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Biomedical subjects

Abraham Aviv

Publications and source records attributed to Abraham Aviv.

At least 19 recordsLinked to original sources
PubMed2006

Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration.

BACKGROUND: Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation. OBJECTIVES: To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles. METHODS: WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed. RESULTS: Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p<0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls. CONCLUSION: The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.

Age Factors↗
PubMed2006

Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.

Aged↗
PubMed2006

Human telomere biology: pitfalls of moving from the laboratory to epidemiology.

Remarkable progress has been made during the last 2 decades in understanding telomere biology at the molecular and cellular levels. Clinical epidemiology research of human telomeres, in contrast, is a discipline just coming into its own. The most important observation in studying human telomere biology is that telomere length is highly variable among humans. Here we explain some of the reasons for this variability and propose several principles that should be considered in conducting epidemiological telomere research. Ignoring these principles could lead to misleading conclusions.

Aged↗
PubMed2006

Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs.

Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an approximate 10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18-80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval [CI] 18%-48%), with a large common environmental effect of 49% (95% CI 40%-58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.

Chromosome Mapping↗
PubMed2006

Telomeres and human somatic fitness.

Mean leukocyte telomere length may be an indicator of biological age, and as such it appears to provide information over and above chronological age of the risk for developing diseases of aging in humans. Here I propose that the mean leukocyte telomere length is an index of "somatic fitness," a concept that breaks down the artificial boundary between aging and diseases of aging. I also propose that, in exceptionally old humans, ultrashort leukocyte telomeres might be a determinant of life span.

Aging↗
PubMed2005

Menopause modifies the association of leukocyte telomere length with insulin resistance and inflammation.

CONTEXT: Leukocyte telomere length is inversely correlated with age, insulin resistance, serum leptin, and smoking. OBJECTIVE: We explored whether menopausal status modifies the relations between leukocyte telomere length and insulin resistance. In addition, we examined the effect of menopause on the relation between leukocyte telomere length and C-reactive protein (CRP), an index of inflammation. DESIGN: This was an observational cohort study. SETTING: The study setting was community based. PARTICIPANTS: A total of 1517 women aged 18-79 yr selected only for belonging to a twin pair and representative of the general population participated in the study. MAIN OUTCOME MEASURE: Leukocyte telomere restriction fragment length (TRFL) was measured. RESULTS: Insulin resistance (expressed in the homeostasis model assessment), leptin, and CRP were inversely correlated with leukocyte TRFL in premenopausal but not postmenopausal women. Insulin resistance, CRP, but not leptin independently accounted for variation in white blood cell TRFL in premenopausal women. CONCLUSIONS: Menopausal status impacts leukocyte telomere length and its relation with insulin resistance and inflammation in women.

Adolescent↗
PubMed2005

The longevity gender gap: are telomeres the explanation?

In this Perspective, we focus on the greater longevity of women as compared with men. We propose that, like aging itself, the longevity gender gap is exceedingly complex and argue that it may arise from sex-related hormonal differences and from somatic cell selection that favors cells more resistant to the ravages of time. We discuss the interplay of these factors with telomere biology and oxidative stress and suggest that an explanation for the longevity gender gap may arise from a better understanding of the differences in telomere dynamics between men and women.

Aged↗
PubMed2005

Calcium adaptation to sodium pump inhibition in a human megakaryocytic cell line.

The unique characteristics of the platelet Na/Ca exchanger, i.e., its dependence on both transmembrane Na and K gradients, render it highly sensitive to Na pump inhibition. In this project, we observed that the human megakaryocytic cell line CHRF-288 expresses both the alpha1- and alpha3-isoforms of the Na-K-ATPase. Inhibition of the Na pump increased the RNA and protein expressions of sarco(endo)plasmic reticulum Ca-ATPase 2b, cytosolic Na and Ca, and the freely exchangeable Ca in the endoplasmic reticulum. These changes occurred in concert with diminished store-operated Ca entry and an increase in the maximal activity of the Na/Ca exchanger. Inhibition of the Na pump by ouabain was more effective in inducing these changes than diminishing medium K. Collectively, these observations point to an integrative effort to counteract the impact of Na pump inhibition by Ca sequestration into the endoplasmic reticulum, diminished Ca entry, and increased activity of the Na/Ca exchanger. The implications of these findings in platelet biology are discussed.

Calcium↗
PubMed2005

Rise in insulin resistance is associated with escalated telomere attrition.

BACKGROUND: Insulin resistance predisposes to cardiovascular disease and shortens human lifespan. We therefore tested the hypothesis that a rise in insulin resistance in concert with gain in body mass is associated with accelerated white blood cell telomere attrition. METHODS AND RESULTS: We measured white blood cell telomere dynamics and age-related changes in insulin resistance and body mass index in young adults of the Bogalusa Heart Study. Over 10.1 to 12.8 years, the relative changes in telomere length were correlated with the homeostasis model assessment of insulin resistance (r=-0.531, P<0.001) and changes in the body mass index (r=-0.423, P<0.001). CONCLUSIONS: These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans.

Adiposity↗
PubMed2005

Proliferation dynamics in cultured skin fibroblasts from Down syndrome subjects.

With a view to better understanding the role of oxidant/antioxidant variables in proliferation dynamics of somatic cells, we explored the relationships among superoxide dismutase (SOD) activity, glutathione peroxidase (Gpx) activity, reactive oxygen intermediates (ROI), and indices of cellular proliferation and senescence in cultured fibroblasts from Down syndrome and normal donors. We found that Down syndrome cells had a significantly slower proliferative rate, but attain replicative senescence at similar population doubling (PD) as control cells. Irrespective of donor origin, the number of PD until replicative senescence was positively correlated with Gpx activity (r = 0.784, P = 0.007). In addition, the presence of exogenous catalase in the growth medium significantly extended the number of PD until replicative senescence (P = 0.011). The loss of telomere repeats per PD was not different between Down syndrome cells and controls. However, SOD activity was inversely correlated with the loss of telomere repeats per PD. Collectively, these findings suggest that replicative senescence ultimately relates to mechanisms downstream to SOD (i.e., Gpx and catalase) and confirmed previous observations about inverse relationships between SOD activity and telomere repeat loss per cellular replication.

Cell Proliferation↗
PubMed2005

Aldosterone and telomere length in white blood cells.

BACKGROUND: Aldosterone accelerates cardiovascular aging by mechanisms that generate reactive oxygen species. Telomere length in white blood cells (WBCs) may be a bioindicator that registers the accruing burden of systemic oxidative stress. The aim of the present study was, therefore, to examine the relationship between plasma aldosterone and telomere length in WBCs. METHODS: We studied 75 normotensive and never-treated mildly hypertensive men whose blood was drawn for the measurements of plasma aldosterone concentration and the terminal restriction fragment (TRF) length in WBCs. RESULTS: The slope of the TRF-age relationship in the entire cohort showed a decrease in telomere length of 26 +/- 5 base pairs per year (r = -0.46, p <.001). Age-adjusted TRF length was the longest in the lowest aldosterone quartile (6.74 +/- 0.12 kb) and shortest in the highest aldosterone quartile (6.36 +/- 0.11 kb), with intermediate TRF lengths in the second and third aldosterone quartiles (analysis of variance [ANOVA] trend test, p =.025). In telomeric attrition equivalence, participants in the upper aldosterone quartile were 15 years older than their peers in the lowest quartile. CONCLUSIONS: The inverse relationship between aldosterone and WBC telomere length suggests not only that aldosterone is pro-oxidant but that elevated concentrations of this hormone might be linked to a higher rate of telomere attrition and perhaps increased biological aging in humans.

Adult↗
PubMed2004

Telomeres and human aging: facts and fibs.

Can telomere dynamics, defined by telomere length and attrition rate, provide information about the biology of human aging above and beyond that provided by chronological age? Accruing data suggest that it can. White blood cells (WBCs) have been used as the primary model in attempts to decipher links between aging, aging-related disorders, and telomere dynamics in humans. The WBC model may be appropriate in clinical settings, provided that we fully appreciate its drawbacks and limitations. On the basis of WBC telomere data, it is evident that age-adjusted telomere length is highly variable, highly heritable, longer in women than men, and shorter in people who harbor a host of age-related disorders, whose common denominators may prove to be increased oxidative stress and inflammation. It appears that shorter age-adjusted WBC telomere length augurs a greater risk of morbidity and premature mortality in the elderly. However, it is unsettled whether human telomere dynamics is only a proxy for fundamental mechanisms that govern the course of aging or a key determinant in its progression.

Aging↗
PubMed2004

Potassium chloride supplementation diminishes platelet reactivity in humans.

The prevalence of occlusive stroke is inversely correlated with potassium intake. We explored the hypothesis that a high potassium intake attenuates platelet reactivity, as expressed in ADP-evoked platelet aggregation. We studied healthy men (n=31) and women (n=42), blacks (n=33) and whites (n=40). In this cohort, we supplemented the habitual intake of 17 men and 21 women with 60 mmol KCl/70 kg body weight per day for 3 days and maintained 14 men and 21 women on their habitual intake. We then compared the change in ADP concentration causing 50% of the maximal initial rate (EC50) of platelet aggregation in the potassium-supplemented versus control groups. Potassium supplementation attenuated platelet reactivity, expressed by an increase in EC50 of platelet aggregation (P=0.0005), which was primarily attributable to an increase in EC50 in whites (P=0.0004). Urinary potassium excretion was significantly lower in blacks than in whites under basal conditions and after potassium supplementation. We conclude that potassium supplementation diminishes platelet reactivity, a phenomenon that provides a link between platelet biology and occlusive stroke.

Adenosine Diphosphate↗
PubMed2004

Survival advantage of cultured human vascular endothelial cells that lost chromosome 13.

We explored the nature of chromosome 13 loss in cultured human vascular endothelial cells (HUVECs). Chromosome 13 loss detected by metaphase and interphase analysis was noted in earlier passages of HUVEC strains with no relation to telomere length or replicative senescence. Ectopic expression of telomerase did not influence the loss of chromosome 13. HUVECs losing chromosome 13 demonstrated increased migratory potential and loss of heterozygosity. Collectively, these observations suggest that the loss of chromosome 13 gives cultured HUVECs a replicative advantage.

Cell Count↗
PubMed2004

Urinary potassium excretion and sodium sensitivity in blacks.

Based on racial differences in urinary potassium excretion and responses to diuretics, we present a model suggesting that a major cause of sodium sensitivity in blacks is an augmented activity of the Na-K-2Cl cotransport in the thick ascending limb of Henle's loop. This would result in an increased ability to conserve not only sodium but also water, and an upward and rightward shift in the operating point of tubuloglomerular feedback, which may cause an increase in the glomerular capillary hydraulic pressure and predilection to glomerular injury with and without hypertension. In this sense, the biological implication of sodium sensitivity in blacks and in humans in general has ramifications above and beyond salt-evoked increase in blood pressure.

Animals↗
PubMed2004

Telomere length and possible link to X chromosome.

BACKGROUND: Because telomeres are eroded during mitosis, telomere length indicates the replicative history of human somatic cells. Clinical markers of ageing--such as pulse pressure and survival--are associated with telomere length. On the basis of findings of studies in twins, telomere length seems to be familial, but little is known about its mode of inheritance. We aimed to investigate the inheritance of telomere length. METHODS: We measured terminal restriction fragment (TRF) length in white-blood-cell DNA taken from individuals from the family-based cohort of the Flemish Study on Environment, Genes, and Health Outcomes. FINDINGS: We recorded no correlation in sex and age adjusted TRF length between spouses (r=-0.05; p=0.70) nor between fathers and sons (r=-0.16; p=0.35). By contrast, we noted robust correlations in TRF length between fathers and daughters (r=0.60; p<0.0001); between mothers and sons (r=0.41; p=0.0017) and daughters (r=0.59; p<0.0001); and among siblings (r> or =0.61; p< or =0.0004). INTERPRETATION: X-linked inheritance of TRF length is the most probable explanation for our findings. Pending confirmation, our observations suggest that the process of ageing might be an X-linked trait.

Adult↗
PubMed2004

Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects.

Recent studies have shown that individuals with shorter telomeres present a higher prevalence of arterial lesions and higher risk of cardiovascular disease mortality. As a group, patients with high blood pressure are at an increased risk for cardiovascular diseases. However, some hypertensive patients are more prone than others to atherosclerotic lesions. The main objective of this study was to examine the relationship between telomere length, as expressed in white blood cells, and carotid artery atherosclerotic plaques in hypertensive males. Data from 163 treated hypertensive men who were volunteers for a free medical examination were analyzed. Extracranial carotid plaques were assessed with B-mode ultrasound. Telomere length was measured from DNA samples extracted from white blood cells. The results of this study show that telomere length was shorter in hypertensive men with carotid artery plaques versus hypertensive men without plaques (8.17+/-0.07 kb versus 8.46+/-0.07 kb; P<0.01). Multivariate analysis showed that in addition to age, telomere length was a significant predictor of the presence of carotid artery plaques. The findings from this study suggest that in the presence of chronic hypertension, which is a major risk factor for atherosclerotic lesions, shorter telomere length in white blood cells is associated with an increased predilection to carotid artery atherosclerosis.

Carotid Artery Diseases↗