Previously we have found that accumulation of DNA damage is a major driver of many features of aging, as revealed by a series of DNA repair-deficient mouse mutants and corresponding human premature aging syndromes. Some DNA repair systems protect preferentially the proliferative compartment of the body such as the bone marrow from accelerated aging, others primarily the postmitotic organs and tissues. For instance, mouse mutants carrying a deficiency in transcription-coupled repair (TCR), which removes DNA lesions blocking transcription to allow resumption of gene expression, display accelerated aging in the neuronal system, liver, kidney and cardiovascular system. Premature aging in TCR mouse mutants is associated in the neuronal system with progressive loss of neurons and neuronal plasticity and histological, behavioral and functional abnormalities of bona fide accelerated neurodegeneration. These mice show many features resembling Alzheimer and Parkinson diseases. As for the vascular system they show accelerated vasodilator dysfunction due to declining endothelial and vascular smooth muscle responses, reduced release of the endothelium-derived relaxing factor nitric oxide, decreased endothelial NO synthase expression and activation, increased vascular cell senescence, enhanced vascular stiffness, and elevated blood pressure, all at a very young age. Using conditional repair mutants we can target aging to any organ, tissue or stage of development. In this way we have found that e.g. Purkinje cells are indispensable for learning but not for retaining novel motor-coordinating abilities. Finally, we discovered that accumulation of DNA damage, which accelerates aging, at the same time triggers an anti-aging ‘survival ‘ response, which redirects resources from growth to maintenance and defense systems, explaining the severe, early cessation of growth of the repair-deficient patients and mice. This response resembles the longevity response induced by dietary restriction and likely represents an attempt to extend the short lifespan. Recently, we found that we can spectacularly delay aging and triple (!) remaining life- as well as healthspan of the premature aging mice by actually applying 30% dietary restriction. This lifespan extension is for mammals unprecedented. Particularly, nutritional interventions induced a spectacular delay in the onset and severity of neurodegeneration and vascular aging parameters, opening unexpected perspectives for prevention of these aging-related conditions and for understanding the underlying mechanisms.