(Hypertension. 1997;29:1067-1072.)
© 1997 American Heart Association, Inc.
Articles |
Reflections on Telomeres, Growth, Aging, and Essential Hypertension
From the Hypertension Research Program and Center for Human and Molecular Genetics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark.
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Abstract |
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 Top Abstract IntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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Abstract Here we review the "telomere hypothesis of cellular aging." We propose that this hypothesis is relevant to our understanding of the roles of genetics as well as growth and development in the etiology of essential hypertension and its cardiovascular complications. Elements of this hypothesis and the speculations that we make can be directly tested using tissues (cells) obtained from human beings.
Key Words: telomere • kidney • atherosclerosis • genetics • chromosomes • diabetes mellitus • aging
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Introduction |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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The genetics of essential hypertension is poorly understood. Why is this? For one thing, essential hypertension is a complex epigenetic disorder with poor phenotypic expressions, and an accurate phenotypic characterization is central to dissecting the genetics of any heritable disease. In addition, the search for genes responsible for heritable diseases is based on the fundamental premise that such genes are defective; ie, they express mutations and encode dysfunctional proteins, which poorly serve the cell and the organism. This paradigm has guided successful investigations of a host of monogenetic diseases, and to some extent, it may also apply to essential hypertension. However, it is also plausible that not all genes that are directly involved in the pathophysiology of essential hypertension and other complex traits are abnormal. For instance, rearrangements of networks of genes, evoked by environmental factors, might give rise to different phenotypic expressions in health and disease states.1 Age-dependent mechanisms whereby these networks of genes are modulated might also differ among individuals. In a subset of individuals, such mechanisms might occur at a relatively early age, whereas in others, they may appear in later years or altogether fail to materialize within the individual's life span. The triggers of these mechanisms might be biological timing devices, ie, biological "fuses" of various lengths and perhaps different "combustion" rates. Telomeres, the ends of chromosomes, fit the characteristics of these putative "fuses" in that their length is established in utero and their rates of attrition, which might be modulated by the environment, are programmed to deliver a finite life span at the cellular and perhaps organismal levels.
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Telomeres, Telomerase, Growth, and Aging |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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In human beings and other mammals, telomeres comprise TTAGGG tandem repeats whose functions, though not fully understood, involve the stabilization of chromosomal ends and the protection of genes located in subtelomeric regions.2 3 4 These subtelomeric regions are rich in genes vital to cellular function. Because of the inability of DNA polymerase to complete replication of the linear chromosomal ends, telomeres progressively shorten with repeated cell division. In tissue culture, most mammalian cells stop replicating after a specific number of divisions. This state is termed cellular senescence. Senescence occurs at least in part when the mean telomere length reaches a critical value. Thus, telomere length might predict the overall replicative potential of cells in vitro. This concept is central to the "telomere hypothesis of cellular aging," which proposes that telomere length is a mitotic clock, regulating cellular life span.2 For mammals, such an idea appears to hold not only in vitro but also at the organismal level in vivo. In human beings, for instance, the mean telomere length of circulating lymphocytes linearly decreases by approximately 40 bp per year.5 6 7 It is noteworthy, however, that the longevity of the cell and organism as a whole depends on multiple factors and that processes underlying aging and senescence are not identical. In addition, telomere length may vary not only among different cell types but also among chromosomes. Telomere attrition might therefore affect gene function of a subset of chromosomes long before the critical point in the mean telomere length is reached and replicative capacity is impaired.
Given that telomeres shorten as a function of the number of cellular divisions, abnormal as well as normal mechanisms exist whereby telomere length is preserved in rapidly growing tissues. One of these mechanisms is the addition of telomeric repeats to chromosomal ends by an RNA-dependent DNA polymerase, the enzyme that is referred to as telomerase.8 9 Malignancy entails a rapid cellular proliferation; thus, most malignant tumors also express telomerase activity.10 11 Likewise, immortalized cell lines frequently exhibit telomerase activity in concert with the stabilization of their telomere lengths.11 12 13 There are, however, unexplained exceptions to these observations; eg, some immortalized cell lines manifest a stable telomere length without evidence of telomerase activity,14 and hematopoietic cells from normal subjects may express some activity of the enzyme.15
Since intrauterine development is expressed by an extremely rapid growth rate, it is not surprising that most fetal tissues demonstrate robust activity of telomerase.16 This contrasts with the lack of an appreciable activity of telomerase in normal somatic cells from most human organs and a substantial though variable reduction in the activity of the enzyme in mouse organs during extrauterine life. In the mouse, for instance, the expression of the RNA component of telomerase decays rapidly in the kidney and liver soon after birth, whereas the expression of the RNA component of brain telomerase, which is marginal at birth, continues to be low thereafter.17 Telomerase activity is readily detected in adult human and mouse germline cells,16 17 in which telomeres are significantly longer than in somatic cells.5 18 In the mouse, telomere lengths within tissues are similar in the newborn, but they differ within tissues in the adult; the most striking differences in the adult are observed between the testis (longest) and kidney and brain (shortest).18 These observations are compatible with the concept that in utero telomere length is synchronized in somatic cells of different tissues and that it reflects a balance between telomerase activity and rapid rates of cellular replication and perhaps apoptosis. After birth, however, the main determinant of telomere length is the replication history of cells in a given tissue. It is therefore of great interest that adult mouse kidneys show relatively short telomeres compared with most other organs.18 Unfortunately, there is no information at present regarding the telomere length and replicative potential of renal cells in humans and which renal cell types (tubular epithelial cells, mesangial cells, interstitial cells, etc) are responsible for the short telomeres in the mature kidney of the mouse.
Although telomere length shortens as a function of age, it manifests substantial variations among human beings of the same age, except for the very old, whose telomere lengths tend to cluster.6 7 The wide scatter in telomere length in the general population might result from (1) different age-dependent rates of telomere attrition, (2) variations in telomere length at birth, with subsequently constant attrition rates in the telomere length as a function of age, and (3) both of these alternatives. The clustering of the mean telomere lengths among the oldest of the elderly suggests the obvious, namely, that people with great longevity represent a selected subset of the population.
Variability in telomere length attrition rates can arise from either different amounts of base pair loss for each division of somatic cells or from variations in the frequencies of these divisions. Limited observations in cultured cells from human beings suggest that the rate of telomere attrition per mean population doubling is constant.19 20 21 Human lymphoblasts, for instance, lose approximately 120 bp per each population doubling in culture. However, further studies are needed to establish the validity and ubiquity of these findings by examining different cell types from a large population of age-matched donors who express different mean telomere lengths. In addition, cultured cells from different donors are exposed in vitro to identical and more or less stable growth conditions, whereas in vivo cells exist under different circumstances that reflect variations in the genetic background and environmental input shaping each individual.
Studies in twins18 show that heritability plays an important role in telomere length—an observation that invokes a role for genetic factors, the intrauterine environment, or both in modifying telomere length. At present, little is known about the timing of activation and suppression of telomerase during gestation and whether variations exist in these important developmental landmarks among tissues and among individuals. Nonetheless, it stands to reason that because of a common genetic background and intrauterine environment, these landmarks would manifest fewer variations in twins compared with other subjects.
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Essential Hypertension and the Kidneys: Roles of Growth and Development |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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How, then, do these diverse observations relate to the etiology of essential hypertension? Essential hypertension is primarily expressed as a function of age. This well-established fact should be closely scrutinized in the context of the "telomere hypothesis of cellular aging" and in light of intriguing observations that link growth of the kidney and soma with essential hypertension in human beings.
The ultimate height and weight of adult humans are largely determined by genetic factors, yet there are poor correlations between birth weight and adult height and weight.22 Only after the first year of life do children's heights show a positive correlation with their ultimate adult height.22 It follows, then, that low-birth-weight infants "catch up" with their genetically determined sizes by an accelerated growth rate during the first year of life. Whereas birth weight poorly correlates with the size of the fully grown adult, epidemiological studies show that low birth weight is a predictor of elevated blood pressure in later years.23 Is it then possible that an accelerated growth after birth is the harbinger for essential hypertension? Studies in laboratory animals24 and children25 suggest such a possibility. Children and adolescents with an accelerated growth, ie, those who are both taller and heavier than their age-matched peers, exhibit blood pressure in the upper range of the blood pressure distribution.25 Moreover, an accelerated rise in blood pressure during pubescence might reflect a predilection to a high blood pressure in adult life.26
Two interesting hypotheses have addressed this question, although from different perspectives, by focusing on the growth of the kidneys in the context of the growth and development of the whole organism (allometry). At the heart of both hypotheses is the concept that essential hypertension might arise from a disproportionality between renal growth and body growth. The evidence that the kidneys play a fundamental role in essential hypertension is compelling.27 Perhaps the most convincing data originate from cross-transplantation experiments in laboratory animals showing that hypertension follows the kidney; ie, blood pressure of the transplant recipient increases if the donor is hypertensive.28 29 The link between hypertension and the kidney also appears to hold in humans, based on studies of renal transplantation.27 30 Accordingly, Brenner and associates31 32 have proposed that the kidneys of low-birth-weight newborns have reduced numbers of nephrons at birth. They further postulate that the resulting diminished filtration rate in low-birth-weight newborns is maintained during growth and triggers a repeated cycle of sodium retention, blood pressure elevation, glomerular hyperfiltration, and in the extreme, accelerated nephron loss as a function of age, resulting in hypertensive nephrosclerosis in adult life. A similar view is held by Weder and Schork.33 They have proposed, on the basis of the demographics of blood pressure in children, adolescents, and adults, that essential hypertension is a recent phenomenon in human evolution, reflecting the inability of the renal system to keep pace with the rapid gain in body mass of modern humans. In essence, Brenner and associates31 32 suggest that in essential hypertension, the kidneys are too small, whereas Weder and Schork33 propose that the body mass is too large. These ideas make a persuasive but by no means definitive case that growth plays a role in essential hypertension.
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Putative Links Between Telomeres, Renal Growth, and Essential Hypertension |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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In human beings, fetal renal mass increases exponentially during the second half of gestation, and nephrogenesis is virtually complete at birth.34 During this period, glomerular filtration rate positively correlates not only with gestational age but also with renal mass and body mass.34 Proportionality of renal mass and function to body mass is also maintained after birth,35 albeit the above hypotheses propose that in individuals susceptible to essential hypertension, renal growth lags behind body growth during this time. What, then, limits renal growth relative to the increase in systemic growth in extrauterine life? The answer to this question is not readily apparent. However, two elements of compensatory renal growth—a process that is clinically and experimentally well characterized—might provide some clues. First, the loss of a kidney during intrauterine life results in full compensatory growth of the remaining kidney; in contrast, this compensation is incomplete and its magnitude inversely relates to age in extrauterine life.36 37 38 39 Second, compensatory renal growth in utero and perhaps shortly after birth is primarily hyperplastic (ie, an increase in cell number) compared with the hypertrophic growth (ie, an increase in cell mass) of the adult kidneys.39
It is reasonable to assume that the kidneys of the low-birth-weight infant attempt to catch up with the accelerated body growth during the first 12 months of extrauterine life by increased hypertrophy and/or hyperplasia. However, hypertrophic growth might be insufficient to accommodate the ultimate growth needs, whereas hyperplastic growth, if it serves to adjust kidney growth with somatic growth, would occur at a price. Since telomerase activity in the soma is suppressed after birth,16 17 18 hyperplastic renal growth would proceed at the expense of shorter telomere length. Such telomere attrition may be minimal when the majority of replicating renal cells participate in the catch-up growth. However, if the task of catching up is the function of a selected subpopulation of progenitor cells, the loss of telomeric sequences from this subpopulation could be substantial. This telomere attrition might further compound the relatively greater telomere loss of cells in the adult kidney compared with other somatic organs, at least on the basis of data from studies on the mouse.18 We therefore envision a scenario in which the telomere length in a subset of cell populations in the kidneys of subjects with low birth weight is prematurely and substantially short; in essence, these cells are prematurely aged. In such cells, genes at the tips of chromosomes whose function might be modulated by telomere length are likely to be activated or suppressed at a relatively earlier age. Some of these genes could play a role in blood pressure control, which is regulated to a large extent by sodium excretion. In this context, not only hypertension but also salt sensitivity are age-dependent phenomena.40 The trade-off for the catch-up of kidney growth with systemic growth in low-birth-weight infants therefore might be an accelerated aging of the kidneys, manifested by earlier onsets of salt sensitivity and essential hypertension.
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Growth, Premature Aging, and Telomeres |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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Thus far we have considered the subject of telomeres in the context of hypotheses that focus on the kidneys as the culprits for the development of essential hypertension. The important query these hypotheses attempt to answer is, What is the reason that low birth weight predisposes to essential hypertension? The potential involvement of telomeres in essential hypertension and its cardiovascular complications can also be viewed from a broader perspective by posing the following two-part question: Why is the birth weight of some infants who are destined to develop essential hypertension low? and is there a common mechanism that produces both low birth weight and the predilection for essential hypertension?
Two ideas have attempted to answer the above questions—one focuses on maternal nutrition41 42 and the other on the enzyme 11ß-hydroxysteroid dehydrogenase.43 Maternal malnutrition and consequently fetal malnutrition have been proposed to cause low birth weight and, at the same time, reset blood pressure at a higher level. One way that resetting of blood pressure at a higher level can occur is by retarded fetal nephrogenesis.44 However, the data supporting this idea have come primarily from studies in rodents in which dams were fed diets of very low protein content. Unless extreme, maternal malnutrition in human beings rarely results in low birth weight. Other environmental factors in industrialized societies, eg, maternal cigarette smoking,45 closely spaced childbirths,46 and low socioeconomic status, are more likely to result in low birth weight.
11ß-Hydroxysteroid dehydrogenase converts cortisol to its inactive metabolites. Mutations in the kidney isoform of this enzyme cause a monogenic form of hypertension47 and perhaps play a role in essential hypertension in African Americans.48 In the placenta, 11ß-hydroxysteroid dehydrogenase protects the fetus from the high levels of maternal cortisol. Edwards and coauthors43 proposed a role for 11ß-hydroxysteroid dehydrogenase in fetal growth retardation and increased cardiovascular risks of low-birth-weight newborns in later years. The hypothesis they put forth is that increased fetal exposure to maternal glucocorticoids, caused by the insufficiency of placental 11ß-hydroxysteroid dehydrogenase, would not only retard fetal growth but also modify blood pressure control and other cardiovascular functions, perhaps via lasting changes in glucocorticoid receptors.
Low birth weight has been linked not only to essential hypertension but also to non–insulin-dependent diabetes mellitus and related coronary heart disease.42 Insulin resistance, certain forms of dyslipidemias, hypercoagulable states, and hypertension might be pleiotropic manifestations of disorders of premature aging with a common genetic background.49 50 Some expressions of these disorders and their progressions might be modified by prematurely short telomeres. Embryogenesis and fetal ontogeny are marked not only by rapid growth but also by apoptosis. Growth retardation in utero might thus reflect an imbalance between these fundamental processes. For instance, could the timing of telomerase activation and suppression be altered in utero so that growth-retarded newborns have shorter telomeres in vital organs, resulting in a predilection for premature aging?
Short telomeres have been observed in two diseases of profound premature aging, namely, Hutchinson-Gilford progeria and Down syndrome. The mean telomere length of fibroblasts from children with Hutchinson-Gilford progeria is shorter than that of fibroblasts from age-matched, normal donors.19 This is consistent with the reduced replicative capacity in culture of cells from donors with Hutchinson-Gilford progeria. It is likely that patients with this disease are born with short telomeres, inasmuch as their fibroblasts do not express a greater telomere loss per cell doubling in vitro. However, as indicated above, the in vitro state might not reflect the in vivo condition. Down syndrome has been termed a "progeria-like syndrome" because a premature aging of the immune system contributes to much of the morbidity and mortality from this genetic disorder. In contrast to patients with Hutchinson-Gilford progeria, the short telomeres of lymphocytes from patients with Down syndrome appear to arise from an accelerated attrition rate, as the decline in the mean telomere length of these cells as a function of age is three times higher in Down syndrome patients than in control subjects.6 An accelerated telomere attrition in Down syndrome may result from increased loss of telomeric sequences per cell doubling or from increased lymphocyte turnover rate in vivo, which could reflect (1) an inherited trait of increased cell proliferation or (2) immune responses to repeated antigenic exposure.
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Distinction Between Primary and Secondary Involvement of Telomeres in Cardiovascular Diseases |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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Understanding the reason for the variation in telomere length among individuals is hence crucial for truly appreciating primary (causative) roles versus secondary (consequential) roles of telomeres in diseases of aging. A recent study has shown that vascular endothelial cells in areas of high hemodynamic stress exhibit shorter telomere length than endothelial cells from regions of the vascular tree with a low hemodynamic stress.51 These observations suggest an accelerated turnover rate of endothelial cells, perhaps because of apoptosis, as a result of increased hemodynamic stress. High blood pressure heightens the hemodynamic stress so that endothelial cell turnover rate might increase in essential hypertension. In addition, there is evidence for increased hyperplastic growth in concert with apoptosis of vascular smooth muscle cells in vitro and in vivo in animal models of genetic hypertension52 53 54 and remodeling of the vascular wall in hypertensive human beings.54 Such alterations are expected to accelerate the rate of telomere attrition of cells of the vascular wall.
Short telomeres of cells of the vascular wall might simply be an epiphenomenon of essential hypertension, or they could play a role in the cardiovascular complications of this disorder by promoting premature aging of blood vessels. Atherosclerosis and endothelial dysfunction, which are common complications of or are associated with essential hypertension, might reflect premature aging and perhaps replicative senescence of cells of blood vessels. Senescent fibroblasts and endothelial cells overexpress plasminogen activator inhibitor type 1.55 56 Plasminogen activator inhibitor type 1 decreases fibrinolytic activity, and its circulating levels are high in insulin-resistant states,57 58 myocardial infarction, and accelerated atherosclerosis.59 60 61 Senescent cells also produce higher levels of insulin-like growth factor binding protein-3.62 63 By binding insulin-like growth factor-I, this substance might cause impairment of tissue regeneration after injury, a phenomenon that is commonly observed in the elderly and subjects with non–insulin-dependent diabetes mellitus.64
The putative involvement of telomeres in the complications of essential hypertension might not be limited to cells that are components of the vascular tree. The initiation and propagation of atheromatous lesions involve the participation of hematopoeitic cells. Increased proliferation of subsets of these cells, which has been implicated in essential hypertension,65 66 67 might contribute to the premature aging of the hematopoeitic as well as the cardiovascular systems. A corollary of the "telomere hypothesis of cellular aging" proposes that the increased incidence of malignancies in older individuals reflects the greater likelihood for telomerase activation by the progressive attrition in telomere length with aging.68 It is of interest to note in this regard that epidemiological studies suggest that hypertension is a risk factor for cancer.69
Collectively, the above speculations underscore the fact that in the final analysis, secondary involvement of telomeres, which triggers complications of essential hypertension, might be as important as the primary causes of this disorder. Individuals who inherit short telomeres in concert with susceptibility genes for essential hypertension would be more likely to manifest accelerated deterioration of their cardiovascular system than others who carry the same susceptibility genes for essential hypertension but are endowed with long telomeres. The "telomere hypothesis of cellular aging" might therefore provide a satisfactory and testable explanation for the diversity of complications of essential hypertension and the present uncertainty as to who would and who would not develop these complications.
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Conclusion |
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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Disorders of premature aging in human beings, including essential hypertension and non–insulin-dependent diabetes mellitus, as well as their complications, almost certainly originate from a spectrum of DNA-related variations, some of which might involve telomeres. The high degrees of inheritance and variability in the mean telomere length among human beings suggest a great diversity in the expressions of disorders that might be linked to telomere function. The predictions of the "telomere hypothesis of cellular aging" can in principle be tested in the context of essential hypertension and other cardiovascular disorders, as long as one recognizes that aging represents the input of a myriad of growth-related processes. Perhaps the first step in testing this hypothesis is to determine the mean telomere length as a function of age in organs and tissues that are directly involved in the pathophysiology of essential hypertension, eg, cellular elements of the arterial tree and the kidneys. These measurements should be performed in normotensive subjects who do not have a known predisposition to essential hypertension, hypertensive subjects, individuals who are predisposed to essential hypertension based on familial history and racial extraction, and individuals who manifest the cardiovascular complications of essential hypertension. It is noteworthy, however, that variations in mean telomere lengths in different disorders and among individuals may arise from telomeres in different chromosomes. For all of these reasons, the formidable task of profiling telomere lengths of all human chromosomes as a function of age in different cell types will make a valuable contribution toward understanding the role of telomeres in health and disease.
Finally, telomeres might also represent an important and thus far missing element in the epigenetic paradigm of complex disorders such as essential hypertension. Epigenesis denotes gene-gene and gene-environment interactions. It entails a progression of succeeding states of biological organization as well as the perpetual rearrangement of networks of genes that starts in utero and ends in the individual's demise. Telomere length, which is established in utero and continuously modified after birth, might bear the lasting signatures of inheritance as well as the effects of the intrauterine and extrauterine environments.
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Footnotes |
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Reprint requests to Abraham Aviv, MD, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Ave, MSB F-464, Newark, NJ 07103-2714.
Received October 2, 1996; first decision November 4, 1996; accepted November 14, 1996.
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TopAbstractIntroductionTelomeres, Telomerase, Growth,...Essential Hypertension and the...Putative Links Between...Growth, Premature Aging, and...Distinction Between Primary and...ConclusionReferences |
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