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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2824-2830
Rapid Telomere Shortening in Children
By
Steven L. Zeichner,
Paul Palumbo,
YanRu Feng,
Xiaodong Xiao,
Dennis Gee,
John Sleasman,
Maureen Goodenow,
Robert Biggar, and
Dimiter Dimitrov
From the HIV and AIDS Malignancy Branch, National Cancer Institute,
Bethesda, MD; the Department of Pediatrics, University of Medicine and
Dentistry of New Jersey, New Jersey Medical School, Newark, NJ; the
Laboratory of Experimental and Computational Biology, National Cancer
Institute, Frederick, MD; the Department of Pediatrics, University of
Florida, Gainesville, FL; and the Viral Epidemiology Branch, National
Cancer Institute, Bethesda, MD.
 |
ABSTRACT |
Telomere shortening may reflect the total number of divisions
experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in
peripheral blood mononuclear cells (PBMCs) obtained longitudinally from
nine different infants during the first 3 years of life (270 bp per
year) is more than fourfold higher than in adults and does not
correlate with telomerase activity. These results show that the rate of
telomere loss changes during ontogeny, suggesting the existence of
periods of accelerated cell division. Because human immunodeficiency
virus (HIV) preferentially infects actively dividing cells, our
observation suggesting accelerated cell division in children may
provide an explanation for some of the distinctive pathogenic features
of the HIV disease in infants, including higher viral loads and more
rapid progression to acquired immunodeficiency syndrome (AIDS).
This is a US government work. There are no restrictions on its use.
| |
INTRODUCTION |
BECAUSE TELOMERES in several different
cell types1-3 shorten as a function of cell doublings in
vitro and of patient age in vivo, telomere length has been proposed to
be a potentially useful marker for the total number of divisions
experienced by a cell and hence as a correlate of the aging process.
Telomere length may serve as a mitotic clock limiting the replicative
capacity of somatic cells.4 However, most studies
concerning telomere length and aging have examined telomere length in
adults, particularly elderly adults. Few studies have specifically
examined telomere lengths, or other correlates of aging, in the very
young, even though infancy is the stage in life when the most profound
developmental changes occur and when cellular replication peaks.
Molecular correlates of the aging process might be expected to show
their most dramatic changes during infancy, particularly for organ
systems, which display the most dramatic developmental changes during
infancy, such as the immune system. If rates of cell turnover vary
during growth and development, the rates of telomere shortening should also change correspondingly. We therefore hypothesized that these changes should be greatest during the periods of life and in the tissues in which cellular replication is maximal. To explore this hypothesis and to obtain baseline values for the rate of telomere shortening in infants, we measured telomere length in the peripheral blood mononuclear cells (PBMCs) of infants.
Because the immune system undergoes such significant changes during the
first years of life and because telomere lengths and the association of
age with telomere length have been extensively studied in the PBMCs of
adults, we determined telomere lengths from serial samples of pediatric
patients over the first years of life. We found that PBMC telomeres
shorten substantially faster in infants than in adults, and that infant
PBMCs contain little telomerase, suggesting that rapid cell turnover
may accompany the developmental processes occurring during infancy in
the cell populations sampled using PBMCs. The infant telomere
shortening rates determined in this study may also serve as a baseline
for comparing telomere shortening rates in patients in which PBMC turnover may be altered, for example human immunodeficiency virus (HIV)
infection or congenital immunodeficiency syndromes. The implied
elevation in cell turnover observed in infants may have additional
ramifications for the pathogenesis of HIV disease in pediatric patients.
| |
MATERIALS AND METHODS |
Patients and cells.
Samples from nine children were collected at multiple times during the
first 3 years of life. These children were born to HIV-infected mothers
and hence at risk for vertically acquired HIV infection. They were
therefore closely followed with a variety of clinical and immunologic
measures, including serial blood sampling (such serial blood samples
would be difficult to obtain from other non-HIV exposed normal children
for ethical reasons). All of the children in this study were determined
not to be infected with HIV and have had clinically normal growth and
development. Samples from two adults followed longitudinally over 8 and
10 years, respectively, because they were considered to be at risk for
HIV infection, but found to be repeatedly uninfected, were used for
comparison. PBMCs were separated with Ficoll-Hypaque (Amersham
Pharmacia, Piscataway, NJ), frozen in cryopreservative in
a controlled rate freezer, and stored in liquid nitrogen. The studies
were approved by the Institutional Review Board (IRB) at the National
Cancer Institute and the IRB at the University of Medicine and
Dentistry of New Jersey.
Telomere length measurements.
The telomere length assay was similar to those already
described.5 In brief, high molecular weight genomic DNA was
prepared (Puregene, Gentra Systems, Inc, Minneapolis, MN) and
quantitated spectrophotometrically. Equal amounts of DNA (1 µg) were digested with AluI (New England Biolabs,
Beverly, MA) to produce a terminal restriction fragment
(TRF), an approximation of the telomere-containing DNA. Equal
quantities of digested DNA were loaded on a 1% 20 × 25 cm
agarose gel in 0.5X Tris-Borate-EDTA (TBE) buffer. A pulsed-field at 6 V/cm for 20 hours at 15°C was used for the electrophoretic separation, using a pulse sequence designed to ensure good separation for sizes between 1 and 37 kb (PPI-200 Programmable Power Inverter; MJ
Research, Watertown, MA). Additional precautions taken to enhance the
accuracy and precision of the TRF measurements included loading three
different markers (for short, 1 to 12 kb, intermediate, 4 to 23 kb, and
relatively high, 10 to 50 kb, sizes) in 12 different lanes of the gel
to control for region to region nonuniformities, which may diminish the
accuracy of the TRF measurements. Images of the gels stained with
ethidium bromide were acquired by a quantitative imaging system
constructed in our laboratory using a video camera and image analysis
software to provide length calibrations and to correct for any
inhomogeneities and nonuninformities across the gel. The DNA was
transferred by standard Southern blotting,6 and the blotted
membranes were hybridized with an alkaline phosphatase (AP)-linked
telomere probe and a probe for the DNA length calibrating standards
(Quick-Light Hybridization Kit; Lifecodes Corp, Stamford, CT). The
blots were exposed to a chemiluminescent AP substrate, and the
resulting signal was acquired with a Bio-Rad Molecular Imager (Bio-Rad,
Hercules, CA) at a resolution of 0.1 mm. The acquired 16-bit images
were initially quantitated using the Bio-Rad Molecular Analyst software
and further analyzed with Scientist (MicroMath Scientific Software,
Salt Lake City, UT).
TRF image analysis.
TRF length was determined by an analysis of the gel images using a
slight modification of a previously published procedure.5 In brief, the signal intensity measured by the Bio-Rad Molecular Imager
was determined for each length element at the highest resolution of 100 µm along each gel lane. The mean telomere length, m, was calculated using the formula m =  Sl/S, where S is the signal intensity of the telomere length element and l is the size of the
telomere length element calculated by a nonlinear regression analysis
as a function of the distance from the wells. The calibration was
performed using the molecular weight standards, which translated the
migration distances into molecular size (kb) and included an additional
correction for possible nonuniformities across the gel.
Telomerase activity assay.
Telomerase activity was quantified by using a polymerase chain reaction
(PCR)-based assay,7 (Oncor, Gaithersburg, MD). The
intensity of the bands produced by the assay was measured and the
relative activity was normalized to that of a human T-lymphocytic cell
line (CEM). The activities assayed in 104 infant PBMC are
described as  , +, or ++, corresponding to the activities
observed in <1, 1, or 2 to 3 CEM cells.
| |
RESULTS |
Rapid changes of telomere length in children.
Figure 1 shows an example of Southern blot
for samples from two children. On gross inspection, changes of telomere
lengths are evident. TRF length data was extracted from such gel images as described in Materials and Methods and compiled in
Tables 1 and
2.
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| Fig 1.
Shown is an example of a Southern blot telomere length
determination for two patients, patient 6 and patient 7, described in
the text and tables. Lanes 1 and 13 and 14 are marker lanes, with the
sizes of the markers indicated at left. Lanes 3 to 7 show the TRFs from
the cells of pediatric patient 6 obtained at the times after birth,
indicated at the top of the figure. Lanes 8 to 12 show the TRFs from
the cells of pediatric patient 7 obtained at the times indicated at the
top of the figure.
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To obtain an overall expression for the rate of telomere change with
time, we fitted the data for each patient by a linear regression
analysis (Fig
2A) and calculated the extrapolated values of the TRF mean lengths for
time 1 month and 36 months (Fig 2B, Table
3). The average TRF lengths were in the same ranges as previously
reported from cross-sectional studies.3 The difference between the telomere lengths at 1 month and 36 months was statistically significant (P = .006, two tailed t-test for paired
samples). The average rate of telomere length shortening between 1 month and 36 months was 270 bp per year. We omitted data obtained at <1 month from this analysis because several children showed a substantial increase in TRF length during the first month of life. However, including these points still produced an accelerated shortening rate compared with adults, 170 bp per year, and the difference in extrapolated TRF length between 0 months and 36 months
was also still significant (P = .0015).
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| Fig 2.
(A) All of the TRF measurements as a function of time for
all of the pediatric patients is shown. (B) TRF measurements as a
function of time plotted for the pediatric patients are shown. TRF
measurements obtained at times <1 month after birth are omitted from
this figure because some patients showed increases in TRF length in the
immediate postnatal period. Least squares linear regression lines are
plotted for each of the patients. Symbols for (A) and (B): ( ),
patient 1; ( ), patient 2; ( ), patient 3; ( ), patient 4; ( ),
patient 5; ( ), patient 6; ( ), patient 7; ( ), patient 8; ( ),
patient 9. (C) TRF lengths for the nine pediatric patients were
predicted from the equations of the lines of (B) and plotted for the
1-month and 36-month time points. (D) TRF lengths as a function of age
were plotted for two uninfected adult patients. (E) TRF lengths as a function of age were
plotted for all of the points obtained from our two adult patients and
for the TRF length obtained at the oldest available age for each of our
pediatric patients.
|
|
Telomere length shortening in adults, including shortening in PBMCs, is
in the range of 30 to 50 bp per year.1,3,8 However, these
results were derived from cross-sectional studies. To confirm our
ability to measure small changes in TRF length in longitudinally
obtained serial samples, we obtained blinded cryopreserved PBMCs from 2 HIV-uninfected adults followed prospectively (initial ages, 28 years
and 30 years, seen for 8 and 10 years, respectively). These individuals
were followed because they were judged to be at risk for HIV infection,
but remained uninfected over the course of the study (Fig 2D, Table 2).
The TRF shortening rate for these adults was 40 and 59 bp per year,
with a composite average of 49 bp per year, which agrees well with
previously found rates of telomere shortening from the cross-sectional
studies. These adult data thus support the observation that the rate of TRF shortening is accelerated during the first 3 years of life.
Our observations of TRF shortening rate for the children and adults
suggested that the two populations had substantially different shortening rates. However, it is possible that telomere length shortening in older children and young adults might also be accelerated compared with that of older adults. We therefore calculated an average
shortening rate using the sample obtained at the oldest age from each
of our infants and the adult samples (see Tables 1 and 2) described
above. Using this analysis, the average TRF change (50 bp per year) was
similar to that calculated from the longitudinal samples from the two
adults and the rates previously described. These results support the
estimates for the rate of telomere length changes from the longitudinal
samples of adults and indicate that after approximately the age of 3, the rate of telomere length change appears to be relatively constant
and similar to the rate in adults.
Two children showed relatively rapid changes in TRF length during the
first several days of life. In these two newborns, the telomere length
was initially short relative to the other patients and then
significantly increased during the first month to reach a maximal
value, after which it began to decline. While it is not clear why the
telomere length increased during the first month of life, it may be due
either to redistribution of new naive cells or to a transient
activation of telomerase. Due to the small number of cells available
from the banked infant samples, it was not possible to subfractionate
the cells and determine the telomere length in different subfractions.
However, we did measure the telomerase activity by a PCR-based assay,
which requires only a small number of cells.
Telomerase activity in PBMCs of newborn children.
The telomerase activity of 104 PBMCs was undetectable (the
level of detection corresponded to the activity of one cell from the
continuous cell line CEM) in the majority of samples (38 of 58) (Table
1). It was at about the limit of detection in 16 of 58 samples, and in
several (four) samples it was relatively high, corresponding to that of
2 to 3 CEM cells. Thus, as in adults, telomerase activity varied
between individuals. We did not observe a correlation of telomerase
activity with absolute TRF length or rate of decline of TRF length.
This, together with the observation that telomerase activities were
generally low, suggests that observed TRF length changes in the infant
cells are unrelated to telomerase activity, thus TRF length changes may
indeed reflect the replicative history of the cells.
| |
DISCUSSION |
Our results indicate that the TRF lengths of PBMCs shorten more rapidly
during the first years of life than do the TRF lengths of PBMCs and
other cell types of adults. If telomeres do shorten by some relatively
constant amount with each somatic cell division, these differences in
shortening rates could either be due to an increased cell replication
rate in infants or to the rapid disappearance during infancy of a long
telomere-containing cell population. Although we can not formally
exclude the second possibility with experimental evidence from
fractionated infant PBMCs, due mainly to the small blood sample volumes
that can be ethically obtained from infants and the present
requirements for reasonably large amounts of chromosomal DNA for the
TRF length assays, we believe that this second possibility is unlikely.
Previously published work has not shown large differences in TRF length
in different cell populations in a given individual.9 Our
experiments (not shown) using fractionated adult PBMCs also failed to
find differences in TRF length in different cell populations.
While our report was in preparation, Frenck et al10
reported a cross-sectional study of TRF lengths in families. Although Frenck et al mention that they could not perform the ideal study, involving measurements of TRF length on serial blood samples from normal children because the IRB at their institution would not approve
the study due to ethical considerations, their study found that TRF
shortening rates were significantly increased during the first few
years of life. The value for the shortening rate obtained in their
study, more than 1,000 bp per year, was somewhat more than the value we
determined, 270 bp per year. Nevertheless, both values are
substantially higher than the  50 bp per year typically found in
studies of adult TRF shortening. Although our larger number of samples
obtained in the first few years of life, our modified electrophoresis
and image analysis techniques (see Materials and Methods), and the
longitudinal nature of the serial sampling strategy used in our study
may have yielded a more refined estimate of child TRF shortening rates,
the findings of elevated child TRF shortening rates from both studies
may hold important implications for immune system development, aging,
and the pathogenesis of immune system and infectious diseases.
The human immune system undergoes striking changes during the first
years of life.11 The neonate has functional deficits in
both the cellular and humoral arms, as well as the phagocytic arm of
the immune system, but by 1 to 3 years of life, the infant immune
system has generally acquired its mature functional capacity. For
example, neonates have a decreased ability to produce antibodies, particularly antibodies against carbohydrate antigens and neonatal T
cells have poor helper function, and a lower proportion of the cells
can produce various cytokines. The gross anatomical features of the
immune system also change significantly during the first years of life.
For example, infants have a comparatively large fraction of body mass
devoted to the lymphoid system, particularly the thymus, which declines
relative to total body mass during childhood. In addition to functional
and anatomical changes in the immune system, lymphocyte numbers change
substantially during the first few years of life. Although the values
display substantial interpatient variability, compared with adults,
infants are born with relatively higher numbers of total lymphocytes.
The median counts increase during the first approximately 6 to 7 months
of life, from about 2,800 in the immediate postnatal period, peaking at
around 3,200 at about 6 months, and then begin to decline, approaching
adult levels after 3 to 4 years. In addition, the relative ratio of CD4
to CD8 cells is somewhat higher at birth (2.5), declining steadily
to about 1.8 by 3 to 4 years.12,13 At the same time, T
cells represent a relatively smaller fraction of the PBMC population of
infants than of adults and the proportion of cells bearing markers
associated with immaturity (eg, CD45RA) decline as infants
age.14,15 These substantial changes in the characteristics
of the infant immune system are likely accompanied by increased rates
of cell turnover.
If the relatively rapid decrease in TRF length during the first months
of life does reflect a real acceleration in the cell replication rate
during infancy, our results support the notion that varying rates of
cellular replication occur at different stages of development or,
perhaps more graphically, that `aging' is not a constant throughout
life. These varying rates of replication may be particularly important
for the development of the immune system, when rapid cell turnover
likely accompanies immune system maturation. Because the rate of
decrease in telomere length is not constant during life, our data from
normal children may serve as a helpful baseline for comparison with
certain pathological conditions, such as HIV infection or congenital
immunodeficiency syndromes, in which the rates of cell turnover may be
either increased or decreased. Several studies have used TRF shortening
to investigate cell turnover rates in adult patients with HIV
infection.16-18 Several features distinguish HIV disease in
infants compared with the disease in adults and because some of these
features may be reflected in varying rates of cell turnover, it may be
helpful to assess cell turnover rates in HIV-infected infants using a variety of techniques, including TRF shortening rates.
The observation that the rates of TRF decrease are accelerated in
infants and hence, that cell turnover may also be increased in infants,
suggests a hypothesis that may to help explain some of the puzzling
features of pediatric HIV disease. Infants with vertically-acquired HIV
disease often suffer from a much more rapid course of disease
progression than adult patients, and infants with vertically-acquired
HIV typically have substantially higher blood viral RNA concentrations
than adults.19-24 HIV preferentially replicates in
activated and dividing cells.25,26 If the PBMCs of infants
turn over more rapidly than those of adults, then the pool of cells
vulnerable to a productive HIV infection should also be increased. This
increased pool of vulnerable cells naturally present in infants may
support increased levels of viral replication, higher amounts of
circulating virus, and therefore more rapid disease
progression.23,24,27-30
| |
ACKNOWLEDGMENT |
The authors thank Drs James Oleske and Robert Yarchoan for
encouragement and support.
| |
FOOTNOTES |
Submitted July 16, 1998; accepted December 28, 1998.
Supported in part by grants from the Elizabeth Glaser Pediatric AIDS
Foundation and from the Centers for Disease Control and Prevention.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Steven L. Zeichner, MD, PhD,
HIV and AIDS Malignancy Branch, National Cancer Institute, National
Institutes of Health, Bldg 10, Room 13N240, Bethesda, MD 20892; e-mail:
zeichner{at}nih.gov.
| |
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A. Aviv
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[Abstract]
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I. Thornley, R. Sutherland, R. Wynn, R. Nayar, L. Sung, G. Corpus, T. Kiss, J. Lipton, J. Doyle, F. Saunders, et al.
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[Abstract]
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K. Wu, N. Higashi, E. R. Hansen, M. Lund, K. Bang, and K. Thestrup-Pedersen
Telomerase Activity Is Increased and Telomere Length Shortened in T Cells from Blood of Patients with Atopic Dermatitis and Psoriasis
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION