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PubMed2003

Constitutive activation of rac1 results in mitochondrial oxidative stress and induces premature endothelial cell senescence.

OBJECTIVE: Oxidative stress has been implicated in cellular senescence and vascular aging. We determined the role and mechanism of the small GTPase rac1 in vascular endothelial cell senescence. METHODS AND RESULTS: Adenoviral-mediated expression of the constitutively active allele of rac1 (rac1V12) in human umbilical vein endothelial cells resulted in mitochondrial oxidative stress with induction of biochemical, molecular, and morphological features of senescence. Suppression of mitochondrial oxidative stress abrogated rac1-induced premature senescence. Rac1V12 expression also resulted in an increase in endothelial ceramide levels. Moreover, premature endothelial cell senescence induced by an exogenous cell-permeable ceramide analog was not suppressed by inhibiting endogenous rac1 signaling. Finally, in human umbilical vein endothelial cells that had undergone replicative senescence, rac1 was not activated, and expression of the dominant-negative rac1 allele (rac1N17) did not suppress mitochondrial oxidative stress. CONCLUSIONS: These findings paint a picture in which the constitutive activation of rac1, via the generation of ceramide, results in mitochondrial oxidative stress and premature endothelial cell senescence. However, they speak against a role for endogenous rac1 activation in the induction of mitochondrial oxidative stress associated with replicative senescence of endothelial cells.

Aging, Premature↗

PubMedDate not supplied

Stress resistance and longevity in selected lines of Drosophila melanogaster.

Five independent populations (lines) of Drosophila melanogaster were selected for female starvation resistance. Females and males from the selected lines were relatively starvation resistant when compared to flies from five control lines. Moreover, flies from selected lines were resistant to other stresses: desiccation, acetone fumes, ethanol fumes, and paraquat (a source of oxygen radicals). Data from a variety of previous studies indicate an association between stress resistance and longevity. In this context, the present study addressed the question of whether flies from the stress-resistant lines were relatively long-lived. Replicate population cages from each selected and control line were used to assess longevity. Neither females nor males from the selected lines were relatively long-lived. In at least some cases, stress resistance may be necessary, but not sufficient, for longevity.

Acetone↗

PubMed1997

Molecular chaperones and the cytoskeleton.

Heat shock proteins, first observed because they are preferentially synthesized by organisms exposed to heat or other physiological stress, are also synthesized constitutively. These proteins are divided into several families, namely, HSP100, 90, 70, 60 (chaperonin), and the small heat shock/alpha-crystallin proteins. They enjoy a wide phylogenetic distribution and are important because they function as molecular chaperones, able to mediate many cellular processes through an influence on higher order protein structure. For example, molecular chaperones assist in the transport of proteins into mitochondria and chloroplasts, as well as influencing clathrin lattice dynamics, viral replication and transcriptional activation. Under conditions of stress, some molecular chaperones prevent denaturation of proteins while others may dissociate protein aggregates, refolding monomers derived therefrom or directing their proteolytic destruction. We present in this review an analysis of the emerging literature on the relationship between molecular chaperones and the cytoskeleton, a collection of polymeric structures consisting of microtubules, microfilaments and intermediate filaments. A recent development in this field is identification of the TCP-1 complex as the eukaryotic cytoplasmic chaperonin which directs folding of cytoskeletal proteins such as alpha/beta/gamma-tubulin, actin and centractin. Moreover, the TCP-1 complex is a centrosomal component, apparently involved in the nucleation of microtubules. Other molecular chaperones recognize one or more cytoskeletal elements and in most cases they modulate the assembly of and/or provide protection for their constituent proteins. For example, HSP70 protects the centrosome and perhaps intermediate filaments during heat shock, and like HSP90, it binds to microtubules. Small heat shock proteins interact with microfilaments and intermediate filaments, affect their polymerization and guard them from heat shock by a phosphorylation-dependent mechanism. We conclude that molecular chaperones have different but cooperative roles in the formation and function of the eukaryotic cell cytoskeleton.

Actins↗

PubMed2001

Restored antioxidant capacity parallels the immunologic and virologic improvement in children with perinatal human immunodeficiency virus infection receiving highly active antiretroviral therapy.

CD3+CD4+ T-lymphocyte numbers, viral load, and serum antioxidant capacity were evaluated in 20 children with perinatal human immunodeficiency virus (HIV) infection one month (T = -1) and one day (T = 0) before and one month (T = 1) and two months (T = 2) after a treatment switch to highly active antiretroviral therapy (HAART). Antioxidant capacity micromol/L) was evaluated by measuring the cuprous ion deriving from a known amount of cupric ion. Compared to control values (998 +/- 113 micromol/L), values in HIV-infected children were lower before HAART (T = -1, 848 +/- 211 micromol/L, P = 0.008; T = 0, 732 +/- 131 micromol/L, P < 0.0001), but similar during HAART (T = 1, 914 +/- 121 micromol/L, P = 0.089; T = 2; 957 +/- 155 micromol/L, P = 0.528; T = 1 and T = 2 vs T = 0, P < 0.0001). Immunologic and virologic improvement paralleled the restored antioxidant capacity. HAART may restore antioxidant capacity suppressing HIV, which inhibits antioxidant capacity. A positive feedback may be triggered since restored antioxidant capacity counterbalances the oxidative stress, which enhances lymphocyte apoptosis and HIV replication.

Adolescent↗

PubMed2003

Oxidant stress is increased during treatment of human immunodeficiency virus infection.

Some diseases and environmental exposures, including those that are risk factors for atherosclerosis, are associated with increased oxidant stress. The objective of this cross-sectional, observational study was to determine whether oxidant stress is increased during human immunodeficiency virus type 1 (HIV-1) infection or its therapy. To quantify oxidant stress, plasma F2 isoprostane (F2-IsoP) concentrations were determined by gas chromatography/mass spectroscopy. A total of 120 subjects were enrolled during routine primary care visits. The median CD4+ T cell count was 341 cells/mm3, the median HIV-1 RNA level was 3.4 log10 copies/mL, and 74% of patients were receiving antiretroviral therapy. Plasma F2-IsoP concentrations were 12-149 pg/mL (median, 31 pg/mL). In univariate analysis, higher F2-IsoP concentrations were associated with lower log10 plasma HIV-1 RNA levels (P=.009) and with efavirenz use (P=.02). Both factors remained associated with plasma F2-IsoP concentrations in multivariate analysis. Oxidant stress associated with therapeutic control of viral replication may have important implications for long-term complications of antiretroviral therapy.

Adult↗

PubMed1987

In support of hassles as a measure of stress in predicting health outcomes.

We investigated the impact of frequently occurring minor stressors (hassles) upon health status in a sample of low-income, elderly persons with osteoarthritis. These individuals are characterized by conditions which are precursors to experiencing stress. Using a modified Hassles scale, we replicated some important findings in a sample demographically distinct from earlier studies on hassles. Specifically, hassles were better predictors of health status than major life change events, and the influence of life change events was indirect, i.e., it increased hassles, which in turn, negatively affected health status. Furthermore, hassles correlated strongly with validated indicators of health status. By replicating earlier studies in a demographically dissimilar sample, and by finding significant correlations between hassles and valid physical health measures, we have strengthened the conceptual development of hassles.

Aged↗

PubMed1990

Endogenous opioids modulate the cardiovascular response to mental stress.

The role of endogenous opioids in the cardiovascular response to mental stress was investigated in two controlled studies. In the first, cardiovascular, hormonal and psychological measures were made in a group of subjects before, during and after presentation of either a mental stress task or a non-stressful control task in the presence of naloxone (8 mg), an opiate antagonist, or an equal volume of saline. The study was carried out in random order and single(subject)-blind. Naloxone specifically enhanced the heart rate response to the stressful task but had no effect on blood pressure, plasma epinephrine or norepinephrine, or feelings of anxiety. Naloxone increased plasma cortisol and ACTH in both stressful and control tasks. A second, double-blind, study replicated the effect on heart rate. An endogenous opioid mechanism thus appears to inhibit the cardiovascular response to stress.

Adolescent↗

PubMed2004

Chronological aging-independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae.

Mutations in RAS2, CYR1, and SCH9 extend the chronological life span in Saccharomyces cerevisiae by activating stress-resistance transcription factors and mitochondrial superoxide dismutase (Sod2). Here we show that mutations in CYR1 and SCH9 also extend the replicative life span of individual yeast mother cells. However, the triple deletion of stress-resistance genes MSN2/MSN4 and RIM15, which causes a major decrease in chronological life span, extends replicative life span. Similarly, the overexpression of superoxide dismutases, which extends chronological survival, shortens the replicative life span and prevents budding in 30-40% of virgin mother cells. These results suggest that stress-resistance transcription factors Msn2/Msn4 negatively regulate budding and the replicative life span in part by increasing SOD2 expression. The role of superoxide dismutases and of other stress-resistance proteins in extending the chronological life span of yeast, worms, and flies indicates that the negative effect of Sod2, Msn2/Msn4/Rim15 on the replicative life span of S. cerevisiae is independent of aging.

DNA-Binding Proteins↗

PubMed1997

Attenuated stress responses in young and old human lymphocytes.

Aging generally is understood to be a period defined by altered responses to physiological stress. At the molecular level, several stress responses involving specific gene expression have been revealed, and thermal stress has been tightly linked to induction of the heat shock gene family (D.A. Jurivich. In E. Bittar (ed.), Principles of Medical Biology, Vol. 4, JAI press, San Diego, 1996, pp. 411-462). Perturbations in heat shock gene transcription consistently have been noted in senescent cells from all species examined thus far. Because heat shock proteins serve several vital functions in the immune system, changes in the thermal stress response could potentially contribute to immunosenescence. Inadequate promoter priming by the transactivator or heat shock genes, heat shock factor 1 (HSF1), is thought to account for age-dependent diminution in expression of these genes, although the exact mechanism for this loss is not clearly understood. We have found that human lymphocytes exhibit an age-dependent loss in HSF1-DNA binding, although a range of binding has been observed in both young and old donor cells. This report characterizes a subset of young and old human donor lymphocytes that are non-responders to thermal stress defined by the absence of HSF1-DNA binding after a 42 degrees C heat shock. Whole cell extracts from these donor cells have the capacity to inhibit HSF1-DNA binding when mixed with pre-activated HSF1 from HeLa cells. This inhibitory activity is lost upon heat denaturation and does not appear to be protease mediated. Serial passage of lymphoblasts recapitulates loss of heat inducible HSF1-DNA observed in old donor lymphocytes, thus suggesting that loss of replicative potential and aging lead to altered stress responses. Uncoupling of the thermal response and its potential relevance to apoptosis and aging are discussed.

Adult↗

PubMed2006

No evidence of chromosome damage in chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in industrialized countries. It is characterized by a progressive airflow limitation resulting from an abnormal inflammatory response of the lungs to inhaled gases and particles. Since oxidative stress is thought to play a role in COPD, and since increased oxidative stress is associated with chromosomal instability in several diseases, we investigated whether such relationship also exists in COPD. Whole blood lymphocytes from 49 COPD patients and 48 age- and sex-matched controls were cultivated in vitro and cytogenetic damage was evaluated by micronucleus (MN) and sister-chromatid-exchange (SCE) assays. In patients with COPD, MN frequency was not significantly different from that of controls. Similarly, SCE frequency did not differ in the two groups suggesting no disturbance in DNA replication. Unlike other diseases characterized by oxidative stress, COPD does not appear to be associated with DNA damage.

Aged↗

PubMed1997

Cell aging in vivo and in vitro.

It has become a staple assumption of biology that there is an intrinsic fixed limit to the number of divisions that normal vertebrate cells can undergo before they senesce, and this limit is in some way related to aging of the organism. The notion of such a limited replicative lifespan arose from the often repeated observation that diploid fibroblasts cannot proliferate indefinitely in monolayer culture, and that the number of divisions before senescence is directly related to the in vivo lifespan of different species. The in vitro evidence is countered by estimates that the number of cell divisions in some organs of rodents and man are one or more orders of magnitude higher than the in vitro limit, with no indication of the degenerative changes seen in culture. Serial transplantation experiments in animals also exhibit many more cell divisions than the in vitro studies, with some indicating an indefinite replicative lifespan. I present evidence that vertebrate cells are severely stressed by enzymatic dispersion and sustain cumulative damage during serial subcultivations. The evidence includes large increases in cell size and its heterogeneity, reductions in replicative efficiency at low seeding densities, appearance of abnormal structures in the cytoplasm, changes in metabolism to a common cell culture type, continuous loss of methyl groups and reiterated sequences from DNA, and a constant rate of decline of growth rate with passage. This evidence is complemented by the reduction induced in the replicative life span of diploid cells by a large array of treatments which have different primary targets in the cells. The most consistent and general observation of cell behavior in aging animals, with only a few exceptions, is a reduction in the rate of cell proliferation. This reduction is perpetuated when the cells are grown in culture, indicating it is an enduring and intrinsic property of the cells rather than a systemic effect of the aging organism. A similar heritable reduction in growth rate can be induced in established cell lines by prolonged incubation at quiescence. The reduction can be exaggerated by subculturing the quiescent cells under suboptimal conditions, just as the effects of age are exaggerated under stress. The constant decline of growth rate that occurs during serial passage of diploid cells may represent a similar decay of cell function. I propose that the limit on replicative lifespan is an artifact that reflects the failure of diploid cells to adapt to the trauma of dissociation and the radically foreign environment of cell culture. It is, however, a useful artifact that has given us much information about cell behavior under stressful conditions. The overall evidence indicates cell in vivo accumulate damage over a lifetime that results in gradual loss of differentiated function and growth rate accompanied by an increased probability for the development of cancer. Such changes are normally held to a minimum by the organized state of the tissues and homeostatic regulation of the organism. The rejection of an intrinsic limit on the number of cell divisions eliminates the need for a cellular clock, such as telomere length, that counts mitoses. I offer a heuristic explanation for the gradual reduction of cell function and growth capacity with age based on a cumulative discoordination of interacting pathways within and between cells and tissues. I also make a case for the use of established cell lines as model systems for studying heritable damage to cell populations that simulates the effects of aging in vivo, and represents a relatively unexplored area of cell biology.

Animals↗

PubMed2004

Initiating cellular stress responses.

The phosphoinositide 3-kinase related kinases (PIKKs) mediate responses to diverse stresses, including DNA double-strand breaks (DSBs), abnormal replication fork progression, the recognition of premature termination codons in mRNAs, and inadequate nutrient availability. Rigorous control of these kinases limits cellular damage and promotes cell viability in the presence of stress. Control mechanisms include the localization of PIKKs into multiprotein complexes at the sites of damage and mediation of protein-protein contacts such that substrates are allowed access to the PIKK catalytic domains.

Animals↗

PubMed2002

Replicative senescence and senescence-like state induced in cancer-derived cells.

Studies on the replicative senescence and premature senescence induced by various stresses in normal somatic cells have provided important clues on the role of telomere shortening and mechanisms involved in aging processes and carcinogenesis. Recent work revealed that cancer cells also are induced to undergo replicative senescence state via telomere shortening as well as to enter a senescence-like state by the activation of cell cycle inhibitory pathways. Although less relevant in terms of aging physiology, studies on these phenomena in cancer cells have yielded important information on telomerase regulation and the roles of tumor suppressors in senescence and immortalization, and are expected to generate valuable anti-cancer strategies. Several features of the phenotypes specific for the senescent and senescence-like states induced in cancer cells are discussed.

Cell Division↗

PubMed2006

Role of oxidative stress and intracellular calcium in nickel carbonate hydroxide-induced sister-chromatid exchange, and alterations in replication index and mitotic index in cultured human peripheral blood lymphocytes.

Human peripheral lymphocytes from whole blood cultures were exposed to either soluble form of nickel carbonate hydroxide (NiCH) (0-60 microM), or of nickel subsulfide (Ni(3)S(2)) (0-120 microM), or of nickel oxide (NiO) (0-120 microM), or nickel sulfate (NiSO(4)) (0-120 microM) for a short duration of 2 h. The treatments occurred 46 h after the beginning of the cultures. The cultures were harvested after a total incubation of 72 h, and sister-chromatid exchange (SCE), replication index (RI), and mitotic index (MI) were measured for each nickel compound. The soluble form of NiCH at 30 microM but those of Ni(3)S(2) and NiO at 120 microM produced significant increase in the SCE per cell compared to the control value, whereas NiSO(4) failed to produce any such significant increase. Except NiSO(4), the soluble forms of NiCH, Ni(3)S(2), and NiO produced significant cell-cycle delay (as measured by the inhibition of RI) as well as significant inhibition of the MI at respective similar concentrations as mentioned above. Pretreatment of human blood lymphocytes with catalase (H(2)O(2) scavenger), or superoxide dismutase (superoxide anion scavenger), or dimethylthiourea (hydroxyl radical scavenger), or deferoxamine (iron chelator), or N-acetylcysteine (general antioxidant) inhibited NiCH-induced SCE, and changes in RI and MI. This suggests the participation of oxidative stress involving H(2)O(2), the superoxide anion radical, the hydroxyl radical, and iron in the NiCH-induced genotoxic responses. Cotreatment of NiCH with either verapamil (inhibitor of intracellular calcium ion ([Ca(2+)](i)) movement through plasma membranes), or dantrolene (inhibitor of [Ca(2+)](i) release from sarcoplasmic reticulum), or BAPTA (Ca(2+) chelator) also inhibited the NiCH-induced responses. These results suggest that [Ca(2+)](i) is also implicated in the genotoxicity of NiCH. Overall these data indicate that various types of oxidative stress including iron-mediated oxidative stress involving the Fenton-Haber/Weiss reaction, and alterations in calcium homeostasis are involved in the genetic damage produced by the soluble form of NiCH.

Adult↗

PubMed1995

The role of oxidative stress in HIV disease.

Evidence has accumulated suggesting that HIV-infected patients are under chronic oxidative stress. Perturbations to the antioxidant defense system, including changes in levels of ascorbic acid, tocopherols, carotenoids, selenium, superoxide dismutase, and glutathione, have been observed in various tissues of these patients. Elevated serum levels of hydroperoxides and malondialdehyde also have been noted and are indicative of oxidative stress during HIV infection. Indications of oxidative stress are observed in asymptomatic HIV-infected patients early in the course of the disease. Oxidative stress may contribute to several aspects of HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss, and increased sensitivity to drug toxicities. Glutathione may play a role in these processes, and thus, agents that replete glutathione may offer a promising treatment for HIV-infected patients. Clinical studies are underway to evaluate the efficacy of the glutathione-repleting agents, L-2-oxothiazolidine-4-carboxylic acid (OTC) and N-acetylcysteine (NAC), in HIV-infected patients.

Antioxidants↗

PubMed1992

The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus.

This review describes the potential role of oxidative stress as a cofactor of disease progression from asymptomatic human immunodeficiency virus (HIV) infection to the acquired immunodeficiency syndrome (AIDS). Oxidative stress is a known activator of HIV replication in vitro through the activation of a factor that binds to a DNA-binding protein, NF-kappa B, which in turn stimulates HIV gene expression by acting on the promoter region of the viral long terminal repeat. Tumor necrosis factor alpha (TNF-alpha), an essential cytokine produced by activated macrophages, is also involved in the activation of HIV infection through similar mechanisms. TNF-mediated cytotoxicity of cells exposed to this substance is related to the generation of intracellular hydroxyl radicals. An indirect argument in favor of the role of oxidative stress in HIV-associated disease progression is the consumption of glutathione (GSH), a major intracellular antioxidant, during HIV infection and progression. GSH is known to play a major role in regulation of T cell immune functions. Oxidative stress may also play an important role in the genesis of cellular DNA damage and, in this context, may be related to HIV-associated malignancies and disease progression. Finally, the role of antioxidants as components of therapeutic strategies to combat HIV disease progression is discussed.

Acquired Immunodeficiency Syndrome↗

PubMed1994

DNA damage-inducible replication of the Escherichia coli chromosome is initiated at separable sites within the minimal oriC.

When Escherichia coli cells are subjected to genetic stress by exposure to agents or conditions that transiently block DNA replication, the mode of DNA replication is profoundly altered. One of the alterations is the induction of inducible stable DNA replication (iSDR) that does not require the initiator protein, DnaA, and occurs despite the presence of rifampin and chloramphenicol, which inhibit the initiation of usual chromosome replication at oriC. It has been demonstrated that iSDR starts primarily from both the oriC and terC regions of the chromosome. To precisely map the iSDR origin (oriM1) located in the oriC region, various oriC fragments were inserted into a plasmid vector derived from pSC101, and the copy number of these plasmid constructs was measured in the presence of rifampin and chloramphenicol after cells were induced for the SOS response by thymine starvation. The results indicated that there are at least two origins for iSDR within the minimal oriC; one (oriM1A) is located between the BamHI (coordinate +1) and the AvaII(155) sites, and the other (oriM1B) between the AvaII(155) and the HindIII(244) sites. Furthermore, a 263 bp fragment containing oriM1, which was placed at the att lambda site of the chromosome, was found to initiate chromosome replication in the presence of the drugs when cells were starved of thymine. Introduction of additional copies of oriM1 into a cell stimulated initiation of iSDR at oriM1 on the chromosome. The result supported the model that iSDR starts from D-loops created between oriM1 sequences and that the amount of D-loops determines the level of the iSDR activity.

Bacterial Proteins↗

PubMed2005

[Senescence: a telomeric limit to immortality or a cellular response to physiologic stresses?].

Cells entering a state of senescence undergo a irreversible cell cycle arrest, associated by a set of functional and morphological changes. Senescence occurs following telomeres shortening (replicative senescence) or exposure to other acute or chronic physiologic stress signals (a phenomenon termed stasis: stress or aberrant signaling-induced senescence). In this review, I discuss the pathways of cellular senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer. Telomere-initiated senescence or loss of telomere function trigger focal recruitement of protein sensors of the DNA double-strand breaks leading to the activation of the DNA damage checkpoint responses and the tumour suppressor gene product, p53, which in turn induces the cell-cycle inhibitor, p21(WAF1). Loss of p53 and pRb function allows continued cell division despite increasing telomere dysfunction and eventually entry into telomere crisis. Immortalisation is an essential prerequisite for the formation of a tumour cell. Therefore, a developing tumour cell must circumvent at least two proliferative barriers--cellular senescence and crisis--to achieve neoplastic transformation. These barriers are regulated by telomere shortening and by the p16(INK4a)/Rb and p53 tumour suppressor pathways. Elucidation of the genes and emerging knowledge about the regulatory mechanisms that lead to senescence and determine the pattern of gene expression in senescent cells may lead to more effective treatments for cancer.

Aging↗