Study: 'Run-down Feeling' With Illness May Last Longer As People Age

A new study, done with mice and published in the Federation of theAmerican Societies of Experimental Biology Journal, suggests thatmiscommunication between the immune system and brain may be to blamefor extended sickness symptoms and other cognitive disorders in elderlypeople and animals with an infection.

"In the course of our other studies on inflammation and aging,we repeatedly saw that old animals suffered an exaggerated inflammatoryresponse in the brain compared to younger adults when their peripheralimmune system was experimentally activated," said Rodney W. Johnson, aprofessor of integrative immunology and behavior in the department ofanimal sciences. "Knowing the role of brain inflammation in behavioraldeficits and neurodegenerative diseases, we felt this could beimportant, especially because immunity is often suppressed in theelderly, making them more susceptible to infections."

Johnson and his colleagues compared behavior in young adult andaged mice that were made temporarily ill by exposure tolipopolysaccharide (LPS), a molecule present on E. coli and othergram-negative bacteria that strongly activates the immune system.

"When a person or pet develops an infection, their behaviorchanges: They stop eating; they become lethargic; they have reducedcognitive abilities," Johnson said.

How do you know a mouse feels sick? Like unhealthy humans, miceshow decreased appetite, weight loss and less social interaction, saidJohnson, who likened his own lack of interest in getting up off thecouch to greet visitors when he is sick to a mouse's lack of curiosityabout new cage mates when it is sick.

LPS injections caused older mice to stop eating for a longeramount of time, lose more weight and show less social behavior thanyounger mice.

"As expected, young adults showed signs of improvement eight hoursafter LPS treatment and fully recovered by the next day, but the agedanimals still were50 to 60 percent depressed," Johnson said. "We've completed follow-upstudies that show aged animals are still depressed three to four dayslater."

Johnson and colleagues also studied how aging affects theresponse of microglial cells -- key immune cells in the brain -- duringa peripheral infection.

It is important that the peripheral immune system inform thebrain of an infection, Johnson said. "The peripheral immune systemsignals microglia to secrete inflammatory cytokines that causebehavioral changes."

In many ways microglia act as the Red Cross, he added. They canconverge upon sites of injury in the brain to scour away neuronaldebris and begin repairs, and during a peripheral infection thecytokines they produce cause behavioral changes that supportconvalescence and healing. However, if microglia overreact, the resultcan be pathological.

Johnson's study, which was published in August, revealed thatolder animals had an exaggerated inflammatory cytokine response in thebrain compared with young animals when the peripheral immune system wasstimulated with LPS.

"In the old animals, the message of a peripheral infection isconveyed to the brain, but the cells in the brain have an exaggeratedresponse and produce more inflammatory cytokines than what is typical,"Johnson said. "The exaggerated response can lead to a more intense andlonger-lasting sickness behavior syndrome."

To study the phenomenon further, Johnson and colleaguesexamined the expression of more than 39,000 genes in the brain usingmicroarray technology. The approach was helpful, because the geneexpression pattern indicated brain inflammation emerged during aging.The emergence of a mild but chronic neuroinflammatory state appears tohave a priming effect on microglial cells, Johnson said.

"Chronic neurodegenerative diseases prime microglia so thatwhen an individual develops a peripheral infection, these cellsoverreact and exacerbate neurodegenerative disease," he said."Peripheral infection is now recognized as a significant risk factorfor relapse for multiple sclerosis, for example, and peripheralinfection is a risk factor for delirium in Alzheimer's patients."

The research suggests that normal aging also may prime microglia, Johnson said.

The six co-authors with Johnson on the study were postdoctoralresearcher Jonathan P. Godbout; research associate Jing Chen; graduatestudents Jayne Abraham, Amy F. Richwine and Brian M. Berg; and Keith W.Kelley, a professor of integrative immunology and behavior in thedepartment of animal sciences.

Funding was provided by theNational Institutes of Health. Godbout, now a professor at Ohio StateUniversity, was supported by a National Research Service Award from theNational Institutes of Health to the U. of I.'s Division of NutritionalSciences.