On Tuesday 15 October prof. Jan Hoeijmakers gave a comprehensive lecture about getting ageing in mice largely under control for a public of over 50 participants. Prof. Hoeijmakers explained how DNA, the carrier of genetic information, is constantly damaged by numerous toxic exogenous agents. To counteract the negative effects of DNA damage a complex genome maintenance apparatus has evolved which consists of an intricate network of DNA repair systems and cell cycle checkpoints.
Prof. Jan Hoeijmakers is an expert in the field of DNA repair and ageing. He studied biology and joined the genetics department of Erasmus Medical Centre (Rotterdam, the Netherlands) after taking his doctoral degree in 1981. Since 1993 he is professor in Molecular Genetics at Erasmus University Rotterdam. Under his leadership, a brand new molecular biological research started in the field of ageing and cancer.
Prof. Hoeijmakers detailed how inherited defects in nucleotide excision repair (NER) are associated with striking clinical heterogeneity, ranging from cancer predisposition to accelerated ageing phenotypes characterized by neuro-developmental deficits. Even different mutations in single NER genes can be linked with such strikingly different phenotypes. Prof. Hoeijmakers’s lab made major contributions to advance our understanding of the molecular basis underlying these conditions, by creating mice that express the human mutations that that mimic the human segmental premature aging disorders and/or cancer-prone phenotypes.
By modulating DNA repair his lab recently succeeded in largely controlling the process of aging in mammals. Introduction of different mutations that confer repair deficiency may accelerate the rate of aging to different extends: lifespan and onset of many aging-related diseases ranging from years to weeks depending on the extent to which repair is compromised. The type of repair defect determines the spectrum of accelerated aging features with or without cancer. Several mouse mutants exhibit the most wide-spread premature aging phenotypes documented to date, including progressive neuro-degeneration (dementia, ataxia, hearing and vision loss), osteoporosis, osteosclerosis, cardiovascular, haematological and immunological aging, thymic involution, cachexia, sarcopenia, early infertility, liver, kidney aging etc. This is accompanied by progressive behavioural/physiological alterations, including spatio-temporal learning and memory deficits, loss of motor coordination, neuronal plasticity, hormonal changes, loss of stem cells, increased cellular senescence and gene expression patterns alike natural aging. Importantly, some mutants appear superior models for Alzheimer’s disease, addressing a tremendous unmet medical need. These observations indicate that DNA damage and genome instability can drive a remarkably wide spectrum of age-related diseases and strengthen the link between genome stability and aging. Conditional repair mutants allowed targeting accelerated aging to any organ, tissue or stage of development. His groups recently showed that nutritional interventions were able of extending the lifespan and delaying aging of repair mutants up to threefold, which for mammals is unprecedented.
The lively discussion that followed the lecture was largely devoted to interpretation of the life extending effect of caloric restriction in the prematurely ageing mouse mutants. These finding were unexpected as the DNA repair mutants are generally having a very high metabolic rate and very few fat reserves. This result may indicate that (over)feeding is causing damage. Future research will be dedicated at unravelling harmful food components and damages that are the principal drivers of the ageing process.