Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice

Abstract

DNA repair-deficient Ercc1Δ/− mice show numerous accelerated aging features limiting lifespan to 4–6 month1–4. 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 model6, responded similarly, extending this observation to other repair mutants. The DR response in Ercc1Δ/− mice closely resembled DR in wild type animals. Interestingly, AL Ercc1Δ/− 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 Ercc1Δ/− 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.

Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

“…Moreover, a recent study reported that a low caloric diet tripled the median lifespan of these mice and significantly reduced the number of γH2AX foci and various other aging associated characteristics [31]. These findings suggest a possible role for cell non-autonomous mechanisms that are responsible for the age-related decline in DNA damage (possibly taking place by the age of 6 months) in addition to the cell-intrinsic decrease in the expression and function of proteins participating in the DNA repair process (such as Ercc1).…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…ATM deficiency results in progressive death of cerebellar Purkinje and granule neurons and consequent impaired control of body movements (Rothblum-Oviatt et al, 2016). Interestingly, DER significantly reduces neurodegeneration and neurological deficits, and increases the lifespan of DNA excision repair-deficient mice (an animal model of accelerated aging) by attenuating the accrual of oxidative DNA lesions (Vermeij et al, 2016). Presumably, by retarding other hallmarks of brain aging, DER can compensate for a genetic defect that causes a dramatic accelerated aging phenotype.…”

RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting

“…Xpg−/− that showed many premature aging symptoms responded similarly. His findings indicate a counterintuitive DR-like therapy for progeroid syndromes and DR-like interventions for preventing neurodegenerative diseases (Vermeij et al, 2016). …”