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Results for “replicative lifespan”

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At least 289 records · Page 16Linked to original sources

PubMed2002

Annotation: the role of prefrontal deficits, low autonomic arousal, and early health factors in the development of antisocial and aggressive behavior in children.

BACKGROUND: This article selectively reviews the biological bases of antisocial and aggressive behavior in children with a focus on low autonomic functioning, prefrontal deficits, and early health factors. RESULTS: Low resting heart rate is thought to be the best-replicated biological correlate of antisocial and aggressive behavior in child and adolescent populations and may reflect reduced noradrenergic functioning and a fearless, stimulation-seeking temperament. Evidence from neuropsychological, neurological, and brain imaging studies converges on the conclusion that prefrontal structural and functional deficits are related to antisocial, aggressive behavior throughout the lifespan. A prefrontal dysfunction theory of antisocial behavior is advanced. This argues that social and executive function demands of late adolescence overload the late developing prefrontal cortex, giving rise to prefrontal dysfunction and a lack of inhibitory control over antisocial, violent behavior that peaks at this age. Birth complications and minor physical anomalies are selectively associated with later violent behavior, especially when combined with adverse psychosocial risk factors for violence. Cigarette smoking during pregnancy may increase the risk for antisocial and violent behavior in later life by disrupting noradrenergic functioning and enhancement of cholinergic receptors that inhibit cardiac functioning. Malnutrition during pregnancy is associated with later antisocial behavior and may be mediated by protein deficiency. CONCLUSIONS: It is argued that early health intervention and prevention studies may provide the most effective way of reversing biological deficits that predispose to antisocial and aggressive behavior in children and adults.

Adolescent↗

PubMed1979

The relationship between RNA content, cell volume and growth potential in ageing human embryonic mesenchymal cells.

Modal cell volume and cellular RNA content were meaume was found to correlate with both culture replication rate and cellular RNA content. This observation suggests that cell volume changes may be related to the rate of cell division during ageing in vitro, and that both cell volume and RNA content may be closely controlled. There was no change in the relative proportions of the major rRNA species during the cultures' lifespan.

Cell Line↗

PubMed1986

Accumulation of DNA fragments in aging Paramecium tetraurelia in axenic and nonaxenic media.

The accumulation of DNA fragments in aging Paramecium tetraurelia after 15 days (or approximately 60 generations) of clonal growth in both axenic and nonaxenic media was assayed by alkaline elution assay. This sensitive technique permits measurement of single-strand breaks in double-stranded DNA. The results obtained indicate that P. tetraurelia aged in axenic medium accumulate more apurinic/apyrimidinic lesions, strand breaks, or single-strand gaps than do P. tetraurelia aged in nonaxenic medium. This implies that cells grown in axenic medium have a shorter lifespan than do cells grown in nonaxenic medium. The accumulation of DNA fragments may be the basic mechanism of aging in P. tetraurelia.

Carbon Radioisotopes↗

PubMed1984

[Effect of rubomycin and its paramagnetic analog on DNA synthesis].

Ruboxyl, a paramagnetic analog of rubomycin, was synthesized and subjected to a preliminary investigation at the Institute of Chemical Physics of the Academy of Sciences of the USSR. The drug is characterized by a higher antitumor activity, broader spectrum and lower general and cardiac toxicity. This is the first attempt of comparative biochemical investigation of rubomycin, ruboxyl and the nitroxyl radical at the level of DNA replication. The effect of these drugs on the synthesis of DNA in the cells of leukemia P-388, the bone marrow and heart of mice was studied. It was shown that the degree and duration of the DNA synthesis inhibition in the tumor cells correlated well with the antitumor activity of the drugs. On the 3rd day after administration rubomycin and ruboxyl induced stimulation of the DNA synthesis in the cells of the bone marrow. This might be explained by transfer of a part of the population of the bone marrow cells from Go phase due to the cytotoxic damages of the proliferating cells. The DNA synthesis stimulation in the bone marrow was most likely associated with the toxic effect of the drugs. No correlation between the cardiotoxicity and inhibition of the DNA synthesis in the heart cells of the mice was observed. The nitroxyl radical showed no biological activity on this model. The average lifespan of the mice treated with the nitroxyl radical was the same as that of the control animals. A decrease in the incorporation of 2-14C-thymidine into DNA of the tumor, bone marrow and heart was observed in the tumor carriers with development of the tumor.

Animals↗

PubMed1985

Genome reorganization during aging of dividing cells.

The study of the effect of low dose rate ionizing radiation on the long-term proliferation of fibroblasts led to the observation that radiation accentuated the growth potential of the cells, favoring events which normally take place during division. These events could be related to the genome reorganization taking place during division. Hence, it was hypothesized (Macieira-Coelho, 1979; Macieira-Coelho, 1980; Macieira-Coelho, 1981) that the long-term proliferation of fibroblasts depends upon the potential for reorganization of the genome, the latter being a self-limiting process. At each division residual quantitative and qualitative changes would accumulate in chromatin, limiting the long-term potential for further rearrangements. The hypothesis was checked looking for quantitative and qualitative changes in DNA through the in vitro lifespan of human fibroblast populations. It was found that at each population doubling in 20% of the cells there is unequal distribution of DNA between sister cells. Results show that this could be due to errors in chromosome assembly and segregation, to loss of DNA, to errors during semiconservative DNA synthesis and to multiple rounds of DNA replication at a single origin. An increased alkali- and thermo-lability of chromatin was found during in vitro aging. At the ultrastructural level after mild decondensation, chromatin fibers were spaced and shorter. After Miller's spreading, most of the chromatin of old cells had lost the nucleosome organization and was fragmented. These chromatin changes became apparent only towards the end of the life span of human embryonic fibroblasts but were already present in a significant fraction of low population doubling level (PDL) fibroblasts from human adults. Almost all cells of low-PDL fibroblasts from the Werner syndrome presented these chromatin changes. In addition, short, unbeaded DNA fragments could be seen in these fibroblasts, occasionally forming circles; they could correspond to transposable elements which detach during the division cycle and fail to reintegrate into chromosomes because of the age-related chromatin structural changes.

Cell Division↗

PubMed1979

Spontaneous mutations balance reproductive selective advantage and genetically determine longevity.

The theory is presented that the genetic potential for longevity of a given species in a protected environment is determined by the rate of predation in the wild and by the frequency of spontaneous mutations. A common genetically determined lifespan representative of rare, long-lived individuals in the wild results from the slight selective advantage conferred by genotypes which do not cause early death. The selective advantage of reproductive rare survivors is limited by the rate of spontaneous mutations from a common potential longevity to those which limit lifespan to shorter times. The equilibrium frequency of life-limiting genes increases exponentially with increasing age when the rate of mutations is uniform for different degrees of life-shortening.

Aging↗

PubMed2006

Structure-activity relationships in platelet-activating factor. Part 14: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 activity.

As HIV-associated dementia prevalence has risen with the lifespan of HIV-infected individuals, there is an important need for antiretroviral and anti-inflammatory drugs targeting the central nervous system. Platelet-activating factor, a mediator of inflammation, is an HIV-induced neurotoxin secreted in the infected brain. In this work, we developed piperazine derivatives bearing a heterocyclic moiety as PAF-antagonists and HIV-1 replication inhibitors with micromolar potency.

Acquired Immunodeficiency Syndrome↗

PubMed1976

Evidence contrary to the protein error hypothesis for in vitro senescence.

A strain of diploid fibroblasts, obtained from the skin of a male infant, was cultured in vitro and cells were tested throughout their lifespan for the appearance of altered glucose-6-phosphate dehydrogenase (G-6-PD) detected either by thermostability studies or by immunotitration. No significant difference was found in the proportion of thermolabile enzyme in 31 young cultures (4.8 +/- 1%, S.E.), in comparison with that in 19 old cultures (4.9 +/- 1%, S.E.). Old cultures had ceased active cell division (49-60 doublings); DNA replication, measured by [3H]thymidine uptake over a period of 24 hours, was limited to less than 5% of these cells. Young cells (5-22 doublings) had a [3H]thymidine labeling index of 75-85%. Titration of G-6-PD activity in extracts of young and old cells with neutralizing antibody directes specifically against G-6-PD failed to detect an increment of enzymatically defective G-6-PD in old cells. The thermostability studies were capable of detecting altered G-6-PD in skin fibroblasts from a female heterozygous for a thermolabile mutant of G-6-PD, and in fibroblasts treated with a proline analogue, azetidine carboxylic acid. The immunotitration technique was also capable of detecting catalytically altered G-6-PD from the thermolabile mutant and G-6-PD inactivated with N-ethylameimide. These findings argue against a protein error catastrophe as the cause of in vitro clonal senescence.

Adult↗

PubMed2004

[Efficacy of therapeutic and prophylactic actions of ultralow doses of antibodies to gamma-interferon in experimental murine model of herpes virus].

The process of the disease due to herpes simplex virus types 1 and 2 (HSV-1 and 2) was studied on white uninbred mice weighing 10 to 12 g. The animals were infected intracerebrally or intraperitoneally. Intraperitoneal contamination of the animals with MS strain of HSV-2 was used for the experimental model of the herpes simplex infection. The prophylactic antiherpes action of ultralow doses of the human gamma-interferon antibodies (ULD of anti-IFN-gamma) at a course of its intragastral administration was evaluated. The preparation was shown to have a significant (p < 0.05) protective effect in a dose of 10 LD50, evident from a 10-fold decrease of the HSV-2 accumulation in the brain, a lower percentage of the animal deaths and an increase of the average lifespan of the animals by 3.3 days. The study of the therapeutic action of ULD of anti-IFN-gamma at a course of its intragastral administration showed that the preparation had no significant positive effect on the disease process in the animals infected with HSV-2 in a dose of 10 LD50. However, a positive effect associated with delayed virus replication in the brain was observed in the study on the therapeutic effect of ULD of anti-IFN-gamma after its intragastral administration to the mice infected with a sublethal dose of the virus.

Animals↗

PubMed1995

Derivation of phenobarbital-responsive immortal rat hepatocytes.

Two lines of rat hepatocytes, designated 6/15 and 6/27, were obtained from carcinogen-treated livers by cultivation in medium containing the liver tumor promoter, phenobarbital (PB). Both lines appeared to be PB-responsive and to have an unlimited in vitro proliferative lifespan, i.e., immortality. The ability of pure 6/27 hepatocytes to form colonies from single cells was strictly dependent upon PB; it was reduced by 97 to 99% in the absence of PB. These hepatocytes were not tumorigenic. For 6/27 hepatocytes in early passages where cultures contained fibroblast contaminants and later when they were a pure culture, PB was able to enhance colony growth from single cells and facilitated population expansion by sustaining DNA synthesis and by inhibiting cell lysis. The 6/15 line displayed PB-dependent colony formation and was not tumorigenic at early passages. At later passages 6/15 hepatocytes were less dependent on PB for colony formation, and they formed hepatocellular carcinoma when transplanted into livers of syngeneic rats. The demonstration that PB sustained the proliferation and viability of hepatocytes with enhanced growth capacity and indefinite proliferative lifespan suggests that PB may be necessary for progression of these chemically initiated hepatocytes to immortal and tumorigenic lines in vitro.

Animals↗

PubMed2004

Estradiol benzoate given 0 or 24 h after the end of a progestagen treatment in postpartum suckled beef cows.

The objective of Experiment 1 was to compare the effects of estradiol benzoate (EB) given 0 or 24h after the end of a progestagen treatment on ovulation and CL formation in anestrous cows. Twenty cows were treated with an intravaginal sponge containing 250 mg of medroxiprogesterone acetate (MPA). At sponge insertion, each cow received 3 mg EB and 10 mg MPA im. At device removal, cows received 0.7 mg EB either at that time (EB0) or 24h later (EB24). Ultrasound examinations and blood sampling to determine plasma progesterone concentrations were performed to detect ovulation and CL formation. Ovulation occurred in 77.8 and 81.8% cows in the EB0 and EB24 groups, respectively. Diameter of the ovulatory follicle (EB0 = 10.9 +/- 0.5mm; EB24 = 12.1 +/- 0.8 mm; P = 0.26) and the interval from sponge removal to ovulation (median = 3 days; P = 0.64) did not differ between treatments. Among the cows that ovulated (n = 16), short-lived CL were present in 2/7 and 2/9 cows in the EB0 and EB24 groups, respectively. Plasma progesterone concentrations and CL area did not differ between treatments (P > 0.05). In Experiment 2, cows were treated with the same protocol as in Experiment 1, but at sponge withdrawal all cows received 250 microg cloprostenol and timed artificial insemination (TAI) was performed 48 h after sponge removal. In Replicate 1 (n = 204 multiparous cows), pregnancy rates were 45.0 and 47.5% for EB0 and EB24, respectively (P > 0.05). In Replicate 2 (n = 69 primiparous cows) pregnancy rate did not differ between EB0 and EB24 (51.4% versus 52.9%). In conclusion, EB given 0 or 24h after the end of a progestagen treatment had the same effect on ovulation rate, time to ovulation, diameter of the ovulatory follicle, incidence of short-lived CL, luteal tissue area, and plasma progesterone concentrations of normal lifespan CL, and pregnancy rate after TAI in suckled beef cows.

Administration, Intravaginal↗

PubMed1991

AIDS: a historical overview.

AIDS has been a recognized clinical entity now for just 10 years. In that time in the United States alone, it is estimated that 1 to 2 million people may be infected with HIV. Estimates of numbers infected worldwide are as high as 10 million. Over these 10 years, considerable progress has been made. The disease and all its protean manifestations have been accurately described. How HIV spreads and where it is spreading have been accurately recorded. The cause is known and well understood, with more detailed information available about HIV than about any other virus. Drugs that slow down the replication of HIV have been discovered and are in widespread use. A cure or vaccine, however, seems unlikely in the near future. The major hope for the present would appear to be continued education to prevent the spread of AIDS and better antiviral agents that will keep HIV suppressed and, ideally, soon allow infected individuals to lead a close-to-normal lifespan (if treatment is commenced at an early-enough stage in the course of the infection).

Acquired Immunodeficiency Syndrome↗

PubMed2004

BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice.

Faithful segregation of replicated chromosomes is essential for maintenance of genetic stability and seems to be monitored by several mitotic checkpoints. Various components of these checkpoints have been identified in mammals, but their physiological relevance is largely unknown. Here we show that mutant mice with low levels of the spindle assembly checkpoint protein BubR1 develop progressive aneuploidy along with a variety of progeroid features, including short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat and impaired wound healing. Graded reduction of BubR1 expression in mouse embryonic fibroblasts causes increased aneuploidy and senescence. Male and female mutant mice have defects in meiotic chromosome segregation and are infertile. Natural aging of wild-type mice is marked by decreased expression of BubR1 in multiple tissues, including testis and ovary. These results suggest a role for BubR1 in regulating aging and infertility.

Aging↗

PubMed2004

DNA damage checkpoint kinase Chk2 triggers replicative senescence.

Telomere shortening in normal human cells causes replicative senescence, a p53-dependent growth arrest state, which is thought to represent an innate defence against tumour progression. However, although it has been postulated that critical telomere loss generates a 'DNA damage' signal, the signalling pathway(s) that alerts cells to short dysfunctional telomeres remains only partially defined. We show that senescence in human fibroblasts is associated with focal accumulation of gamma-H2AX and phosphorylation of Chk2, known mediators of the ataxia-telangiectasia mutated regulated signalling pathway activated by DNA double-strand breaks. Both these responses increased in cells grown beyond senescence through inactivation of p53 and pRb, indicating that they are driven by continued cell division and not a consequence of senescence. gamma-H2AX (though not Chk2) was shown to associate directly with telomeric DNA. Furthermore, inactivation of Chk2 in human fibroblasts led to a fall in p21(waf1) expression and an extension of proliferative lifespan, consistent with failure to activate p53. Thus, Chk2 forms an essential component of a common pathway signalling cell cycle arrest in response to both telomere erosion and DNA damage.

Blotting, Western↗

PubMed2005

Establishment, differentiation, electroporation, viral transduction, and nuclear transfer of bovine and porcine mesenchymal stem cells.

Mesenchymal stem cells (MSCs) reside in the bone marrow and have the potential for multilineage differentiation, into bone, cartilage, and fat, for example. In this study, bovine and porcine MSCs were isolated, cultured to determine their replication ability, and differentiated with osteogenic medium and 5-azacytine. Both bovine and porcine undifferentiated MSCs were electroporated and virally transduced to test the efficiency of genetic modification and the maintainance of differentiation ability thereafter. Nuclear transfer experiments were carried out with bovine and porcine MSCs, both at the undifferentiated state and following differentiation. Our results indicate that bovine and porcine MSCs have limited lifespans in vitro--approximately 50 population doublings. They can be efficiently differentiated and characterized along the osteogenic lineage by morphology, alkaline phosphatase, Von Kossa, oil red stainings, and RT-PCR. Electroporation and selection induce high levels of EGFP expression in porcine but not in bovine MSCs. Following genetic modification, MSCs retain their pluridifferentiation ability as parental cells. Cloned embryos derived from bovine and porcine undifferentiated MSCs and their derivatives along the osteogenic lineage give rise to consistently high preimplantation development comparable to adult fibroblasts.

Animals↗

PubMed1990

SV40 T antigen alone drives karyotype instability that precedes neoplastic transformation of human diploid fibroblasts.

To define the role of SV40 large T antigen in the transformation and immortalization of human cells, we have constructed a plasmid lacking most of the unique coding sequences of small t antigen as well as the SV40 origin of replication. The promoter for T antigen, which lies within the origin of replication, was deleted and replaced by the Rous sarcoma virus promoter. This minimal construct was co-electroporated into normal human fibroblasts of neonatal origin along with a plasmid containing the neomycin resistance gene (neo). Three G418-resistant, T antigen-positive clones were expanded and compared to three T antigen-positive clones that received the pSV3neo plasmid (capable of expressing large and small T proteins and having two origins of replication). Autonomous replication of plasmid DNA was observed in all three clones that received pSV3neo but not in any of the three origin minus clones. Immediately after clonal expansion, several parameters of neoplastic transformation were assayed. Low percentages of cells in T antigen-positive populations were anchorage independent or capable of forming colonies in 1% fetal bovine serum. The T antigen-positive clones generally exhibited an extended lifespan in culture but rarely became immortalized. Large numbers of dead cells were continually generated in all T antigen-positive, pre-crisis populations. Ninety-nine percent of all T antigen-positive cells had numerical or structural chromosome aberrations. Control cells that received the neo gene did not have an extended life span, did not have noticeable numbers of dead cells, and did not exhibit karyotype instability. We suggest that the role of T antigen protein in the transformation process is to generate genetic hypervariability, leading to various consequences including neoplastic transformation and cell death.

Antigens, Viral, Tumor↗

PubMed2004

Activation of the epidermal growth factor receptor by respiratory syncytial virus results in increased inflammation and delayed apoptosis.

Respiratory syncytial virus (RSV) preferentially infects lung epithelial cells. Infection by RSV leads to an extended inflammatory response, characterized by the release of interleukin-8 (IL-8). Activation of ERK MAP kinase is required for both RSV-induced inflammation and the extended survival of infected cells. In this study, we analyzed the role of the epidermal growth factor receptor (EGFR) in RSV activation of ERK. We demonstrate for the first time that RSV activates EGFR in lung epithelial cells. Activation of EGFR results in increased ERK activity, contributing to both the inflammatory response (IL-8 release) and prolonging the survival of RSV-infected cells. Inhibition of EGFR with siRNA decreased both ERK activation and IL-8 production after RSV. In analyzing the effect of EGFR activation on survival of RSV-infected cells, we found that EGFR activation by RSV resulted in ERK-dependent alterations in the balance of pro- versus anti-apoptotic Bcl2 proteins. RSV altered the balance between pro- and anti-apoptotic Bcl2 proteins (increased BclxL and decreased BimEL) increasing the relative amount of pro-survival proteins. This occurred in an EGFR-dependent manner. This study supports an important role for EGFR activity in the lifespan and inflammatory potential of RSV-infected epithelial cells.

Apoptosis↗

PubMed1998

Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells.

Normal human cells undergo a limited number of divisions in culture and enter a non-dividing state called replicative senescence. Senescence is accompanied by several changes, including an increase in inhibitors of cyclin-dependent kinases and telomere shortening. The mechanisms by which viral oncogenes reverse these processes are not fully understood, although a general requirement for oncoproteins such as human papillomavirus E6 and E7 has suggested that the p53 and Rb pathways are targeted. Expression of the catalytic component of telomerase, hTERT, alone significantly extends the lifespan of human fibroblasts. Here we show that telomerase activity is not sufficient for immortalization of human keratinocyte or mammary epithelial cells: we find that neither addition of hTERT nor induction of telomerase activity by E6, both of which are active in maintaining telomere length, results in immortalization. Inactivation of the Rb/p16 pathway by E7 or downregulation of p16 expression, in combination with telomerase activity, however, is able to immortalize epithelial cells efficiently. Elimination of p53 and of the DNA-damage-induced G1 checkpoint is not necessary for immortalization, neither is elimination of p19ARF.

Breast↗