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Published on: May 28, 2011
Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric
Susan W P Wijnhoven1, Rudolf B Beems, Marianne Roodbergen
1National Institute of Public Health and the Environment, Laboratory of Toxicology, Pathology and Genetics, Bilthoven, The Netherlands.
Abstract:
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.
Insights
Trichothiodystrophy (TTD) linked to XPD gene mutations causes premature aging and shorter lifespans. Xpd(TTD) mice exhibit accelerated aging and signs of caloric restriction, suggesting a DNA damage-aging connection.
Area of Science:
- Genetics
- Molecular Biology
- Aging Research
Background:
- Trichothiodystrophy (TTD) is a genetic disorder associated with mutations in DNA repair genes, notably XPD.
- Patients with XPD mutations exhibit premature aging phenotypes and reduced lifespan, implicating DNA damage in the aging process.
Purpose of the Study:
- To investigate novel pathological features in Xpd(TTD) mutant mice that support a premature aging phenotype.
- To explore the relationship between accelerated aging, DNA damage accumulation, and potential compensatory mechanisms like caloric restriction in Xpd(TTD) mice.
Main Methods:
- Utilized Xpd(TTD) mutant mice as a model system to study TTD-related pathologies.
- Performed detailed pathological analysis to identify and characterize aging-related symptoms.
Main Results:
- Xpd(TTD) mice display a shortened lifespan and a segmental progeroid (premature aging) phenotype.
- Accelerated aging pathology in these mice is unexpectedly accompanied by indicators resembling caloric restriction (CR).
Conclusions:
- The findings reinforce the link between DNA damage accumulation, impaired DNA repair (specifically nucleotide excision repair - NER), and the aging process.
- The observed CR-like symptoms in Xpd(TTD) mice may represent a metabolic adaptation to mitigate oxidative stress (ROS production) and prolong survival.
