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PubMed2001

Longevity of dual chamber pacemakers: device and patient related determinants.

In 382 patients with three different dual chamber pulse generators, the median time interval to battery depletion was 98.3 months. Cox regression analysis revealed the following variables as significant predictors of battery longevity: programmed pacing rate, energy of the stimulation output, mode of stimulation (i.e., proportion of paced cycles in one or two chambers), battery capacity, and internal sensing current of the pacemaker. Although 27% of all patients died before the service life of the pacemaker was over and despite a rate of premature reoperations of 8.6%, the majority of pacemaker patients (55%) fully used the expected battery life span of the pulse generator. Patients who died before the pacemaker had reached its end of service were significantly older at implantation than patients who survived until pacemaker replacement. The vast majority (92%) of patients received another dual chamber pulse generator when replacement was required. These data underline the need for long-lasting dual chamber devices.

Aged↗
PubMed2003

Variability in implantable cardioverter defibrillator pulse generator longevity between manufacturers.

ICDs are used frequently to treat malignant ventricular arrhythmias. Despite the expanding role of these devices, little is known about the manufacturer variability in the performance of ICD generators. The purpose of this study is to explore the indications for ICD pulse generator replacement and to examine performance differences between the three major manufacturers of ICDs in the United States. The authors performed a retrospective review of ICD pulse generators that were implanted and replaced at Massachusetts General Hospital between February 1998 and March 2002. During the study period, 50 (7%) of the 707 devices in the study cohort were replaced. The most common indication for pulse generator replacement was related to battery performance followed by device recall, upgrade to a dual chamber device, and pulse generator malfunction. After exclusion of the recalled devices, a significantly higher number of pulse generators manufactured by St. Jude Medical (14/229) required replacement for battery depletion or prolonged change times during the study period compared with devices from Guidant (2/220) or Medtronic (0/273), P = 0.003 and P < 0.0001, respectively. This difference was attributable to reduced longevity in the Angstrom series of defibrillators.

Defibrillators, Implantable↗
PubMed2000

The impact of media composition and petite mutation on the longevity of a polyploid brewing yeast strain.

Ageing in Saccharomyces cerevisiae is a finite phenomenon, determined by replicative, rather than chronological lifespan. Yeast physiological condition is known to influence industrial fermentation performance, however, until recently cellular senescence has not been considered as a brewing yeast stress factor. A polyploid lager yeast (BB11) and a brewery isolate, exhibiting petite mutation were analysed for longevity. It was observed that mitochondrial deficiency induced a reduction in lifespan. In addition, replicative capacity was perceived to be dependent on environmental conditions.

Culture Media↗
PubMed2002

Lipoaugmentation for aging hands: a comparison of the longevity and aesthetic results of centrifuged versus noncentrifuged fat.

BACKGROUND: Fat augmentation has long been utilized by cosmetic surgeons for volume restoration of the face and hands. However, it is not clear which methods of fat preparation optimize survival and aesthetic results. The need for centrifugation of the fat prior to augmentation has been debated in the literature. OBJECTIVE: To evaluate the long-term efficacy of fat transplantation to the hands using centrifuged versus noncentrifuged fat. METHODS: Fourteen patients underwent fat augmentation to the hands utilizing 10 ml of centrifuged fat in one hand and 10 ml of noncentrifuged fat in the contralateral hand in a randomized, double-blind comparison study. Evaluation intervals were at 1, 3, and 5 months at which time aesthetic results, vein prominence, and depth of metacarpal space were evaluated. RESULTS: At 1 month the subjective and objective preference was the hand with the noncentrifuged fat in 75% of patients, even though vein prominence and depth of metacarpal space were higher in that group. By 3 months the preferred result was centrifuged fat in 62.5% of patients; 25% had equal results and 12.5% preferred the noncentrifuged fat. By 5 months the subjective and objective preference was for the centrifuged fat in 100% of patients. This preference was supported by a lower score in vein prominence and depth of metacarpal space in that group. CONCLUSION: This preliminary study supports the use of centrifuged fat compared to noncentrifuged fat for longevity and improved aesthetic results at 3 and 5 months for fat augmentation of the aging hands.

Adipose Tissue↗
PubMed1988

[Comparison of the longevity of tsetse flies (Glossina morsitans morsitans Westwood, 1850) infected with trypanosomes (Trypanosoma nannomonas congolense Broden, 1904) and uninfected tsetse flies].

This preliminary note results from a comparative study on susceptibility to pyrethroid insecticides of tsetse flies infected and not with trypanosomes. Trypanosoma infection increases the susceptibility to insecticides as previous study showed it (Golder et al., 1982, 1984). Moreover, infected control flies showed a significant lower longevity than uninfected ones.

Animals↗
PubMed2000

Independent factors associated with longevity of prosthetic pulmonary valves and valved conduits.

OBJECTIVE: To evaluate the age dependence of variables predictive of pulmonary valve prosthesis replacement, we conducted the following analysis. METHODS: Retrospective analysis of 945 operations in 726 patients undergoing placement of pulmonary valve prostheses was performed. Age was identified as a strong independent predictor of valve failure. The database was stratified into age-based subsets and predictors of valve replacement were identified within each subset. RESULTS: For the entire cohort, freedom from valve replacement at 5 years was 81%. Younger age was strongly associated with decreased time to valve replacement by multivariable analysis (hazard ratio: 0.71/log-year, P <.001). Other independent factors included diagnosis, type of prosthesis, and time-dependent requirement for pulmonary valve stent placement. Important predictors of valve failure varied among age groups and are as follows: for Age Less Than 3 Months: valve type; for Age 3 Months To Less Than 2 Years: smaller normalized valve prosthesis size; for Age 2 Years To Less Than 13 Years: sex, smaller normalized valve prosthesis size, placement of endovascular stents, and valve type; for Age 13 Years To 65 Years: smaller normalized valve prosthesis size, placement of endovascular stents, and increased number of previous valve placements. CONCLUSION: Age is a dominant risk factor predictive of pulmonary valve prosthesis failure. A significant interaction exists between age and the effects of diagnosis, valve type, and size on prosthetic pulmonary valve longevity.

Adolescent↗
PubMed1999

The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway.

Inactivation of the tumor suppressor PTEN gene is found in a variety of human cancers and in cancer predisposition syndromes. Recently, PTEN protein has been shown to possess phosphatase activity on phosphatidylinositol 3,4,5-trisphosphate, a product of phosphatidylinositol 3-kinase. We have identified a homolog of PTEN in Caenorhabditis elegans and have found that it corresponds to the daf-18 gene, which had been defined by a single, phenotypically weak allele, daf-18(e1375). By analyzing an allele, daf-18(nr2037), which bears a deletion of the catalytic portion of CePTEN/DAF-18, we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1, which encode an insulin receptor-like molecule and the catalytic subunit of phosphatidylinositol 3-kinase, respectively. In addition, daf-18(nr2037) dramatically shortens lifespan, both in a wild-type background and in a daf-2 mutant background that normally prolongs lifespan. The lifespan in a daf-18(nr2037) mutant can be restored to essentially that of wild type when combined with a daf-2 mutation. Our studies provide genetic evidence that, in C. elegans, the PTEN homolog DAF-18 functions as a negative regulator of the DAF-2 and AGE-1 signaling pathway, consistent with the notion that DAF-18 acts a phosphatidylinositol 3,4,5-trisphosphate phosphatase in vivo. Furthermore, our studies have uncovered a longevity-promoting activity of the PTEN homolog in C. elegans.

Amino Acid Sequence↗
PubMed1999

Kinetic stability as a mechanism for protease longevity.

The folding of the extracellular serine protease, alpha-lytic protease (alphaLP; EC 3.4.21.12) reveals a novel mechanism for stability that appears to lead to a longer functional lifetime for the protease. For alphaLP, stability is based not on thermodynamics, but on kinetics. Whereas this has required the coevolution of a pro region to facilitate folding, the result has been the optimization of native-state properties independent of their consequences on thermodynamic stability. Structural and mutational data lead to a model for catalysis of folding in which the pro region binds to a conserved beta-hairpin in the alphaLP C-terminal domain, stabilizing the folding transition state and the native state. The pro region is then proteolytically degraded, leaving the active alphaLP trapped in a metastable conformation. This metastability appears to be a consequence of pressure to evolve properties of the native state, including a large, highly cooperative barrier to unfolding, and extreme rigidity, that reduce susceptibility to proteolytic degradation. In a test of survival under highly proteolytic conditions, homologous mammalian proteases that have not evolved kinetic stability are much more rapidly degraded than alphaLP. Kinetic stability as a means to longevity is likely to be a mechanism conserved among the majority of extracellular bacterial pro-proteases and may emerge as a general strategy for intracellular eukaryotic proteases subject to harsh conditions as well.

Enzyme Stability↗
PubMed2000

A longevity assurance gene homolog of tomato mediates resistance to Alternaria alternata f. sp. lycopersici toxins and fumonisin B1.

The phytopathogenic fungus Alternaria alternata f. sp. lycopersici (AAL) produces toxins that are essential for pathogenicity of the fungus on tomato (Lycopersicon esculentum). AAL toxins and fumonisins of the unrelated fungus Fusarium moniliforme are sphinganine-analog mycotoxins (SAMs), which cause inhibition of sphingolipid biosynthesis in vitro and are toxic for some plant species and mammalian cell lines. Sphingolipids can be determinants in the proliferation or death of cells. We investigated the tomato Alternaria stem canker (Asc) locus, which mediates resistance to SAM-induced apoptosis. Until now, mycotoxin resistance of plants has been associated with detoxification and altered affinity or absence of the toxin targets. Here we show that SAM resistance of tomato is determined by Asc-1, a gene homologous to the yeast longevity assurance gene LAG1 and that susceptibility is associated with a mutant Asc-1. Because both sphingolipid synthesis and LAG1 facilitate endocytosis of glycosylphosphatidylinositol-anchored proteins in yeast, we propose a role for Asc-1 in a salvage mechanism of sphingolipid-depleted plant cells.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells.

The longevity assurance gene (LAG1) and its homolog (LAC1) are required for acyl-CoA-dependent synthesis of ceramides containing very long acyl chain (e.g. C26) fatty acids in yeast, and a homolog of LAG1, ASC1, confers resistance in plants to fumonisin B(1), an inhibitor of ceramide synthesis. To understand further the mechanism of regulation of ceramide synthesis, we now characterize a mammalian homolog of LAG1, upstream of growth and differentiation factor-1 (uog1). cDNA clones of uog1 were obtained from expression sequence-tagged clones and sub-cloned into a mammalian expression vector. Transient transfection of human embryonic kidney 293T cells with uog1 followed by metabolic labeling with [4,5-(3)H]sphinganine or L-3-[(3)H]serine demonstrated that uog1 conferred fumonisin B(1) resistance with respect to the ability of the cells to continue to produce ceramide. Surprisingly, this ceramide was channeled into neutral glycosphingolipids but not into gangliosides. Electrospray tandem mass spectrometry confirmed the elevation in sphingolipids and revealed that the ceramides and neutral glycosphingolipids of uog1-transfected cells contain primarily stearic acid (C18), that this enrichment was further increased by FB(1), and that the amount of stearic acid in sphingomyelin was also increased. UOG1 was localized to the endoplasmic reticulum, demonstrating that the fatty acid selectivity and the fumonisin B(1) resistance are not due to a subcellular localization different from that found previously for ceramide synthase activity. Furthermore, in vitro assays of uog1-transfected cells demonstrated elevated ceramide synthase activity when stearoyl-CoA but not palmitoyl-CoA was used as substrate. We propose a role for UOG1 in regulating C18-ceramide (N-stearoyl-sphinganine) synthesis, and we note that not only is this the first case of ceramide formation in mammalian cells with such a high degree of fatty acid specificity, but also that the N-stearoyl-sphinganine produced by UOG1 most significantly impacts neutral glycosphingolipid synthesis.

Animals↗
PubMed2003

Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors.

Overexpression of upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene (LAG1), selectively induces the synthesis of stearoyl-containing sphingolipids in mammalian cells (Venkataraman, K., Riebeling, C., Bodennec, J., Riezman, H., Allegood, J. C., Sullards, M. C., Merrill, A. H. Jr., and Futerman, A. H. (2002) J. Biol. Chem. 277, 35642-35649). Gene data base analysis subsequently revealed a new subfamily of proteins containing the Lag1p motif, previously characterized as translocating chain-associating membrane (TRAM) protein homologs (TRH). We now report that two additional members of this family regulate the synthesis of (dihydro)ceramides with specific fatty acid(s) when overexpressed in human embryonic kidney 293T cells. TRH1 or TRH4-overexpression elevated [3H](dihydro)ceramide synthesis from l-[3-3H]serine and the increase was not blocked by the (dihydro)ceramide synthase inhibitor, fumonisin B1 (FB1). Analysis of sphingolipids by liquid chromatography-electrospray tandem mass spectrometry revealed that TRH4 overexpression elevated mainly palmitic acid-containing sphingolipids whereas TRH1 overexpression increased mainly stearic acid and arachidic acid, which in both cases were further elevated upon incubation with FB1. A similar fatty acid specificity was obtained upon analysis of (dihydro)ceramide synthase activity in vitro using various fatty acyl-CoA substrates, although in a FB1-sensitive manner. Moreover, in homogenates from TRH4-overexpressing cells, sphinganine, rather than sphingosine was the preferred substrate, whereas no preference was seen in homogenates from TRH1-overexpressing cells. These findings lend support to our hypothesis (Venkataraman, K., and Futerman, A. H. (2002) FEBS Lett. 528, 3-4) that Lag1p family members regulate (dihydro)ceramide synthases responsible for production of sphingolipids containing different fatty acids.

Acyl Coenzyme A↗
PubMed2004

Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas.

In this study, endogenous long chain ceramides were measured in 32 human head and neck squamous cell carcinoma (HNSCC) and 10 nonsquamous head and neck carcinoma tumor tissues, as compared with adjacent noncancerous tissues, by liquid chromatography/mass spectroscopy. Interestingly, only one specific ceramide, C(18:0)-ceramide, was selectively down-regulated in the majority of HNSCC tumor tissues. On the other hand, in nonsquamous tumor tissues, this selectivity for C18-ceramide was not detected. These data suggested the hypotheses that decreased levels of C18-ceramide might impart a growth advantage to HNSCC cells and that increased generation of C18-ceramide may be involved in the inhibition of growth. These roles were examined by reconstitution of C18-ceramide at physiologically relevant concentrations in UM-SCC-22A cells (squamous cell carcinoma of hypopharynx) via overexpression of mammalian upstream regulator of growth and differentiation factor 1 (mUOG1), a mouse homologue of longevity assurance gene 1 (mLAG1), which has been shown to specifically induce the generation of C18-ceramide. Liquid chromatography/mass spectroscopy analysis showed that overexpression of the mLAG1/mUOG1 resulted in increased levels of only C(18:0)-ceramide by approximately 2-fold, i.e. concentrations similar to those of normal head and neck tissues. Importantly, increased generation of C18-ceramide by mLAG1/mUOG1 inhibited cell growth (approximately 70-80%), which mechanistically involved the modulation of telomerase activity and induction of apoptotic cell death by mitochondrial dysfunction. In conclusion, this study demonstrates, for the first time, a biological role for LAG1 and C18-ceramide in the regulation of growth of HNSCC.

Animals↗
PubMed2004

Reasons for restorative therapy and the longevity of restorations in adults.

The aim of this study was to obtain information on the restorative dental care of adults in Finland. A random sample of private dentists was drawn from the register, and in spring 2000 they were sent a questionnaire requesting them to record information for each restoration placed during one ordinary working day. A total of 800 dentists were contacted and 548 responded. The dentists reported placement of 3,455 restorations. Of these, 5% were Class I, 36% were Class II, 13% were Class III, 9% were Class IV, 21% were Class V, and 16% were extensive restorations including 4 or more surfaces. Overall, composite resin was the most common restorative material, and it was used in 79% of the restorations, whereas amalgam was used in 50%, compomers in 4%, and glass ionomers (either conventional or resin-modified) in 7% of cases. In 5%, of the cases, the tooth was restored with indirect restorative methods, using either gold or ceramic materials. Of the treatments, 65% were replacements of previous restorations. Secondary caries was the most common reason for replacement (36%, 52%, and 41% for composite, glass ionomer, and amalgam, respectively). Other common reasons were fractures of the tooth or restoration (23%, 11%, and 22% for composite, glass ionomer, and amalgam, respectively) and lost composite restorations (16%). The median age of failed restorations was 15 years for amalgam, 6 years for composite, and 7 years for conventional glass ionomer. Although the longevity of tooth coloured restorations was shorter than that of amalgam, comparisons with our previous studies indicate improved survival periods for tooth coloured materials.

Adolescent↗
PubMed2002

Melatonin, longevity and health in the aged: an assessment.

This brief review considers the potential role of melatonin in the processes of aging, the prolongation of life span and health in the aged. Studies completed to date generally suggest that exogenously administered melatonin may serve to extend life span in invertebrates, but evidence supporting this conclusion in mammals is less compelling. Thus, any conclusion regarding a role for melatonin in extending normal longevity, particularly in mammals, would be premature. With regard to deferring the signs of chemically-induced neurodegenerative conditions in experimental animals, the data are remarkably strong and there is a modicum of evidence that in humans with debilitating diseases melatonin may have some beneficial actions. Indeed, this should be one focus of future research since as the number of elderly increases in the population, the frequency of costly age-related diseases will become increasingly burdensome to both the patient and to society as a whole.

Age Factors↗
PubMed1999

A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor-ligand complex.

We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II- restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64-76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR-ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR-ligand complexes.

Amino Acid Sequence↗
PubMed2000

TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo.

Mature dendritic cells (DCs) are powerful antigen presenting cells that have the unique capacity to migrate to the T cell zone of draining lymph nodes after subcutaneous injection. Here we report that treatment of antigen-pulsed mature DCs with tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a TNF family member, before immunization enhances their adjuvant capacity and elicits improved T cell priming in vivo, such that both primary and memory T cell immune responses are enhanced. By enumerating migratory DCs in the draining lymph nodes and by studying their function in stimulating naive T cells, we show that one of the underlying mechanisms for enhanced T cell responses is an increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell areas of lymph nodes. These results suggest that the longevity and abundance of mature DCs at the site of T cell priming influence the strength of the DC-initiated T cell immunity in situ. Our findings have the potential to improve DC-based immunotherapy; i.e., the active immunization of humans with autologous DCs that have been pulsed with clinically significant antigens ex vivo.

Adjuvants, Immunologic↗
PubMed2005

Accessibility and longevity of Internet citations in a clinical AIDS journal.

Little is known about the accessibility and longevity of Internet references in medical and scientific journals. This is particularly problematic in the ever changing field of HIV/AIDS. We examined all issues of AIDS Patient Care and STDs between 2001 and 2004 to test the use and accessibility of Internet citations during this period. The results were compared to findings from a similar evaluation by Hester and colleagues in 2004 of oncology journals. We found that Internet referencing increased from a mean of 0.7% (range, 0.0%-2.1%) of all citations in 2001 to a mean of 3.5% (range, 0.0%-11.2%) in 2004. As the period of time increased from an article's publication, the proportion of inactive Internet references increased (21.3% [1 year] to 41.7% [4 years]). These findings demonstrate the need to adapt new citation policies to facilitate the accessibility of referenced Internet information.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Scientific and ethical concerns regarding engineering human longevity.

The goal of biogerontological research is to elucidate the biological factors underlying adverse age-related changes in structure and function of molecules, cells, tissues, and organisms. In spite of the considerable progress achieved so far, it is still too early to predict what strategies will be both safe and effective at preventing, delaying, or reversing these changes in humans, and whether such strategies will also increase longevity.

Aging↗