Telomere dynamics in rhesus monkeys: no apparent effect of caloric restriction.

The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its association with TL is unknown. Using linear regression analysis, TLs (as measured by Southern blot analysis) of skeletal muscle (a postmitotic tissue that largely represents early development TL), fat, leukocytes, and skin were tested for effects of age, sex, and diet in 48 control and 23 calorie restriction rhesus monkeys. After controlling for the individual's muscle mean TL, differences between leukocytes muscle and skin muscle were significantly associated with age (p = .002; p = .002) and sex (p = .003; p = .042), but not calorie restriction (p = .884; p = .766). Despite an age-dependent shortening of TL in leukocytes and skin, calorie restriction did not significantly affect TL dynamics in these samples.

Leukocyte telomere length and mortality in the Cardiovascular Health Study.

BACKGROUND: Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent. METHODS: We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews. RESULTS: A total of 468 (41.2%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4% female, and 14.8% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95% confidence interval: 1.32-5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant. CONCLUSION: These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.

Telomere length and its associations with oxidized-LDL, carotid artery distensibility and smoking.

Oxidative stress is a key factor driving the aging of cells and arteries. Studies suggest that white blood cell (WBC) telomere length is an index of systemic aging. We, therefore, investigated the association between WBC telomere length and oxidized-LDL, and vascular aging, expressed by the distensibility of the carotid artery. We studied a random population sample of 216 non-smokers and 89, smokers. In all subjects, age and gender- adjusted telomere length was inversely correlated with plasma oxidized-LDL (regression coefficient = -0.656 kb/mg/dL; p=0.0006). Independent of gender, age and mean blood pressure, carotid distensibility increased with telomere length (2.33+/- 1.18 10-3/kPa/kb; p=0.05) but decreased with higher plasma levels of oxidized LDL (-10.7+/- 3.91 10-3/kPa/ mg/dL; p=0.006). Adjusted for gender and age, smokers' telomere length was shorter (6.72 vs 6.91 kb; p=0.014) and plasma oxidized-LDL level higher (0.52 vs 0.46 mg/dL; p=0.03) than in non-smokers. Higher level of oxidized-LDL, is associated with shorter WBC telomeres and increased stiffness of the carotid artery. Smoking is marked by increased oxidative stress in concert with shortened WBC telomere length.

Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

Leukocyte telomere length is inversely correlated with plasma Von Willebrand factor.

INTRODUCTION: Leukocyte telomere length (LTL) is short, while the plasma level of Von Willebrand (VWF) is high in persons with atherosclerosis. Moreover, both short LTLs and high VWF levels are observed in individuals who display risks for atherosclerosis, including hypertension, obesity, insulin resistance, cigarette smoking and low socio-economic status. We examined the association between LTL and VWF plasma levels to test the hypothesis that high levels of VWF promote an increase in the turnover of blood cells, including leukocytes. Such a process would heighten the rate of age-dependent LTL attrition, ultimately resulting in shortened LTL. METHODS: We studied 3 cohorts: the ADELAHYDE study (age 60-87years), the ERA study (age 41-88years) and the Longitudinal Study of Aging Danish Twins (LSADT) (age 73-94years). RESULTS: Multiple regression analysis with LTL as the dependent variable, and age, sex and VWF as the independent variables showed that LTL was inversely correlated with VWF in the ADELAHYDE (beta=-0.125, p<0.001) and the ERA study (beta=-0.148, p=0.010). The LSADT displayed VWF x age interaction, which was incorporated into the model, showing that LTL was also inversely correlated with VWF (beta=-0.057, p=0.04). CONCLUSIONS: The inverse relationship between LTL and VWF, observed in 3 different populations, suggests that LTL might be linked to the coagulative status of the individual. Further research will be required to confirm our observations and their clinical ramifications.

Higher circulating levels of IGF-1 are associated with longer leukocyte telomere length in healthy subjects.

Mutations that inhibit the insulin-like growth factor-1 (IGF-1) extend the lifespan of worms, flies and mice. However, it appears that relatively low circulating levels of IGF-1 in humans are associated with aging-related diseases and diminished longevity. As leukocyte telomere length (LTL) is ostensibly a biomarker of human aging, we examined the relationship between LTL and blood IGF-1 in a healthy cohort. Our sample comprised 476 healthy, unrelated Caucasians (208 men and 268 women), aged 16-104 years, living in the West Coast of Southern Italy. We measured LTL by Southern blots and IGF-1 by enzyme-linked immunoassay. Both IGF-1 and LTL diminished with age (IGF-1, r=-0.601, P<0.001; LTL, r=-0.706, P<0.001). Age-adjusted LTL was positively associated with IGF-1 level throughout the age range of the cohort (r=0.270, P<0.001). IGF-1 accounted for about 10% of the inter-individual variation in LTL over and above the effect of age. Our findings suggest that both circulating IGF-1 and LTL are indices of healthy aging in humans. Further research will be necessary to establish whether LTL will ultimately be used in clinical settings as an index of healthy aging.

Association of leukocyte telomere length with echocardiographic left ventricular mass: the Framingham heart study.

BACKGROUND: Leukocyte telomere length (LTL) decreases over the adult life course owing to the cumulative burden of oxidative stress, inflammation, and exposure to vascular risk factors. Left ventricular (LV) mass is a biomarker of long-standing exposure to cardiovascular disease risk factors. We hypothesized that LTL is related inversely to LV mass. METHODS AND RESULTS: We related LTL (measured by Southern blot analysis) to echocardiographic LV mass and its components (LV diastolic dimension and LV wall thickness) in 850 Framingham Heart Study participants (mean age 58 years, 58% women) using multivariable linear regression with adjustment for age, sex, height, weight, systolic blood pressure, hypertension treatment, and smoking. Overall, multivariable-adjusted LTL was positively related to LV mass (beta-coefficient per SD increase 0.072; P=0.001), LV wall thickness (beta=0.053; P=0.01), and LV diastolic dimension (beta=0.035; P=0.09). We observed effect modification by hypertension status (P for interaction=0.02 for LV mass); LTL was more strongly associated with LV mass and LV wall thickness in individuals with hypertension (beta-coefficient per SD increment of 0.10 and 0.08, respectively; P<0.01 for both). Participants with hypertension who were in the top quartile of LV mass had LTL that was 250 base pairs longer than those in the lowest quartile (P for trend across quartiles=0.009). CONCLUSIONS: In contrast to our expectation, in the present community-based sample, LTL was positively associated with LV mass and wall thickness, especially so in participants with hypertension. These data are consistent with the hypothesis that longer LTL may be a marker of propensity to LV hypertrophy.

Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study.

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.

Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study.

OBJECTIVE: This study examined the relationships of high-density lipoprotein cholesterol (HDL-C) with LTL and the rate of its shortening. BACKGROUND: Diminished levels of HDL-C are associated with an increased risk for atherosclerosis. Shortened leukocyte telomere length (LTL) also entails an increased atherosclerotic risk. METHODS: We studied 472 Whites and 190 African Americans (AfAs) enrolled in the Bogalusa Heart Study. Subjects were examined serially 3-13 times for HDL-C over an average period of 27.8 years from childhood through young adulthood. LTL was measured twice during adulthood at a mean age of 31.5 years (baseline exam) and 37.8 years (follow-up exam). HDL-C trajectories with age were constructed and the area under the curve (AUC) was used as a measure of cumulative HDL-C levels. RESULTS: Multivariate regression analyses showed that LTL was positively associated with HDL-C in childhood (regression coefficient (bp per mg/dL) beta=3.1, p=0.024), adulthood (beta=4.4, p=0.058) and AUC from childhood to adulthood (beta=12.2, p=0.0004) in the combined sample of AfAs and Whites. The association between LTL and HDL-C AUC was stronger in females (beta=18.5, p<0.001) than in males (beta=2.9, p=0.590) (difference in slopes p=0.037). A slower rate of LTL shortening per year was associated with higher HDL-C AUC in the total sample (p=0.033), adjusting for baseline LTL. CONCLUSIONS: As HDL-C exerts anti-oxidant and anti-inflammatory effects and LTL registers the accruing burden of oxidative stress and inflammation, the association between HDL-C and LTL might be explained by the lifelong status of oxidative stress and inflammation.

Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa Heart Study.

Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995-1996) and follow-up (2001-2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the "end-replication problem" contribute to telomere shortening in vivo.

Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study.

Leukocyte telomere length (LTL) is ostensibly a bio-indicator of human aging. Here we report that African Americans have longer LTL than whites. We studied cross-sectionally 2453 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (age = 30-93 years) and the Bogalusa Heart Study (age = 19-37 years), comprising 1742 whites and 711 African Americans. We measured LTL by Southern blots of the terminal restriction fragments length. In 234 participants, telomere repeats were also measured by quantitative polymerase chain reaction (qPCR). Adjusted for age and body mass index (BMI), the respective leukocyte telomere lengths (mean +/- SEM) were considerably longer in African Americans than in whites both in the Family Heart Study (7.004 +/- 0.033 kb vs. 6.735 +/- 0.024 kb, p < 0.0001) and the Bogalusa Heart Study (7.923 +/- 0.063 kb vs. 7.296 +/- 0.039 kb, p < 0.0001). We confirmed the racial effect on LTL by qPCR (3.038 +/- 0.565 T/S units for African Americans vs. 2.714 +/- 0.487 T/S units for whites, p < 0.001). Cross-sectionally, sex- and BMI-adjusted LTL became shorter with age (range 19-93 years) at a steeper slope in African Americans than in whites (0.029 kb year(-1) vs. 0.020 kb year(-1), respectively, p = 0.0001). We suggest that racial difference in LTL arises from a host of interacting biological factors, including replication rates of hematopoietic stem cells.

Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice.

We examine whether increased oxidative stress in vivo promotes telomere shortening in CAST/Ei mice. We explored the effects of L-buthionine sulfoximine treatment (BSO) on telomere length. BSO shortened telomere length in white fat, brown fat, skin, tail, and testis in concert with diminished tissue glutathione content, increased tissue carbonyl content, and increased plasma advanced oxidized protein products. Telomerase activity was mainly detected in testis but no reduction of telomerase activity was observed in response to BSO. In conclusion, BSO-mediated increase in systemic oxidative stress shortens telomeres in several tissues of the mouse. The variable effect of BSO treatment on telomere length in different tissue may result from their different adaptive antioxidative capacity.

Association of leukocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the Framingham Heart Study.

BACKGROUND: Leukocyte telomere length (LTL) chronicles the cumulative burden of oxidative stress and inflammation over a life course. Activation of the renin-angiotensin-aldosterone system is associated with increased oxidative stress and inflammation. Therefore, LTL may be related to circulating biomarkers of the renin-angiotensin-aldosterone system. METHODS AND RESULTS: We evaluated the cross-sectional relations of LTL (dependent variable) to circulating renin and aldosterone concentrations and the renin-to-aldosterone ratio (all logarithmically transformed; independent variables) in 1203 Framingham Study participants (mean age, 59 years; 51% women). We used multivariable linear regression and adjusted for age, blood pressure, hypertension treatment, smoking, diabetes mellitus, body mass index, hormone replacement therapy, serum creatinine, and the urine sodium-to-creatinine ratio. Overall, multivariable-adjusted LTL was inversely related to renin (beta coefficient per unit increase, -0.038; P=0.036), directly related to aldosterone (beta=0.099; P=0.002), and inversely related to the renin-to-aldosterone ratio (beta=-0.049; P=0.003). Relations of LTL to biomarkers were stronger in those with hypertension, although a formal test of interaction was not statistically significant (P=0.20). Individuals with hypertension displayed significant associations of LTL with renin (beta=-0.060; P=0.005), aldosterone (beta=0.134; P=0.002), and renin-to-aldosterone ratio (beta=-0.072; P<0.001). Participants with hypertension who were in the top tertile of the renin-to-aldosterone ratio had LTL that was 182 base pairs shorter relative to those in the lowest tertile. CONCLUSIONS: In our community-based sample, LTL was shorter in individuals with a higher renin-to-aldosterone ratio, especially in participants with hypertension. Additional investigations are warranted to confirm our observations.

Telomere length and mortality: a study of leukocytes in elderly Danish twins.

Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL(50)) and shortest 25% (mTRFL(25)) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL(50): 0.59, 95% CI: 0.52, 0.66; mTRFL(25): 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters. Leukocyte telomere dynamics might help explain the boundaries of the human life span.

The association between physical activity in leisure time and leukocyte telomere length.

BACKGROUND: Physical inactivity is an important risk factor for many aging-related diseases. Leukocyte telomere dynamics (telomere length and age-dependent attrition rate) are ostensibly a biological indicator of human aging. We therefore tested the hypothesis that physical activity level in leisure time (over the past 12 months) is associated with leukocyte telomere length (LTL) in normal healthy volunteers. METHODS: We studied 2401 white twin volunteers, comprising 2152 women and 249 men, with questionnaires on physical activity level, smoking status, and socioeconomic status. Leukocyte telomere length was derived from the mean terminal restriction fragment length and adjusted for age and other potential confounders. RESULTS: Leukocyte telomere length was positively associated with increasing physical activity level in leisure time (P< .001); this association remained significant after adjustment for age, sex, body mass index, smoking, socioeconomic status, and physical activity at work. The LTLs of the most active subjects were 200 nucleotides longer than those of the least active subjects (7.1 and 6.9 kilobases, respectively; P= .006). This finding was confirmed in a small group of twin pairs discordant for physical activity level (on average, the LTL of more active twins was 88 nucleotides longer than that of less active twins; P= .03). CONCLUSIONS: A sedentary lifestyle (in addition to smoking, high body mass index, and low socioeconomic status) has an effect on LTL and may accelerate the aging process. This provides a powerful message that could be used by clinicians to promote the potentially antiaging effect of regular exercise.

Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women.

BACKGROUND: Vitamin D is a potent inhibitor of the proinflammatory response and thereby diminishes turnover of leukocytes. Leukocyte telomere length (LTL) is a predictor of aging-related disease and decreases with each cell cycle and increased inflammation. OBJECTIVE: The objective of the study was to examine whether vitamin D concentrations would attenuate the rate of telomere attrition in leukocytes, such that higher vitamin D concentrations would be associated with longer LTL. DESIGN: Serum vitamin D concentrations were measured in 2160 women aged 18-79 y (mean age: 49.4) from a large population-based cohort of twins. LTL was measured by using the Southern blot method. RESULTS: Age was negatively correlated with LTL (r = -0.40, P < 0.0001). Serum vitamin D concentrations were positively associated with LTL (r = 0.07, P = 0.0010), and this relation persisted after adjustment for age (r = 0.09, P < 0.0001) and other covariates (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity; P for trend across tertiles = 0.003). The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs (P = 0.0009), which is equivalent to 5.0 y of telomeric aging. This difference was further accentuated by increased concentrations of C-reactive protein, which is a measure of systemic inflammation. CONCLUSION: Our findings suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases.

Telomere dynamics in macaques and humans.

In humans, telomere length in proliferating tissues shortens with age--a process accelerated with age-related diseases. Thus, telomere length and attrition with age in the nonhuman primate may serve as a useful paradigm for understanding telomere biology in humans. We examined telomere parameters in tissues of young and old Macaca fascicularis and compared them with several tissues from humans. Macaque telomeres were variable in length and exhibited partial synchrony (equivalence) within animals. They were longer than humans, partially because of longer subtelomeric segments. As skeletal muscle telomere length was unchanged with age, we used it as an internal reference to offset interanimal variation in telomere length. We identified age-dependent telomere attrition in lung, pancreas, skin, and thyroid. Similar to humans, telomerase activity was detected in spleen, thymus, digestive tract, and gonads. We conclude that factors that modify telomere attrition and aging in humans may also operate in the macaque.

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.

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.

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.