductive interstitial heat therapy of intracranial tumors in man

Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm.

Mutation analyses in the nematode, Caenorhabditis elegans, and mice have identified genes that increase their life-span via hormonal signal transduction, i.e. the insulin/insulin-like growth factor-1 (IGF-1) pathway in nematodes, and the growth hormone (GH)-thyriod stimulating hormone (TSH)-prolactin system in Snell dwarf mouse mutants. We have shown that the GH deficiency due to Pit1 mutation in the long-lived Snell dwarf mice may decrease circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway. The data presented are consistent with our hypothesis that the decreased circulating insulin levels resulting from the Pit1 mutation mimics a physiological state similar to that proposed to occur in the long-lived C. elegans, daf-2 mutant. Our studies demonstrate a series of changes in components of the insulin/IGF-1-signaling pathway that suggest a reduction-of-function of this pathway in the aged dwarf. These include a decreased IRS-2 pool level, a decrease in PI3K activity and its association with IRS-2 and decreased docking of p85alpha to IRS-2. Our data also suggest a preferential docking of IRS-2-p85alpha-p110alpha in the aged dwarf liver and IRS-2-p85alpha-p110beta in the aged control. We speculate that the preference for the p110alpha-containing complex may be a specific characteristic of a downstream segment of the longevity-signaling cascade. We conclude that the Pit1 mutation may result in physiological homeostasis that favors longevity, and that the Snell dwarf mutant conforms to the nematode longevity paradigm

Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse.

Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell dwarf (Pit1(dw)/Pit1(dw)) mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the dwarf mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85alpha to IRS-2; (c) docking of p85alpha to p110alpha or p110beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRbeta-IRS-1-PI3K pathway is attenuated in the Snell dwarf mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InRbeta and the docking of p85alpha to IRS-1 are attenuated in the aged Snell dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell dwarf mouse and conforms to the nematode longevity paradigm