Connection with Cancer and Aging

Jan Hoeijmakers' team identified which repair processes primarily protect from cancer and which from accelerated aging and succeeded in getting grip on the aging process in mice by modulating DNA repair and, surprisingly, by nutritional interventions.

The acceleration of specific aging features strictly correlate with the severity of defects in specific repair pathways. The spectrum of accelerated aging symptoms (which organs age fast) is determined by the type of repair defect (which pathway is affected). E.g., transcription-coupled repair, which removes DNA lesions that physically stall transcription, primarily protects post-mitotic tissues such as the neuronal system from accelerated aging, cross-link repair the proliferative organs such as the hematopoietic system. Conditional repair mutants allowed targeting accelerated aging to any organ, tissue or stage of development, for instance, mice in which only the cerebellum or heart exhibit dramatic accelerated aging. The hypomorphic Ercc1Δ/-mutant, affected in 4 repair pathways, displays the most wide-spread premature aging phenotypes documented to date for any mammal: progressive neurodegeneration (dementia, ataxia, loss of hearing, vision, neuronal plasticity, etc.), 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, overall frailty and gene expression patterns alike natural aging. Importantly, this mutant is a superior model for Alzheimer and other neurodegenerative diseases addressing a tremendous unmet medical need, consistent with the notion that aging is the most important risk factor for proteinopathies.