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DISCUSSION
Human aging syndromes
Aging is a very complex and multi-factorial process. Despite intense speculations
for many decades, the molecular basis for aging is um'esolved. One line of aging
research involves the human segmental progeroid syndromes for which the
causative genes have been identified. These include Werner syndrome, Bloom
syndrome, ataxia telangiectasia, xeroderma pigmentosum and Cockayne syndrome
[5,25-27] and also ERCCI- and telomerase-deficient mice display features of
accelerated aging [28-30]. Despite the fact that the clinical picture in each of these
syndromes resembles aging incompletely and some symptoms are even congenital,
they may shed light on the multifactorial molecular mechanism underlying the
complex pathology of aging. Interestingly, all mentioned progeroid syndromes are
associated with abberant DNA metabolism and a number point to the involvement
of DNA damage. Photosensitive TTD is mostly caused by mutations in the XPD
gene [12], which is involved in NER and basal transcription and therefore complies
with the rule. Interestingly, TID mice display a range of pleiotropic premature
aging symptoms including cachexia, reduced life span, kyphosis, osteoporosis,
reduced female fertility, sebaceous gland hyperplasia and early graying. Some of
these features (growth failure, reduced life span and skeletal abnOlmalities) are also
observed in Cockayne syndrome [6]. Considering this report on TID mice, the
clinical description of photosensitive TID patients [II] and the many parallels with
CS [15], trichothiodystrophy may also be considered as a segmental progeroid
syndrome.
Features of premature aging in TTD mice
TTD mice have a generally aged appearance and die prematurely. Adipose tissue
hypoplasia, mild anemia and reduction of the branched-chain amino acids in blood
of TTD mice demonstrate that the cachectic appearance and early death are caused
by starvation. Similarly, 4 out of 5 TID patients harboring the XPD R722w allele,
mimicked in the mouse germline, died before age 4 from dehydration, cachexia and
respiratory infection [31].
In TID mice we detected increased plasma levels of I-methyl histidine, an
endproduct in anserine degradation, a muscle tissue-specific protein [32 J. Its
accumulation indicates that muscle degradation occurs, probably to serve as carbon
source in gluconeogenesis. Osteoporosis in TTD mice and patients [23] could be a
secondary effect of starvation, because in human aging osteoporosis is associated
with muscle weakening and inactivity. However, no strict correlation between
severeness of cachexia and osteoporosis is found in TID mice or patients. Possibly,
aberrant vitamin or hOmlone levels or autonomous effects of the TTD mutation on
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