Aging and cancer: are telomeres and telomerase the connection?

There is substantial evidence for the progressive loss of the telomeric ends of chromosomes during aging, both in cell culture and in vivo. The loss of telomeres may eventually induce antiproliferative signals that result in cellular senescence. A hypothesis gaining prominence is that the activation of telomerase, a ribonucleoprotein enzyme that is important in maintaining telomere length stability, is necessary for the sustained growth of most tumors. The interrelationships between telomere shortening and aging, and how activation of telomerase may be necessary for cells to become immortal and malignant, are reviewed here.     

Heterochromatin organization of a natural yeast telomere. Recruitment of Sir3p through interaction with histone H4 N terminus is required for the establishment of repressive structures

The chromatin organization of eukaryotic telomeres is essential for telomeric function and is currently receiving great attention. In yeast, the structural organization of telomeres involves a complex interplay of telomeric proteins that results in the formation of heterochromatin. This telomeric heterochromatin involves homotypic and heterotypic protein interactions that have been summarized in a general model. Recent analyses have focused on the study of the structural complexity at yeast telomeres to the level of specific nucleosomes and of the distribution of protein complexes in a natural telomeric region (LIII). In this report, we further analyze the structural complexity of LIII and the implication of this structure on telomeric silencing. It is shown that the establishment of repressive heterochromatin structures at LIII requires the recruitment of Sir3p through interaction with the N terminus of histone H4. The establishment of such structures does not require acetylation of any of four lysines located in the H4 N terminus (lysines 5, 8, 12, and 16).     

A theoretical framework for the study of adult cognitive plasticity.

Does plasticity contribute to adult cognitive development, and if so, in what ways? The vague and overused concept of plasticity makes these controversial questions difficult to answer. In this article, we refine the notion of adult cognitive plasticity and sharpen its conceptual distinctiveness. According to our framework, adult cognitive plasticity is driven by a prolonged mismatch between functional organismic supplies and environmental demands and denotes the brain's capacity for anatomically implementing reactive changes in behavioral flexibility (i.e., the possible range of performance and function). We distinguish between 2 interconnected but distinct cognitive outcomes of adult cognitive plasticity: alterations in processing efficiency and alterations in representations. We demonstrate the usefulness of our framework in evaluating and interpreting (a) increments in frontal brain activations in the course of normal aging and (b) the effects of cognitive training in adulthood and old age. Finally, we outline new research questions and predictions generated by the present framework and recommend design features for future cognitive-training studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexual differences in branched chain amino acid metabolism into fatty acids and cholesterol in Harderian gland of golden hamster

PURPOSE: To investigate the telomere hypothesis of cellular aging as the mechanism for cell cycle arrest in normal human corneal endothelium. METHODS: The corneal endothelium and epithelium from 21 human corneas from 13 donors 5 weeks to 84 years of age were dissected and frozen at -70 degrees C. Purified DNA, digested with the restriction enzyme, HinfI, was run on 0.7% agarose gels, probed with radiolabeled (AATCCC)4, and exposed to a phosphor screen. The length of the terminal restriction fragment (TRF) was determined by densitometry. RESULTS: The cells of the corneal endothelium had TRF lengths ranging from 11.0 to 14.0 kbp (mean, 12.2 +/- 0.9). Corneal epithelial specimens showed TRF lengths that were always less than (mean, 10.4 +/- 1.0; range 9.0-12.0) the corresponding endothelial TRF lengths. Human corneal endothelial cells, transformed with human papillomavirus type 16 oncogenes E6 and E7, showed decreasing TRF lengths from 11 kbp at population doubling level (PDL) 15 to 9.5 kbp at PDL 73. Neither the endothelial and epithelial cells from human donors nor the transformed pre-immortalized human endothelial cells showed evidence of telomerase activity. CONCLUSIONS: Human corneal endothelial cells have long telomeres throughout life. Their limited replicative ability does not appear to result from critically short telomere lengths.     

Genetics of longevity

Recent studies on the genetics of aging in the yeast Saccharomyces cerevisiae, the roundworm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster have converged revealing the central role of metabolic capacity and resistance to stress in determining life span. Signal transduction has emerged from these studies as an important molecular mechanism underlying longevity. In their broad features, the results obtained in these genetic models are applicable to the dietary restriction paradigm in mammals, suggesting a general significance. It will be of interest to determine whether many of the molecular details will also pertain. The examination of centenarian populations for the frequency of certain alleles of pertinent genes may provide insights into the relevance of the conclusions of studies in invertebrates to human aging. These population genetic studies can be augmented by mechanistic studies in transgenic mice.     

Extension of life-span by introduction of telomerase into normal human cells

Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.     

The effect of aging on hydrogen embrittlement of a nickel alloy

The effect of aging at 500° C on the hydrogen embrittlement tendency of a cold worked Ni-base superalloy was investigated in a series of experiments which included hydrogen charging studies, mechanical tests in hydrogen and in air, and fractographic and slip line investigations. Embrittlement tendency increased (time-to-failure decreased) markedly during the first hour of aging and then remained constant until about 1000 h aging time, whereupon it increased rapidly again. The short-time embrittlement could be accounted for either by a mechanism involving segregation of P to grain boundaries or by one involving planar slip induced by short-range order. The hydrogen charging studies indicated that hydrogen uptake decreases during aging, a result which is not consistent with the P segregation hypothesis. The increase in embrittlement at long aging times is most readily explained in terms of planar slip induced by long range order. Tensile tests over a range of strain rates suggested that accelerated transport of hydrogen by dislocation dragging of hydrogen atmospheres is involved in embrittlement. Formerly Graduate Assistant, Dept. of Met. Eng. & Mat. Sci., University of Notre Dame     

矿冶设备液压传动起重、升降机构分析

叙述了矿冶设备起重、升降机构采用机械传动、液压传动和气压传动的优缺点,重点说明了液压传动的特点。介绍了由增速滑轮组演变为油缸-链条（钢丝绳）倍速升降机构和由省力滑轮组演变为液压马达一链条倍力升降机构的工作原理和应用特点。     

Extragenital malignant mixed mesodermal tumor: case report and review of the literature

The hypothesis is presented that our life span is genetically programmed and that it is possible that a defect in produced proteins encoded by the 'longevity' gene is a cause of aging. A study of correlations between defective enzyme activity in two diseases characterized by premature aging (progeria and Werner's syndrome) could assist in elucidating the common mechanism for all aging processes.     

Natural history of sucking patterns in infant goats: A comparative study.

Examined temporal organization of sucking patterns, the phase interaction of sucking and other rhythmical motor patterns, and the effects of feeding on sucking rate in 26 Nubian goats. No changes in sucking rate were noted over the 1st 3 mo. The precise rate concordance between sucking and tail movements suggested that peripheral motor rhythms are regulated by a central sequencing mechanism which in turn is modulated by organismic and peripheral factors. A comparison of sucking patterns in 10 human infants and Ss indicates that qualitative species differences in the prefunctional organization of sucking influence the nature of the interaction between sucking performance and organismic or peripheral factors. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Deformation bands, the LEDS theory, and their importance in texture development: Part II. Theoretical conclusions

The facts regarding “regular” deformation bands (DBs) outlined in Part I of this series of articles are related to the low-energy dislocation structure (LEDS) theory of dislocation-based plasticity. They prompt an expansion of the theory by including the stresses due to strain gradients on account of changing selections of slip systems to the previously known dislocation driving forces. This last and until now neglected driving force is much smaller than the components considered hitherto, principally due to the applied stress and to mutual stress-screening among neighbor dislocations. As a result, it permits a near-proof of the LEDS hypothesis, to wit that among all structures which, in principle, are accessible to the dislocations, that one is realized which has the lowest free energy. Specifically, the temperature rises that would result from annihilating the largest DBs amount to only several millidegrees Centigrade, meaning that they, and by implication the entire dislocation structures, are close to thermodynamical equilibrium. This is in stark contrast to the assumption of the presently widespread self-organizing dislocation structures (SODS) modeling that plastic deformation occurs far from equilibrium and is subject to Prigogine’s thermodynamics of energy-flow-through systems. It also holds out promise for future rapid advances in the construction of constitutive equations, since the LEDS hypothesis is the principal basis of the LEDS theory of plastic deformation and follows directly from the second law of thermodynamics in conjunction with Newton’s third law. By contrast, all other known models of metal plasticity are in conflict with the LEDS hypothesis. In regard to texture modeling, the present analysis shows that Taylor’s criterion of minimum plastic work is incorrect and should be replaced by the criterion of minimum free energy in the stressed state. Last, the LEDS hypothesis is but a special case of the more general low-energy structure (LES) hypothesis, applying to plastic deformation independent of the deformation mechanism. It is thus seen that plastic deformation is one of nature’s means to generate order, as a byproduct of the entropy generation when mechanical work is largely converted into heat.