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osteosclerosis, carly depigmentation of hair, sebaceous gland hyperplasia, reduced
female fertility and starvation. TTD mice are a valuable experimental model to
study a possible link between compromised genome functioning (transcription)
induced by DNA damage and the process of aging.
RESULTS
Tluough regular observation of a large group of aging TTD mice and wild-type
littelTI13tes, we noticed that TTD mice develop an overall aged appearance (see
Figure 1) at a young age. This, together with the reduced lifespan and characteristic
stagnation of development tTiggered us to conduct a more systematic analysis of
specific parameters indicative of premature aging. For proper comparison all mice
were in a 50% C57BLl6 and 50% 129 background.
Cutaneous features of premature aging
As reported previously, both skin and hair keratinocytes display abnormalities at
late stages of the telTI1inal differentiation process [20]. A more prominent granular
and cornified layer in the skin is associated with reduced expression of the SPRR2
gene which is considered a marker for late stages of terminal differentiation of skin
keratinocytes [21]. Similarly, TID hairs are brittle due to a deficiency in the group
of cystein-rich matrix proteins. These proteins crosslink hair keratin filaments and
are expressed at the end of the differentiation program [22]. Another hair
abnormality we observed frequently in aging TTD mice was depigmentation, for
which the onset and manifestation was heterogeneous but which was significantly
earlier and more frequent than the sporadic cases of graying we noticed in wild-type
littem13tes. A clear example is shown in Figure 2a with a large patch of gray hairs,
which are completely devoid of melanin granules (not shown). Other TTD mice
exhibited more subtle depigmentation (e.g. brown instead of black).
Besides brittle and depigmented, TrD hairs also had a greasy appearance.
Histologic analysis showed that hyperkeratosis in the outer and inner root sheet
resulted in follicular plugging and dilatation. Moreover, hyperplasia of the
sebaceous gland was observed frequently (Figure 2b). Sebaceous gland cells are
indistinguishable between wild-type and TTD mice indicative of their benign
nature. Moreover, no malignant conversions were detected, neither in aging mice
nor in skin of mice subjected to an UV- or a chemical-induced skin cancer protocol
(de Boer et aI., submitted). Both graying and sebaceous gland hyperplasia are
features of human aging.
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