This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jeanclos, E. Articles by Aviv, A. Search for Related Content PubMed PubMed Citation Articles by Jeanclos, E. Articles by Aviv, A. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Related Collections Other etiology Genetics of cardiovascular disease Other Vascular biology

(Hypertension. 2000;36:195.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Telomere Length Inversely Correlates With Pulse Pressure and Is Highly Familial

Elisabeth Jeanclos; Nicholas J. Schork; Kirsten O. Kyvik; Masayuki Kimura; Joan H. Skurnick; Abraham Aviv

From the Hypertension Research Center (E.J., M.K., A.A.) and the Department of Preventive Medicine and Community Health (J.H.S.), University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; the Department of Epidemiology and Biostatistics (N.J.S.), Case Western Reserve University, Cleveland, Ohio; the Program for Population Genetics and Department of Biostatistics (N.J.S.), Harvard University School of Public Health, Boston, Mass; the Jackson Laboratory (N.J.S., J.H.S.), Bar Harbor, Maine; and the Danish Twin Register (K.O.K.), Genetic Epidemiology Research Unit, Institute of Community Health, Odense University, Denmark.

Correspondence to Abraham Aviv, Room F-464, MSB, Hypertension Research Center, University of Medicine and Dentistry of New Jersey, 185 S Orange Ave, Newark, NJ 07103-2714. E-mail avivab{at}umdnj.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging.

Key Words: blood pressure • pulse • age • twins

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Telomeres, the ends of chromosomes, undergo attrition (shortening) in their length with each replicative cycle of cultured somatic cells (reviewed in References ^{1 4} ). This process also occurs in vivo because an inverse relation exists between telomere length in replicating somatic cells and the age of human beings who have donated these cells (References ^{5 9} ; reviewed in References ^{1 4} ). Thus, the replicative history of somatic cells is a major determinant of telomere length. Another determinant of telomere length is heredity, since the high variability in this parameter among human beings is to a large extent genetically determined.⁵ Recent experimental data support the concept that telomeres might serve as "biological clocks," pacing not only life span at the cellular level but also aging at the systemic level. These data show that (1) the prevention of telomere attrition by the forced expression in cultured somatic cells of the catalytic component of telomerase, the reverse transcriptase that adds telomere repeats onto the ends of chromosomes, postpones replicative senescence^{10 11} and (2) the "knockout" of telomerase in the mouse amplifies some characteristics associated with systemic aging in later generations of mice that exhibit substantially shortened telomere length.¹²

At least 2 fundamental questions therefore arise with respect to the clinical implications of telomere biology. First, can the length of telomeres serve as an in vivo indicator of biological aging of replicating somatic cells in different organ systems of humans? A related question is: Is the aging of tissues from persons who are genetically endowed with long telomeres likely to occur later in life or at a slower pace than of tissues from persons who inherit short telomeres? Second, which biological parameters can serve as indicators of aging in human beings, since for obvious reasons chronological age (which is determined by calendar time) is a poor criterion for biological aging?

In light of these considerations, this work had 2 goals. The first goal was driven by the following concept. Since in industrialized nations pulse pressure increases with age,¹³ pulse pressure might serve as a phenotype of cardiovascular aging. We therefore examined whether pulse pressure correlates with telomere length. The second goal was to examine whether telomere length is familial.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Subjects
DNA samples from white blood cells (WBCs) of 98 healthy twins (10 monozygotic and 39 dizygotic twin pairs) from the Danish Twin Register¹⁴ were selected to be studied. The ages of the subjects were 18 to 44 years. The twin pairs were identified in 1994 by responses to a questionnaire. They were selected for further investigation after they reported negative history for major metabolic, cardiovascular, and chronic inflammatory and infectious diseases. Clinical evaluation of and blood collection from the co-twins of each twin pair were done on the same day. Evaluation included a physical examination with measurements of height, weight, and blood pressure. Blood pressure was carefully measured by a standard mercury sphygmomanometer, and the mean of 3 measurements was taken. Measurements were performed in a sitting position after 5 minutes of complete rest. Zygosity was established by HLA-typing and by serological analyses of blood enzyme systems.

Approval to perform this research was obtained from the Danish Central Scientific Ethics Committee. Consent to send DNA to the United States was provided by the regional Scientific-Ethics Committee. Approval to perform the research was also granted by the Institutional Review Board of the University of Medicine and Dentistry of New Jersey–New Jersey Medical School.

Measurement of Terminal Restriction Fragment Length
DNA samples were coded in Odense University by means of numbers and the letters A and B, denoting the 2 co-twins of each twin pair. No other information (ie, zygosity, blood pressure, age, gender) was revealed by the code. The samples were digested overnight with restriction enzymes Hinf I (10 U) and RsaI (10 U) (Boehringer Mannheim). Eighteen DNA samples (5 µg each) from different individuals and 4 DNA ladders (1 kb DNA ladder plus 1 DNA/Hind III Fragments; GIBCO Life Technologies) were resolved in a 0.5% agarose gel (20x20 cm) at 50 V (GNA-200 Pharmacia Biotech). Duplicates from the same samples were resolved on different gels. The letter coding (ie, A and B) enabled the running of DNA samples from each twin pair on the same gel. After 16 hours, the DNA was depurinated for 30 minutes in 0.25N HCl, denatured for 30 minutes in 0.5 mol/L NaOH/1.5 mol/L NaCl, and neutralized for 30 minutes in 0.5 mol/L Tris, pH 8, 1.5 mol/L NaCl. The DNA was transferred for 1 hour to a nylon membrane, positively charged (Boehringer Mannheim) with the use of a vacuum blotter (Appligene, ONCOR). The membranes were then hybridized at 65°C with the telomeric probe (digoxigenin 3'-end labeled 5'-[CCCTAA]₃) overnight in 5xSSC, 0.1% Sarkosyl, 0.02% SDS and 2% Blocking reagent (Boehringer Mannheim). The membranes were washed at room temperature, 3 times in 2xSSC, 0.1% SDS each for 15 minutes and once in 2xSSC for 15 minutes. The digoxigenin-labeled probe was detected by the digoxigenin luminescent detection procedure (Boehringer Mannheim) and exposed on x-ray film. The mean terminal restriction fragment (TRF) length was measured as described before.¹⁵ After completion of all TRF measurements in all samples, the numbers were decoded for data analysis.

Data Analysis
To assess the relation of measured factors (eg, gender, blood pressure, age) with telomere length while controlling for gross genetic effects on these phenotypes, we used a linear model with random effect or "variance component" terms (eg, see References ^{16 18} ). Let y₁ and y₂ denote telomere length values collected from a twin pair. Assume that the twin pair trait value vector, Y=[y₁,y₂], can be modeled with an appropriate bivariate distribution (eg, bivariate normal) with mean vector, µ, and variance-covariance matrix, , which can be partitioned in the following way:

(1)

where ²_a and ²_r are estimable variance components terms characterizing gross additive genetic effects (ie, aggregate additive effects of many loci), and random or "error" effects, respectively. The coefficient terms preceding these variance terms are 2x2 coefficient matrices relating the variance components to the twin pair trait values. Thus, K is the kinship coefficient matrix with off-diagonal elements equaling 1.0 for MZ twins and 0.5 for DZ twins, and I is the identity matrix.

Assume further that µ can be modeled as µ=f(X B), where X is vector of covariates (ie, gender, age) and B is an estimable regression parameter vector. For gender, men were assigned a value of 1.0 and women a value of 0.0. We assumed a linear relation between Y and X. The variance component terms and the parameter vector B can be estimated by maximum likelihood. Since we assumed bivariate normality of telomere length among twins and a linear relation between Y and X, the relevant log-likelihood equation is:

(2)

Because more than 1 twin pair was collected, the log-likelihood equation was determined as the sum of the individual log-likelihood for each twin pair. Thus, our proposed model is essentially a standard regression model with dependent (paired) observations and special covariance structure. To test the relation of a measured factor, for example, pulse pressure, with telomere length, we tested the significance of the regression coefficient for that factor by using likelihood ratio tests. To safeguard against robustness issues, log-transformed variables were also tested. Note that heritability can be estimated as H=²_a/(²_a+²_r). Because our model can accommodate multiple factors in the analysis, we also performed stepwise regressions that could determine the set of factors related to a chosen dependent variable that are statistically optimal and independent in their effects.¹⁹ It must be emphasized that by not directly testing other sources of "familial aggregation" beyond additive genetic effects (eg, shared diets, lifestyles, housing), any estimate of heritability from our analysis probably is biased. This is true for all twin and standard estimators of heritability that are not exhaustive in terms of the influences that they model.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Table 1 summarizes general characteristics of the subjects, ignoring the relatedness of the twins. Reliability of the measurements of TRF length is described in Figure 1, which provides a scatterplot of the 2 TRF determinations and a plot of their difference versus the mean of the determinations.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Subjects Participating in the Study

View larger version (22K): [in this window] [in a new window]   Figure 1. Scatterplot showing relation between first and second TRF length measurements made on each subject. The 2 measurements were performed 3 months apart. Dashed line represents line of identity. Solid line is regression line taking second measurement as a function of first measurement (equation: TRF2=0.136+0.985 TRF1 (r=0.963). Inset shows difference between first and second measurements plotted against mean of the 2 measurements. Solid line indicates mean difference (-0.009 kb). Dotted lines represent mean±2 SD (SD=0.296 kb).

Table 2 describes the results of the analysis of the relation between each of the measured factors and TRF length, systolic blood pressure, diastolic blood pressure, and pulse pressure in univariate or pairwise settings. We also present the estimated percentage of variation in each primary variable that was explained by additive genetic random effects, after accounting for the effect of the measured factor. There was no significant correlation between TRF length and age within the age range of subjects in this group. However, gender showed a significant relation with TRF length in that women had longer TRF (also see Table 1). Of the blood pressure parameters, pulse pressure, which was correlated with age, showed the strongest relation with TRF length. TRF length was correlated positively with diastolic blood pressure but negatively with systolic blood pressure (Table 2), which is consistent with a negative relation between TRF length and pulse pressure. In addition, TRF length and pulse pressure were found to be highly heritable.

View this table: [in this window] [in a new window]   Table 2. Pairwise Relations Between TRF Length, Blood Pressure, and Concomitant Factors

The most parsimonious multivariate model (from the use of a stepwise regression analysis) for TRF length included only pulse pressure (slope=-0.01 kb/mm Hg, P<0.01; first row of Table 3). The most parsimonious multivariate model for pulse pressure included gender, age, and TRF length, which suggests that the relation between TRF length and pulse pressure is independent of gender and age.

View this table: [in this window] [in a new window]   Table 3. Most Parsimonious Multiple Regression Models for TRF Length and Blood Pressure

Figure 2 offers a graphical depiction of the relation between TRF length and pulse pressure, ignoring the relatedness of the twins. The parameters of the linear regression are Pulse Pressure=107.57-6.54 TRF (r=-0.30, P=0.0032). The parameters of the regression describing the relation between TRF length and pulse pressure in which average measures for each twin pair are plotted against each other are as follows: Pulse Pressure=111.0-6.93 TRF (r=-0.33, P=0.024). We note that for the multivariate models whose results are described in Table 3, some variables were not considered as potential predictor variables because of collinearity with other variables. Thus, systolic blood pressure and diastolic blood pressure were not considered in analyses involving pulse pressure because pulse pressure is defined by systolic and diastolic blood pressure values. We also note that the correlation between mean arterial pressure and TRF was negligible (r=0.07). The consequence is that in multiple regression models, pulse pressure was a significant predictor of TRF but mean arterial pressure was not. When pulse pressure and TRF were adjusted for mean arterial pressure, the partial correlation of pulse pressure and TRF (Figure 2) was actually stronger (r=-0.33). Although height was correlated with pulse pressure in this cohort (r=0.37, P=0.0002), height was not correlated with TRF (r=0.11, P=0.27). Height thus had little impact on the explanatory relation between TRF and pulse pressure; the partial correlations coefficient of pulse pressure and TRF after adjustment for height was r=-0.28, P=0.0005.

View larger version (15K): [in this window] [in a new window]   Figure 2. Relation between pulse pressure and TRF length. Regression line represents best-fit linear regression of pulse pressure on TRF.

Finally, analyses of the variables after log-transformation did not change the results appreciably (data not shown).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main finding of this work was that pulse pressure was inversely correlated with the TRF length in WBCs. This finding suggests that individuals who are endowed with relatively longer telomeres manifest a relatively narrow pulse pressure. In addition, this work showed that the mean length of telomeres and pulse pressure were highly familial. Our findings are discussed below.

In industrialized nations, systolic blood pressure continuously rises throughout life (Reference ²⁰ ; reviewed in Reference ¹³ ). Diastolic blood pressure also rises in early life, but it tends to level off or even decline in older persons. Hence, pulse pressure manifests progressive widening as a function of age. Arterial aging, particularly expressed by stiffness of central elastic arteries, is a major but not the only factor that determines pulse pressure; other determinants include left ventricular ejection rate and stroke volume. Perhaps the most important variable that determines central arterial stiffness is chronological age.^{20 21 22} However, factors that might enhance the biological aging of the vasculature, including essential hypertension,²³ non–insulin-dependent diabetes mellitus,²⁴ and a high salt intake,²⁵ have been independently shown to increase arterial stiffness. Collectively, these observations suggest that aortic pulse pressure might serve as a phenotype of biological aging of central arteries (for review, see Reference ²⁶ ) and is a predictor of cardiovascular mortality and morbidity.^{27 28 29 30}

We note, however, that the subjects in our study were as young as 18 years old. Therefore, their brachial pulse pressure was probably higher than that of their aortic or carotid pulse pressure, given their increased heart rate and amplification of the brachial systolic blood pressure.^{22 26} In addition, it is well established that height is a major determinant of the relation between pulse pressure and heart rate.^{26 31 32} Although in our cohort, height did not provide an explanation for the relation between pulse pressure and TRF length, height (and body mass index) must be evaluated as confounding factors in large-scale examinations of the TRF and pulse pressure.

Some variations may exist in telomere length among somatic cells, probably as the result of different proliferative rates of tissues. Yet, in comparison to other persons, persons who exhibit either relatively short or long telomeres in one type of a proliferative somatic cell, respectively, express relatively short or long telomeres in other somatic cells (Reference ³³ ; also K. Okuda and A. Aviv, unpublished data). Thus, the relation between TRF length and pulse pressure in the brachial artery might hold not only for telomeres in WBCs but also for telomeres in other replicating cells, including vascular endothelial cells⁸ and vascular smooth muscle cells.³⁴ These cells play a pivotal function in blood pressure control and vascular aging. In addition, it is unlikely that height is a factor in heritability of TRF length, since no relation was observed in our cohort between TRF length and height.

Not only pulse pressure but also the TRF changes with age.^{5 6 7 8 9} It appears, however, that different phases in the rate of telomere attrition exist throughout life.³⁵ The initial phase (ie, birth to 5 years) is marked by a relatively high rate of telomere attrition. The subsequent phase that includes adolescence and young adulthood is marked by an apparent stabilization of telomere length. Thereafter, telomere attrition resumes at a slower rate than during the first 5 years of life. The majority of subjects we studied were within the age range in which the rate of telomere attrition slows down or levels off altogether, accounting for the lack of correlation between the telomere length and age in this group.

In this study, we found that the TRF length in WBCs was highly familial, for example, confirming observations by Slagboom et al⁵ showing heritability of TRF length in lymphocytes. There is evidence that the TRF length differs among subpopulations of WBCs (eg, References ⁷ and ³⁶ ), but as indicated earlier, the differences in the TRF length within subpopulations of somatic cells are far smaller than differences in the TRF length among persons of the same age. For instance, in the same donor, differences in telomere length between naïve and memory T lymphocytes could at most reach 2 kb,⁷ whereas differences in WBCs or lymphocytes among donors of the same age could be as high as 5 kb.^{5 37} Thus, the respective findings by Slagboom et al⁵ and us in lymphocytes and WBCs indicate that high heritability of TRF length is likely to be expressed in all cell types. This conclusion was also reached by Martens et al.³³

There are substantial data about heritabilities of systolic and diastolic blood pressures (reviewed in Reference ³⁸ ) but little information about heritability of pulse pressure.³⁹ Heritabilities of systolic and diastolic blood pressures in this study were higher than in previous reports.³⁸ This may be due to the fact that our model did not accommodate other unmeasured factors, such as shared diets, living conditions, and so forth, which could contribute to similarity in twin values and be erroneously attributed to genetic effects.

We propose that to gain a better appreciation of the link between telomere biology and vascular aging in human beings, large-scale investigations should be undertaken to explore further the relation between telomere length and pulse pressure at a wide age range.

	Acknowledgments

 
Elisabeth Jeanclos is a postdoctoral fellow of the American Heart Association, Northeastern Consortium, Heritage Affiliate; Nicholas J. Schork is supported in part by National Institute of Health grants RR03655-11 from NCRR and HL-94011 and HL-54998 from the National Heart, Lung, and Blood Institute; Kirsten O. Kyvik was supported by the Danish Diabetes Association, Novo Nordic Foundation, and Sygekassernes Helsefond; Masayuki Kimura was partially supported by a grant-in-aid from the American Heart Association; and Abraham Aviv was partially supported by National Institutes of Health grant HL-47906. We thank Dr Anthanase Benetos for reading the manuscript and for his valuable comments.

Received December 20, 1999; first decision January 11, 2000; accepted February 29, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Greider CW. Telomeres and senescence: the history, the experiment, the future. Curr Biol 1998; 8:R178–R181.

2. Blackburn EH. Telomeres: no end in sight. Cell. 1994;77:621–623.[Medline] [Order article via Infotrieve]

3. Broccoli D, Cooke H. Aging, healing, and the metabolism of telomeres. Am J Hum Genet. 1993;52:657–660.[Medline] [Order article via Infotrieve]

4. Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991;256:271–282.[Medline] [Order article via Infotrieve]

5. Slagboom PE, Droog S, Boomsma DI. Genetic determination of telomere size in humans: a twin study of 3 age groups. Am J Hum Genet. 1994;55:876–882.[Medline] [Order article via Infotrieve]

6. Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Choen D, Harley CB. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet. 1993;52:661–667.[Medline] [Order article via Infotrieve]

7. Weng NP, Levine BL, June CH, Hodes RJ. Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci U S A. 1995;92:11091–11094.

8. Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci U S A. 1995;92:11190–11194.

9. Effros RB. Replicative senescence in the immune system: Impact of the Hayflick limit on T-cell function in the elderly. Am J Hum Genet. 1998;62:1003–1007.[Medline] [Order article via Infotrieve]

10. Bodnar AG, Quellete M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright HE. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279:349–352.[Abstract/Free Full Text]

11. Morales CP, Holt SE, Quellete M, Kaur KJ, Yan Y, Wilson KS, White MA, Wright WE, Shay JW. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet. 1999;21:115–118.[Medline] [Order article via Infotrieve]

12. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999;96:701–712.[Medline] [Order article via Infotrieve]

13. Whelton PK, He J, Klag MJ. Blood pressure in Westernized population. In: Swales JD, ed. Textbook of Hypertension. London, UK: Blackwell Scientific Publications; 1994:11–21.

14. Kyvik KO, Green A, Beck-Nielsen H. The New Danish Twin Register: establishment and analysis of twinning rates. Int J Epidemiol. 1995;24:589–596.[Abstract/Free Full Text]

15. Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of human fibroblasts. Nature. 1990;345:458–460.[Medline] [Order article via Infotrieve]

16. Schork NJ. The design and use of variance component models in the analysis of human quantitative pedigree data. Biometrical J. 1993;4:387–405.

17. Schork NJ. Extended multipoint identity-by-descent analysis of human quantitative traits: efficiency, power, and modeling considerations. Am J Hum Genet. 1993;53:1306–1319.[Medline] [Order article via Infotrieve]

18. Searle SR, Casella G, McCulloch CE. Variance Components. New York, NY: John Wiley; 1992.

19. Neter J, Wasserman W, Kutner MH. Applied Linear Statistical Models. Homewood, Ill: Richard D. Irwin; 1985.

20. Franklin SS, Gustin W IV, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study Circulation. 1997;96:308–315.[Abstract/Free Full Text]

21. Bramwell JC, Hill AV, McSwiney BA. The velocity of the pulse wave in man in relation to age as measured by the hot-wire sphygmograph. Heart. 1923;10:233–255.

22. Avolio AP, Deng FQ, Li WQ, Luo YF, Huang ZD, Xing LF, O’Rourke MF. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation. 1985;71:202–210.[Abstract/Free Full Text]

23. Gribbin B, Pickering TG, Sleight P. Arterial distensibility in normal and hypertensive man. Clin Sci. 1979;56:413–417.[Medline] [Order article via Infotrieve]

24. Salomaa V, Riley W, Kark JD, Nardo C, Folsom AR. Non–insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes: the ARIC study: Atherosclerosis Risk in Communities Study. Circulation. 1995;91:1432–1443.[Abstract/Free Full Text]

25. Avolio AP, Clyde KM, Beard TC, Cooke HM, Ho KK, O’Rourke MF. Improved arterial distensibility in normotensive subjects on a low salt diet. Arteriosclerosis. 1986;6:166–169.[Abstract/Free Full Text]

26. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries. Theoretical, Experimental and Clinical Principles. 4th ed. London/Sydney/Auckland; Arnold: 1998:347–376.

27. Darne B, Girerd X, Safar M, Cambien F, Guize L. Pulsatile versus steady component of blood pressure: a cross-sectional analysis on cardiovascular mortality. Hypertension. 1989;13:392–400.[Abstract/Free Full Text]

28. Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1998;32:560–564.[Abstract/Free Full Text]

29. Verducchia P, Schillaci C, Borgioni C, Ciucci A, Pede S, Procellati C. Ambulatory pulse pressure: a potent predictor of cardiovascular risk in hypertension. Hypertension. 1998;32:983–988.[Abstract/Free Full Text]

30. Domanski MJ, Davis BR, Pfeffer MA, Kastantin M, Mitchell GF. Isolated systolic hypertension: prognostic information provided by pulse pressure. Hypertension. 1999;34:375–380.[Abstract/Free Full Text]

31. Westerhof N, Elzinga G. Normalized input impedance and arterial decay-time over heart period are independent of animal size. Am J Physiol. 1991;261:R126–R133.[Abstract/Free Full Text]

32. Milnor WR. Aortic wavelength as a determinant of the relation between heart rate and body size in mammals. Am J Physiol. 1979;237:R3–R6.[Abstract/Free Full Text]

33. Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, Chavez EA, Ward RK, Lansdorp PM. Short telomeres on human chromosome 17p. Nat Genet. 1998;18:76–80.[Medline] [Order article via Infotrieve]

34. Okuda K, Khan MY, Skurnick J, Kimura M, Aviv H, Aviv A. Telomere attrition of the human abdominal aorta: relationship with age and atherosclerosis. Atherosclerosis. In press.

35. Frenck RW Jr, Blackburn EH, Shannon KM. The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci U S A. 1998;95:5607–5610.

36. Weng NP, Granger L, Hodes RJ. Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci U S A. 1997;94:10827–10832.

37. Jeanclos E, Krolewski A, Skurnick J, Kimura M, Aviv H, Warram JH, Aviv A. Shortened telomere length in white blood cells of patients with IDDM. Diabetes. 1998;47:482–486.[Abstract]

38. Ward R. Familial aggregation and genetic epidemiology of blood pressure. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press; 1990:81–100.

39. Darlu P, Sagnier PP, Bois E. Evidences pour une transmission genetique de la pulsatilte arterielle. C R Acad Sci III. 1994;317:62–69.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				L. Mollica, I. Fleury, C. Belisle, S. Provost, D.-C. Roy, and L. Busque No Association Between Telomere Length and Blood Cell Counts in Elderly Individuals J Gerontol A Biol Sci Med Sci, September 1, 2009; 64A(9): 965 - 967. [Abstract] [Full Text] [PDF]

				C. Cipriano, S. Tesei, M. Malavolta, R. Giacconi, E. Muti, L. Costarelli, F. Piacenza, S. Pierpaoli, R. Galeazzi, M. Blasco, et al. Accumulation of Cells With Short Telomeres Is Associated With Impaired Zinc Homeostasis and Inflammation in Old Hypertensive Participants J Gerontol A Biol Sci Med Sci, July 1, 2009; 64A(7): 745 - 751. [Abstract] [Full Text] [PDF]

				L. S.M. Wong, H. Oeseburg, R. A. de Boer, W. H. van Gilst, D. J. van Veldhuisen, and P. van der Harst Telomere biology in cardiovascular disease: the TERC-/- mouse as a model for heart failure and ageing Cardiovasc Res, February 1, 2009; 81(2): 244 - 252. [Abstract] [Full Text] [PDF]

				J. Huzen, D. J. van Veldhuisen, and P. van der Harst Letter by Huzen et al Regarding Article, "Association of Leukocyte Telomere Length With Circulating Biomarkers of the Renin-Angiotensin-Aldosterone System: The Framingham Heart Study" Circulation, November 4, 2008; 118(19): e688 - e688. [Full Text] [PDF]

				J. A Nettleton, A. Diez-Roux, N. S Jenny, A. L Fitzpatrick, and D. R Jacobs Jr Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA) Am. J. Clinical Nutrition, November 1, 2008; 88(5): 1405 - 1412. [Abstract] [Full Text] [PDF]

				W. R. W. Wilson, K. E. Herbert, Y. Mistry, S. E. Stevens, H. R. Patel, R. A. Hastings, M. M. Thompson, and B. Williams Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease Eur. Heart J., November 1, 2008; 29(21): 2689 - 2694. [Abstract] [Full Text] [PDF]

				L. S.M. Wong, R. A. de Boer, N. J. Samani, D. J. van Veldhuisen, and P. van der Harst Telomere biology in heart failure Eur J Heart Fail, November 1, 2008; 10(11): 1049 - 1056. [Abstract] [Full Text] [PDF]

				M. Mangino, S. Brouilette, P. Braund, N. Tirmizi, M. Vasa-Nicotera, J. R. Thompson, and N. J. Samani A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans Hum. Mol. Genet., August 15, 2008; 17(16): 2518 - 2523. [Abstract] [Full Text] [PDF]

				R. Farzaneh-Far, R. M. Cawthon, B. Na, W. S. Browner, N. B. Schiller, and M. A. Whooley Prognostic Value of Leukocyte Telomere Length in Patients With Stable Coronary Artery Disease: Data From the Heart and Soul Study Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1379 - 1384. [Abstract] [Full Text] [PDF]

				C. J. O'Donnell, S. Demissie, M. Kimura, D. Levy, J. P. Gardner, C. White, R. B. D'Agostino, P. A. Wolf, J. Polak, L. A. Cupples, et al. Leukocyte Telomere Length and Carotid Artery Intimal Medial Thickness: The Framingham Heart Study Arterioscler Thromb Vasc Biol, June 1, 2008; 28(6): 1165 - 1171. [Abstract] [Full Text] [PDF]

				U. Svenson, K. Nordfjall, B. Stegmayr, J. Manjer, P. Nilsson, B. Tavelin, R. Henriksson, P. Lenner, and G. Roos Breast Cancer Survival Is Associated with Telomere Length in Peripheral Blood Cells Cancer Res., May 15, 2008; 68(10): 3618 - 3623. [Abstract] [Full Text] [PDF]

				M. Kimura, J. v. B. Hjelmborg, J. P. Gardner, L. Bathum, M. Brimacombe, X. Lu, L. Christiansen, J. W. Vaupel, A. Aviv, and K. Christensen Telomere Length and Mortality: A Study of Leukocytes in Elderly Danish Twins Am. J. Epidemiol., April 1, 2008; 167(7): 799 - 806. [Abstract] [Full Text] [PDF]

				M. F. Haussmann and R. A. Mauck Telomeres and Longevity: Testing an Evolutionary Hypothesis Mol. Biol. Evol., January 1, 2008; 25(1): 220 - 228. [Abstract] [Full Text] [PDF]

				N. Tentolouris, R. Nzietchueng, V. Cattan, G. Poitevin, P. Lacolley, A. Papazafiropoulou, D. Perrea, N. Katsilambros, and A. Benetos White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria Diabetes Care, November 1, 2007; 30(11): 2909 - 2915. [Abstract] [Full Text] [PDF]

				B. C. Capell, F. S. Collins, and E. G. Nabel Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes Circ. Res., July 6, 2007; 101(1): 13 - 26. [Abstract] [Full Text] [PDF]

				A. B. Weder Evolution and Hypertension Hypertension, February 1, 2007; 49(2): 260 - 265. [Full Text] [PDF]

				J. Collerton, C. Martin-Ruiz, A. Kenny, K. Barrass, T. von Zglinicki, T. Kirkwood, B. Keavney, and Newcastle 85+ Core Study Team Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study Eur. Heart J., January 10, 2007; (2007) ehl437v1. [Abstract] [Full Text] [PDF]

				A. Aviv, A. M Valdes, and T. D Spector Human telomere biology: pitfalls of moving from the laboratory to epidemiology Int. J. Epidemiol., December 1, 2006; 35(6): 1424 - 1429. [Abstract] [Full Text] [PDF]

				S. J. Lee, J. Liu, A. M. Westcott, J. A. Vieth, S. J. DeRaedt, S. Yang, B. Joe, and G. T. Cicila Substitution Mapping in Dahl Rats Identifies Two Distinct Blood Pressure Quantitative Trait Loci Within 1.12- and 1.25-Mb Intervals on Chromosome 3 Genetics, December 1, 2006; 174(4): 2203 - 2213. [Abstract] [Full Text] [PDF]

				J. J. Fuster and V. Andres Telomere Biology and Cardiovascular Disease Circ. Res., November 24, 2006; 99(11): 1167 - 1180. [Abstract] [Full Text] [PDF]

				A. Aviv Telomeres and human somatic fitness. J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2006; 61(8): 871 - 873. [Abstract] [Full Text] [PDF]

				G. Perez-Rivero, M. P. Ruiz-Torres, J. V. Rivas-Elena, M. Jerkic, M. L. Diez-Marques, J. M. Lopez-Novoa, M. A. Blasco, and D. Rodriguez-Puyol Mice Deficient in Telomerase Activity Develop Hypertension Because of an Excess of Endothelin Production Circulation, July 25, 2006; 114(4): 309 - 317. [Abstract] [Full Text] [PDF]

				T. Kunieda, T. Minamino, T. Katsuno, K. Tateno, J.-i. Nishi, H. Miyauchi, M. Orimo, S. Okada, and I. Komuro Cellular Senescence Impairs Circadian Expression of Clock Genes In Vitro and In Vivo Circ. Res., March 3, 2006; 98(4): 532 - 539. [Abstract] [Full Text] [PDF]

				M. F Haussmann, D. W Winkler, and C. M Vleck Longer telomeres associated with higher survival in birds Biol Lett, June 22, 2005; 1(2): 212 - 214. [Abstract] [Full Text] [PDF]

				A. Aviv, J. Shay, K. Christensen, and W. Wright The Longevity Gender Gap: Are Telomeres the Explanation? Sci. Aging Knowl. Environ., June 8, 2005; 2005(23): pe16 - pe16. [Abstract] [Full Text]

				M. D. Edo and V. Andres Aging, telomeres, and atherosclerosis Cardiovasc Res, May 1, 2005; 66(2): 213 - 221. [Abstract] [Full Text] [PDF]

				A. Aviv Telomeres and Human Aging: Facts and Fibs Sci. Aging Knowl. Environ., December 22, 2004; 2004(51): pe43 - pe43. [Abstract] [Full Text]

				E. S. Epel, E. H. Blackburn, J. Lin, F. S. Dhabhar, N. E. Adler, J. D. Morrow, and R. M. Cawthon From the Cover: Accelerated telomere shortening in response to life stress PNAS, December 7, 2004; 101(49): 17312 - 17315. [Abstract] [Full Text] [PDF]

				A. L. Serrano and V. Andres Telomeres and Cardiovascular Disease: Does Size Matter? Circ. Res., March 19, 2004; 94(5): 575 - 584. [Abstract] [Full Text] [PDF]

				A. Benetos, J. P. Gardner, M. Zureik, C. Labat, L. Xiaobin, C. Adamopoulos, M. Temmar, K. E. Bean, F. Thomas, and A. Aviv Short Telomeres Are Associated With Increased Carotid Atherosclerosis in Hypertensive Subjects Hypertension, February 1, 2004; 43(2): 182 - 185. [Abstract] [Full Text] [PDF]

				S. Brouilette, R. K. Singh, J. R. Thompson, A. H. Goodall, and N. J. Samani White Cell Telomere Length and Risk of Premature Myocardial Infarction Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 842 - 846. [Abstract] [Full Text] [PDF]

				H. Cherif, J. L. Tarry, S. E. Ozanne, and C. N. Hales Ageing and telomeres: a study into organ- and gender-specific telomere shortening Nucleic Acids Res., March 1, 2003; 31(5): 1576 - 1583. [Abstract] [Full Text] [PDF]

				A. Aviv Chronology Versus Biology: Telomeres, Essential Hypertension, and Vascular Aging Hypertension, September 1, 2002; 40(3): 229 - 232. [Abstract] [Full Text] [PDF]

				A. Aviv Hypothesis : Pulse Pressure and Human Longevity Hypertension, April 1, 2001; 37(4): 1060 - 1066. [Abstract] [Full Text] [PDF]

				F. C. Luft Twins in Cardiovascular Genetic Research Hypertension, February 1, 2001; 37(2): 350 - 356. [Abstract] [Full Text] [PDF]

				A. Benetos, K. Okuda, M. Lajemi, M. Kimura, F. Thomas, J. Skurnick, C. Labat, K. Bean, and A. Aviv Telomere Length as an Indicator of Biological Aging : The Gender Effect and Relation With Pulse Pressure and Pulse Wave Velocity Hypertension, February 1, 2001; 37(2): 381 - 385. [Abstract] [Full Text] [PDF]

				P. Hamet, N. Thorin-Trescases, P. Moreau, P. Dumas, B.-S. Tea, D. deBlois, V. Kren, M. Pravenec, J. Kunes, Y. Sun, et al. Workshop: Excess Growth and Apoptosis : Is Hypertension a Case of Accelerated Aging of Cardiovascular Cells? Hypertension, February 1, 2001; 37(2): 760 - 766. [Abstract] [Full Text] [PDF]

				T. Minamino, H. Miyauchi, T. Yoshida, Y. Ishida, H. Yoshida, and I. Komuro Endothelial Cell Senescence in Human Atherosclerosis: Role of Telomere in Endothelial Dysfunction Circulation, April 2, 2002; 105(13): 1541 - 1544. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jeanclos, E. Articles by Aviv, A. Search for Related Content PubMed PubMed Citation Articles by Jeanclos, E. Articles by Aviv, A. Pubmed/NCBI databases OMIM Compound via MeSH Substance via MeSH Related Collections Other etiology Genetics of cardiovascular disease Other Vascular biology