Abstract IA001: DNA damage repair: Impact on aging and cancer and applications of nutritional interventions

Abstract

Abstract Rare DNA repair syndromes display strong cancer predisposition and/or premature aging, indicating that DNA damage underlies both, consistent with the notion that age is the most important risk factor for cancer. We have generated a series of DNA-repair-deficient mouse mutants, and discovered that defects in transcription-coupled repair cause accelerated, segmental aging and overprotect from cancer, whereas global genome repair defects are predominantly associated with cancer. When combined aging is dramatically accelerated, indicating a dose-dependent causal relationship. We also found that premature aging triggers a potent anti-aging ‘survival response’, which suppresses growth (IGF1) and enhances resilience and defenses, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting progeroid mutants to actual DR tripled lifespan, and drastically retarded accelerated aging, most notably neurodegeneration. We also found that DR lowered DNA damage, explaining how DR counteracts aging and cancer and why DNA repair mutants overrespond to DR. Interestingly, expression profiles of progeroid mutants showed gradual decline of expression in a genelength-dependent manner, due to genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. This transcription stress is also prominent in normal aging of many (post-mitotic) tissues and explains protein aggregation in dementias. DR largely alleviated transcription stress and hence 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 repair-deficient children. Our findings identify DNA damage as main cause of aging, establish repair-deficient mice as models for interventions to promote healthy aging, explain the molecular anti-aging, anti-cancer mechanism of DR and the aging component of proteinopathies based on transcription stress and promote counterintuitive DR-like interventions for progeroid syndromes, for preventing neurodegenerative diseases and ischemia reperfusion damage in surgery and for improving chemotherapy outcome and reducing side effects. Citation Format: Jan H Hoeijmakers. DNA damage repair: Impact on aging and cancer and applications of nutritional interventions [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA001.