DNA repair and aging
Evidence that DNA damage has a huge impact on the ageing process comes from different human inherited disorders, in which genes are affected that are involved in genome maintenance, like Trichothiodystrophy (TTD), Cockayne Syndrome (CS) and Werner Syndrome (WS), the first two being affected in genes that are involved in NER. Patients suffering from these diseases show many features of segmental premature ageing such as neurodegeneration, osteoporosis, sarcopenia, growth deficiency, fat redistribution, graying and loss of hair, wrinkled skin, and shortened life span.
To further test the hypothesis that DNA damage accumulation leads to ageing, Hoeijmakers et al. developed a large series of mouse models in which the genes for several DNA repair proteins were mutated. One of the mouse models generated mimics a mutation that was found in patients suffering from Trichothiodystrophy (TTD). This mouse phenotypically resembles the patient to a striking degree, including the characteristic features of brittle hair, scaly skin as well as early cessation of development and reduced life span. Mouse models were also developed on the basis of other inherited DNA repair deficiencies such as Cockayne Syndrome (CS). Subsequent systematic studies revealed a litany of other characteristics that in general are connected or directly linked to ageing, including but not limited to early development of hearing loss, eye problems, fat redistribution, osteoporosis and neurodegeneration.
DNage has exclusive access to a number of different mouse models that exhibit diverse features and different rates of ageing or lifespan (in utero, 3 weeks, 2, 5, and 18 months), which can be specifically used for applied research like intervention studies with possible anti-aging compounds as well as for the identification of new targets and biomarkers for age-related diseases like osteoporosis and neurodegeneration
Therapeutic intervention:
The ultimate proof linking accumulated DNA damage to ageing was shown through therapeutic intervention studies. As the mice carried mutations in crucial DNA repair enzymes in DNA repair pathways, Hoeijmakers hypothesised that the rapid ageing phenotype was due to DNA damage caused by endogenous sources like oxygen radicals, which are very reactive molecules that can damage DNA. In healthy cells there is a tight balance between the free radicals that invoke DNA damage and the DNA repair mechanism repairing the lesions. However, even in the presence of efficient repair, damage by oxygen radicals could still accumulate and give rise to mutations resulting in transcription and replication blocks, ultimately leading to cell cycle arrest and cell death resulting into ageing. Oxygen radicals can be neutralized by antioxidants and preliminary studies to test the free radical hypothesis have shown spectacular results. Hoeijmakers has shown that the CSB/XPA mice, which live only 15 days on average, survived up to 21 days upon treatment with two separate molecules that neutralize the damaging effect of oxygen radicals. Both molecules are naturally occurring compounds with a long history of safe use.
New Developments:
Cellular assays
DNage has set up several high-throughput cell-based screening assays as a first line assay for the identification of candidate compounds for the treatment of age-related disease.
Biomarkers
An integrated approach to identify new targets and biomarkers has been initiated with a focus on specific diseases; Cockayne Syndorme, Osteoporosis and Neurodegeneration. Identification of such biomarkers will proof a leap forward in the development of our lead products.
Conditional knock out models
DNage is currently developing and validating new DNA repair mutants, specifically models in which DNA repair genes (and therefore ageing) can be induced and studied in an organ-specific or tissue-specific manner. back to top