Aging appears remarkably plastic: e.g. suppressing insulin/IGF signalling extends lifespan in numerous

species. However, progeroid syndromes link with genome instability. We have generated DNA-repair-

deficient mouse mutants displaying wide-spread accelerated aging. For instance, Ercc1 ∆/- mice, carrying multiple repair defects show extensive multi-morbidity, limiting lifespan to 4-6 month. To counteract the premature aging these mutants also mount an anti-aging ‘survival response’, which suppresses growth and enhances maintenance, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting these mutants to actual (30%) DR tripled lifespan, and drastically retarded accelerated aging, most notably neurodegeneration. We also found that DR lowered DNA damage, explaining its anti-aging effect and why repair mutants overrespond to DR. Interestingly, Ercc1 ∆/- liver expression profiles showed progressive decline of transcription upon aging, preferentially affecting long genes, due to genome-wide accumulation of stochastic, transcription-blocking lesions. This transcription stress is also prominent in normal aging of many (post-mitotic) tissues and explains protein aggregation in proteinopthies. DR alleviates transcription stress and prolongs genome function. I will present phenotypes of conditional DNA repair models targeting aging to selected organs, striking parallels with Alzheimer’s disease and the first remarkable results translating these concepts from mice to rare progeroid children.

Our findings identify DNA damage as main cause of systemic aging, reveal untapped potential of

nutritional interventions for reducing transcription stress in neurodegeneration and other aging-associated pathologies. Additionally, the ‘survival response’ triggered by pretreatment short-term fasting strongly reduces ischemia reperfusion injury in surgery and organ transplantation and improves chemo-

radiotherapy outcome in cancer treatment.