Impact of low-dose radiation in inducing mitochondria dependent inflammaging - A new model for cellular senescence

Abstract

Recent advances in the field of aging have identified cellular senescence as one of the major hallmarks of aging and the accumulation of senescent cells in a biological system is associated with inflammation and many age associated disorders. Extensive research is focused towards studying and characterising senescent cells and discovering novel techniques to eliminate them. However, a critical aspect of studying senescent cells is having the most physiologically relevant model system to work with. In this context, a novel low dose, fractionated but chronic exposure radiation model was characterised to mimic the physiological conditions of damage accumulation. The signaling pathway associated with initiating senescence in this model was elucidated in the initial phase of the study, followed by identification of key players contributing to increased inflammation in response to damage accumulation. In the low-dose chronic radiation exposure model, early changes in mitochondrial dynamics were examined and an increase in mitochondrial ROS without any nuclear DNA damage was recorded. These early changes were associated with an increase in the number of dysfunctional mitochondria, along with a change in membrane polarization and an increase in mitochondrial DNA damage, leading to greater nuclear DNA damage and increased inflammation over more extended periods. Dissecting this mitochondrial signaling to the nucleus is essential to understand the onset of the senescence program. I will discuss several findings from my study wherein a distinct role for mitochondrial ROS is revealed in various facets of cellular senescence and aging. In the second part of the study, heightened response in inflammatory status was recorded as the downstream effect of damage accumulation in the low-dose, chronic radiation exposure model of senescence. An association was drawn between the increase in the pro-inflammatory cytokines secreted from cells and the increased expression levels of innate immune DNA sensing system present in the cytoplasm. Inhibitor studies validated the role of the DNA sensing system pointing towards the possibility of mitochondrial DNA leakage into the cytoplasm from dysfunctional mitochondria in the low-dose, chronic radiation exposure model. I will discuss several findings from my study wherein different DNA sensing systems will be discussed and their role in the recognising damage will be studied in the low-dose, chronic radiation exposure model of senescence.