Aging and Cellular Maintenance
One question with regards to aging and cell fate reprogramming relates to whether the age of a cell and its amenability to be reprogrammed are coupled. If uncoupled, any cell of an older animal should bear the same reprogramming potential compared to a younger animal. We therefore investigate whether known C. elegans aging mutants with altered live spans also show differences in cell fate reprogramming efficiency. Another interesting aspect is that regulation of lifespan and safeguarding/maintaining mature cells might be directly coupled in the sense of the same factor is involved in regulating both processes.
C. elegans is one of the prime model organisms to study aging due to the short life cycle which makes the assessment of life span alteration straightforward. The ease of applying genetics makes C. elegans a powerful system for testing candidate genes with respect to a role in aging but also for using forward and reverse genetics to identify new factors.
Furthermore, we found that a chromatin regulator is crucial for muscle maintenance and normal aging. Mutants show strong motility defects in addition to a shortened lifespan. Genetic analysis revealed that loss of the chromatin regulator causes myopathy by affecting a chromatin remodeling complex and premature aging by affecting a histone deacetylase). Moreover, by examining primary human myoblasts of laminopathy patients (collaboration with Simone Spuler’s group), we discovered that human homologs are diminished or mis-localized to the cytoplasm. Laminopathy patients carry a mutation in the Lamin A/C gene and often suffer from myopathy. Additionally, some patients show symptoms of premature aging that parallel the phenotypes of worms. To further characterize the impact of epigenetic regulation we established a laminopathy disease model vy expressing Lamin A/C proteins carrying mutations from individual laminopathy patients in C. elegans. We generated transgenic animals that display similar muscle phenotypes as observed in the patients. These transgenic animals allow genetic screens for the identification of regulatory pathways involved in laminopathy, which could provide valuable targets for future therapeutic approaches.