bluuebunny/crossref_metadata_2025 huggingface dataset:
The Extent and Significance of Telomere Loss with Age
Authors: BAIRD DUNCAN M. , KIPLING DAVID
Published: July 2004

Abstract: By imposing a limit on the proliferative life span of some human cell types, telomere loss and the subsequent onset of replicative senescence have been proposed to contribute to age‐related disease. Although there is a large body of in vitro data to reveal the mechanisms by which telomere erosion triggers senescence, technical limitations have hampered our ability to understand the full extent of telomere erosion in vivo. Thus far, we have evidence of age‐related telomere loss; however, the lack of resolution of existing technologies does not allow us to determine if telomere erosion is extensive enough to trigger replicative senescence in vivo. This coupled with the considerable interindividual heterogeneity, and the overlap in telomere lengths between young and elder individuals, render any correlation weak and the significance unclear. However, recent technical developments, including adaptations of quantitative telomere fluorescence, in situ hybridization (Q‐FISH), and the PCR‐based single telomere length analysis (STELA), have increased the resolution of telomere length analysis. These technologies promise to provide the evidence required to address the full extent and significance of telomere loss in the human aging process. Here, we review published data on the dynamics of telomere erosion with age in the human body.
Measurement of the 4,834‐bp Mitochondrial DNA Deletion Level in Aging Rat Liver and Brain Subjected or Not to Caloric Restriction Diet
Authors: CASSANO P , LEZZA A M S , LEEUWENBURGH C , CANTATORE P , GADALETAa M N
Published: July 2004

Abstract: Several studies have demonstrated an age‐related accumulation of the amount of a specific 4834‐bp mitochondrial DNA (mtDNA) deletion in different tissues of rat (liver, brain, and skeletal muscle). We investigated the influence of a caloric restriction diet (CR) on a selected age‐associated marker of mtDNA damage, as the 4834‐bp deletion, using quantitative real‐time PCR. The mtDNA deleted level has been determined with respect to the mitochondrial D‐loop level, using specific primers and TaqMan probes for each target. In liver we found an age‐related increase of the deletion level (twofold) that was reversed and brought back to the adult level by a CR diet. On the contrary, in the brain the age‐related increase of the deletion level (eightfold) was not affected by CR at all. The different effect of the CR on the deletion level in liver and brain might be a further element supporting the tissue‐specificity of the aging process.
Investigation of the Signaling Pathways Involved in the Proliferative Life Span Barriers in Werner Syndrome Fibroblasts
Authors: DAVIS TERENCE , FARAGHER RICHARD G. A. , JONES CHRISTOPHER J. , KIPLING DAVID
Published: July 2004

Abstract: Werner syndrome (WS) fibroblasts enter replicative senescence after a reduced in vitro life span. Although this has been postulated as causal in the accelerated aging seen in this disease, controversy remains as to whether WS is showing the acceleration of a normal cellular aging mechanism or, instead, the occurrence of a novel WS‐specific process. To address this, we analyzed the signaling pathways involved in senescence in WS fibroblasts. Cultured WS fibroblasts underwent senescence after ∼20 population doublings, with the majority of the cells having a 2N DNA content. This was associated with high levels of the CdkIs p16 and p21. Senescent WS cells reentered the cell cycle after microinjection of a p53‐neutralizing antibody. Similarly, presenescent WS fibroblasts expressing the E6 and/or E7 oncoproteins bypassed M1 and ultimately reached a second proliferative life span barrier, which strongly resembled the second life span barriers found in normal cells for growth dynamics, cellular morphology, and expression of p16 and p21. The strong similarity between the signaling pathways triggering cell cycle arrest in WS and normal fibroblasts provides support for the defect in WS causing the acceleration of a normal aging mechanism and validates the use of WS as a model for some aspects of human aging.
Mechanism of Telomere Shortening by Oxidative Stress
Authors: KAWANISHI SHOSUKE , OIKAWA SHINJI
Published: July 2004

Abstract: We investigated whether oxidative stress, which contributes to aging, accelerates the telomere shortening in human cultured cells. The terminal restriction fragment (TRF) from WI‐38 fibroblasts irradiated with UVA (365‐nm light) decreased with increasing of the irradiation dose. Furthermore, UVA irradiation dose‐dependently increased the formation of 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine (8‐oxodG) in both WI‐38 fibroblasts and HL‐60 cells. In order to clarify the mechanism of the acceleration of telomere shortening, we investigated site‐specific DNA damage induced by UVA irradiation in the presence of endogenous photosensitizers using 32P 5′ end‐labeled DNA fragments containing telomeric oligonucleotide (TTAGGG)4. UVA irradiation with riboflavin induced 8‐oxodG formation in the DNA fragments containing telomeric sequence, and Fpg protein treatment led to chain cleavages at the central guanine of 5′‐GGG‐3′ in telomere sequence. Human 8‐oxodG‐DNA glycosylase introduces a chain break in a double‐stranded oligonucleotide specifically at an 8‐oxodG residue. The amount of 8‐oxodG formation in DNA fragment containing telomere sequence [5′‐CGC(TTAGGG)7CGC‐3′] was approximately five times more than that in the DNA fragment containing nontelomere sequence [5′‐CGC(TGTGAG)7CGC‐3′]. Furthermore, H2O2 plus Cu(II) caused DNA damage, including 8‐oxodG formation, specifically at the GGG sequence in the telomere sequence (5′‐TTAGGG‐3′). It is concluded that the formation of 8‐oxodG at the GGG triplet in telomere sequence induced by oxidative stress could participate in acceleration of telomere shortening.
Low Levels of mtDNA Deletion Mutations in ETS Normal Fibers from Aged Rats
Authors: PAK JEONG W. , AIKEN JUDD M.
Published: July 2004

Abstract: The objectives were (1) to determine whether deletion mutations occur in phenotypically normal type I and type II fibers, (2) to quantify the levels of both deletion mutant and wild‐type (wt) mtDNA (nondeletion) within single normal fibers containing mutant mtDNA, and (3) to quantify the amount of wt mtDNA in genotypically and phenotypically normal type I and type II fibers. Deletion mutations in normal fibers are not restricted to specific fiber types, although clonal accumulation of mtDNA deletion mutations and subsequent ETS abnormalities occur exclusively in type II fibers.
Age‐Related Muscle Loss and Progressive Dysfunction in Mechanosensitive Growth Factor Signaling
Authors: GOLDSPINK GEOFFREY
Published: July 2004

Abstract: Loss of muscle mass and function (sarcopenia) is one of the most marked problems associated with aging because it has major healthcare as well as socioeconomic implications. The growth hormone/IGF‐I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF‐I. Also, there are local as well as systemic forms of IGF‐I that have different functions. We cloned two different IGF‐Is that are expressed by skeletal muscle, and both are derived from the IGF‐I gene by alternative splicing. One of these is expressed in response to physical activity, which has now been called “mechanogrowth factor” (MGF). The other is similar to the systemic or liver type (IGF‐IEa) and is important as the provider of mature IGF‐I required for upregulating protein synthesis. MGF differs from systemic IGF‐IEa in that it has a different peptide sequence that is responsible for activating muscle satellite (stem) cells. Therefore, it appears these two forms of IGF‐I have different actions and that they are important regulators of muscle growth. Growth hormone treatment apparently upregulates the level of IGF‐I gene expression, and when it is combined with resistance exercise more is spliced toward MGF. This results in an increase in muscle cross‐sectional area in the elderly subjects who otherwise would produce less MGF. The possibility of ameliorating sarcopenia using MGF delivered as a peptide or by gene therapy will be discussed.
What Do Hormones Have to Do with Aging? What Does Aging Have to Do with Hormones?
Authors: HARMAN S MITCHELL
Published: July 2004

Abstract: It is clear that aging results in alterations of endocrine physiology, which in turn appear to contribute to development of the senescent phenotype. How the underlying basic aging process or processes cause the endocrine cell dysfunctions leading to hormone imbalance is far from clear, but oxidative alteration of cell membranes is an attractive candidate mechanism that might be susceptible to some degree of global remediation.
Functional Efficiency of the Senescent Cells: Replace or Restore?
Authors: PARK SANG CHUL , CHO KYUNG A. , JANG IK SOON , KIM KYUNG TAE , RYU SUNG JIN
Published: July 2004

Abstract:It is generally accepted that aging is a phenomenon of irreversibility, inevitability, and universality with parenchymal loss and functional decline. Consequently, the major goals of aging research are focused on the development of a replace strategy of the aged organs or cells, based on immortalizing tools, stem cells, or artificial substitutes. Recently, however, a new concept of functional recovery has been introduced on the basis of the functional restoration of the responsiveness of the senescent cells toward a variety of agonists, including growth factors. The aging phenotypes of hyporesponsiveness and morphological alteration are shown to be readily adjusted by modulation of the several membrane‐associated molecules, named gatekeeper molecules, among which caveolin is one of the major determinants. Caveolin is the essential component of the caveolae, responsible for regulation of signal transduction, endocytosis and trancytosis, and cytoskeletal arrangement via its scaffolding domain. The caveolin status is associated strictly with cellular transformation, if depleted, and with senescent phenotype, if overexpressed. Therefore, simple reduction of caveolin status in senescent cells leads to restoration of the functional responsiveness to mitogenic stimuli and even of the cellular shape. These data strongly suggest that the gatekeeper molecules, represented by caveolin, may play the prime role in determination of the senescent phenotypes. From these results, it can be summarized that the replace principle would not necessarily be the essential one, but the restore principle can be somehow substituted for the betterment of the aged cells and organisms.
Growth Hormone Alters Components of the Glutathione Metabolic Pathway in Ames Dwarf Micea
Authors: BROWN‐BORG HOLLY M. , RAKOCZY SHARLENE G. , UTHUS ERIC O.
Published: July 2004

Abstract: Reduced signaling of the growth hormone (GH)/insulin‐like growth factor‐1(IGF‐1)/insulin pathway is associated with extended life span in several species. Ames dwarf mice are GH and IGF‐1 deficient and live 50‐64% longer than wild‐type littermates (males and females, respectively). Previously, we have shown that Ames mice exhibit elevated levels of antioxidative enzymes and lower oxidative damage. To further explore the relationship between GH and antioxidant expression, we administered GH or saline to dwarf mice and evaluated components of the glutathione (GSH) synthesis and degradation system. Growth hormone treatment significantly elevated kidney gamma‐glutamyl‐cysteine synthetase protein levels in 3‐ and 12‐month‐old dwarf mice. In contrast, the activity of the GSH degradation enzyme, gamma‐glutamyl transpeptidase, was suppressed by GH administration in brain (P < .05), kidney (P < .01), heart (P < .005), and liver (P < .06). Activity levels of the detoxification enzyme, glutathione‐S‐transferase, were also suppressed in kidney tissues at 3 and 12 months of age and in 12‐month‐old dwarf liver tissues (P < .05). Taken together, the current results along with data from previous studies support a role for growth hormone in the regulation of antioxidative defense and, ultimately, life span in organisms with altered GH or IGF‐1 signaling.
The Proinflammatory Phenotype of Senescent Cells: The p53‐Mediated ICAM‐1 Expression
Authors: KLETSAS DIMITRIS , PRATSINIS HARRIS , MARIATOS GIORGOS , ZACHARATOS PANAYOTIS , GORGOULIS VASSILIS G.
Published: July 2004

Abstract: Senescent cells are characterized by the activation of the tumor suppressor protein p53 and consequently their inability to proliferate. However, their phenotype is not restricted to the exhaustion of their replicative potential, as they also exhibit a proinflammatory phenotype, which could possibly contribute to the aging process. Intercellular adhesion molecule‐1 (ICAM‐1) is one of the molecules involved in inflammatory response that is overexpressed in senescent cells and aged tissues. Although the role of the nuclear factor‐kappaB (NF‐κB) signaling cascade is crucial in ICAM‐1 activation, we have shown that p53 directly activates the expression of ICAM‐1 in an NF‐kB‐independent manner. This may link p53 to ICAM‐1 function and consequently to the aging process and to various age‐related pathologies.
Short‐Term Caloric Restriction and Sites of Oxygen Radical Generation in Kidney and Skeletal Muscle Mitochondria
Authors: GREDILLA RICARDO , PHANEUF SHARON , SELMAN COLIN , KENDAIAH SUMA , LEEUWENBURGH CHRISTIAAN , BARJA GUSTAVO
Published: July 2004

Abstract: Mitochondrial free radical generation is believed to be one of the principal factors determining aging rate, and complexes I and III have been described as the main sources of reactive oxygen species (ROS) within mitochondria in heart, brain, and liver. Moreover, complex I ROS generation of heart and liver mitochondria seems especially linked to aging rate both in comparative studies between animals with different longevities and in caloric restriction models. Caloric restriction (CR) is a well‐documented manipulation that extends mean and maximum longevity. One of the factors that appears to be involved in such life span extension is the reduction in mitochondrial free radical generation at complex I. We have performed two parallel investigations, one studying the effect of short‐term CR on oxygen radical generation in kidney and skeletal muscle (gastrocnemius) mitochondria and a second one regarding location of mitochondrial ROS‐generating sites in these same tissues. In the former study, no effect of short‐term caloric restriction was observed in mitochondrial free radical generation in either kidney or skeletal muscle. The latter study ruled out complex II as a principal source of free radicals in kidney and in skeletal muscle mitochondria, and, similar to previous investigations in heart and liver organelles, the main free radical generators were located at complexes I and III within the electron transport system.
Mechanism of Superoxide‐Mediated Damage Relevance to Mitochondrial Aging
Authors: AFANAS'EV I B
Published: July 2004

Abstract: The damaging effects of superoxide in mitochondria leading to pathological disorders and aging are well documented and usually ascribed to superoxide's role as a precursor of reactive free radical species. However, the latest findings point out the importance of the nucleophilic properties of superoxide and its ability to regulate heterolytic enzymatic processes. Hypothetical mechanisms of superoxide mediation of phosphorylation and dephosphorylation reactions with participation of protein kinases and the apoptotic protein BAD are considered.
Glutathione Metabolism during Aging and in Alzheimer Disease
Authors: LIU HONGLEI , WANG HONG , SHENVI SWAPNA , HAGEN TORY M. , LIU RUI‐MING
Published: July 2004

Abstract: The concentration of glutathione (GSH), the most abundant intracellular nonprotein thiol and important antioxidant, declines with age and in some age‐related diseases. The underlying mechanism, however, is not clear. The previous studies from our laboratory showed that the age‐dependent decline in GSH content in Fisher 344 rats was associated with a downregulation of glutamate cysteine ligase (GCL), the rate‐limiting enzyme in de novo GSH synthesis. Our recent studies further indicated that the activity and mRNA content of glutathione synthase (GS), which catalyzes the second reaction in de novo GSH synthesis, were also decreased with age in some tissues. No age‐associated change was observed in glutathione reductase or γ‐glutamyl transpeptidase activities. Also, although GSH content declined with age in both male and female mice, male mice experienced more dramatic age‐associated decline in many tissues/organs than female mice. Furthermore, we found that GSH content was significantly decreased in the red blood cells from male Alzheimer disease patients, which was associated with decreases in GCL and GS activities. Finally, we showed that estrogen increased GSH content, GS and GR activities, and GCL gene expression in the liver of both male and female mice. Taken together, our results suggest that (1) GCL plays a critical role in maintaining GSH homeostasis under both physiological and pathological conditions; (2) decreased GSH content may be involved in AD pathology in humans; and (3) estrogen increases GSH content in mice by multiple mechanisms.
Alpha‐Lipoic Acid Increases Na+K+ATPase Activity and Reduces Lipofuscin Accumulation in Discrete Brain Regions of Aged Rats
Authors: ARIVAZHAGAN P , PANNEERSELVAM C
Published: July 2004

Abstract: A convincing link between oxidative stress and neurodegenerative diseases has been found with the knowledge that it actually damages neuronal cells in culture. We analyzed the effect of dl‐α‐lipoic acid on lipofuscin and Na+K+ ATPase in discrete brain regions of young and aged rats. In aged rats, the level of lipofuscin was increased, and the activity of Na+K+ATPase was decreased. Intraperitoneal administration of lipoic acid to aged rats led to a duration‐dependent reduction and elevation in lipofuscin and enzyme activity, respectively, in the cortex, cerebellum, striatum, hippocampus, and hypothalamus of the brain. These results suggest that lipoic acid, a natural metabolic antioxidant, should be useful as a therapeutic tool in preventing neuronal dysfunction in aged individuals.
The Bud Scar‐Based Screening System for Hunting Human Genes Extending Life Span
Authors: CHEN CUIYING , CONTRERAS ROLAND
Published: July 2004

Abstract: We developed a high‐throughput screening system that allows identification of genes prolonging life span in the budding yeast Saccharomyces cerevisiae. The method is based on isolating yeast mother cells with an extended number of cell divisions as indicated by the increased number of bud scars on their surface. Fluorescently labeled wheat germ agglutinin (WGA) was used for specific staining of bud scars. Screening of a human HepG2 cDNA expression library in yeast resulted in the isolation of several yeast transformants with a potentially prolonged life span. The budding yeast S. cerevisiae, one of the favorite models used to study aging, has been studied extensively for the better understanding of the mechanisms of human aging. Because human disease genes often have yeast counterparts, they can be studied efficiently in this organism. One interesting example is the WRN gene, the human DNA helicase, which participates in the DNA repair pathway. The mutation of the WRN gene causes Werner syndrome showing premature‐aging phenotype. Budding yeast contains WRN homologue, SGS1, and its mutation results in shortening yeast life span. The knowledge gained from the studies of budding yeast will benefit studies in humans for better understanding of aging and aging‐related disease.
Senescence Marker Protein‐30 as a Novel Antiaging Molecule
Authors: FENG DONGYUN , KONDO YOSHITAKA , ISHIGAMI AKIHITO , KURAMOTO MASASHI , MACHIDA TAKEO , MARUYAMA NAOKI
Published: July 2004

Abstract: Senescence marker protein‐30 (SMP30), composed of 299 amino acids, has an approximate molecular mass of 32‐34 kDa and has a pI 4.9 in charge. The amino acid alignment from various animal species revealed a highly conserved structure. SMP30 has an enzyme activity hydrolyzing sarin, soman, and tabun, known as lethal toxic nerve chemicals. We analyzed the organophosphatase activity of SMP30 using DFP as a substrate. This DFPase activity is revealed in a dose‐dependent manner in the presence of magnesium ions. We investigated the intracellular localization of SMP30. It is localized in both the cytoplasm and nucleus. To confirm the presence of SMP30 in the nucleus, we prepared nuclear and cytoplasmic extracts from isolated cultured hepatocytes. Western blotting showed that SMP30 was detected in both extracts. Because the expression is reduced by carbon tetrachloride, one can speculate that the expression is modulated by oxidative stress increased with aging.
Alternative Pathways Might Mediate Toxicity of High Concentrations of Superoxide Dismutase
Authors: KOWALD AXEL , KLIPP EDDA
Published: July 2004

Abstract: One of the most important antioxidant enzymes is superoxide dismutase (SOD), which catalyzes the dismutation of superoxide radicals to peroxide. The gene for CuZnSOD lies in humans on chromosome 21, and its activity is increased in patients with Down syndrome. However, instead of being beneficial, increased lipid peroxidation is associated with this increased expression, and also studies on bacteria and transgenic animals show that high levels of SOD actually lead to increased lipid peroxidation and hypersensitivity to oxidative stress. Using mathematical models, we investigated the question of how overexpression of SOD can lead to increased oxidative stress, although it is an antioxidant enzyme. We considered several possibilities that have been proposed in the literature, such as CuZnSOD‐catalyzed hydroxyl radical formation, superoxide‐mediated inhibition of membrane peroxidation, and short‐circuiting of the Cu(I)ZnSOD/Cu(II)ZnSOD redox cycle. We found that one of the proposed mechanisms under certain circumstances is able to explain the increased oxidative stress caused by SOD. Furthermore, we identified an additional mechanism that agrees well with experimental observations. We call it the “alternative pathway” mechanism, because it depends on superoxide radicals having alternative pathways besides their reaction with SOD. The alternative pathway mechanism is a very general explanation for SOD‐associated oxidative stress, because it does not depend on the specific type of SOD, nor on the redox status of the cell. We therefore think that it might be the common mechanism for the detrimental effects seen in cells and organisms with increased levels of the different forms of superoxide dismutase.
Senescence Marker Protein‐30 Knockout Mouse as an Aging Model
Authors: MARUYAMA NAOKI , ISHIGAMI AKIHITO , KURAMOTO MASASHI , HANDA SETSUKO , KUBO SACHIHO , IMASAWA TOSHIYUKI , SEYAMA KUNIAKI , SHIMOSAWA TATSUO , KASAHARA YASUSHI
Published: July 2004

Abstract: A mouse strain lacking SMP30 can be regarded as a strain showing ultimate decrease of the SMP30 molecule. After three months of age, SMP30‐KO mice had an increased mortality rate, compared with the SMP30‐WT mice, all of which remained alive. Electron microscopic observation of the hepatocytes from 12‐month‐old SMP30‐KO mice revealed many empty vacuoles, presumably lipid droplets, abnormally enlarged mitochondria with indistinct cristae, and exceptionally large lysosomes filled with electron‐dense bodies. The total hepatic triglyceride concentration of SMP30‐KO mice was approximately 3.6‐fold higher than that of the age‐matched wild type. Similarly, the total hepatic cholesterol of SMP30‐KO mice reached an approximate 3.3‐fold greater value than that of the comparative group. Total hepatic phospholipids of SMP30‐KO mice achieved an approximately 3.7‐fold higher level compared with that of the wild‐type mice. The cells from SMP30‐KO mice were sensitive to apoptotic reagents. Those results supported the idea that SMP30 has an antiapoptotic function with wide spectrum. These findings indicate that SMP30‐KO mice are highly susceptible to various harmful reagents. This strain might be a useful tool for aging and biological monitoring.
Lack of Correlation between Mitochondrial Reactive Oxygen Species Production and Life Span in Drosophila
Authors: MIWA SATOMI , RIYAHI KUMARS , PARTRIDGE LINDA , BRAND MARTIN D.
Published: July 2004

Abstract: The free radical theory of aging proposes that mitochondrial production of reactive oxygen species (ROS) determines the rate of aging. Supporting this hypothesis, longer‐lived species produce fewer ROS than shorter‐lived ones, and calorically restricted rodents live longer and produce fewer ROS than controls. We studied such correlation in Drosophila melanogaster in caloric restriction and in mutant flies overexpressing the mitochondrial adenine nucleotide translocase (ANT). Caloric restriction extended life span, but there was no significant difference in mitochondrial ROS production compared with controls. ANT overexpressers had significantly lower ROS production (because they had lower membrane potential), but their life span was not extended compared to wild type. Our results show two examples in which mitochondrial ROS production and life span are not correlated.
Malondialdehyde and Measures of Antioxidant Activity in Subjects from the Belfast Elderly Longitudinal Free‐Living Aging Study
Authors: REA I M , McMASTER D , DONNELLY J , McGRATH L T , YOUNG I S
Published: July 2004

Abstract: Glutathione and glutathione peroxidase activity are important components in the complex body defense against oxidative damage. In this study, we have measured malondialdehyde (MDA) as a marker of oxidative stress, the antioxidant glutathione (GSH), and activity of the antioxidant enzyme (GSHPx), in a cohort of free‐living elderly subjects from the Belfast Elderly Longitudinal Free‐living Aging STudy (BELFAST), hypothesizing that free‐living Senieur‐approximated nonagenarians might demonstrate enhanced antioxidant defense mechanisms. The main finding in the BELFAST octo/nonagenarians was that plasma antioxidant glutathione increased in nonagenarian compared with septo/octogenarian subjects (P= .015), whereas conversely antioxidant glutathione peroxidase activity fell in the nonagenarian group (P < .0001). In the same subject group, malondialdehyde, a measure of lipid peroxidation, showed no change across the age groups (P= .73). These results might overall represent a situation in which elderly survivors in the BELFAST study have evolved a sort of free radical/antioxidant equilibrium as a mechanism of successful aging.
Regenerative Medicine: Antagonic‐Stress® Therapy in Distress and Aging. I. Preclinical Synthesis—2003
Authors: RIGA D , RIGA S , SCHNEIDER F
Published: July 2004

Abstract: Repetitive and cumulative distress (acute and/or chronic, psychic and/or biologic) and aging processes (impairment phenomena, agglomerated, and accumulated with the passing of life and senescence periods), as well as distress ⇔ aging reciprocal amplification‐accelerating‐aggravation relationships require strong and rational (etiopathogenic) therapeutic interventions. Therefore, the drug, Antagonic‐Stress® (AS)—a new integrative therapy, with specific synergistic formula, being patented worldwide—becomes an important solution in distress, senescence, and their related pathologies. In acute (contention) stress, AS treatment significantly decreased rat mortality, number and surface of stomach ulcerations, nonesterified fatty acids (NEFAs), and increased superoxide dismutase (SOD) from blood. In chronic psychic stress, live nerve cells selectively isolated from rat cerebral cortex were highly protected by the administration of AS. In addition, antistress and antiaging homeostatic actions of AS were demonstrated in accelerated senescence (aging + distress) at multiple brain levels: on functional anabolism [increase in total ribonucleic acids (RNA), total proteins (TP), and water‐soluble proteins (WSP)]; on functional catabolism [decrease in water‐insoluble proteins (WIP)]; on structural anabolism (increased regeneration of free ribosomes, rough endoplasmic reticulum, mitochondria, and Nissl bodies); on structural catabolism (lipofuscinolysis and ceroidolysis, neurono‐glial transfer of lipopigment continuously processed and dissoluted, and finally capillary elimination). Preclinical research with AS demonstrated important regenerative processes in the key organs (liver, heart, and brain), which mostly suffer due to both distress and senescence.
Delaying the Mitochondrial Decay of Aging
Authors: AMES BRUCE N.
Published: July 2004

Abstract: Mitochondrial dysfunction may be a principal underlying event in aging, including the degenerative diseases of aging such as brain degeneration. Mitochondria provide energy for basic metabolic processes, and their decay with age impairs cellular metabolism and leads to cellular decline. Progress over the last decade in delaying the mitochondrial decay of aging is reviewed.
Interventions in Aging and Age‐Associated Pathologies by Means of Nutritional Approaches
Authors: KITANI KENICHI , YOKOZAWA TAKAKO , OSAWA TOSHIHIKO
Published: July 2004

Abstract: So‐called antioxidant strategies have not been shown convincingly to be effective in increasing life spans of animals. Thus, the general consensus of experimental gerontology in the last century was that the only reproducible means of prolonging survivals of animals is the calorie restriction paradigm. As a challenge against this dogma, we attempted to examine the effect of two potent antioxidants, one tetrahydrocurcumin (a biotransformed metabolite of curcumin contained in turmeric of Indian curry) and the other green tea polyphenols.
Absolute versus Relative Caloric Intake: Clues to the Mechanism of Calorie/Aging‐Rate Interactions
Authors: ANSON R MICHAEL
Published: July 2004

Abstract: It has been suggested that the influence of caloric intake on aging rate is not due to the absolute number of calories ingested. Instead, aging rate is altered only when there is a disparity between the actual caloric intake and that which would be ingested if the food supply were unlimited. This review will discuss a few of the studies supporting this viewpoint.
Acetyl‐l‐Carnitine Dietary Supplementation to Old Rats Increases Mitochondrial Transcription Factor A Content in Rat Hindlimb Skeletal Muscles
Authors: PESCE V , FRACASSO F , MUSICCO C , LEZZA A M S , CANTATORE P , GADALETA M N
Published: July 2004

Abstract: Acetyl‐l‐carnitine (ALCAR) fed to old rats has been reported to partially restore mitochondrial function and ambulatory activity. The results of the effect of ALCAR dietary supplementation to 28‐month‐old rats on mitochondrial transcription factor A (TFAM) content of rat hindlimb skeletal muscles are reported.
An Appetite for Death
Authors: KOOCHMESHGI JALAL
Published: July 2004

Abstract: A diverse array of organisms live longer under dietary restriction. Here, a hypothesis is proposed as a framework for interpreting this phenomenon. Dietary restriction is explained in terms of evolution and antagonistic pleiotropy. Focusing on the decline in reproductive capacity seen in dietary restriction, it is submitted that “normal” appetite is geared toward producing a neuroendocrine and metabolic internal milieu optimized for reproduction, with long‐term detrimental effects on health as a by‐product. In dietary restriction experiments, the animal is prevented from eating enough to attain this internal milieu and, as a by‐product, lives longer.
Long‐Lived αMUPA Transgenic Mice Exhibit Increased Mitochondrion‐Mediated Apoptotic Capacity
Authors: TIROSH OREN , SCHWARTZ BETTY , ZUSMAN IGOR , KOSSOY GEORGE , YAHAV SHLOMO , MISKIN RUTH
Published: July 2004

Abstract: Caloric restriction (CR) is currently the only therapeutic intervention known to attenuate aging in mammals, but the mechanisms underlying this phenomenon are still poorly understood. To study this issue, the transgenic model of αMUPA mice, which previously were reported to spontaneously eat less and live longer compared with their wild‐type (WT) control mice, were used. Currently, two transgenic lines that eat less are available, thus implicating the transgenic enzyme, that is, the urokinase‐type plasminogen activator (uPA), in causing the reduced appetite. Recently, several changes in the αMUPA liver were noted, at the mitochondrial and cellular level, which consistently pointed to an enhanced capacity to induce apoptosis. In addition, αMUPA mice showed a reduced level of serum IGF‐1 and a reduced incidence of spontaneously occurring or carcinogen‐induced tumors in several tissues. Overall, the αMUPA model suggests that long‐lasting, moderately increased apoptotic capacity, possibly linked in part to modulation of serum IGF‐1 and mitochondrial functions, could play a role in the attenuation of aging in calorically restricted mice.
Effect of Caloric Restriction on the 24‐Hour Plasma DHEAS and Cortisol Profiles of Young and Old Male Rhesus Macaques
Authors: URBANSKI H F. , DOWNS J L , GARYFALLOU V T , MATTISON J A , LANE M A , ROTH G S , INGRAM D K
Published: July 2004

Abstract: Although dietary caloric restriction (CR) can retard aging in laboratory rats and mice, it is unclear whether CR can exert similar effects in long‐lived species, such as primates. Therefore, we tested the effect of CR on plasma levels of dehydroepiandrosterone sulfate (DHEAS), a reliable endocrine marker of aging. The study included six young (∼10 years) and ten old (∼25 years) male rhesus macaques, approximately half of the animals in each age group having undergone >4 years of 30% CR. Hourly blood samples were collected remotely for 24 hours, through a vascular catheter, and assayed for DHEAS and cortisol. Both of these adrenal steroids showed a pronounced diurnal plasma pattern, with peaks occurring in late morning, but only DHEAS showed an aging‐related decline. More importantly, there was no significant difference in plasma DHEAS concentrations between the CR animals and age‐matched controls. These data fail to support the hypothesis that CR can attenuate the aging‐related decline in plasma DHEAS concentrations, at least not when initiated after puberty.
Aging, Exercise, and Phytochemicals Promises and Pitfalls
Authors: JI LI LI , PETERSON DAVID M.
Published: July 2004

Abstract: Phytochemicals are emerging comprehensive and versatile sources of antioxidants to be consumed to enhance the body's defenses against harmful reactive oxygen species generated endogenously or exogenously. Tocols, favonoids, and phenolic acids compose the majority of this class of antioxidants, although more complex compounds may also be involved, such as ginsenosides. In vitro and in vivo studies have demonstrated convincingly that dietary supplementation of phytochemicals has beneficial effects against certain types of pathogenesis, disease, cancer, and aging. There is evidence that these effects are related to the ability of phytochemicals to promote the antioxidant defense system and reduce oxidative stress and damage in the cell. However, due to their structural and chemical diversity and complexity, many of the benefits as well as potential adverse effects remain to be examined.
Aging, Exercise, and Cardioprotection
Authors: POWERS SCOTT K. , QUINDRY JOHN , HAMILTON KARYN
Published: July 2004

Abstract: Myocardial ischemia‐reperfusion (I‐R) injury is a major contributor to the morbidity and mortality associated with coronary artery disease. The incidence of I‐R events is greatest in older persons, and studies also indicate that the magnitude of myocardial I‐R injury is greater in senescent individuals compared to younger adults. Regular exercise has been confirmed as a pragmatic countermeasure to protect against I‐R‐induced cardiac injury. Specifically, endurance exercise has been proven to provide cardioprotection against an I‐R insult in both young and old animals. Proposed mechanisms to explain the cardioprotective effect of exercise include the induction of myocardial heat shock proteins (HSPs), improved cardiac antioxidant capacity, and/or elevation of other cardioprotective proteins. Of these potential mechanisms, evidence indicates that elevated myocardial levels of heat shock proteins or antioxidants can provide myocardial protection against I‐R injury. At present, which of these protective mechanisms is essential for exercise‐induced cardioprotection remains unclear. Understanding the molecular basis for exercise‐induced cardioprotection is important in developing exercise paradigms to protect the heart during an I‐R insult.
Mechanisms in Muscle Atrophy in Immobilization and Aging
Authors: BAR‐SHAI MARINA , CARMELI ELI , COLEMAN RAYMOND , REZNICK ABRAHAM Z.
Published: July 2004

Abstract: The purpose of this report was to study the effects of four weeks of hindlimb immobilization on acid phosphatase activity of old rats in comparison with the profile obtained after similar treatment in young rats.
Effect of Physical Activity Levels on Bone Strength
Authors: KIKKAWA KAZUTOSHI
Published: July 2004

Abstract: The present study employs statistical analysis using age as the covariate and seeks to provide cross‐sectional data concerning the relationship between bone strength and levels of physical activities among Japanese.
Naturally Long‐Lived Animal Models for the Study of Slow Aging and Longevity
Authors: HOLMES DONNA J.
Published: July 2004

Abstract: Judicious selection of new animal models for the study of basic aging processes must combine feasibility and good use of the comparative method with evidence of antiaging adaptations, like the ability to combat oxidative damage to cells and tissues. A number of vertebrate species already in use or being developed as new biomedical models lend themselves very well to laboratory studies of aging, including small birds, bats, and mole‐rats.
The Extreme Aged: Sampling, Measurement, and Statistical Models in Cross‐Sectional Estimation and Forecasting
Authors: CORDER LARRY S.
Published: July 2004

Abstract: Little effort has been directed toward studying the relationship between morbidity and mortality at exceptional ages, perhaps for no better reason than it has been difficult to do given available data resources. Two study innovations/adjustments are required to adequately represent count data with reports of health from aged sample persons. These design features are oversampling of the exceptional group and linkage to detailed administrative reports. The National Long‐Term Care Survey (NLTCS) has made it possible to study health and functioning in the context of exceptional longevity.
Demographics of Human Supercentenarians and the Implications for Longevity Medicine
Authors: COLES L STEPHEN
Published: July 2004

Abstract: Demographers have forecast that there are going to be a great many more older adults in the next few decades. This will have great implications for longevity medicine. The Gerontology Research Group, affiliated with the UCLA School of Medicine, has compiled and maintained a Table of Worldwide Living Supercentenarians (persons 110 years or older) for the last 4 years, shedding important light on the biological limits of human morbidity and mortality and providing a realistic perspective on the problem of long‐term interventions that can reasonably be achieved in the near future.
Cardiovascular Disease Delay in Centenarian Offspring: Role of Heat Shock Proteins
Authors: TERRY DELLARA F. , McCORMICK MAEGAN , ANDERSEN STACY , PENNINGTON JAEMI , SCHOENHOFEN EMILY , PALAIMA ELIZABETH , BAUSERO MARIA , OGAWA KISHIKO , PERLS THOMAS T. , ASEA ALEXZANDER
Published: July 2004

Abstract: Cardiovascular disease is a major cause of morbidity and mortality of older Americans. We have demonstrated recently that centenarian offspring, when compared with age‐matched controls, avoid and/or delay cardiovascular disease and cardiovascular risk factors. Given recent evidence suggesting that higher circulating levels of HSP70 predict the future development of cardiovascular disease in established hypertensives and a recent study demonstrating a decrease in HSP60 and HSP70 with advancing age, we hypothesized that HSP70 levels would be lower in centenarian offspring compared with controls. The circulating serum concentration of HSP70 in 20 centenarian offspring and 9 spousal controls was analyzed using a modified HSP70 ELISA method. Centenarian offspring showed approximately 10‐fold lower levels of circulating serum HSP70 compared with spousal controls (P < .001). The exact biological significance of the extremely low levels of circulating serum HSP70 observed in centenarian offspring thus far is not clear. However, circulating HSP has been shown to correlate in diseases or disorders in which there is destruction or damage to target tissues or organs, including cardiovascular diseases and numerous autoimmune disorders. We hypothesize that low levels of circulating serum HSP70 may be an indicator of a healthy state and point to longevity of the host; therefore, our results suggest that levels of circulating serum HSP70 may be a marker for longevity.
The Reliability‐Engineering Approach to the Problem of Biological Aging
Authors: GAVRILOV LEONID A. , GAVRILOVA NATALIA S.
Published: July 2004

Abstract: We applied reliability theory to explain aging of biological species and came to the following conclusions: (1) Redundancy is a key notion for understanding aging and the systemic nature of aging in particular. Systems, which are redundant in numbers of irreplaceable elements, do deteriorate (i.e., age) over time, even if they are built of nonaging elements. (2) An apparent aging rate or expression of aging (measured as age differences in failure rates, including death rates) is higher for systems with higher redundancy levels. (3) Redundancy exhaustion over the course of life explains the observed compensation law of mortality (mortality convergence at later life) as well as the observed late‐life mortality deceleration, leveling‐off, and mortality plateaus. (4) Living organisms seem to be formed with a high load of initial damage, and therefore their life span and aging patterns may be sensitive to early‐life conditions that determine this initial damage load during early development.
Emerging Area of Aging Research: Long‐Lived Animals with “Negligible Senescence”
Authors: GUERIN JOHN C.
Published: July 2004

Abstract: Field observations have suggested for quite some time that certain fish, turtles, and invertebrates have extremely long maximum life span potential. Age validation techniques have since confirmed these observations, but scientific analysis to understand the genetic and biochemical basis of this longevity has occurred only recently. The Centenarian Species and Rockfish Project now encompasses 13 pilot research projects, including such diverse investigations as histology, a cDNA library, and mitochondrial mutation analysis. In this document, the term “negligible senescence” is defined, and its background is given; age validation techniques are listed, and the various projects to date, including research results, are summarized.
Immortal Ethics
Authors: HARRIS JOHN
Published: July 2004

Abstract:This article draws on ideas published in my “Intimations of Immortality” essay inScience(Vol. 288, No. 5463, p. 59, April 7, 2000) and my “Intimations of Immortality—The Ethics and Justice of Life Extending Therapies” in editor Michael Freeman'sCurrent Legal Problems(Oxford University Press 2002: 65‐97). This article outlines the ethical issues involved in life‐extending therapies. The arguments against life extension are examined and found wanting. The consequences of life extension are explored and found challenging but not sufficiently daunting to warrant regulation or control. In short, there is no doubt that immortality would be a mixed blessing, but we should be slow to reject cures for terrible diseases that may be an inextricable part of life‐extending procedures even if the price we have to pay for those cures is increasing life expectancy and even creating immortals. Better surely to accompany the scientific race to achieve immortality with commensurate work in ethics and social policy to ensure that we know how to cope with the transition to parallel populations of mortals and immortals as envisaged in mythology.
Biogerontologists' Duty to Discuss Timescales Publicly
Authors: DE GREY AUBREY D. N. J.
Published: July 2004

Abstract: Aging is unpopular with the general public—but, it would seem, only up to a point. Treatments that claim (sometimes justifiably) to extend the total and/or healthy life span of elderly people, or even just make them look younger, are welcomed with open wallets throughout the world. If, however, one suggests to the typical nonbiologist—or even to the typical nongerontologist biologist—that we should therefore aim, in due course, to take this desire to its logical conclusion and bring aging under the same degree of control that we currently have over most infectious diseases, one is nearly always met with strong and sometimes strident opposition. I argue here that the prevalence of this outright irrationality is largely the fault of gerontologists themselves. Most people harbor a deep‐seated fear of profound change in their lives and embrace it only after extensive soul‐searching to convince themselves of its benefit. It cannot and should not be denied that a postaging world would be as profoundly different from today's as we can imagine. Hence, when given the opportunity to postpone sober consideration of its pros and cons, most people leap at that opportunity. It is provided to them by the nearly universal refusal of gerontologists to speculate about the timescales within which truly effective rejuvenation therapies may be developed. I suggest that this reticence, while appropriate in purely scientific fields, is hugely irresponsible in a biomedical discipline, because of its potential to delay the development of such therapies by denying them the funding that would be forthcoming if society had greater optimism concerning their foreseeability. Arguments that such funding, and/or the public's trust in scientists, would be short‐lived if timescale predictions were not borne out are too flimsy to outweigh this. A further danger is the avoidable loss of life following the development of rejuvenation therapies that would result from inadequate ability to provide them universally; here again, scientists today can minimize this loss of life by agitating for forward planning by government, which will only occur when policymakers' minds are concentrating on timescale predictions.
Report on the Open Discussion on the Future of Life Extension Research
Authors: DE GREY AUBREY D. N. J.
Published: July 2004

Abstract: Following a highly stimulating series of talks on the social and ethical implications of greatly extended life spans, a discussion of the issues was held, in which a series of straw polls was conducted. An alarming conclusion from these polls was that most participants thought it either probable or “not improbable” that comprehensive functional rejuvenation of middle‐aged mice would be possible within 10‐20 years, but also felt that biogerontologists should not yet discuss timescales (either for mouse rejuvenation or similar progress in humans) in society at large. This combination of views may be very dangerous, as it assumes that humanity will need little forward planning to transition smoothly from its current almost universal fatalism concerning the defeat of aging to a widespread appreciation of its foreseeability or even imminence.