Uncoupling pathology and aging effects of DNA damage

Genomic instability and telomere attrition are primary hallmark of aging, and an underlying cause for other hallmarks such as senescence, accelerated aging syndromes, and cancer. Interestingly, some mutations in components of these pathways, such as Telomerase (TERT), Bloom (BLM) and Werner (WRN) proteins, differentially contribute to either accelerated aging, cancer or both. Here, using a proteomic approach we leverage the African killifish, the shortest-lived vertebrate, to obtain systematic understanding of seven tissues during healthy vertebrate aging, as well as a genetic model of telomere attrition. Our findings highlight the role of age- and disease-related inflammation and muscle loss (known as sarcopenia) and pre-cancerous changes. Using our proteomic dataset, histology, and physiological readouts we are currently characterizing key difference between healthy aging and pathology. In addition, mouse models for Werner syndrome require inbreeding on a telomerase knockout background for several generations, as laboratory mice have up to 10-fold longer telomeres when compared to Humans or killifish. Thus, we are generating and characterizing a novel Werner syndrome model in the African Killifish, which will allow for rapid exploration of disease phenotypes. Furthermore, we are developing genetic approaches for rescuing disease phenotypes – particularly focusing on circulating factors, modulating the immune system, and DNA damage surveillance. Ultimately, our findings could allow us to uncouple the physiological implications of DNA damage in healthy aging from pathology.