Preventing or delaying late life cognitive impairment and dementia through lifestyle interventions is one of the greatest global challenges of the 21st century. The long preclinical phase of dementia offers an ideal time window for prevention measures, but the best timing and target group is not known. In this regard, it will become essential to understand why some elderly at-risk individuals are resistant to developing significant brain pathology and why in those with manifested brain pathology, some individuals are resilient against cognitive decline. In DIVERT-AD, I aim to unravel how modifiable lifestyle factors contribute to resistance and resilience to dementia by exploiting longitudinal population brain imaging. The key objectives are to determine whether a favourable lifestyle profile in mid- and late-life can attenuate (1) higher early-life risk of developing neuropathology, and/or (2) the adverse effect of neuropathology on cognition and then (3) to apply this knowledge to one of the first population-based positron emission tomography investigations of amyloid pathology, the key hallmark of Alzheimer’s disease. To achieve these goals, I will combine genetics, lifestyle, neuropsychology and brain imaging data from three large population-based cohorts, the Rotterdam Study, Framingham Heart Study and UK Biobank, including a total of ~47,000 participants. Neuropathology will be first determined by magnetic resonance imaging techniques measuring neurodegenerative and vascular pathologies and will be later refined by molecular imaging of amyloid plaques (~700 participants). Advanced epidemiological methods will be used to account for time-varying effects of lifestyle measures and confounders. Results from DIVERT-AD will provide unique insights into the impact of lifestyle factors on the brain and cognition in the preclinical phase of dementia. In turn, these insights are of major importance for developing targeted prevention strategies.

We pioneered an initially highly controversial connection between DNA damage and (accelerated) aging. In the previous ERC grant ‘DamAge’ we reached the stage that (segmental) aging in DNA repair-deficient mice can be largely controlled. The severity of the repair defect determines the rate of segmental aging; the repair pathways affected influence which organs age fast; conditional repair mutants allow targeting accelerated aging to any organ. Importantly, we found that dietary restriction (DR), the only universal intervention known to delay aging, extends remaining life- and healthspan in progeroid Ercc1Δ/- mutants by 200% (see Vermeij et al., Nature 2016 and fig.2). Also Xpg-/- progeroid repair mice strongly benefit from DR, generalizing this finding. The prominent Alzheimer- and Parkinson-like neurodegeneration is even retarded up to 30-fold(!) disclosing powerful untapped reserves unleashed by 30% less food, with enormous clinical potential. Also we discovered that in accelerated and normal aging gene expression declines due to accumulating stochastic transcription-blocking lesions and that DR counteracts genomic dysfunction. In Dam2Age we will focus on the cross-talk between DNA damage, aging and DR with emphasis on the relevance for normal aging, elucidate underlying mechanisms and use our unique -for DR research superior- mouse models and a variety of novel assays to search for effective nutritional-pharmacological DR mimetics. This serves as a stepping stone towards potent universal therapy for a range of repair-deficient progeroid syndromes and prevention of many aging-related diseases, most urgently dementia’s, to promote sustained health.

Asbestos is one of the major occupational carcinogens. The European Union has an extensive history of protecting workers and consumers against asbestos and even adopted a resolution 2012/2065(INI) ‘on asbestos related occupational health threats and prospects for abolishing all existing asbestos’ last year. Although asbestos is banned, it is still massively present in the built environment. Millions of workers & consumers in the EU were, and still are, for many years exposed to asbestos fibres, despite all measures. Inhalation of even very low quantities of asbestos fibres tremendously increases the risk of developing Malignant Mesothelioma (MM). The IARC reported 8.100 MM deaths in 2010 in the EU. Despite all EU actions, MM incidence is still increasing. MM is a highly fatal disease with a poor median survival time from first signs of illness to death around 12 months despite aggressive treatments. To date there is no curative therapy for MM. MM is considered as an extremely therapy-resistant disease. Chemotherapy consisting of a combination of pemetrexed and cisplatin is considered standard of care with a median survival increase of 3 months (9-12 months). The department of pulmonary diseases of the Erasmus MC, Rotterdam, The Netherlands, in collaboration with international partners, have developed a promising personalised immunotherapy for MM with very limited adverse effects. The first clinical results show a considerably prolonged average survival with limited adverse events (24 months, twice as long). The EMA and the FDA granted this therapy Orphan Designation: autologous dendritic cells pulsed with allogeneic tumour cell lysate for the treatment of malignant mesothelioma (EU: 16 January 2014 - EU/3/13/1229; FDA – US: 06 May 2014). The objective for the project is to deliver the scientific & registration package for market approval by the EMA of a novel immuno therapeutic approach to treat MM. This includes the execution of a phase II/III clinical trial.