Cell and Developmental Biology Programme Björg Schumacher

03/12/202414:00R_473.10_AULACell and Developmental Biology ProgrammeBjörg SchumacherInstitute for Genome Stability in Aging and Disease University of Cologne"A DREAM Master Regulator of Genome Stability and Aging by the Clock yet without a Program"Host: Benito Mestres, MartaAbstract:1 Institute for Genome Stability in Aging and Disease, Medical Faculty, Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD) Research Centre and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany

Aging is an inherent property of somatic tissues, while germ cells indefinitely perpetuate the genetic information. Consequently, germline genomes could be indefinitely maintained, while somatic genomes only have limited genome maintenance capacities. Using the C. elegans model, we identified the DREAM repressor as master regulator that limits the expression of DNA repair genes in the soma. DREAM mutants showed elevated DNA repair gene expression, augmented DNA repair and resistance to distinct types of DNA damage. The DREAM regulation of DNA repair is highly conserved from nematodes to humans. Pharmacological inhibition of DREAM in vivo could reduce DNA damage accumulation and retinal degeneration in a progeroid mouse model. We propose that DREAM targeting could provide a novel therapeutic avenue for delaying age-related degeneration and lower cancer risk by conferring germline-like DNA repair capacities to the soma.

Consistent with the causal role of DNA damage in aging, we found that accumulation of stochastic variation is sufficient for predicting chronological and biological age. We determined that an age predictor that is solely built on noise accumulation could predict age across mammalian, and species acceleration and deceleration in human smoker and calorie restricted mice, respectively, as well as age reversal upon cellular reprogramming. Our data indicate that the accuracy of aging clocks is compatible with the evolutionary theory of aging that suggests an increasing loss of regulation resulting in accumulation of stochastic variation in biological parameters to underlie the aging process.