While not yet rising to the level of definitive proof and quantification of risk, a fair-sized body of evidence suggests that persistent viral infection by herpesviruses and the like can drive the onset and progression of age-related disease. This work is largely focused on the brain and neurodegenerative conditions, but if the primary mediating mechanism is increased chronic inflammation, one could imagine that viral infection is important in the progression of aging more generally. With advancing age, the immune system reacts in increasingly maladaptive ways to rising levels of biochemical damage and altered cell behaviors. Constant, unresolved inflammatory signaling - and the reactions of cells to that signaling - is damaging to tissue structure and function.
Today's open access paper discusses the present consensus view of the role of viral infection on brain aging. As the authors point out, inflammation may be important, but a range of other mechanisms are likely involved. As is usually the case for any aspect of aging, it is one thing to list involved mechanisms, but quite another to know their relative importance. The research community is fairly good at identifying mechanisms. Understanding which of those underlying mechanisms are more versus less important to any specific outcome is vital to the effective development of therapies, but unfortunately it is very challenging in practice to discover this information by any means other than trial and error. Thus trial and error remains the order of the day in the development of therapies.
Neurotropic Viruses as Acute and Insidious Drivers of Aging
In the central nervous system, neurotropic viruses are a major stressor and, therefore, a major driver of aging. Epidemiological studies of multiple large biobanks have shown that patients with a history of neurological viral infection are thirty times more likely to develop a neurodegenerative disease. In addition to the pressures of viral proteins during active infection, acute and chronic viral infections disrupt the homeostasis of the cell. This occurs throughout life, with acute causes of neurodegeneration (e.g., hemorrhagic or ischemic stroke, traumatic brain injury) and chronic conditions (e.g., viral latency, metabolic disease) compounding, often synergistically.
Here, we define aging, outline the impact viruses have on the brain, and identify the overlapping pathways of viral pathogenesis and age-related neurodegeneration. Previously proposed "Hallmarks of Aging" range in number but can be generally described by three categories: altered proteostasis, genomic compromise, and senescence. Neurotropic viruses manipulate each of these categories, driving rapid neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD), and more progressive neurodegenerative conditions like Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD).
Through our contextualization of myriad basic science papers, we offer explanations for premature aging via viral induction of common stress response pathways. Viruses induce many stresses: dysregulated homeostasis by exogenous viral proteins and overwhelmed protein quality control mechanisms, DNA damage through direct integration and epigenetic manipulation, immune-mediated oxidative stress and immune exhaustion, and general energy theft that is amplified in an aging system. Overall, this highlights the long-term importance of vaccines and antivirals in addition to their acute benefits.
View the full article at FightAging
