The impact of DNA damage and repair on ageing and sustained health
J. Hoeijmakers
Molecular Genetics, Erasmus Medical Center, Rotterdam.
The molecular basis underlying ageing and ageing-related diseases is one of the main unsolved questions in biology. Ageing in various model organisms appears remarkably plastic: e.g. suppressing insulin signalling extends lifespan in worms flies and mice. On the other hand, virtually all premature aging syndromes in man provide a link with genome instability. We have generated mouse models which strikingly mimic human DNA repair deficiency syndromes and display wide-spread accelerated aging. For instance, DNA repair-deficient Ercc1∆/- mice defective in 3 or more repair pathways show numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit an anti-aging ‘survival response’, which suppresses growth and enhances maintenance, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting these progeroid, dwarf mutants to actual DR resulted in the largest lifespan increase recorded in mammals. Thirty percent 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. Repair-deficient Xpg-/- mice also showing many premature aging symptoms responded similarly to DR, extending this observation beyond Ercc1. The DR response in Ercc1∆/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1∆/- liver expression profiles showed gradual preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Phenotypes of conditional DNA repair models targeting aging to selected organs will be presented exhibiting striking parallels with Alzheimer’s disease. Our findings strengthen the link between DNA damage and aging, establish Ercc1∆/- mice as powerful model for identifying interventions to promote healthy aging, 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 DR-like interventions for preventing neurodegenerative diseases.
J. Hoeijmakers
Molecular Genetics, Erasmus Medical Center, Rotterdam.
The molecular basis underlying ageing and ageing-related diseases is one of the main unsolved questions in biology. Ageing in various model organisms appears remarkably plastic: e.g. suppressing insulin signalling extends lifespan in worms flies and mice. On the other hand, virtually all premature aging syndromes in man provide a link with genome instability. We have generated mouse models which strikingly mimic human DNA repair deficiency syndromes and display wide-spread accelerated aging. For instance, DNA repair-deficient Ercc1∆/- mice defective in 3 or more repair pathways show numerous accelerated aging features limiting lifespan to 4-6 month. Simultaneously they exhibit an anti-aging ‘survival response’, which suppresses growth and enhances maintenance, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting these progeroid, dwarf mutants to actual DR resulted in the largest lifespan increase recorded in mammals. Thirty percent 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. Repair-deficient Xpg-/- mice also showing many premature aging symptoms responded similarly to DR, extending this observation beyond Ercc1. The DR response in Ercc1∆/- mice resembled DR in wild type animals including reduced insulin signaling. Interestingly, ad libitum Ercc1∆/- liver expression profiles showed gradual preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. Phenotypes of conditional DNA repair models targeting aging to selected organs will be presented exhibiting striking parallels with Alzheimer’s disease. Our findings strengthen the link between DNA damage and aging, establish Ercc1∆/- mice as powerful model for identifying interventions to promote healthy aging, 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 DR-like interventions for preventing neurodegenerative diseases.
