Cellular Senescence in Traumatic Brain Injury: Evidence and Perspectives

Abstract

Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy - however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.

Keywords: brain trauma; cellular senescence; chronic traumatic encephalopathy; concussion; mild traumatic brain injury.

Figure 1

Proposed mechanism by which mTBI leads to brain dysfunction through DNA damage-induced cellular senescence. From reviewing the literature, we propose several immediate effects of mTBI including inflammation, excitotoxicity, oxidative stress, tau dysfunction, and DNA damage which encompasses all the aforementioned features. DNA damage induces cellular senescence when persistent, leading to structural and functional alterations in cells, chromatin modifications changing gene expression signatures, and inflammation by way of the senescence-associated secretory phenotype (SASP). We propose that senescence mostly affects glial cells, resulting in their dysfunction. Cellular senescence acts as a positive feedback loop, with reduced DNA repair and SASP leading to chronic levels of DNA damage and inflammation. We propose that the induction of cellular senescence in this way leads to chronic brain dysfunction and symptoms that are associated with mTBI, including neurodegenerative diseases in the long-term.