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AGING
The complex process of aging involves age-related decline of physiological
functions necessary for fertility and survival of an organism. The molecular basis of
aging remains largely obscure but a role for oxidative stress (the oxidative damage
theory of aging) is anticipated. Furthennore, an essential role of maintenance of
genomic integrity in aging is demonstrated by several human segmental progeroid
syndromes and mouse models exhibiting aspects of aging. These include WeIner
and Bloom syndromes, ataxia telangiectasia and knockout mouse models for the
l7ITR and ERCCl genes, all of which have a defect in genes involved in DNA
metabolism.
TID mice display several premature aging features and may provide a valuable
model to find a molecular clue to certain aspects of aging (Chapter 6). Reduced life
span in TID mice is associated with physical decline later in life due to starvation.
Cutaneolls symptoms of aging include early depigmentation and sebaceolls gland
hyperplasia and TTD mice display spinal kyphosis, osteoporosis and atrophy of
female gonads. According to the repair/transcription syndrome hypothesis, the
repair defect of TTD mice cannot explain these aging features, because they are not
apparent in XPA mice, which display an even more severe NER defect.
Consequently, a transcriptional defect is more likely to be involved, although a
combined defect in transcription and repair cannot be excluded. In this respect, it is
of interest to note that TID is mostly associated with mild sensitivity to genotoxic
agents and a partial NER defect. To investigate the relation between repair and the
presumed transcription-associated cutaneous and progeroid symptoms, we crossed
TID mice into a completely NER-deficient XPA background. Strikingly,
completely NER-deficient XPA/TTD mice display TTD features like growth
impainnent, spinal kyphosis, hyperkeratosis and starvation much earlier in life
and/or to a much more severe extent. This suggests a relation between impairment
of repair of (endogenously generated) DNA damage and the onset of premature
aging symptoms in TTD. We postulate the following hypothesis. In every cell, low
steady state levels of endogenous lesions are induced which can be repaired by
NER, having limited consequence for the organism. However, these low levels of
lesions somehow hamper the crippled transcription apparatus of the TTD cell,
causing a reduced transcription capacity. It is not unlikely that TFIIH is actively
involved in repair of these lesions, and that depletion of transcription is somehow
related to this involvement. We postulate that a complete NER deficiency in
XP A/TTD mice results in a higher level of lesions, a more severe depletion of
transcription and as a consequence more prominent clinical symptoms. Similarly,
the non-NER features of the TCR-deficient CSB mouse model are strongly
enhanced in completely NER-deficient XPA/CSB double mutant mice (van der
Horst, unpublished data). Considering the involvement of CSB with tTanscription,
this implies that also these CS features are due to lesion-induced transcription
deficiency. In this rationale, transcription deficiency may also underlie certain
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