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DNA Damage and Repair and its Impact on Healthy Ageing

Dam2Age

Start Date
End Date
Total Funding
€ 2 251 719
Funding Programme
European Countries Involved

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.

Project partners

Erasmus Universitair Medisch Centrum Rotterdam

 
Acknowledgement
Alzheimer Europe's database on research projects was developed as part of the 2020 Work Plan which received funding under an operating grant from the European Union’s Health Programme (2014–2020).