Shared Phenotypes Among Segmental Progeroid
Syndromes Suggest Underlying Pathways of Aging
Anne C. Hofer,1Rosie T. Tran,1Owais Z. Aziz,1Woodring Wright,2
Giuseppe Novelli,3Jerry Shay,2and Marc Lewis4
1Plan II, The University of Texas at Austin.
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas.
3Department of Biopathology and Diagnostic Imaging, Tor Vergata University, Rome, Italy.
4Department of Psychology, The University of Texas at Austin.
Segmental progeroid syndromes are those whose phenotypes resemble accelerated aging. Here
we analyze those phenotypes and hypothesize that short telomeres produce the same group of
symptoms in a variety of otherwise unrelated progeroid syndromes. Specific findings are the
following: (a) short telomeres in some progeroid syndromes cause an alopecia/osteoporosis/
fingernail-atrophy group of symptoms; (b) fingernail atrophy in progeroid syndromes resembles
the natural slowing of nail growth that occurs in normal aging and nail growth velocity, and may
be a marker of replicative aging in keratinocyte stem cells; (c) alopecia and reduced hair diameter
parallel the nail results; (d) osteoporosis in Dyskeratosis Congenita resembles age-related
osteoporosis, but the same is not true of other progerias; and (e) gray hair is associated with short
telomeres, but may also involve reactive oxygen species. On the basis of these results, we make
several predictions and discuss how the segmental quality of progeroid syndromes may provide
insight into normative aging.
example, is a symptom of both Nijmegen Breakage
Syndrome (NBS) and Hutchinson-Gilford Progeria Syn-
drome (HGP), but the two diseases are otherwise very
different. In NBS, a disruption in homologous DNA repair
of double strand breaks, along with failure to halt at the S-
phase checkpoint, leads to symptoms such as anemia,
webbed toes, and cafe ´ au lait spots; in HGP, a weakened,
dysfunctional inner nuclear wall leads to absence of
subcutaneous fat, atherosclerosis, and wormian bones. Gray
hair does not, in contrast, appear in either Bloom Syndrome
or in Cockayne Syndrome, both of which have causes very
different from those of NBS, HGP, and each other. Table 1
lists progeroid syndromes (which for simplicity we will
hereafter call progerias), a brief description of their causes,
and a representative synopsis of their symptoms. Gray
hair appears in six of the eleven diseases shown. Other
symptoms such as nail atrophy and osteoporosis also occur
in some progeroid syndromes but not in others.
Why do shared symptoms such as gray hair occur in so
many progerias, but not in all of them? Is the mechanism
that causes gray hair the same in all six progerias and is it
the same mechanism that causes gray hair in natural aging?
In this article we will consider those questions for a number
of symptoms that co-occur in a specific subgroup of
progerias. We will also consider one possible explanation
for the co-occurrence of those symptoms, discuss relevant
mechanisms, and make predictions. Although we will
mention several non-aging symptoms in passing, they lie
outside of our present focus and will be discussed in depth
ROGEROID syndromes with very different causes
sometimes share symptoms in common. Gray hair, for
PROGERIAS WITH SYMPTOMS IN COMMON
Figure 1 shows symptoms that the progerias have in
common. For example, the darkest column shows that two
progerias (Rothman-Thomson Syndrome [RTS] and Werner
Syndrome) share the symptom of osteosarcoma; the lightest
column shows that three progerias (Ataxia Telangiectasia,
NBS, and Bloom Syndrome) share the symptom of cafe ´ au
lait spots. Figure 1 contains only a subset of all shared
symptoms, chosen to make a point that will be clarified later.
In addition, symptoms that are superficially similar or that
lack explanatory power because they occur in almost all
The third column of Figure 1 shows that four progerias
share the symptoms of nail atrophy, alopecia, and osteopo-
rosis. Atrophic nails are small and thin, and often fail to grow
to the end of the finger or toe (1). Hypoplastic (underdevel-
nails unless they occupy the mild end of a disease continuum
Dyskeratosis Congenita). In trichothiodystrophy, for exam-
ple, nails and hair become brittle and break due to
transcription-related sulfur deficiency, but they do not
progress to either nail atrophy or to alopecia and so that
disease is not included in the red column of Figure 1.
Nail atrophy can occur for secondary reasons such as shoe
trauma or scarring from the disease lichen planus, and as the
occasional side effect of some peripheral vascular disorders
(e.g., leprosy), but it is almost never a primary disease
symptom. In fact, we searched more than 7000 diseases and
conditions (see ‘‘Scope of Literature Review’’) and found
nail atrophy mentioned as a symptom in just five. Four of
Journal of Gerontology: BIOLOGICAL SCIENCES
2005, Vol. 60A, No. 1, 10–20
Copyright 2005 by The Gerontological Society of America
by guest on November 4, 2015
Canada Syndrome (CCS), has not fully been studied or
classified, but it has much in common with the progerias, and
it may represent an unrecognized addition to that family of
diseases. We will discuss CCS separately a little later.
Nail atrophy is not only a rare symptom, but it also co-
occurs with two other less rare, but relatively uncommon
symptoms, alopecia and osteoporosis. The four progerias in
the third column are, in fact, the only diseases in the
literature that share these three symptoms. It is improbable
that the association is coincidental, and we will argue that
a single underlying process unites them. We begin with
a discussion of fingernails.
THE FINGERNAIL SYSTEM
The fingertip (Figure 2A) is an unusually safe place for
DNA. To understand just how safe it is, consider the effect of
Table 1. Brief, Representative Descriptions of Progeroid Syndromes and Causes
Rothmund-Thompson Syndrome (RTS):Mutation in RECQ4 helicase in two-thirds of cases. Commonly thought to be a DNA repair defect but no evidence
that RTS patients are sensitive to chemotherapy or UV. Some skeletal problems present at birth. Swelling,
blistering rash appears at 3–10 months postpartum, then grows into poikiloderma. Juvenile cataracts reported in
some series of patients, not in others. Other symptoms include small stature and photosensitivity, osteoporosis,
alopecia (some with no hair problem though), gray hair, dystrophic/atrophic nails, osteosarcoma at median age
11.4. Life span is normal in the absence of cancer.
Mutation in RECQ3/WRN which encodes the WRN helicase/exonuclease. Symptoms usually first noticed
around puberty when no growth spurt develops. Gray hair and alopecia follow, then sclerotic skin, diabetes, and
osteoporosis. Other symptoms include diabetes mellitus, cataract (variously described), hypogonadism,
immunodeficiency, nail atrophy, birdlike facies, and senile dementia. Schizophrenia is ten times normal rate.
Death occurs in mid to late 40s.
LMNA mutation leads to truncated Lamin A protein and a weakened, dysfunctional inner nuclear wall. Infants look
normal at birth but alopecia appears in the first year. Growth failure in the second year and the start of
progressive loss of subcutaneous fat. Atherosclerosis, osteoporosis, nail altrophy, gray hair, thin skin, beaked
nose, high pitched voice. Median age at death is about 13.
The X-linked (DKC1 mutation) and AD (TERC mutation) forms greatly reduce active telomerase levels leading to
nail atrophy, osteoporosis, alopecia, gray hair, wrinkled skin, poikiloderma, hypertension, oral mucosal
leukoplakia, and increased cancer, especially epithelial and hematopoietic types. Bone marrow failure is the
principle cause of death. The milder AR form (cause unknown) has mainly hematopoietic symptoms.
Age of onset, severity, range of symptoms, and age at death vary widely, probably due to hereditary differences
in telomere length.
ATM mutation affects downstream phosphorylation in DNA damage repair and cell cycle control. Scleral
telangiectasias appear after age 3 along with photosensitivity and scleroderma. No mental problems at first, but
deterioration occurs over time. Cerebellar ataxia appears when the child begins to walk. Gray hair, lymphoma and
leukemia, wrinkled skin, immunodeficiency, reduced reflexes, and cafe ´ au lait spots. Death from recurrent
respiratory infection in adolescence or early adulthood.
Mutations in NBS1 (in most cases), a gene phosphorylated by ATM, disrupts homologous DNA repair. Microcephaly
at, or around, birth with postnatal growth retardation and decline in mental function. Also photosensitivity,
immunodeficiency, predisposition to cancer, gray hair, telangiectasias, and cafe ´ au lait spots. Death from
respiratory infections, but greater risk of death from malignancy (lymphoma is elevated 1000 fold).
Caused by RECQ2/BLM helicase. Growth deficiency at birth leads to final small, proportionate stature.
Telangiectasias appear on face, ears, sclerae along with cafe ´ au lait spots, photosensitivity, and erythema. Long
narrow face appears birdlike. Also, immunodeficiency and diabetes mellitus. Leukemias develop at mean age 22;
solid tumors develop in survivors at mean age 35. Life expectancy depends on presence of malignancy and its
response to treatment.
Defects in nucleotide excision repair (global genome repair, transcription coupled repair, or both) produces seven
complementation groups (XP-A- to XP-G), all of which are components of transcription factor TFIIH.
Dysfunction in DNA polymerase-eta produces the XP-V type. Symptoms depending on subtype may include
photosensitivity, skin atrophy, early-onset skin cancers, poikiloderma, microcephaly, low intelligence, and
mild to severe neurological features.
Transcription problem in XP-D and (rarely) XP-B (see XP entry) affects transcription in TFIIH. One reported case of
third complementation group (TTD-A). Brittle (‘‘tiger tail’’) hair and nails due to sulfur deficiency, photosensitivity,
ichthyotic skin, loss of subcutaneous fat, birdlike facies, aged appearance, cataracts, delayed physical and mental
development, microcephaly, hypogonadism, respiratory infections, and digestive problems. Death between age 3
and 30 depending on severity.
Types I (classic) and II (congenital) both caused by defects in transcription coupled repair (see xeroderma
pigmentosum). Infants are normal at birth but develop early growth failure, microcephaly, a narrow face, and a
beaked nose. Photosensitivity leads to thin, dry skin with rashes and telangiectasias. Demyelination in the central
and peripheral nervous systems, with accompanying mental retardation and deafness. Also respiratory problems,
pigmentary retinal degeneration, thin, dry hair, dental abnormalities, and delayed puberty. Death from Type I occurs
in the second or third decade, death from Type II at about age 7.
Mutation in B4GALT7 affects glycosylation of Decorin, a collagen handling protein, and leads to failure to thrive,
small face, short stature, narrow chest, psychomotor retardation, osteopenia, sparse scalp hair, loose, elastic skin,
long slender fingers and toes.
Werner Syndrome (WS):
Hutchinson-Gilford Progeria (HGP):
Dyskeratosis Congenita (DKC):
Ataxia Telangiectasia (AT):
Nijmegen Breakage Syndrome (NBS):
Bloom Syndrome (BS):
Xeroderma Pigmentosum (XP):
Cockayne Syndrome (CS):
Ehlers Danlos, Progeroid Form (ED):
by guest on November 4, 2015
350 nm UVA light on skin versus nails. In fair skin, most
UVA light is reflected from the surface, but 37% penetrates
the epidermis to a depth of 60 lm (2). There, passing through
the rising columns of epidermal keratinocytes, UVA leaves
a trail of damaged DNA in the form of pyrimidine dimers. By
the time the light reaches the stem cells in the rete ridges of
the basal layer, it still has 10% of its original damaging
power (2). That much radiation is not a short-term concern in
normal skin, but in progerias with DNA repair problems
the resultant dimers block transcription and replication;
this blockage can be lethal to cells. The result is erythema,
actinic keratosis, photoaging, cancer, and other problems of
But photodamage does not affect fingernails. Even
xeroderma pigmentosum, an extremely photosensitive dis-
ease with severe skin reactions, has no fingernail symptoms.
The reason is that fingernail stem cells and their transient
amplifying cell (TAC) progeny are buried three times deeper
in nails than they are in skin (see, for example, 3). As the nail
TACs reproduce, leave the basal layer, and rise through the
nail matrix, they are protected by the nail plate, which acts
as a UV sunscreen (4). By the time those keratinocytes join
the nail plate, they are enucleated, condensed, and immune
Although nail keratinocytes escape photodamage, no
cycling cell can escape the dangers of replication. Fingernail
TACs replicate frequently and, like all replicating cells, each
time they do they lose an average of 50–100 bp of DNA
because of the end replication problem (5,6) and subsequent
processing of the resulting 39 overhang. The loss is not
crucial in early life because humans are born with about
15 kb of disposable TTAGGG tandem repeats (telomeres) at
the ends of their chromosomes. But with replication those
protective telomeres shorten. The danger is not so much in
the shortening itself, but rather in the loss of the second
protective role of telomeres, that of capping chromosomes
and preventing the cell from mistakenly treating their ends as
double strand breaks. The telomere achieves that protected
state by, among other things, looping back and tucking its 39
overhang into the double stranded upstream telomeric DNA
(7). The result is a large telomere loop, ending in a smaller
displacement loop, which is held in place by critical proteins
such as TRF2 (reviewed in 8). As telomeres shorten, this end
protection is lost, possibly because critical proteins are
unable to maintain the loop. The result is either senescence,
or in some instances, end-to-end fusions that create a fusion-
breakage-bridge cycle (9).
by shortening telomeres by replacing some lost repeats using
the cellular reverse transcriptase enzyme, telomerase. Hair
keratinocyte stem cells, for example, have weak telomerase
activity, and there is strong activity in their rapidly dividing
TAC progeny (10). The amount of telomerase present is not,
however, sufficient to fully maintain telomeres and so
keratinocyte telomeres get progressively shorter with age.
Telomerase has not been studied in nails, but it is found in
Figure 1. Shared symptoms in progeroid symptoms.
HOFER ET AL.
by guest on November 4, 2015
highly replicative cells of skin (11), gastrointestinal tract-
stomach-intestine (12), bone marrow (13), testes (14), and
generally in all systems affected in the telomerase disorder,
In some cases, such as Werner Syndrome, the capping
loop may be lost before the telomeres become excessively
short. As a result, Werner Syndrome cells senesce more
quickly than normal cells, but possibly with longer telomeres
(15). That scenario is not fully proven, but an emerging
concept is that short-telomere problems are probably due to
loop (capping) malfunctions (e.g., 16). Nevertheless, short
telomeres have been established in certain of the progerias,
whereas capping problems have not. For that reason, we will
refer to those progerias as having a problem of short telo-
meres with the understanding that the final problem may be
loss of capping.
It is generally believed that with each replication, the cell
must transiently untie the capping loop, copy its DNA,
replace some of the lost telomere repeats (if active telo-
merase is present), and retie the loop (reviewed in 17). If
lost repeats are not replaced (as happens in Dyskeratosis
Congenita), or if the mechanism that closes the displacement
loop is dysfunctional, as may happen in Werner Syndrome
(16), telomeres progressively shorten and eventually cause
the cell to enter senescence or apoptosis. This loss of
replicative ability is the likely cause of fingernail atrophy.
The pattern of diseases in Figure 1 supports the idea that nail
atrophy is telomere driven. Figure 1 divides the progerias
into the six that have short telomeres—Dyskeratosis
Congenita (18), HGP (19), Werner Syndrome (15), Ataxia
Telangiectasia (20), NBS (21)—and the five that do not.
Nail atrophy occurs only in progerias that have short
Nail atrophy does not, however, occur in every short-
telomere progeria. The two exceptions, however, Ataxia
Telangiectasia and NBS, strengthen the evidence for
telomere involvement with nails. Unlike those in the other
progerias in this category, the telomeres in Ataxia
Telangiectasia and NBS do not shorten because of increased
DNA replication problems. Instead, in both diseases, cells
with DNA double strand breaks fail to halt for repairs at the
S-phase checkpoint; this failure is a problem that eventually
leads to a fusion-bridge-breakage cycle and short telomeres.
Because of the repair problem in these two diseases,
chromosomes that acquire normal DNA damage should
have short telomeres. But, as we have already explained,
there is little DNA damage in the nail system. Thus, in nails,
Ataxia Telangiectasia and NBS difficulties in damage repair
should not create a problem. With little damage to repair,
telomeres in Ataxia Telangiectasia and NBS nail stem cell
Figure 2. The fingernail system (A), hair (B), and basic multicellular unit (C).
by guest on November 4, 2015
keratinocytes should not shorten, and hence, nail atrophy
should not, and does not, occur.
The short-telomere group contains one provisional entry–
RTS. Two-thirds of RTS cases are caused by mutations in
the RECQ4 helicase (22,23); the remaining one-third of
cases have an unknown cause. RTS has the nail-alopecia-
osteoporosis triad seen in other short-telomere diseases, but
its telomeres have not been studied. The symptom pattern of
the disease suggests that short telomeres might occur in
RTS, especially in bone progenitors where the RECQ4
protein is highly expressed. Against this prediction weighs
the fact that life span is shortened in all of the progerias in
which short telomeres have been established, but life span is
not shortened in RTS. It is possible, then, that RTS either
does not have short telomeres or its effect on telomeres is
more subtle, as is the case in Werner Syndrome. We are
currently testing various aspects of these predictions.
The fifth disease with nail atrophy is CCS, Cronkhite
Canada Syndrome. The age of diagnosis (range 31–86,
mean 55) of CCS is later than that of most progeroid
syndromes, but similar to that of Werner Syndrome, and
many of its symptoms indicate accelerated aging. Alopecia,
hyperpigmentation, vitiligo, anemia, gastrointestinal carci-
noma, cataracts, loss of taste, and malabsorption (50% die of
malnutrition) are common. There are more than 100 case
reports of CCS in the literature, but few research studies,
and the disease remains rare and mysterious.
An interesting implication of the telomere explanation for
nail atrophy is that the velocity at which nails grow should
be a non-invasive marker of telomere status. That is, the
shorter the telomeres, the more senescent cells there should
be in the system, and the more slowly the nail should grow.
Moreover, nail growth velocity should be a marker that is
not sensitive to the confounding effects of most DNA
damage and damage repair. In the next section we elaborate
on that idea.
FINGERNAIL ATROPHY MIRRORS NORMAL AGING
Do the nail growth velocity data tell us anything about
normal aging? A literature that predates the discovery of the
role of telomeres in replication suggests that it does.
Orentreich and Sharp (24) demonstrated that fingernail
growth velocity changes predictably with age. In one cross-
sectional study of 257 human subjects, they found that nail
growth velocity increased linearly to a peak of 0.83 mm per
week at about 25 years old, then decreased linearly
thereafter by 0.5% per year. Orentreich and colleagues
followed that study with a twelve-year longitudinal study of
27 beagles (25). Nail growth velocity in the dogs increased
linearly until age 3, then decreased by 3% per year through
age 15. The beagle result is notable for its parallel to the
human data. Beagles live about one fifth the life span of
humans; correspondingly, the dogs’ nail growth velocity
rose and declined 5 times faster than the human decline.
When Orentreich looked at a contemporaneous study of
rat nail growth velocity (26), he found something un-
expected. The velocity of nail growth did not decline in rats
over their three-year life span. Why should rat nails act
differently from beagle and human nails? The explanation,
so elusive in its own time, is less of a puzzle now. Many
species of laboratory rat have very long telomeres (e.g., 27),
and telomerase is active in many of their cells. In fact, their
telomeres are so long (about four times longer than those of
humans) that there is not enough shortening in the rat life
span to make a difference in many aging symptoms,
including, as Lavelle showed, nail growth. It is difficult to
explain why rat nails differ from those of other animals by
any means other than the link between nail atrophy and
Oddly, fingernail growth velocity may be more than
a marker of telomere length; it might also be a marker of
length of life. About a decade after Orentreich’s studies,
Williams and colleagues (28) and Short and colleagues (29)
reported a relationship between nail growth velocity and
aging in pigtailed macaques. The finding inspired Coe and
Ershler to measure nail growth a year later in their colony of
rhesus monkeys, but that team did not immediately report
their result. Thirteen years later, however, while looking at
the relationship between natural killer cells and aging, the
two researchers recalled the nail data. So much time had
passed that 12 of their original monkeys had died and the
authors were able to compare their single measurement of
nail growth velocity, taken more than a decade earlier, with
the number of years beyond the experiment that each animal
had survived and with the age of each animal at death (30).
Fingernail growth velocity was a surprisingly good pre-
dictor, correlating significantly with both years of survival
(r¼.67, p , .02) and age at death (r¼.57, p , .05). Given
the other links that have been established between telomeres
and mortality (e.g., 31), the relationship of nail growth rate
to survival is interesting.
The conclusion that follows from the forgoing discussion
is that fingernail growth may be a noninvasive marker of
telomere status. If so, it is a telomere marker that is not
sensitive to the confounding effects of DNA damage and
damage repair problems. Measuring nail growth velocity
could provide information about telomere status in a re-
markably short time. For example, Orentreich and colleagues
(25) described a method for measuring nail growth velocity
to accuracies of 0.1 lm over periods as short as 15 minutes
using a split-image range finder adapted to a trinocular
microscope and a fixed reference object cemented to the nail
fold. Such a non-invasive measure could have many uses.
For example, the longitudinal nature of caloric restriction
studies makes short-term measures of efficacy difficult to
obtain. Measurement of nail growth velocity using modern
equivalent of the split-image range finder might produce
a non-invasive assessment of treatment effects within a few
weeks after the start of a caloric restriction experiment. The
simpler but slower procedure of marking the nail and
measuring nail growth with calipers might also provide
a continuous way to monitor telomere changes.
Alopecia is the second symptom shared by the short-
telomere progerias. Although the genetics of hair loss are
growing clearer (reviewed in 32), a link between short
telomeres and baldness has not previously been noticed. The
existence of such a link is not, however, surprising. Hair is
similar to nails in the extent to which it is protected from
HOFER ET AL.
by guest on November 4, 2015
damage. Hair keratinocyte stem cells are located in the
bulge (Figure 2B) (33) which is the deepest part of the
‘‘permanent’’ hair shaft, and are protected from most UV
damage. During anagen (the growth phase of the hair cycle),
these stem cells create TACs which migrate far more deeply
to the basement membrane that surrounds the invaginated
follicular papilla (FP). There the TACs produce cells
that rise, terminally differentiate, enucleate, and join the
cortex of the growing hair shaft. As with nails, these hair
keratinocyte TACs are not immune to replication problems.
Therefore, the fact that alopecia is found in all of the
progerias in which nail atrophy occurs and in none of the
progerias in which it does not occur is unsurprising and
confirmatory to the short-telomere explanation.
HAIR DIAMETER IS REDUCED IN AGING AND IN
We propose that the equivalent to nail growth velocity is
not hair growth velocity, but rather, hair shaft diameter. That
is because hair growth velocity is simultaneously regulated
by two opposing factors: (a) the number of differentiated
hair keratinocytes generated by the TACs; and (b) the
diameter of the hair.
The role of keratinocyte TACs has already been dis-
cussed. The role of hair diameter is a little more complex.
Hair diameter is determined by the FP: the larger the FP, the
thicker the hair shaft (34). The size of the FP is determined
at the start of each anagen hair cycle when specialized
fibroblasts migrate to the interior of the FP. The more those
fibroblasts replicate during this growth period, the larger the
final size of the FP (35), and the wider the subsequent hair
shaft. Thus, hair diameter changes with each hair cycle.
With age, there is a decline in both the keratinocyte and
fibroblast progenitor populations. The decline in keratino-
cyte progenitors slows hair growth; the decline in fibroblast
progenitors and subsequent reduced hair diameter means
that fewer keratinocytes are needed to lengthen the hair, so
hair grows faster. Because of the simultaneous contribution
of these two opposing factors, hair growth velocity varies
unpredictably with age.
Although hair diameter and keratinocyte activity interact
with regard to hair growth velocity, hair diameter is in-
dependent of the number of keratinocyte TACs; increasing
the number of active keratinocytes does not increase the
diameter of the hair. Hair diameter is, therefore, a measure
of the replicative ability of the FP fibroblast progenitors.
On the basis of our results with nails, we expect that with
age, shortening telomeres will lead to fewer active fibroblast
progenitors in the FP and, therefore, hair diameter will
decrease. Studies of the matter confirm this expectation;
both the number of active fibroblast progenitors in the FP
(36) and hair diameter (e.g., 37–40) decrease with age. The
effect is, in fact, so strong that it consistently appears despite
influences of hormones (which also affect hair diameter) and
other factors (40).
Our earlier nail result suggests that hair diameter should
decrease in the four short-telomere progerias with replica-
tion problems. There are no formal studies of hair diameter
in any progeria, but the clinical literature often refers to
hair in those four progerias as ‘‘fine’’ (41,42). With the
exception of the progeroid form of Ehlers-Danlos Syn-
drome, in which hair is described as curly and fine, no other
progeria is described by that term. (The curliness in Ehlers-
Danlos Syndrome suggests that the hair is being flattened as
it passes through the follicle.) The single histological study
looking at hair in the progerias (an RTS model mouse) (43)
found that FPs were significantly reduced in the RTS mice
versus controls, thereby confirming the clinical impression
that hair in the short-telomere progerias is ‘‘fine.’’ Thus, hair
diameter, like nail growth velocity, may reflect telomere
shortening both in natural aging and in some progerias.
OSTEOPOROSIS IN SOME PROGERIAS MAY DEPEND
Osteoporosis is the surprising third member of the short-
telomere symptom triad—‘‘surprising’’ because there is no
evidence linking loss of bone mass to telomeres, and no
obvious pathway from bone remodeling to hair or nail
growth. Again, the symptom occurs only in the short-
telomere progerias (with the single exception of a note in
emedicine, http://www.emedicine.com/, stating that in
Cockayne Syndrome ‘‘osteoporosis may occur’’).
Bone remodeling is carried out by the Basic Multicellular
Unit (BMU). At the front of the BMU is a team of large,
multinucleated osteoclasts which dissolve existing bone
in a sealed compartment on their ruffled undersides. At
the back of the BMU is a trailing group of individual
osteoblasts, each rebuilding some of the bone lost during the
passage of the osteoclasts (Figure 2C). Osteoporosis occurs
when osteoclasts resorb more bone than osteoblasts resupply
(reviewed in 44). There are many ways for that to happen,
but osteoporosis in old age occurs because fewer BMUs are
made and because the osteoblasts secrete less osteoid, the
collagen-rich bone-rebuilding material. Thus, there are
fewer BMUs working to remodel bone, and the passage of
each BMU produces a net loss. The result is a slow, steady
erosion of bone and loss of bone microarchitecture.
Although osteoporosis in the progerias may be due to
shortened telomeres (see, for example, 45 and 46), some
researchers believe that telomerase itself is the problem.
Telomerase is required for progenitor cells to differentiate
into osteoblasts in mice (47) and possibly in humans as well.
If so, then the telomerase problems in Dyskeratosis
Congenita would explain osteoporosis in that disease.
Problems with differentiation are more likely to affect
osteoblasts than osteoclasts because the pool of immediate
osteoclast progenitors is 2500 times larger than the pool
of osteoblast precursors (48). Osteoblasts are, therefore,
unlikely to ever be rate limiting (48). Because osteoblasts
regulate entry of osteoclasts into the bone-remodeling
system, it is reasonable to expect that fewer BMUs will be
produced; the same situation is seen in normal aging.
The foregoing scenario is unlikely to be true for
Rothmund-Thomson Syndrome, which has no obvious
connection to telomerase, or for Werner Syndrome, which
has a pattern of osteoporosis very unlike that seen in normal
aging, including a 60%þ incidence, severe involvement of
the limbs, and symmetric osteosclerosis of the hands (49,50)
and again, no obvious link to telomerase. In HGP the picture
is more interesting. It is our observation that symptoms in
by guest on November 4, 2015
that disease are almost entirely attributable to the progeny of
mesenchymal stem cells in bone marrow (which make
adipocytes, myoblasts, chondrocytes, ligament cells, and
osteoblasts). It is possible then that HGP is caused by
a failure of mesenchymal stem cells to differentiate resulting
in fewer osteoblasts, hence fewer BMUs, and osteoporosis.
This is an idea that deserves further investigation, especially
into (a) the question of telomerase in differentiation of
mesenchymal stem cells and (b) the potential role of the
mechanical weakening of the inner nuclear wall (51–54) that
occurs in HGP.
Although there is no obvious connection between short
telomeres and osteoporosis, the grouping of this symptom
with nail atrophy and alopecia suggests that there is some
link, probably not because of a common pathway, but
rather, because of a single process that independently affects
the telomeres of progenitor cells in each of the three sys-
tems. The same seems to be true of gray hair as well.
GRAY HAIR IS ASSOCIATED WITH SHORT-TELOMERE
Gray hair occurs in all six short-telomere progerias and in
no others, so it too may be caused by shortened telomeres.
Cross-species studies support this view. For example, Mus
musculus has long (up to 60 kb) telomerase-active telomeres
(55) that shorten only fractionally over the animal’s lifetime.
Blasco and colleagues (56) asked what would happen if that
mouse’s telomeres did shorten, and they produced a line of
telomerase-null (Terc ?/?) knockout mice to answer the
question. By the third generation, mouse telomeres had
shrunk by 15 kb and, at middle age, the knockout mice had
dramatically more gray hair (and alopecia) than did control
mice (57). The knockouts also grayed earlier. Flow-FISH
analysis confirmed that both gray hair and alopecia inversely
correlated with telomere length. At the sixth generation,
differences between experimental and control mice were
still growing. Samper and colleagues (58) completed the
logic of the original experiment by crossing late genera-
tion telomerase-null mice with Terc þ/? mice, thereby
reintroducing telomerase into the systems of some progeny.
Those progeny had normal mouse telomere lengths, and
many symptomsof premature
(including graying; personal communication, M. Blasco,
April 21, 2004).
How might short telomeres lead to gray hair? An analysis
of the situation calls for a brief digression into the phy-
siology of hair pigmentation and graying. Hair is pig-
mented by melanocytes located among the keratinocytes on
the FPs. Each time the growth part of the hair cycle begins
(anagen), a new population of melanocytes migrates to the
FP from a stem cell reservoir located in the outer root sheath
at about the midpoint of the hair follicle (59). Each
melanocyte supplies pigment to between one and five
follicular hair keratinocytes (60) throughout the entire
growth period (up to 10 years) (59). That pigment, melanin,
is manufactured inside the melanocyte within membrane-
bounded organelles called melanosomes. The melanin, still
in its melanosome, is transferred to keratinocytes via
dendritic connections. Once inside the keratinocyte, the
package is degraded and the pigment absorbed.
Gray hair can occur when any part of the pigmentation
process is disturbed (for example, if melanogenesis fails, or
if transfer of melanosomes to keratinocytes does not go
smoothly). There are other ways that gray hair can occur,
but oddly, the one cause not listed among them is cellular
senescence. Senescence does occur in melanocytes, but
senescent melanocytes produce more, not less, melanin
(61,62). In skin, for example, moles are thought to be
senescent melanocyte clones (62,63). Consequently, we
cannot draw the otherwise obvious conclusion that short
telomeres cause senescent melanocytes, less melanin, and
hence, gray hair.
If telomere-driven senescence does not cause gray hair,
then what does? And why are Ataxia Telangiectasia and
NBS involved with gray hair when they were not involved
with the nail atrophy and alopecia symptoms? The answer
may lie with another suspected agent of aging, reactive
oxygen species (ROS).
The most common cause of gray hair is a reduction in the
active melanocyte population (61). Estimates vary, but after
age 30 the number of melanocytes that supply pigment to
hair drops between 10% and 20% each decade (60,64),
thereby providing the basis for the rule that 50% of the
population is 50% gray by age 50 (9). A widely held theory
(e.g., 9,64) is that this loss of melanocytes is caused by
ROS, and indeed melanogenesis produces hydrogen perox-
ide and reactive quinone intermediates (65,66) which can
cause cross-links, single strand breaks, and other types of
DNA damage (67). Existing evidence suggests ROS damage
to nuclear and mitochondrial DNA leads to mutations in
active melanocytes (59).
The link between ROS theory and the short-telomere
progerias lies in the fact that ROSs are preferentially
attracted to the GGG sequences at the 59 end on the telomere
(68). In particular, hydrogen peroxide preferentially cleaves
59-RGGG-39 (69). It is possible, therefore, that long telo-
meres protect against ROS damage occurring elsewhere in
the DNA. As telomeres shorten, this protection is lost and
stress-induced premature senescence, or apoptosis, results.
According to this theory, gray hair is based entirely on the
shortness of telomeres, not on why they are short. More
specifically, persons with Werner Syndrome or one of the
other three replication-based progerias have gray hair
because their telomeres shorten due to inability to restore
lost repeats, whereas those persons with Ataxia Telangiec-
tasia or NBS have short telomeres because of breakage. But
persons with any of the six progerias have short telomeres
and hence are vulnerable to gray hair.
Hair melanocytes are particularly vulnerable to these
problems because of their increased exposure to ROS and
their long life spans. This link between ROSs and short
telomeres is attractive, and a recent serendipitous finding
supports it. Chronic myeloid leukemia is a hematopoietic
stem cell malignancy in which the Abelson oncogene (which
encodes a tyrosine kinase) transfers from chromosome 9 to
the BCR region of chromosome 22. The fused gene encodes
a protein thought responsible for the disease. In 1999, a drug
aimed at treating the disease, imatinib mesylate, entered
phase 2 clinical trials. Imatinib is a selective tyrosine kinase
inhibitor that blocks phosphorylation of an ATP binding site
HOFER ET AL.
by guest on November 4, 2015
of the fused gene product. But imatinib also inhibits the c-
Kit tyrosine kinase receptor, which is on a pathway that
activates promoter for the tyrosinase pigmentation gene
(70). Mutations in the homologous c-kit gene in mice
produce a white coat; mutations in c-Kit in humans produce
piebaldism (71). It was, therefore, predicted that blocking
the c-Kit receptor with imatinib might have an unwelcome
side effect—gray hair. The two-year study showed that
imatinib was indeed an effective treatment for chronic
myeloid leukemia (72) and that it did indeed have a side
effect. It repigmented gray hair. The result was published in
the New England Journal of Medicine as a serendipitous
finding and an interesting puzzle (73).
Shortly thereafter, Brummendorf and colleagues (74)
independently reported a second peculiar finding; peripheral
blood leukocytes in people who had responded to the
imatinib had longer telomeres than did those in people who
had not responded. It is possible that selective cloning
occurred, but the authors provided convincing evidence
against that possibility. It looks very much as if imatinib
restored telomere length to migrating melanocyte TACs
arriving at the start of a new hair cycle, and that that
restoration led to repigmentation of gray hair. An in-
teresting, albeit impractical test of this idea would be the
administration of imatinib to people with Ataxia Telangi-
ectasia. Immortalization of Ataxia Telangiectasia cells by
ectopic expression of hTERT rescues the short-telomere
phenotype without affecting the DNA repair/breakage
problem (75). It follows, then, that if imatinib restored
pigment to gray hair in Ataxia Telangiectasia, the original
cause was likely to have been short telomeres, rather than
the breakage problem.
DO SHORT-TELOMERE PROGEROID SYNDROMES
RESEMBLE NORMATIVE AGING?
Table 2 shows that symptoms seen in short-telomere
progerias are similar to those seen in normal aging, but there
are two important differences: symptoms in the progerias
usually are more severe than those in normal aging, and
symptoms that appear in a specific order in aging often
appear in a different order in the progerias. For example,
nail growth slows in normal aging, but it arrests completely,
or nearly so, in the short-telomere progerias. Eyebrow
thinning follows loss of scalp hair in aging, but precedes
loss of scalp hair in the progerias.
These differences between normal aging and progeria are
predictable under the hypothesis that telomeres are involved
in hair and nail symptoms. In nails, for example, it is
reasonable to assume that a slow loss of keratinocyte
progenitor cells with age will slow growth velocity. The
resultant thinning nails and stuttering growth failure create
beads and ridges (see Table 2, column 1). In the short-
telomere progerias, where keratinocyte progenitors fail more
quickly, beads and ridges are likely to be correspondingly
more pronounced, and the slowed growth seen in aging is
more likely to turn into complete arrest.
Differences in the order in which symptoms appear in
aging and progeria are also predictable. For example, with
the quick shortening of telomeres in progerias, the first hairs
to thin should be the ones that cycle most rapidly rather than
the ones most vulnerable to hair loss. It follows that in
normal aging the vulnerable scalp hair should thin before
eyebrows and lashes, but in the progerias, the faster cycling
eyebrows and lashes should thin before scalp hair.
The situation with osteoporosis is less clear. Only
Table 2. Physiological Changes in Hair, Nails, and Osteoporosis and Comparative Aging Versus Short Telomere Progeroid
Syndrome Phenotypes (Six Syndromes for Gray Hair, Four for all Others).
Physiological Changes in AgingAging Phenotype Progeroid Syndrome Phenotype
Alopecia; reduced hair diameter: progressively
fewer active fibroblast progenitors leads to
smaller follicular papilla thus, smaller diameter
(fine) hair; a shortened hair growth cycle (ana-
gen) and a longer resting phase make remaining
hairs less apparent.
Hair loss is among the early symptoms observed.
Loss is most prominent in scalp, but occurs in
other types of hair including eyebrows,
eyelashes, axillay, and body. Hair diameter
peaks at age 30, then declines linearly
Hair is normal at birth, but hair loss is among the
early symptoms observed. Large scale loss oc-
curs in all types of hair generally beginning
with eyebrows and eyelashes. Remaining hair
Graying: Active melanocyte population diminishes
by 10%–20% per decade after age 30. Remain-
ing melanocytes contain fewer and smaller mel-
anosomes. Degradation of defective
melanosomes by autophago-lysosomes ob-
Graying begins on the scalp, but occurs later in
Gray hair, usually first appears when hair loss
begins and occurs in all types of hair more or
Nails: Stuttering changes in nail growth velocity
are thought to create beading. Nail thinning or
possibly whirls of progenitor cells are thought
to cause longitudinal ridges, Presumed reduc-
tion in the progenitor population slows growth.
Growth speed peaks at age 25, then linearly
decreases by .5% per year.
Longitudinal ridges and nail beading ridges and
nail beading after age 40. Nails are often thin
and may split of crack.
Nail dystrophy followed by dramatically slowed or
completely arrested nail growth and atrophy.
Nails usually thin (but sometimes thick) and
may split or crack.
Bone density: Number of bone remodeling units is
reduced, osteoblasts secrete less osteoid so each
unit produces a net loss especially in trabecular
and cortical bone. Increased fractures in hip,
humerus, and pelvis.
Bone mass peaks at age 25, 1%–2% per year loss
of cortical and trabecular bone mass at
age 45–55, produces deficits after age 70.
Hip and vertebral fractures are most common.
WS: 60%–100% lifetime incidence, unusual distri-
bution (limbs), bilateral osteosclerosis of hands.
DKC: theoretically similar to aging, no empirical
RTC: osteoporosis with skeletal defects and exten-
sive remodeling. HG-progeria: Apparent lack of
interstitial and appositional and bone
by guest on November 4, 2015
Dyskeratosis Congenita resembles normal aging in its rate
of onset and areas affected (76). Werner Syndrome has
a much higher incidence of osteoporosis than is seen in
normal aging [estimates range from 60% (49) to almost
100% (50) of all cases], and it includes osteosclerosis
(abnormal bone density), a symptom rarely seen in normal
aging. Rothmund-Thomson Syndrome has an onset rate
more in line with normal aging, but it too includes
osteosclerosis and extensive bone remodeling. Osteoporosis
in HGP is also different from normal aging, in that the
underlying problem is bone development, not bone loss.
Thus, although the co-occurrence of osteoporosis in only
the short-telomere progerias is interesting, in view of the
dissimilarity of the overall picture to normal aging in all but
Dyskeratosis Congenita, the relationship between short
telomeres and osteoporosis remains conjectural.
Finally, we note that although the short-telomere
progerias have very different causes and a wide variety of
symptoms, they are very similar in the particular hair loss,
graying, and nail symptoms that occur (Table 2). For
example, in the four progerias with short telomeres due to
replication problems, nails are short and dystrophic with
beading and longitudinal ridges, progressing to atrophy.
Pictures depicting nail changes in the various progerias
(e.g., 76,77) sometimes also show great cracking, splitting,
and separation of the nail plate from the nail bed (a
consequence of nail atrophy), but no other dystrophies are
common. All of these symptoms can be attributed to
telomere shortening. Conversely, symptoms that are not
attributable to telomeres are not reported. Nail pitting, nail
plate softening, spooning, clubbing, claw-like changes,
white nails (leukonychia), and the many other types of
symptoms that are attributable to problems with keratin,
enucleation, nail plate construction, or any processes other
than telomere shortening, do not normally occur. The same
is true in hair. Thus, although all nail and hair symptoms
increase with age, those that we have identified as belonging
to the short-telomere progerias are most common, which
suggests that the short telomeres are a reasonable model for
hair and nail symptoms in aging.
IF THE PROGERIAS ARE SEGMENTAL, IS AGING MODULAR?
As George Martin (78) observed, the progerias are
segmental diseases. Each captures some, but not all, of the
symptoms of aging. But when the same group of symptoms
appears together in several progerias and nowhere else, it is
reasonable to hypothesize that they may have a similar
underlying cause. Here we show that short telomeres are
potentially such a cause for the nail atrophy, alopecia, and
gray hair symptoms. We also show that at least one of those
symptoms, nail growth velocity, may be tied to natural
aging. Short telomeres are not the sole cause of aging and
perhaps not even a major part of it—that is the lesson of
Dyskeratosis Congenita, an entirely telomere-driven disease.
But our analysis has shown that short telomeres contribute
to at least four symptoms and probably to others and, as
such, they represent a kind of module of aging. Other
modules probably exist. ROSs, for example, appear to
contribute to many symptoms of aging, but they too do not
explain all aging symptoms. A possible scenario then, is that
the aging phenotype is caused by a limited number of
modules, each contributing its own group of symptoms,
some of which are unique, and some of which overlap the
symptoms of other modules. The method that we have used
here is one way of untangling those interdependencies to
determine which symptoms are attributable to one module,
that of short telomeres.
Our approach of looking at different properties of
progerias in different systems works because each progeria
operating within a system of the body can be considered
a natural experiment. Other natural experiments may be
available. The limbus of the cornea and the pregermative
zone in the lens are two populations with unique proper-
ties—the lens is especially interesting because it captures
changes in a permanent sediment of cells for which devel-
opmental history is known. Cataracts are seen in several
progerias but were not included in our analysis because the
scenario is too complex and the symptom appears in too
many diseases to consider fully. Such cross-system analyses
may, however, uncover insights into aging that are not
readily available from single-system studies.
SCOPE OF LITERATURE REVIEW
We searched OMIM (Online Mendelian Inheritance In
OMIM) and emedicine (http://www.emedicine.com/) to
obtain initial data. OMIM is the database of human genes
and genetic disorders developed by the National Center for
Biotechnology Information and maintained at The Johns
Hopkins University. The site currently contains just over
15,000 entries, but we confined our search to well-defined
diseases and syndromes by restricting ourselves to the 4535
entries that contain clinical synopses. emedicine is a large
clinical knowledge base established in 1996 for physicians.
Its 7000 disease and disorder entries are produced and
maintained by 10,000 physician authors. Submissions go
through four levels of peer review, and are continuously
We supplemented those searches with numerous medical
texts, in part, because diagnosis of fingernail problems is not
standardized and many sources had to be consulted to get an
understanding of the range and degree of the nail problems
for each progeria. Major medical texts (1,79–84) and one
research monograph (85) were included. Other texts were
consulted on a limited basis. We obtained additional infor-
mation on systems, symptoms, and diseases from several
dozen major review articles and numerous original research
publications. We regret that, in many cases, overlapping
information and space limitation forced us to choose which
of several equally incisive articles to cite.
Will Clark, Jessica Ho, Vincent Kuo, Sarah Kuykendall, Alexander
F. Mark, Naren Venkatsan, and Jason Yeh made early contributions to
the study of the progeroid syndromes discussed in this article.
A. C. Hofer, R. T. Tran, and O. Z. Aziz contributed equally to this article.
Figure 2 was drawn by Susanna Douglas, Electronic Specialist in the
Department of Psychology at The University of Texas at Austin.
HOFER ET AL.
by guest on November 4, 2015
Address correspondence to Marc Lewis, PhD, Department of Psychol-
ogy, The University of Texas at Austin, Austin, Texas, 78703. E-mail:
1. Pardo-Castillo V, Pardo O. Diseases of the Nails. 3rd Ed. Springfield,
IL: Charles C. Thomas; 1960.
2. Anderson R. Tissue optics and photoimmunology. In: Parrish J, Kripke
M, Morrison W, eds. Photoimmunology. New York: Plenum Medical;
3. Ross M, Kaye G, Pawlina W. Histology: A Text and Atlas. 4th Ed. New
York: Lippincott Willaims & Wilkins; 1995.
4. Parker SG, Diffey BL. The transmission of optical radiation through
human nails. Br J Dermatol. 1983;108:11–16.
5. Olovnikov AM. [Principle of marginotomy in template synthesis of
polynucleotides]. Dokl Akad Nauk SSSR. 1971;201:1496–1499.
6. Watson J. Origin of concatameric T4 DNA. Nat New Biol. 1972;239:
7. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end
in a large duplex loop. Cell. 1999;97:503–514.
8. de Lange T. Protection of mammalian telomeres. Oncogene. 2002;21:
9. Keough EV, Walsh RJ. Rate of graying of human hair. Nature.
10. Ramirez RD, Wright WE, Shay JW, Taylor RS. Telomerase activity
concentrates in the mitotically active segments of human hair follicles.
J Invest Dermatol. 1997;108:113–117.
11. Yasumoto S, Kunimura C, Kikuchi K, et al. Telomerase activity in
normal human epithelial cells. Oncogene. 1996;13:433–439.
12. Bachor C, Bachor OA, Boukamp P. Telomerase is active in normal
gastrointestinal mucosa and not up-regulated in precancerous lesions. J
Cancer Res Clin Oncol. 1999;125:453–460.
13. Hiyama K, Hirai Y, Kyoizumi S, et al. Activation of telomerase in
human lymphocytes and hematopoietic progenitor cells. J Immunol.
14. Wright WE, Piatyszek MA, Rainey WE, Byrd W, Shay JW.
Telomerase activity in human germline and embryonic tissues and
cells. Dev Genet. 1996;18:173–179.
15. Schulz VP, Zakian VA, Ogburn CE, et al. Accelerated loss of telomeric
repeats may not explain accelerated replicative decline of Werner
syndrome cells. Hum Genet. Jun 1996;97:750–754.
16. Machwe A, Xiao L, Orren DK. TRF2 recruits the Werner syndrome
(WRN) exonuclease for processing of telomeric DNA. Oncogene.
17. Wei C, Price M. Protecting the terminus: t-loops and telomere end-
binding proteins. Cell Mol Life Sci. 2003;60:2283–2294.
18. Mitchell JR, Wood E, Collins K. A telomerase component is defective
in the human disease dyskeratosis congenita. Nature. 1999;402:
19. Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts
replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A.
20. Metcalfe JA, Parkhill J, Campbell L, et al. Accelerated telomere
shortening in ataxia telangiectasia. Nat Genet. 1996;13:350–353.
21. Ranganathan V, Heine WF, Ciccone DN, et al. Rescue of a telomere
length defect of Nijmegen breakage syndrome cells requires NBS and
telomerase catalytic subunit. Curr Biol. 2001;11:962–966.
22. Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, Lindor
NM, et al. Mutations in RECQL4 cause a subset of cases of Rothmund-
Thomson syndrome. Nat Genet. 1999;22:82–84.
23. Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between
osteosarcoma and deleterious mutations in the RECQL4 gene in
Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003;95:669–674.
24. Orentreich N, Sharp N. Keratin replacement as an aging parameter.
J Soc Cosmet Chem. 1967;18:537–547.
25. Orentreich N, Markofsky J, Vogelman J. The effect of aging on the rate
of linear nail growth. J Invest Dermatol. 1979;73:126–130.
26. Lavelle C. The effect of age on the rate of nail growth. J Gerontol.
27. Makarov VL, Lejnine S, Bedoyan J, Langmore JP. Nucleosomal
organization of telomere-specific chromatin in rat. Cell. 1993;73:
28. Williams D, Short R, Bowden D. Fingernail growth rate as a biomarker
of aging in the pigtailed macaque (Macaca nemestrina). Exp Gerontol.
29. Short R, Williams DD, Bowden DM. Cross-sectional evaluation of
potential biological markers of aging in pigtailed macaques: effects of
age, sex, and diet. J Gerontol. 1987;42:644–654.
30. Coe CL, Ershler WB. Intrinsic and environmental influences on immune
senescence in the aged monkey. Physiol Behav. 2001;73:379–384.
31. Cawthon R, Smith K, O’Brien E, Sivatchenko A, Kerber R. Asso-
ciation between telomere length in blood and mortality in people aged
60 years or older. Lancet. 2003;361:393–395.
32. Novelli G. Genetics of Baldness. In: Reeve E, ed. Encyclopedia of
Genetics. London: Fitzroy Dearborn Publishers; 2001:511–515.
33. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the
bulge area of pilosebaceous unit: implications for follicular stem cells,
hair cycle, and skin carcinogenesis. Cell. 1990;61:1329–1337.
34. Van Scott EJ, Ekel TM. Geometric relationships between the matrix
of the hair bulb and its dermal papilla in normal and alopecic scalp.
J Invest Dermatol. 1958;31:281–287.
35. Tobin DJ, Gunin A, Magerl M, Handijski B, Paus R. Plasticity and
cytokinetic dynamics of the hair follicle mesenchyme: implications for
hair growth control. J Invest Dermatol. 2003;120:895–904.
36. Oberste-Lehn H. Effects of aging on the papillary hair follicles and on
the eccrine sweat glands. In: Montagna W, ed. Advances in the Biology
of Skin.Vol 6. Oxford, England: Pergamon Press; 1965:17–34.
37. Barman JM, Astore I, Pecoraro V. The normal trichogram of the adult.
J Invest Dermatol. 1965;44:233–236.
38. Birch MP, Messenger JF, Messenger AG. Hair density, hair diameter
and the prevalence of female pattern hair loss. Br J Dermatol. 2001;
39. Courtois M, Loussouarn G, Hourseau C, Grollier JF. Ageing and hair
cycles. Br J Dermatol. 1995;132:86–93.
40. Sagsoz N, Kamaci M, Orbak Z. Body hair scores and total hair
diameters in healthy women in the Kirikkale Region of Turkey. Yonsei
Med J. 2004;45:483–491.
41. Pesce K, Rothe MJ. The premature aging syndromes. Clin Dermatol.
42. Vennos EM, James WD. Rothmund-Thomson syndrome. Dermatol
43. Hoki Y, Araki R, Fujimori A, et al. Growth retardation and skin
abnormalities of the Recql4-deficient mouse. Hum Mol Genet. 2003;
44. Seeman E. Reduced bone formation and increased bone resorption:
rational targets for the treatment of osteoporosis. Osteoporos Int. 2003;
45. Yudoh K, Matsuno H, Nakazawa F, Katayama R, Kimura T. Re-
constituting telomerase activity using the telomerase catalytic subunit
prevents the telomere shorting and replicative senescence in human
osteoblasts. J Bone Miner Res. 2001;16:1453–1464.
46. Yudoh K, Nishioka K. Telomerized presenescent osteoblasts prevent
bone mass loss in vivo. Gene Ther. 2004;11:909–915.
47. Liu L, DiGirolamo CM, Navarro PA, Blasco MA, Keefe DL.
Telomerase deficiency impairs differentiation of mesenchymal stem
cells. Exp Cell Res. 2004;294:1–8.
48. Parfitt AM. Osteoclast precursors as leukocytes: importance of the area
code. Bone. 1998;23:491–494.
49. Goto M. Clinical characteristics of Werner Syndrome and other
premature aging syndromes: pattern of aging in progeroid syndromes.
In: Goto M, Miller RW, eds. From Premature Gray Hair to Helicase—
Werner Syndrome: Implications for Aging and Cancer. Tokyo: Japan
Scientific Societies Press and S. Karger AG; 2001:27–39.
50. Masuda T, Akasaka Y, Ito K, Ishikawa Y, Ishii T, Tahara H. Pathology:
Werner Syndrome and normal aging. In: Goto M, Miller RW, eds. From
Premature Gray Hair to Helicase—Werner Syndrome: Implications for
51. Goldman RD, Shumaker DK, Erdos MR, et al. Accumulation of mutant
lamin A causes progressive changes in nuclear architecture in Hutchinson-
Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2004;101:
52. Eriksson M, Brown WT, Gordon LB, et al. Recurrent de novo point
mutations in lamin A cause Hutchinson-Gilford progeria syndrome.
by guest on November 4, 2015
53. Lammerding J, Schulze PC, Takahashi T, et al. Lamin A/C deficiency
causes defective nuclear mechanics and mechanotransduction. J Clin
54. De Sandre-Giovannoli A, Bernard R, Cau P, et al. Lamin a truncation in
Hutchinson-Gilford progeria. Science. 2003;300:2055.
55. Zijlmans JM, Martens UM, Poon SS, et al. Telomeres in the mouse
have large inter-chromosomal variations in the number of T2AG3
repeats. Proc Natl Acad Sci U S A. 1997;94:7423–7428.
56. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor
formation by mouse cells lacking telomerase RNA. Cell. 1997;91:
57. Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and
cancer in aging telomerase-deficient mice. Cell. 1999;96:701–712.
58. Samper E, Flores JM, Blasco MA. Restoration of telomerase activity
rescues chromosomal instability and premature aging in Terc?/? mice
with short telomeres. EMBO Rep. 2001;2:800–807.
59. Van Neste D, Tobin DJ. Hair cycle and hair pigmentation: dynamic
interactions and changes associated with aging. Micron. 2004;35:
60. Tobin DJ, Paus R. Graying: gerontobiology of the hair follicle
pigmentary unit. Exp Gerontol. 2001;36:29–54.
61. Commo S, Gaillard O, Bernard BA. Human hair greying is linked to
a specific depletion of hair follicle melanocytes affecting both the bulb
and the outer root sheath. Br J Dermatol. 2004;150:435–443.
62. Bennett DC, Medrano EE. Molecular regulation of melanocyte
senescence. Pigment Cell Res. 2002;15:242–250.
63. Bennett DC. Human melanocyte senescence and melanoma suscepti-
bility genes. Oncogene. 2003;22:3063–3069.
64. Yaar M, Gilchrest BA. Ageing and photoageing of keratinocytes and
melanocytes. Clin Exp Dermatol. 2001;26:583–591.
65. Meyskens FL Jr, McNulty SE, Buckmeier JA, et al. Aberrant redox
regulation in human metastatic melanoma cells compared to normal
melanocytes. Free Radic Biol Med. 2001;31:799–808.
66. Nappi AJ, Vass E. Hydrogen peroxide generation associated with the
oxidations of the eumelanin precursors 5,6-dihydroxyindole and 5,6-
dihydroxyindole-2-carboxylic acid. Melanoma Res. 1996;6:341–349.
67. von Zglinicki T, Saretzki G, Docke W, Lotze C. Mild hyperoxia
shortens telomeres and inhibits proliferation of fibroblasts: a model for
senescence? Exp Cell Res. 1995;220:186–193.
68. Oikawa S, Kawanishi S. Site-specific DNA damage at GGG sequence
by oxidative stress may accelerate telomere shortening. FEBS Lett.
69. Henle ES, Han Z, Tang N, Rai P, Luo Y, Linn S. Sequence-specific
DNA cleavage by Fe2þ-mediated fenton reactions has possible
biological implications. J Biol Chem 1999;274:962–971.
70. Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase
inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit
and platelet-derived growth factor receptors. J Pharmacol Exp Ther.
71. Fleischman RA, Saltman DL, Stastny V, Zneimer S. Deletion of the c-
kit protooncogene in the human developmental defect piebald trait.
Proc Natl Acad Sci U S A. 1991;88:10885–10889.
72. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and
cytogenetic responses to imatinib mesylate in chronic myelogenous
leukemia. N Engl J Med. 2002;346:645–652.
73. Etienne G, Cony-Makhoul P, Mahon FX. Imatinib mesylate and gray
hair. N Engl J Med. 2002;347:446.
74. Brummendorf T, Ersoz I, Hartmann U, et al. Normalization of
previously shortened telomere length under treatment with imatinib
argues against a preexisting telomere length deficit in normal
hematopoietic stem cells from patients with chronic myeloid leukemia.
Ann N Y Acad Sci. 2003;996:26–38.
75. Wood LD, Halvorsen TL, Dhar S, et al. Characterization of ataxia
telangiectasia fibroblasts with extended life-span through telomerase
expression. Oncogene. 2001;20:278–288.
76. Dokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and
aplastic anaemia. Blood Rev. 2003;17:217–225.
77. Dokal I. Dyskeratosis congenita. A disease of premature ageing.
78. Martin GM. Genetic syndromes in man with potential relevance to the
pathobiology of aging. Birth Defects Orig Artic Ser. 1978;14:5–39.
79. Baran R, Dawber R, de Berker DAR, Haneke E, Tosti A, eds. Diseases
of the Nail and Their Management. 3rd Ed. London: Blackwell Science
80. Scriver C, Beaudet A, Sly W, Valle D. The Metabolic & Molecular
Bases of Inherited Disease. 8th Ed. New York: McGraw-Hill; 2001.
81. Rich P, Scher R. An Atlas of Diseases of the Nail. Illustrated Edition.
New York: CRC Press-Parthenon Publishers; 2003.
82. Yanoff M, Duker J. Ophthalmology. 1st Ed. London: Mosby Inter-
83. Nordlund J, Boissy R, Hearing V, King R, Ortone J, eds. The Pig-
mentary System: Physiology and Pathophysiology. 1st Ed. New York:
Oxford University Press; 1998.
84. Zaias N. The Nail in Health and Disease. Norwalk (CT): Appleton &
85. Goto M, Miller R, eds. From Premature Gray Hair to Helicase—
Werner Syndrome: Implications for Aging and Cancer. Tokyo: Japan
Scientific Societies Press and S. Karger AG; 2001.
Received June 21, 2004
Accepted August 26, 2004
Decision Editor: James R. Smith, PhD
HOFER ET AL.
by guest on November 4, 2015