ESTABLISHING AN IN VITRO AGEING MODEL IN HUMAN PLURIPOTENT STEM CELLS AND NEURAL DERIVATIVES TO MODEL NEURONAL AGING

Abstract

Since aging is the largest risk factor of neurodegenerative diseases, we theorise that the aging hallmarks contribute to neuronal degradation and death. The exact molecular causes of neurodegenerative diseases are still unknown. Current animal neuronal aging models do not explain the pathology of neurodegenerative diseases. Hence, this study introduces a novel in vitro neuronal aging model that utilises human pluripotent stem cells (hPSCs) with specific aging risk gene mutations, TERT and SIRT3, using the CRISPR/Cas9 technology to generate neurons exhibiting aging phenotypes such as DNA damage, senescence and mitochondrial dysfunction among others. Transcriptome analysis revealed common molecular mechanisms involved in neuronal aging, including some novel genes and pathways between the TERT and SIRT3 deficient neurons such as extracellular matrix and synaptic deregulation pathways that may lead to neurodegeneration. Therefore, our in vitro aging system hopes to uncover the molecular contributions of neuronal aging to neurodegeneration, complementing other models of aging.