Wijnhoven Susan W P, Beems Rudolf B, Roodbergen Marianne, van den Berg Jolanda, Lohman Paul H M, Diderich Karin, van der Horst Gijsbertus T J, Vijg Jan, Hoeijmakers Jan H J, van Steeg Harry
National Institute of Public Health and the Environment, Laboratory of Toxicology, Pathology and Genetics, Bilthoven, The Netherlands.
DNA Repair (Amst). 2005 Nov 21;4(11):1314-24. doi: 10.1016/j.dnarep.2005.07.002. Epub 2005 Aug 22.
Trichothiodystrophy (TTD) patients with a mutation in the XPD gene of nucleotide excision repair (NER) have a short life span and show various features of premature aging, thereby linking DNA damage to the aging process. Xpd(TTD) mutant mice share many features with TTD patients, including a shorter life span, accompanied by a segmental progeroid phenotype. Here we report new pathology features supportive to the premature aging phenotype of Xpd(TTD) mice. Strikingly, accelerated aging pathology is accompanied by signs suggestive of caloric restriction (CR), a condition usually linked to retardation of age-related pathology and life extension. Accelerated aging symptoms in Xpd(TTD) mice are most likely due to accumulation of endogenously generated DNA damage and compromised transcription leading to cell death, whereas CR symptoms may reflect the need of Xpd(TTD) mice to reduce metabolism (ROS production) in an attempt to extend their life span. Our current findings in Xpd(TTD) mice further strengthen the link between DNA damage, repair and aging.
核苷酸切除修复（NER）的XPD基因突变的毛发硫营养不良（TTD）患者寿命较短，并表现出各种早衰特征，从而将DNA损伤与衰老过程联系起来。Xpd（TTD）突变小鼠与TTD患者有许多共同特征，包括较短的寿命，并伴有节段性早衰表型。在此，我们报告了支持Xpd（TTD）小鼠早衰表型的新病理特征。令人惊讶的是，加速衰老病理伴随着提示热量限制（CR）的迹象，热量限制通常与延缓年龄相关病理和延长寿命有关。Xpd（TTD）小鼠的加速衰老症状很可能是由于内源性产生的DNA损伤积累和转录受损导致细胞死亡，而CR症状可能反映了Xpd（TTD）小鼠为延长寿命而减少新陈代谢（活性氧产生）的需求。我们目前在Xpd（TTD）小鼠中的发现进一步加强了DNA损伤、修复与衰老之间的联系。
