bluuebunny/crossref_metadata_2025 huggingface dataset:
Diverse but Converging Paths to European Union Membership: Poland and Turkey in Comparative Perspective
Authors: Önis Ziya
Published: July 2004

The study considers some of the key forces that have resulted in a marked divergence, at least until recently, in the fortunes of two candidate countries, Poland and Turkey, on the path to European Union membership. The more rapid progress made by Poland in this regard is explained on the basis of the systematic interaction of domestic political forces and international influences that generates virtuous or vicious cycles in terms of EU membership. The reforming elites in Poland with the help of a highly vocal civil society and mobilization from below were able to display considerable unity and commitment toward satisfying EU norms. In contrast, the “power elite” in Turkish society failed to display a similar degree of unity and commitment. Popular mobilization on a similar scale was also lacking in Turkey. In addition, the more powerful signals provided by the EU itself has helped to ease the task of reformers in Poland, helping to produce a virtuous cycle in the process.
From Neo-Liberalism to National Interests: Ideology, Strategy, and Party Development in the Euroscepticism of the Czech Right
Authors: Hanley Seán
Published: July 2004

The euroscepticism of the Czech Civic Democratic Party (ODS) is well known but has been rarely examined in detail. This is surprising, given how poorly ODS fits the profile of eurosceptic parties. These are usually marginal radical groupings. This article maps the developing euroscepticism of the Czech centre-right between 1991 and 2002. It notes a shift from a euroscepticism stressing neo-liberalism and Czech and Central European distinctness to one stressing the defence of “national interests” against German-inspired eurofederalism. Existing explanations of ODS euroscepticism present it as simultaneously ideologically dogmatic and opportunistic. A similar ideology-versus-strategy dichotomy informs much emerging euroscepticism literature. Such new centre-right parties in post-communist Europe, which originated as vehicles for post-communist transformation, challenge this view. As they become strategically and ideologically exhausted in an era of increasingly “normal” party competition, euroscepticism may enable them to combine ideological renewal and the development of new catchall appeals.
Challenging the Amyloid Cascade Hypothesis: Senile Plaques and Amyloid‐β as Protective Adaptations to Alzheimer Disease
Authors: LEE HYOUNG‐GON , CASADESUS GEMMA , ZHU XIONGWEI , TAKEDA ATSUSHI , PERRY GEORGE , SMITH MARK A.
Published: July 2004

Abstract: Ever since their initial description over a century ago, senile plaques and their major protein component, amyloid‐β, have been considered key contributors to the pathogenesis of Alzheimer disease. However, counter to the popular view that amyloid‐β represents an initiator of disease pathogenesis, we herein challenge dogma and propose that amyloid‐β occurs secondary to neuronal stress and, rather than causing cell death, functions as a protective adaptation to the disease. By analogy, individuals suffering from altitude sickness nearly always have elevated levels of hemoglobin. However, while hemoglobin is toxic to cells in culture and increased erythropoiesis at sea level can be deadly, it is clear that the increases in hemoglobin occurring at altitude are beneficial. Amyloid, like hemoglobin, may also be beneficial, in this case, following neuronal stress or disease. Although controversial, a protective function for amyloid‐β is supported by all of the available literature to date and also explains why many aged individuals, despite the presence of high numbers of senile plaques, show little or no cognitive decline. With this in mind, we suspect that current therapeutic efforts targeted toward lowering amyloid‐β production or removal of deposited amyloid‐β will only serve to exacerbate the disease process.
The Role of Viruses and of APOE in Dementia
Authors: Itzhaki R F , Dobson C B , Shipley S J , Wozniak M A
Published: July 2004

Abstract: The virus, herpes simplex virus type 1 (HSV1), when present in brain, acts together with the type 4 allele of the APOE gene, a known susceptibility factor in Alzheimer disease (AD), to confer a strong risk of AD; in carriers of the other two main alleles of the gene, the virus does not confer a risk. It also has been shown that the outcome of infection in the case of five diseases known to be caused by viruses is determined by APOE. It is hoped that the discovery of the involvement of HSV1 in AD will lead to future antiviral therapy and possibly to immunization against the virus in infancy.
Decay of Mitochondrial Metabolic Competence in the Aging Cerebellum
Authors: BERTONI‐FREDDARI CARLO , FATTORETTI PATRIZIA , GIORGETTI BELINDA , SOLAZZI MORENO , BALIETTI MARTA , DI STEFANO GIUSEPPINA , CASOLI TIZIANA
Published: July 2004

Abstract: Cytochemically evidenced cytochrome oxidase activity was morphometrically measured in the cerebellar cortex of adult and old rats. The ratio (R) between the area of the precipitate due to the cytochemical reaction and the overall area of each mitochondrion was calculated. While in adult rats an inverse correlation between mitochondrial size and R values (r=−.905) was envisaged, in old animals increasing values of R were paired by increases in mitochondrial area (r= .561). Paired‐quartile comparisons of the R values from adult and old animals documented a marked age‐related impairment of the mitochondrial metabolic competence in small (I quartile: −31.6%) and medium‐sized (II quartile: −26.4; III quartile: −16.4) mitochondria, while large organelles showed the lowest age‐related decrease (IV quartile: −3.0%). The present findings support that a marked dysfunction of small and medium‐sized mitochondria contributes to the significant decay of energy metabolism currently reported in physiological aging.
Cytochrome Oxidase Activity in Hippocampal Synaptic Mitochondria during Aging: A Quantitative Cytochemical Investigation
Authors: BERTONI‐FREDDARI CARLO , FATTORETTI PATRIZIA , GIORGETTI BELINDA , SOLAZZI MORENO , BALIETTI MARTA , CASOLI TIZIANA , DI STEFANO GIUSEPPINA
Published: July 2004

Abstract: Synaptic mitochondria, cytochemically positive to cytochrome oxidase (COX) activity, were investigated by morphometric methods in the hippocampal dentate gyrus of adult and old rats. The number of mitochondria/μm3 of tissue (Nv), the volume fraction occupied by mitochondria/μm3 of tissue (Vv), the average mitochondrial volume (V), the longer mitochondrial diameter (Fmax), and the ratio R:mitochondrial area/overall area of the cytochemical precipitate due to COX activity were measured on COX‐positive organelles. In old animals, Nv, Vv, V, and Fmax increased at a not significant extent; R was not significantly decreased. The complement (%) of longer organelles was higher in old animals. COX activity is currently considered an endogenous marker of neuronal oxidative metabolism; thus, although our findings refer to the discrete subpopulation of COX‐positive organelles located at synaptic terminals, they support that changes of mitochondrial ultrastructure and metabolic competence may contribute to the age‐related alterations of neuronal performances.
Vitamin E Deficiency and Aging Effect on Expression Levels of GAP‐43 and MAP‐2 in Selected Areas of the Brain
Authors: CASOLI TIZIANA , DI STEFANO GIUSEPPINA , DELFINO ALESSIA , FATTORETTI PATRIZIA , BERTONI‐FREDDARI CARLO
Published: July 2004

Abstract: The expression levels of GAP‐43 and MAP‐2, two proteins involved, respectively, in axonal and dendritic remodeling, in control adult (11 months), old (24 months), and vitamin E‐deficient (11 months) rats were evaluated. mRNA levels were determined by means of a quantitative in situ hybridization procedure in subregions of hippocampus and cerebellum. Though a general trend can be observed indicating a reduction in GAP‐43 expression in aging as compared to adult animals and an increase in vitamin E‐deprived rats in comparison with adult animals, no statistically significant change was found in any region analyzed. In the same way, MAP‐2 mRNA levels show an increase in vitamin E‐deprived rats in comparison with other groups tested; only one variation was statistically significant, namely the increase in cerebellar cortex MAP‐2 nRNA levels in vitamin E‐deficient versus adult rats. These results suggest that oxidative stress and aging negatively affect neuroplasticity, showing different characteristics at the dendritic and axonal levels.
Motor and Cognitive Recovery Induced by Bone Marrow Stem Cells Grafted to Striatum and Hippocampus of Impaired Aged Rats: Functional and Therapeutic Considerations
Authors: FERNÁNDEZ CARIDAD I. , ALBERTI ESTEBAN , MENDOZA YISSEL , MARTÍNEZ LISIS , COLLAZO JAIME , ROSILLO JUAN C. , BAUZA JOSÉ Y.
Published: July 2004

Abstract: Impairments in motor coordination and cognition in normal and pathological aging are often accompanied by structural changes, that is, loss of synapses and neurons. Also, it has been shown recently that bone marrow stem cells can give origin to cells of different tissues, including neural cells. Given the therapeutic implications of increasing health and functional possibilities in the aged brain, we have tested the effects of rat femur bone marrow stem cells (rBMSCs) grafting to the striatum hippocampus of aged rats with motor or cognitive deficits, respectively. Bone marrow cells were transduced with an adenovirus driving the expression of green fluorescence protein (GFP) and other classic stains to determine their migration, engraftment, differentiation, and associated behavioral recovery. Five weeks after it, control and grafted rats were re‐evaluated with the Morris Water Maze test, Passive avoidance, open‐field, motor coordination, and Marshall tests and perfused. Brains were processed and analyzed for fluorescent protein expression. GFP was detected in cells with some differentiation degree into neural‐like cells. Their exact phenotype is yet to be determined. A significant functional recovery was observed 6 weeks after grafting, suggesting a trophic interaction between rBMSCs and the aged/dystrophic host brain, or with the host brain progenitor cells and/or by increasing the number of functional cells at striatum or hippocampus, suggesting that the aging brain keeps its functional plasticity as well as that BMSCs are interesting candidates for cell replacement therapies in neurodegenerative disorders.
Response of the Senescent Heart to Stress: Clinical Therapeutic Strategies and Quest for Mitochondrial Predictors of Biological Age
Authors: ROSENFELDT FRANKLIN , MILLER FRANCIS , NAGLEY PHILLIP , HADJ ANTHONY , MARASCO SILVANA , QUICK DEAHNE , SHEERAN FREYA , WOWK MICHELLE , PEPE SALVATORE
Published: July 2004

Abstract: The aging heart has an impaired response to many kinds of stress. In clinical practice, there is a need for senescence‐specific therapies to protect against stress and for biochemical markers of senescence to identify those patients most in need of therapy. In isolated rat hearts, in human tissues, and in a clinical trial, we have shown previously that coenzyme Q10 has the ability to protect the heart against stress especially in senescence. We recently have devised a regimen of therapy to protect the senescent heart against stress, combining metabolic therapy (coenzyme Q10, alpha lipoic acid, magnesium orotate, and omega 3 polyunsaturated fatty acids) with physical exercise and mental stress reduction. The preliminary results of this program are promising. In an endeavor to predict the likely response of individual senescent hearts to stress, we correlated the tissue load of mitochondrial DNA deletions and total cellular mitochondrial DNA copy number in human cardiac tissue with recovery of the same tissue from ischemia/reperfusion stress. We found that these mitochondrial markers actually were less predictive of impaired response to stress than age alone. We conclude that the aging heart has a diminished capacity to recover from stress that is not readily predictable by cardiac content of intact mitochondrial DNA and that this recovery can be improved by metabolic therapy combined with physical exercise and mental stress reduction.
Acute Coronary Syndrome, Comorbidity, and Mortality in Geriatric Patients
Authors: TANEVA E , BOGDANOVA V , SHTEREVA N
Published: July 2004

Abstract: Morbidity and mortality rates from heart diseases are highly represented in geriatric‐aged patients, but these patients also have supporting diseases. Acute coronary syndrome includes unstable angina and acute myocardial infarction with and without ST elevation. The aim of this study was to make a retrospective morbidity analysis of patients admitted to the emergency department. The study is made for a period of three years (from 1998 to 2000). It includes 588 patients divided by age (395 were 65‐75 years old; 193 were older than 75 years) and sex (there were 326 men and 262 women). Comorbidity and mortality were investigated. Patients with one, two, three, and more than three supporting diseases were 6.29%, 23.13%, 68.53%, and 2.04%, respectively, of the total number. The most frequent geriatric patients had heart failure, followed by endocrinological diseases (type 2 diabetes, obesity, struma), neurological diseases (insultus, paresis), and chronic kidney diseases (pielonephritis, nephrolithiasis). The combination of hypertension, heart failure, and type 2 diabetes had the highest comorbidity frequency. The mortality rate for 1998 was 8.81%, for 1999 7.74%, and for 2000 13.41%. The mortality rate at the first 12 hours at the beginning of the acute coronary syndrome was 66.6%. Geriatric patients suffer from many diseases, and at the beginning of the onset of acute coronary syndrome they have multiorganal failure. Elderly patients are a high‐risk contingent in intensive coronary care units.
Macrophages of the Adrenal Cortex: A Morphological Study of the Effects of Aging and Dexamethasone Administration
Authors: ALMEIDA HENRIQUE , FERREIRA JORGE , NEVES DELMINDA
Published: July 2004

Abstract: Macrophages are present throughout the adrenal cortex, particularly in the deeper layers. They locate next to parenchyma cells, which secrete glucocorticoids under the regulation of the pituitary adrenocorticotropic hormone (ACTH). Blockade of ACTH secretion is followed by adrenocortical cell atrophy and apoptosis, an effect likely to cause an increase in local macrophage number and phagocytic activity. The purpose of the current study was to verify this effect and ascertain its age‐related variation after ACTH blockade. Male rats at five different ages ranging from 2 to 24 months were divided into two groups, which were injected with dexamethasone phosphate or saline for 3 days. The adrenals were processed for morphological and morphometric study. The age‐related increase in macrophage number seen in a survey of the sections was confirmed in the quantitative study: a significant increase in volume density (Vv), numerical density (Nv), and cell volume was found in both groups; Vv and Nv were higher in treated rats. These findings in the deeper layers of the cortex suggest a continuous process of phagocytosis, likely of parenchyma dead cells or their debris, which increases further after ACTH blockade. An additional modulatory effect of macrophages also may occur because of their secretory role.
Total Deletion of in Vivo Telomere Elongation Capacity: An Ambitious but Possibly Ultimate Cure for All Age‐Related Human Cancers
Authors: DE GREY AUBREY D. N. J. , CAMPBELL F CHARLES , DOKAL INDERJEET , FAIRBAIRN LESLIE J. , GRAHAM GERRY J. , JAHODA COLIN A. B. , PORTERG ANDREW C. G.
Published: July 2004

Abstract: Despite enormous effort, progress in reducing mortality from cancer remains modest. Can a true cancer “cure” ever be developed, given the vast versatility that tumors derive from their genomic instability? Here we consider the efficacy, feasibility, and safety of a therapy that, unlike any available or in development, could never be escaped by spontaneous changes of gene expression: the total elimination from the body of all genetic potential for telomere elongation, combined with stem cell therapies administered about once a decade to maintain proliferative tissues despite this handicap. We term this therapy WILT, for whole‐body interdiction of lengthening of telomeres. We first argue that a whole‐body gene‐deletion approach, however bizarre it initially seems, is truly the only way to overcome the hypermutation that makes tumors so insidious. We then identify the key obstacles to developing such a therapy and conclude that, while some will probably be insurmountable for at least a decade, none is a clear‐cut showstopper. Hence, given the absence of alternatives with comparable anticancer promise, we advocate working toward such a therapy.
Insights into Aging Obtained from p53 Mutant Mouse Models
Authors: DUMBLE MELISSA , GATZA CATHERINE , TYNER STUART , VENKATACHALAM SUNDARESAN , DONEHOWER LAWRENCE A.
Published: July 2004

Abstract: Cancer suppression is an integral component of longevity in organisms with renewable tissues. A number of genes in the mammalian genome function in cancer prevention, and some of these have been directly implicated in longevity assurance. One such longevity assurance gene is the tumor suppressor p53, a transcription factor that is mutated or dysregulated in most human cancers. Early studies have linked p53 to the induction of cellular senescence, whereas recent reports implicate it as a potential regulator of organismal aging. We have shown by gene inactivation studies that loss of p53 function enhances tumor susceptibility and reduces longevity in the mouse. A recent serendipitously generated p53 mutant allele resulted in a hypermorphic version of p53 that displays increased cancer resistance, yet also mediates decreased longevity. The reduced longevity is accompanied by the accelerated onset of a variety of aging phenotypes. These include a 20% decrease in median life span, early osteoporosis, lordokyphosis, organ atrophy, delayed wound healing, and a reduced regenerative response after various stresses. Since the initial characterization of these mutant mice, we have attempted to elucidate the underlying molecular and cellular mechanisms that could be influencing the early aging phenotypes. Molecular studies of the p53 mutant allele product indicate that it induces an increase in p53 activity in both in vitro and in vivo contexts. The age‐associated loss of organ cellularity and reduced tissue regenerative responses in the mutant mice are consistent with an accelerated loss of stem cell functional capacity. Our model is that enhanced growth inhibitory activity of p53 produces an earlier loss of the ability of stem cells to produce adequate numbers of progenitor and mature differentiated cells in each organ. Currently, we are performing stem cell functional assays from p53 mutant and wild‐type mice to test this model. One challenge for the future will be to find ways to manipulate p53 function to provide increased cancer resistance, yet still enhance overall organismal longevity.
Cancer as “Rejuvenescence”
Authors: UKRAINTSEVA SVETLANA V. , YASHINA ANATOLY I.
Published: July 2004

Abstract:Comparative analysis of malignant and senescent cells shows that their phenotypic features are in many instances contrary. Cancer cells do not “age”; their metabolic and growth characteristics are opposite to those observed with cellular aging (both replicative and functional). In many such characteristics, cancer cells resemble embryonic cells. One can say that cancer manifests itself as a local uncontrolled “rejuvenation” in an organism. Available evidence from human and animal studies suggests that the opposite phenotypic features of aging and cancer arise from the opposite regulation of common genes, such as those participating in apoptosis/growth arrest or in growth signal transduction pathways in the cell. For instance, in aging cells and organisms, proto‐oncogenes are often downregulated, while tumor suppressors are permanently expressed. In cancer cells the situation is just the opposite: the proto‐oncogenes are commonly overexpressed, while tumor suppressors are downregulated. This fact may have various applications for the development of new antiaging and anticancer treatments. First, genes that are oppositely regulated in cancer and aging could be candidate targets for antiaging interventions. Their “cancerlike” regulation, if strictly controlled, might help to rejuvenate the aging organism. Recent evidence from human and animal studies in support of this view is discussed. Second, the fact that cancer cells do not “age” implies that these cells may have a survival advantage in the surrounding of senescent cells. This could be a partial reason for an increase in the risk of cancer with age, because the proportion of senescent cells increases in an organism with age, too. In such a situation, the rejuvenation of normal cells surrounding the tumor might be a perspective anticancer treatment. For instance, a controlled activation of oncogenes in normal host cells or the grafting of young proliferating cells (such as embryonic stem cells) in the area near a malignant tumor might help to supplant cancer cells rather than to kill them.
Heat Shock Protein 47 Expression in Aged Normal Human Fibroblasts: Modulation by Salix alba Extract
Authors: NIZARD CARINE , NOBLESSE EMMANUELLE , BOISDÉ CÉCILLE , MOREAU MARIELLE , FAUSSAT ANNE‐MARIE , SCHNEBERT SYLVIANNE , MAHÉ CHRISTIAN
Published: July 2004

Abstract: Heat shock protein (HSP) 47 is a specific chaperone of procollagen. This heat shock protein is responsible for the correct three‐dimentional organization of procollagen and its control‐quality prior secretion. The aim of the study is to evaluate the level of HSP 47 in aged, photoaged, and senescent fibroblasts and its modulation by a plant extract (Salix alba). The level of HSP 47 and/or procollagen expression in fibroblasts was measured by real‐time RT‐PCR (mRNA transcripts) and by flow cytometry (immunochemistry technique for measurement of arbitrary fluorescence intensity). Immunochemistry techniques and confocal microscopy were used to vizualize the cellular localization of HSP 47 and procollagen. These parameters were compared with different age donors, nonsenescent, and senescent fibroblasts. Fibroblasts were irradiated by a noncytotoxic dose of UVA (6 J/cm2), and HSP 47 level was evaluated. S. alba extract was tested for its capacity to modulate HSP 47 expression. Colocalization of HSP 47 and procollagen was shown by confocal microscopy, indicating that HSP 47 could play a role of procollagen molecular chaperone in the cellular model. It was also shown that the HSP 47 level is decreased in old‐donor cells, senescent, and irradiated cells. This decrease can be modulated by a S. alba extract (polyphenols rich) in a dose‐dependent manner. The evaluation of HSP 47 expression in the experimental conditions can lead to a new approach of aging and photoaging, pointing out the implication of this chaperone in these pathophysiologic phenomena. Modulation of HSP 47 expression by this family of molecules could be of cosmetic and/or dermatologic interest.
Genetic Correction of Mitochondrial Diseases: Using the Natural Migration of Mitochondrial Genes to the Nucleus in Chlorophyte Algae as a Model System
Authors: GONZÁLEZ‐HALPHEN DIEGO , FUNES SOLEDAD , PÉREZ‐MARTÍNEZ XOCHITL , REYES‐PRIETO ADRIÁN , CLAROS M GONZALO , DAVIDSON EDGAR , KING MICHAEL P.
Published: July 2004

Abstract: Mitochondrial diseases display great diversity in clinical symptoms and biochemical characteristics. Although mtDNA mutations have been identified in many patients, there are currently no effective treatments. A number of human diseases result from mutations in mtDNA‐encoded proteins, a group of proteins that are hydrophobic and have multiple membrane‐spanning regions. One method that has great potential for overcoming the pathogenic consequences of these mutations is to place a wild‐type copy of the affected gene in the nucleus, and target the expressed protein to the mitochondrion to function in place of the defective protein. Several respiratory chain subunit genes, which are typically mtDNA encoded, are nucleus encoded in the chlorophyte algae Chlamydomonas reinhardtii and Polytomella sp. Analysis of these genes has revealed adaptations that facilitated their expression from the nucleus. The nucleus‐encoded proteins exhibited diminished physical constraints for import as compared to their mtDNA‐encoded homologues. The hydrophobicity of the nucleus‐encoded proteins is diminished in those regions that are not involved in subunit‐subunit interactions or that contain amino acids critical for enzymatic reactions of the proteins. In addition, these proteins have unusually large mitochondrial targeting sequences. Information derived from these studies should be applicable toward the development of genetic therapies for human diseases resulting from mutations in mtDNA‐encoded polypeptides.
Where and When Do Somatic mtDNA Mutations Occur?
Authors: KHRAPKO KONSTANTIN , EBRALIDSE KONSTANTIN , KRAYTSBERG YEVGENYA
Published: July 2004

Abstract: It is generally assumed that somatic mtDNA mutations are originally created in the cells where these mutations are currently found. Accumulating data indicate, however, that cells with a particular mtDNA mutation tend to “cluster,” that is, occur repeatedly within a given sample, but not in the others. Clusters likely are clonal, which implies that mtDNA mutations do not originate in the cells that currently carry them, but rather in those cells' progenitors, such as stem or satellite cells, or even earlier in the development. Importantly, a majority of mtDNA mutations appear to belong to such clusters, and thus mutational events in progenitor cells may be one of the major sources of mtDNA mutations in healthy aging tissue. More research including the analysis of multiple samples per individual is needed to confirm the existence of clustering and to distinguish between the possible clustering mechanisms.
Lysosomal Redox‐Active Iron Is Important for Oxidative Stress‐Induced DNA Damage
Authors: KURZ TINO , LEAKE ALAN , VON ZGLINICKI THOMAS , BRUNK ULF T.
Published: July 2004

Abstract: Data show that specifically chelating lysosomal redox‐active iron can prevent most H2O2‐induced DNA damage. Lysosomes seem to contain the major pool of redox‐active labile iron within the cell. Under oxidative stress conditions, this iron may then relocate to the nucleus and play an important role for DNA damage by taking part in Fenton reactions.
Age‐Related Endocrine Dysfunction in Nonhuman Primates
Authors: GONCHAROVA N D. , LAPIN B A.
Published: July 2004

Abstract: Peculiarities of functioning of some parts of the endocrine system (the pineal gland, pancreatic gland, hypothalamic‐pituitary‐adrenal axis, and hypothalamic‐pituitary‐testicular axis) in an aging nonhuman primate model (Papio hamadryas and Macaca mulatta) are described in this article. It has been established that basal activity of some endocrine functions (glucocorticoid, corticotropic, pancreatic, male estradiol producing) varies little with age. Other functions significantly decrease (DHEA/DHEAS‐producing, pineal, testicular) or increase (male gonadotropic) with age. In contrast with basal activity, pronounced age‐related changes in response to specific stimuli were detected in all endocrine functions. Old baboons and rhesus monkeys exhibited a delay of the normalization of the pituitary‐testicular axis, adrenal cortex, and pancreatic gland function after their activation in response to specific stimuli, such as LHRH, CRH, ACTH, and glucose. Old monkeys also demonstrate decreased HPA axis sensitivity to glucocorticoid regulation by negative feedback and the HPT axis to inhibitory effect of prolonged administration of LHRH agonist. Age‐related changes in reactions of endocrine functions in response to specific stimulating and inhibiting stimuli indicate impaired resiliency of these functions. Age‐related endocrine changes perhaps play a pathophysiological role in age function disorders of hormonocompetent tissues and organs and age pathology.
Secretion of Melatonin in Healthy Elderly Subjects: A Longitudinal Study
Authors: NG YING KIN N M K , NAIR N P V , SCHWARTZ G , THAVUNDAYIL J X , ANNABLE L
Published: July 2004

Abstract: We report on a 10‐year longitudinal study on 24‐h serum melatonin secretion (AUC) in healthy human subjects. Fifty women and 53 men (aged 42‐83 yr) participated in the study initially. Of these, 18 women and 15 men were followed for 6 consecutive years. Results: (a) Cross‐sectional analysis (n = 103): A significant (R=−.49, P= .0001) decline in AUC melatonin with age was found in women, but not in men. (b) Longitudinal analysis (n = 33): Repeated‐measure ANOVAs for women (n= 18): Time: linear F1,17= 5.14, P= .037. The AUC increased by about 40% over the six‐year period. In men, there were no significant changes. Conclusion: In agreement with most cross‐sectional studies, an inverse relationship was found between melatonin secretion and age. However, the longitudinal study showed an increase in melatonin secretion, indicating the presence of putative compensatory mechanisms during healthy aging. Changes in melatonin secretion were gender specific, occurring in women only.
Iron Accumulation during Cellular Senescence
Authors: KILLILEA DAVID W. , WONG STEPHANIE L. , CAHAYA HENDRY S. , ATAMNA HANI , AMES BRUCE N.
Published: July 2004

Abstract: Iron accumulates as a function of age and is associated with the pathology of numerous age‐related diseases. These changes may be caused by altered iron homeostasis at the cellular level, yet this is poorly understood. Therefore, changes in iron content in primary human fibroblasts were studied in culture models of cellular senescence. Total iron content increased exponentially during cellular senescence, reaching ∼10‐fold higher levels than young cells. Increasing intracellular iron levels through iron‐citrate supplementation or decreasing intracellular iron levels using iron‐selective chelators had little effect on cellular life span and markers of cellular senescence when used at subtoxic doses. However, accelerating cellular senescence with low‐dose H2O2 also accelerated senescence‐associated iron accumulation. Delaying cellular senescence with N‐tert‐butyl‐hydroxylamine (NtBHA) attenuated senescence‐associated iron accumulation. Furthermore, H2O2 or NtBHA had no effect on iron intracellular levels in immortalized fibroblasts. Thus, iron accumulation is not a cause, but a consequence of normal cellular senescence in vitro. Senescence‐associated iron accumulation may contribute to the increased oxidative stress and cellular dysfunction seen in senescent cells.
Investigations on the Nature of the Cost of Reproduction: Susceptibility to Heat Stress in Fruitflies
Authors: KOOCHMESHGI JALAL , LADONNI SHADI , HOSSEINI‐MAZINANI SEYED MEHDI
Published: July 2004

Abstract: Studies in various species have shown that changes in reproductive activity result in inverse changes in life span. It is interesting to know how this “cost of reproduction” is incurred. It is possible that reproductive activity renders the organism more vulnerable to stress and that accumulated damage has a role in the observed decrease in life span. Previously, other investigators had shown that mated female fruitflies have significantly shorter life spans than virgin females. We compare mated and virgin young fruitflies for susceptibility to lethal heat stress. Preliminary results suggest that mated fruitflies are significantly more susceptible to heat stress than virgin ones.
No Increase in Senescence‐Associated β‐Galactosidase Activity in Werner Syndrome Fibroblasts after Exposure to H2O2
Authors: de MAGALHÃES JOÃO PEDRO , MIGEOT VALÉRIE , MAINFROID VÉRONIQUE , de LONGUEVILLE FRANÇOISE , REMACLE JOSÉ , TOUSSAINT OLIVIER
Published: July 2004

Abstract: Normal human diploid fibroblasts (HDFs) exposed to a single H2O2 subcytotoxic stress display features of premature senescence, termed stress‐induced premature senescence (SIPS). In this work, our aim was to study SIPS in Werner syndrome (WS) fibroblasts, derived from a patient with WS, a disease resembling accelerated aging. The subcytotoxic dose for WS fibroblasts was found to be inferior to that of normal HDFs, indicating WS fibroblasts are more sensitive to hydrogen peroxide than normal HDFs. SA β‐gal activity has been shown to occur both in vitro and in vivo, and we studied the proportion of WS cells positive for SA β‐gal. Intriguingly, the percentage of positive cells did not increase with the dose of H2O2 used. Contrary to other HDFs, the DNA‐binding activity of p53 in WS fibroblasts did not increase in SIPS. We found, based on our results, that WS fibroblasts feature an altered stress response and do not reach SIPS from H2O2. We suggest that the proportion of cells that in normal HDFs would enter SIPS instead die in WS fibroblasts. Last, we propose that aging derives from a loss of integrity of the chromatin structure, which occurs faster in WS patients.
Aging and Vitamin E Deficiency Are Responsible for Altered RNA Pathways
Authors: MALATESTA MANUELA , BERTONI‐FREDDARI CARLO , FATTORETTI PATRIZIA , BALDELLI BEATRICE , FAKAN STANISLAV , GAZZANELLI GIANCARLO
Published: July 2004

Abstract: Fibrillar centers (FCs), dense fibrillar (DFC) and granular (GC) components in nucleoli, and perichromatin granules (PGs) in nucleoplasm were measured by morphometry. FC size and their nucleolar surface fraction significantly decreased in aging and vitamin E deficiency. The GC and DFC nucleolar fraction was unchanged in adult and old rats, but in vitamin E‐deficient animals GC increased and DFC decreased significantly. PG density significantly increased in aging and decreased in vitamin E deficiency. The quantitative evaluation of immunolabeled transcription and splicing factors revealed that polymerase II and SC‐35 significantly decreased in old and vitamin E‐deficient versus adult animals. Fibrillarin and snRNPs did not change between adult and old rats, but were significantly lower in vitamin E‐deficient rats. These data document altered RNA pathways in aging and vitamin E deficiency. Considering the antioxidant role of vitamin E, they lend further support to the importance of free radical production and control in the aging process.
Prolongevity Medicine: Antagonic‐Stress® Drug in Distress, Geriatrics, and Related Diseases. II. Clinical Review—2003
Authors: RIGA S , RIGA D , SCHNEIDER F
Published: July 2004

Abstract: Distress and senescence, their reciprocal aggravating‐quickening connections, and their related pathologies have a large worldwide impact on healthcare systems in this new millennium. For this reason, Antagonic‐Stress® (AS)—an advanced integrative therapy, with specific synergistic composition, and patented internationally—represents a significant strategy in health, aging, and longevity. Clinical research with AS proves the drug's efficacy in the management of distress (neurotic, stress‐related, and affective disorders; behavioral syndromes associated with physiological disturbances and physical factors; mental and behavioral disorders due to psychoactive substance uses) and psychogeriatrics [organic, including symptomatic, mental disorders (OMD)]. Specific multiaxial psychopathological instruments and psychometric tests in multiple assessments used for gerontopsychiatry demonstrated strong improvements after AS administration in early‐moderate stages of Alzheimer or vascular dementia, as well as in other OMD. In addition, comparative clinical studies evinced the superiority of AS (synergistic multitherapy) versus monotherapy [meclofenoxate (MF), piracetam (PA), pyritinol (PT), and nicergoline (NE), respectively]. These comparative clinical trials agreed closely with comparative preclinical research and confirmed AS synergistic homeostatic, adaptogenic, antioxidative, cerebrovascular, neurometabolic, and nootropic actions. Also, the AS protective actions against oxidative stress recommend this orthomolecular therapy in stress, aging, and free radical pathology.
Development of Calorie Restriction Mimetics as a Prolongevity Strategy
Authors: INGRAM DONALD K. , ANSON R MICHAEL , DE CABO RAFAEL , MAMCZARZ JACEK , ZHU MIN , MATTISON JULIE , LANE MARK A. , ROTH GEORGE S.
Published: July 2004

Abstract: By applying calorie restriction (CR) at 30‐50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset of age‐related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create “caloric restriction mimetics” has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. Drugs that inhibit glycolysis (2‐deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated brain‐derived neurotrophic factor. Further life span analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field.
Reproductive Switch and Aging: The Case of Leptin Change in Dietary Restriction
Authors: KOOCHMESHGI JALAL
Published: July 2004

Abstract: We have proposed that normal food intake is geared toward optimizing the internal milieu for reproduction, despite some components of this milieu being detrimental to health. In dietary restriction, the animal is prevented from eating enough to attain or maintain reproductive capacity and this particular milieu does not materialize. Life extension occurs as a by‐product. This idea provides a framework for exploring biomolecular changes in dietary restriction and their relevance to aging. Leptin is a case in point: here, a decrease in leptin level in dietary restriction is explored in the light of leptin's role in the complex signaling system of reproductive switch.
Caloric Restriction Modulates Early Events in Insulin Signaling in Liver and Skeletal Muscle of Rat
Authors: ZHU MIN , DE CABO RAFAEL , LANE MARK A. , INGRAM DONALD K.
Published: July 2004

Abstract: Mutations that extend life span in C. elegans suggest that the insulin/IGF‐1 signaling (IS) pathway may play a key role in retarding aging and extending life span by caloric restriction (CR). To evaluate this hypothesis, male rats were subjected to either AL (ad libitum) or CR (40% from AL) for 2 and 25 months, and then the effects of CR on the early events in the IS pathway in liver and muscle were assessed. The results indicated that aging was accompanied by a significant decline in insulin receptor tyrosine phosphorylation (pY‐IR) upon insulin stimulation in both tissues, which was correlated with a significant increase in the activity of protein tyrosine phosphatase 1B (PTP‐1B). However, these alterations with age were attenuated by 25CR. Parallel changes observed in liver mRNA of CR rats were upregulated insulin receptor (IR), IGF‐1R and IRS‐1, but increased expression of IR mRNA was dissociated with the IR protein in 25CR rats. The expression of liver mRNAs involved in lipid metabolism was also analyzed. In contrast to 25AL rats, the expression of mRNAs for PPARs (α, δ, and γ) was significantly increased in 25CR rats. SREBP‐1c and fatty acid synthase were reduced, and other genes were increased, including hormone‐sensitive lipase and PGC‐1 by CR. The data suggest that the normal function of insulin receptor in liver and muscle is required for successful aging. An altered expression of transcription of a number of genes involved in lipid metabolism may also contribute to modulation of the IS pathway by CR.
Regular Exercise: An Effective Means to Reduce Oxidative Stress in Old Rats
Authors: GOTO SATARO , RADÁK ZSOLT , NYAKAS CSABA , CHUNG HAE YOUNG , NAITO HISASHI , TAKAHASHI RYOYA , NAKAMOTO HIDEKO , ABEA RYOICHI
Published: July 2004

Abstract: A healthy diet and regular exercise are among the major factors that influence quality of life (QOL) in old age. Exercise is believed to be beneficial to improve QOL, retarding age‐related decline of physiological functions and preventing age‐related diseases. Regular physical exercise can possibly improve age‐related functional decline and delay onset of age‐related diseases by attenuating potentially harmful oxidative damage and suppressing inflammatory processes even in older age.
Early‐Life Programming of Aging and Longevity: The Idea of High Initial Damage Load (the HIDL Hypothesis)
Authors: GAVRILOV LEONID A. , GAVRILOVA NATALIA S.
Published: July 2004

Abstract: In this study, we test the predictions of the high initial damage load (HIDL) hypothesis, a scientific idea that early development of living organisms produces an exceptionally high load of initial damage, which is comparable with the amount of subsequent aging‐related deterioration accumulating during the rest of the entire adult life. This hypothesis predicts that even small progress in optimizing the early‐developmental processes can potentially result in a remarkable prevention of many diseases in later life, postponement of aging‐related morbidity and mortality, and significant extension of healthy life span.
Testing the Free Radical Theory of Aging in Bats
Authors: BRUNET ROSSINNI ANJA K.
Published: July 2004

Abstract: The extended longevity of bats, despite their high metabolic rates, may provide insight to patterns and mechanisms of aging. I tested the free radical theory of aging as an explanation for the extreme longevity of the little brown bat, Myotis lucifugus (maximum life span potential [MLSP] = 34 years). In a comparative study, I measured whole‐organism oxygen consumption and mitochondrial hydrogen peroxide production in brain, heart, and kidney tissues from M. lucifugus and short‐tailed shrews, Blarina brevicauda (MLSP = 2 years). As predicted by the free radical theory of aging, M. lucifugus produced approximately half the amount of hydrogen peroxide as B. brevicauda. In addition, I compared oxygen consumption and hydrogen peroxide production of adult (∼1 year) and juvenile (fully developed and fledged young of the year) M. lucifugus to assess oxidative damage to mitochondria (measured as an increase in hydrogen peroxide production) due to the high metabolic rate associated with flight. Contrary to my prediction, juveniles had significantly higher levels of hydrogen peroxide production than adults. I propose that the decreased free radical production in adults is the result of within‐individual selection of efficient mitochondria due to selective pressure created by the high energetic demands of flight.
Does Exceptional Human Longevity Come with a High Cost of Infertility?: Testing the Evolutionary Theories of Aging
Authors: GAVRILOVA NATALIA S. , GAVRILOV LEONID A. , SEMYONOVA VICTORIA G. , EVDOKUSHKINA GALINA N.
Published: July 2004

Abstract: The purpose of this study is to test the prediction of the evolutionary theory of aging that human longevity comes with the cost of impaired reproductive success (higher infertility rates). Our validation study is based on the analysis of particularly reliable genealogical records for European aristocratic families using a logistic regression model with childlessness as a dependent (outcome) variable, and woman's life span, year of birth, age at marriage, husband's age at marriage, and husband's life span as independent (predictor) variables. We found that the woman's exceptional longevity did not increase her chances of being infertile. It appears that the previous reports by other authors of high infertility among long‐lived women (up to 50% infertility) are related to incomplete data, that is, births of children not reported. Thus, the concept of the high cost of infertility for human longevity is not supported by the data when these data are carefully cross‐checked, cleaned, and reanalyzed.
Functional Aging and Gradual Senescence in Zebrafish
Authors: KISHI SHUJI
Published: July 2004

Abstract: Zebrafish (Danio rerio) has been recognized as a powerful model for genetic studies in developmental biology. Recently, the zebrafish system also has given insights into several human diseases such as neurodegenerative, hematopoietic, and cardiovascular disease, and cancer. Because aging processes affect these and various other human disorders, it is important to compare zebrafish and mammalian senescence. However, the aging process of zebrafish remains largely unexplored, and little is known about functional aging and senescence in zebrafish. In our initial studies to assess aging phenotypes in zebrafish, we have identified several potential aging biomarkers in an ongoing search for suitable ones on zebrafish aging. In aging zebrafish, we detected senescence‐associated β‐galactosidase activity in skin and oxidized protein accumulation in muscle. On the other hand, we did not observe lipofuscin granules (aging pigments), which accumulate in postmitotic cells, in muscle of zebrafish with advancing age. Consistently, there were continuously proliferating myocytes that incorporated BrdU in muscle tissues of the aged fish. Moreover, we demonstrated that zebrafish have constitutively abundant telomerase activity in adult somatic tissues implicating unlimited replicative ability of cells throughout their lives. Although some stress‐associated markers are upregulated and minor histological changes are observed during the aging process of zebrafish, our studies together with other evidence of remarkable reproductive and regenerative abilities suggest that zebrafish show very gradual senescence. By using those biological and biochemical aging markers already characterized in normal zebrafish, transgenic fish analyses and genetic mutant fish screens can be readily performed. These efforts will help to elucidate the role and molecular mechanisms of common or different pathways of aging among vertebrates from fish to humans and also will contribute to the discovery of potential drugs applicable to age‐associated diseases in the future.
Collective Suttee: Is It Unjust to Develop Life Extension if It Will Not Be Possible to Provide It to Everyone?
Authors: DAVIS JOHN K.
Published: July 2004

Abstract: If we can anticipate that life extension will be too expensive to provide to everyone, is that a reason not to research and develop it?Collective suttee is the policy of inhibiting or prohibiting life extension on such grounds: just as widows are killed on their husbands' funeral pyres, potential Methuselahs would not be allowed to outlive everyone else. However, in other contexts we judge that taking from the haves is unjustified when doing so confers a merely marginal benefit—or no benefit—to the have‐nots. By this standard, collective suttee is probably unjustified, for the burdens borne by the have‐nots are likely to be too small to justify denying extra decades or centuries to those who can afford it.