New approaches to addressing ageing-related diseases
DNA – the double-helical molecule that carries our genetic information – is constantly being damaged. This happens for example when we are exposed to UV light or certain chemicals, and it occurs spontaneously. It is an unavoidable reality of daily life. An inability to repair this DNA however can lead to increased disease risk, and significantly influence the ageing process. “DNA contains the instructions for all living organisms,” explains Dam2Age project coordinator Jan Hoeijmakers from the Erasmus University Medical Centre in the Netherlands. “If the instructions for life get damaged, then things may go wrong.”
DNA repair defects and ageing
Hoeijmakers has dedicated his professional life to studying the link between DNA repair and ageing, and in particular the occurrence of DNA repair defects in children. The Dam2Age project, supported by the European Research Council (ERC), is very much the continuation of research work that he began in the early 1980s. “At that time, very little was known about DNA repair defects,” he says. “We knew that in very rare cases, children are born with an inability to repair the damage caused to DNA by UV in sunlight.” A key discovery made by Hoeijmakers and his colleagues was that DNA repair defects not only dramatically increase cancer susceptibility, they also result in premature ageing. In other words, the skin of children affected by this condition was being aged through UV exposure. Hoeijmakers studied other rare diseases linked to defects in the body’s DNA repair system, such as trichothiodystrophy (TTD), and developed the first TTD mouse model. This enabled him to study the same DNA repair defects in mice as found in children, and again his studies showed that an inability to repair DNA damage is central to accelerated ageing.
Link between DNA damage and abnormal ageing
This work helped Hoeijmakers to secure a series of ERC grants. These projects – with Dam2Age the culmination – have enabled Hoeijmakers and his team to better understand the mechanisms behind this link. “We found that mice with impaired DNA repair mechanisms were using their energy to build up resistance,” adds Hoeijmakers. “They suppressed growth in order to boost their resilience to try to delay their rapid ageing.” This also explains why children with defective DNA repair systems tend not to grow. Hoeijmakers next took an orthodox approach to treating the condition – he put the mice on a diet. “We know that calorie restriction can delay ageing,” he notes. “We wanted to see if mice with DNA repair defects placed on diets might live longer than those with unlimited food.”
Towards therapies for ageing-related diseases
For Hoeijmakers, the results have been impressive. Mice with unlimited food died between 12 and 26 weeks, usually from neurodegeneration. Mice given 30 % less food however tended to live up to three times as long. “There is no doubt that this approach strongly delayed ageing,” says Hoeijmakers. “Especially significant was the delay in neurological ageing.” Reduced calorie intake was also applied to several children with DNA repair defects. Over the space of a few months, a number of functional improvements, including speech and mobility occurred – simply as a result of less food. Hoeijmakers found that calorie restriction leads to less DNA damage. These results could herald a new chapter in tackling rare diseases linked to DNA damage. They may also help advance the search for effective new therapies that address age-related diseases, such as Alzheimer’s.
Keywords
Dam2Age, DNA, cancer, ageing, Alzheimer’s, disease, TTD, UV