Final Report Summary - DAMAGE (DNA damage and the connection with cancer, premature aging and longevity)
Previously, we pioneered an initially highly controversial, but now rock-solid connection between DNA damage and (accelerated) aging. ERC grant ‘DamAge’ allowed not only to further consolidate the relationship between DNA damage, repair and aging but even succeeded in getting grip on aging in mice by modulating DNA repair and surprisingly by nutritional interventions. The rate of specific accelerated aging features was found to strictly correlate with the severity of defects in specific repair pathways. The spectrum of accelerated aging symptoms (which organs age fast) appeared to be determined by the type of repair defect (which pathway is affected). E.g. transcription-coupled repair primarily protects post-mitotic tissues such as the neuronal system from accelerated aging, cross-link repair the proliferative organs e.g. bone marrow. Conditional repair mice allow targeting accelerated aging to any organ, tissue or stage of development. The Ercc1∆/- mutant, affected in at least 3 repair pathways, exhibits the most wide-spread premature aging phenotypes documented for any mammal: progressive neurodegeneration (dementia, ataxia, loss of hearing, vision and neuronal plasticity), osteoporosis, cardiovascular, hematological and immunological aging, thymic involution, cachexia, sarcopenia, early infertility, liver, kidney aging etc., accompanied by progressive behavioral-physiological-hormonal alterations, loss of stem cells, increased cellular senescence and gene expression patterns alike natural aging. Importantly, this mutant is found to be a far superior model for Alzheimer’s disease than current models, addressing a tremendous unmet medical need.
Rapid accumulation of unrepaired DNA damage in these mice causes premature cell death and senescence, but triggers also an anti-aging ‘survival response’ likely in an attempt to extend lifespan. This response suppresses growth, enhances maintenance and resembles the longevity response induced by dietary restriction (DR). Remarkably, subjecting the 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 wt animals including reduced insulin signaling. Interestingly, ad libitum Ercc1∆/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect expression of long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. These 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.
Rapid accumulation of unrepaired DNA damage in these mice causes premature cell death and senescence, but triggers also an anti-aging ‘survival response’ likely in an attempt to extend lifespan. This response suppresses growth, enhances maintenance and resembles the longevity response induced by dietary restriction (DR). Remarkably, subjecting the 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 wt animals including reduced insulin signaling. Interestingly, ad libitum Ercc1∆/- liver expression profiles showed preferential extinction of expression of long genes, consistent with genome-wide accumulation of stochastic, transcription-blocking lesions, which affect expression of long genes more than short ones. DR largely prevented this decline of transcriptional output, indicating that DR prolongs genome function. These 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.