Diet restriction delays accelerated aging and genomic stress in DNA repair deficient mice

DNA repair-deficient Ercc1(Δ/−) mice show numerous accelerated aging features limiting lifespan to 4–6 month(1–4). Simultaneously they exhibit a ‘survival response’, which suppresses growth and enhances maintenance, resembling the anti-aging response induced by dietary restriction (DR)(1,5). Here we report that subjecting these progeroid, dwarf mutants to 30% DR tripled median and maximal remaining lifespan, and drastically retarded numerous aspects of accelerated aging, e.g. DR animals retained 50% more neurons and maintained full motoric function, even far beyond the lifespan of ad libitum (AL) animals. Repair-deficient, progeroid Xpg(−/−) mice, a Cockayne syndrome model(6), responded similarly, extending this observation to other repair mutants. The DR response in Ercc1(Δ/−) mice closely resembled DR in wild type animals. Interestingly, AL Ercc1(Δ/−) liver showed preferential extinction of expression of long genes, a phenomenon we also observe in several normal aging tissues. This is consistent with accumulation of stochastic, transcription-blocking lesions, affecting long genes more than short ones. DR largely prevented declining transcriptional output and reduced γH2AX DNA damage foci, indicating that DR preserves genome function by alleviating DNA damage. Our findings establish Ercc1(Δ/−) mice as powerful model for interventions sustaining health, reveal untapped potential for reducing endogenous damage, provide new venues for understanding the molecular mechanism of DR, and suggest a counterintuitive DR-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.