Contribution of Cellular Senescence and Brain Aging to Cognitive Dysfunction in GWI
Abstract
Gulf War Illness (GWI) affects >30% of military personnel who served in the 1991 Gulf War. Some of the most troubling health issues related to GWI include difficulties with memory and concentration. Some Veterans with GWI also display mood and sleep problems, chronic pain, and debilitating fatigue. Epidemiological and animal model studies have suggested multiple possible causes for GWI. These symptoms often correlate with changes in magnetic resonance imaging (MRI) brain scans. GW Veterans also appear to be showing signs of accelerated aging, developing chronic diseases and cognitive problems at a rate from 10 to 15 years older than themselves. However, the physiological cause of these changes has remained largely unknown to this point, making treatment development a challenge. We plan to address these issues in the current proposal. Drs. Shetty and Sullivan have both done extensive research on GWI and have shown that exposure to a mixture of toxic chemicals, including pesticides and pyridostigmine bromide (PB) anti-nerve gas pills were associated with the cognitive and other symptoms of GWI. Investigations in Dr. Shetty s laboratory using a rat model have shown that exposure to low doses of PB and personal pesticides (DEET and permethrin) with moderate stress for four weeks results in chronic brain impairments and difficulties with memory and mood. These brain changes include the chronic activation of microglia, which are resident immune cells in the brain. In healthy conditions, these immune cells in the brain serve as housekeeping cells, gobble up the dead cells and the excess proteins and waste products in the brain, and destroy and eat the invading microorganisms. In chronic brain diseases, they become hyperactive and start producing inflammasomes within their cytoplasm, which release chemical messengers. Such structures maintain chronic inflammation by releasing harmful and tissue-destroying chemical messengers called proinflammatory cytokines into the brain. Such cytokine chemical messengers cause sickness behavior and brain fog with symptoms such as impaired memory and concentration, fatigue, headaches, and aches and pains. Recent preliminary studies in Dr. Shetty s laboratory using a rat model of chronic GWI suggested that persistent neuroinflammation in chronic GWI is accompanied by increased senescent cells in the brain and the circulating blood. Cells acquire senescence due to stress and damage at the molecular level. These cells permanently lose their ability to divide but persist as dysfunctional cells and continuously secrete substances that can kill or at least cause sickness to cells around them. For example, the substances secreted by these cells can inhibit autophagy, a process within cells facilitating the controlled breaking down of cell parts and proteins that do not work or are no longer needed, thus helping cell survival by recycling cell parts. Thus, dysfunctional senescent cell accumulation in the brain contributes to chronic unrelenting inflammation, which can cause cognitive, memory, and sleep problems. Therefore, eliminating these dysfunctional senescent cells is increasingly considered a therapeutic strategy to improve brain function in conditions where dysfunctional senescent cells accumulate in the brain (e.g., Alzheimer s disease). In this context, drugs capable of eliminating/decreasing such dysfunctional senescent cells might improve the brain function of Veterans afflicted with chronic GWI. We will measure the extent of dysfunctional senescent cells in the circulating blood and brain of rats with chronic GWI. Then, we will assess whether measuring dysfunctional senescent cells in the circulating blood could predict premature brain aging via imaging markers in GW Veterans and GWI rats. We will do this by using stored blood and MRI brain scans of Veterans with GWI and those without from the BBRAIN repository led by Dr. Sullivan. We will t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310972
Entities
People
- Ashok Shetty
Organizations
- Texas A&M Health Science Center
- United States Army