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

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

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

CONCENTRATION DEPENDENCE OF FRENKEL PAIR DEFECT ANNEALING IN ELECTRON IRRADIATED Ta AND Nb.

The present work is an investigation into the dose dependence of he annealing spectra of Ta and Nb from 15 to 285K after bombardment with 2.2 MeV electrons. Ta and Nb samples were irradated to different defect concentrations, then simulateouusly annealed isochronally from 14.7 up to 285K. In Ta recovery peaks were observed at 23, 51, 65, 123, and 170K. The position of the peak near 170K is dose dependent and shows the characteristics of a second-order reaction. In Nb recovery peaks were observed at 26.5, 58, 95 and 135K. The peak at 95K is dose dependent and follows second-order kinetics initially with an apparent shit to higher order toward the end of the stage. A two-interstitial model seems to give the best fit to the data

Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice.

Several murine models demonstrate that mammalian longevity can be increased by single gene mutations affecting endocrine signalling, particularly via the GH/IGF-1 axis. In this study, we identify age-independent patterns of hepatic gene expression characteristic of long-lived Snell (Pit1(dw/dwJ)) dwarf mice. Comparative microarray analysis of young and aged male livers was performed to discover specific genes differentially expressed between Pit1(dw/dwJ) and control mice. Further examination by real-time RT-PCR confirmed that transcripts encoding HMG-CoA synthase-1, HMG-CoA reductase, farnesyl diphosphate synthase, isopentenyl pyrophosphate isomerase, mevalonate decarboxylase, squalene epoxidase, lanosterol demethylase, malic enzyme and apolipoprotein A-IV were significantly decreased in both male and female Pit1(dw/dwJ) livers at 3-5 and 24-28 months of age. In contrast, transcripts encoding the beta(3)-adrenergic receptor, lipoprotein lipase, PPAR gamma and a very low-density lipoprotein receptor homologue were increased significantly in dwarf livers relative to age-matched controls. These studies reveal enduring transcriptional changes characteristic of Pit1(dw/dwJ) dwarf mice that involve genes regulating cholesterol biosynthesis, fatty acid metabolism and lipoprotein homeostasis. Linked to global energy metabolism, this stable shift in hepatic gene expression may contribute to longevity determination by influencing particular metabolic functions often compartmentalized within the mitochondrion and peroxisome; further this metabolic shift may also parallel many transcriptional changes induced by caloric restriction