A Translational and Mechanistic Perspective on Targeting Central Nervous System Correlates of "Accelerated Aging" in Gulf War Illness
Abstract
Approximately one-third of the deployed First Gulf War Veterans continue to suffer from a chronic, multisystem disorder called Gulf War Illness (GWI) that has dramatically affected their well-being and productivity among other devastating impacts on overall quality of life. The First Gulf War ended over 25 years ago, but we still do not have a clear understanding of the pathobiology of GWI and effective therapies for the management of GWI are elusive. It is now agreed upon that toxic chemical exposures during the War deployment, particularly the chronic, low-dose organophosphate exposures, were a major cause of GWI development. However, it is only in the recent past that we have started to understand how a chemical exposure from two decades ago still maintains a chronic multisymptom illness even when the precipitating factors from the Iraqi War theatre are no longer present. This has been possible because of the application of epigenetic tools to GWI research. Epigenetics is the study of changes in gene regulation without changes to the DNA sequence. Simply put, epigenetics directs how genes are read by cells. Many external factors such as environmental exposures, diet, and aging can modify epigenetic processes that can turn genes “on,” making them active, or turn genes “off,” making them dormant. These epigenetic changes can persist even in the absence of the initial factors that triggered them, and importantly they can be reversed by drug treatments. Research has indicated that epigenetic alterations may mediate toxicity from pesticides and may be involved in the development of depression. Therefore, understanding GWI-related epigenetic changes can not only offer important insights into the pathobiology of GWI, but also lead to treatment options that effectively treat GWI symptoms. There are several epigenetic mechanisms, including DNA methylation and histone modifications that switch genes “on” or “off” to modulate behavioral outcome. Investigators are addressing epigenetics in GWI and changes in DNA methylation and histone modification have been reported in GWI Veterans and GWI rodent models. While these studies indicate that epigenetic change has occurred in GWI, they have limited explanatory power. Some studied aggregate effects at many genes but are unable to say much about the role of specific genes. Others focused on blood, but we need to look at the brain to understand how epigenetics affects mood and behavior. Therefore, to proceed to a detailed, mechanistic understanding of GWI epigenetic effects, we need to progress to a fine-grained understanding of the changes occurring at specific genes in the brain, which is what we propose here. Recent clinical papers from GWI researchers reported that GWI Veterans exhibited chronic metabolic conditions normally seen in people a decade older than them. The central nervous system (CNS) is particularly vulnerable to the aging process, and one of the most dramatic effects observed is deteriorating memory function. We have extensively studied changes in neuronal Ca2+ handling mechanisms in the context of both aging and GWI. Epigenetic factors are also increasingly being recognized as centrally important to the aging process. We therefore hypothesized whether such "accelerated aging" patterns could also have CNS correlates that could underlie GWI mood disorders and behavioral, cognitive impairments. This is an important knowledge gap in GWI research, and this study would investigate whether neuro-epigenetic changes represent a causal link between organophosphate exposure, accelerated aging, and the persistence of GWI neurological morbidities. Using a combination of behavioral, imaging, and epigenetic tools, we began to systematically explore this question and observed that GWI rats resembled naïve, non-GWI rats that were twice their age in terms of their hippocampal Ca2+ levels, lipofuscin accumulations, DNA methylation status, and cognitive performanc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010278
Entities
People
- Laxmikant S. Deshpande
Organizations
- United States Army
- Virginia Commonwealth University