Abstract: By studying mouse mutants and human syndromes deficient in transcription-coupled repair (TCR) we discovered a very strong connection between time-dependent accumulation of DNA damage interfering with transcription and systemic aging, particularly in post-mitotic tissues. As a consequence, TCR-deficient mouse mutants and corresponding human patients display widespread accelerated aging, most prominently neurodegeneration, caused by DNA-damage-driven, age-related transcriptional stress leading to a strong decline and skewing of gene expression. This dysbalanced transcriptional output in turn causes a disbalance in translational output, and in protein stoichiometry leading to increasing proteostatic stress, which allows aggregation-prone proteins to escape from proteolysis. This explains aging as the most important risk factor for all proteinopathies including Alzheimer, Parkinson and Huntington Disease. We also found that reduced calorie intake reduces DNA damage accumulation and thereby delays aging and dramatically improves neurofunction in both progeroid mouse mutants and human patients.