Why do older people emerge from, say, hip surgery and an infection with impaired cognitive functions? And what if chronic and enhanced pain could be treated with a single injection of gene therapy?
On a recent morning, an auditorium full of older adults mused over those questions. Steven F. Maier and Linda R. Watkins, distinguished professors of psychology and neuroscience at the University of Colorado, offered a dizzying array of answers.
Maier and Watkins, who run a CU laboratory of behavioral neuroscience, appeared in south Denver as part of the CU Science Sampler series of âLectures from the Cutting Edge,â which is organized by the Colorado Academy of Lifelong Learning.
On five Wednesdays between late February and the end of March, adult learners gathered to hear leading experts from the stateâs premier research university talk about what they do and why it matters.
The presentations have ranged from astrophysics, geological sciences, atmospheric sciences and integrative physiology.
Maier dove into an examination of cognitive decline with aging. âThereâs been very little research directed at why we lose cognitive function as we age in a normal way,â Maier observed.
Additionally, he noted, decline in cognitive function is often preceded by surgery, heart attack or infection. âMany of us know people who came out of the hospital after hip surgery not only with a scar on their hip, but their mind is gone.â
The events that precipitate mental declines often happen in the bodyâs periphery, outside the brain, which is protected by a blood-brain barrier. âSo how do you get from hip surgery to memory loss?â
A common factor in surgery, illness and other health problems is inflammation, Maier noted. There must be a mechanism by which the inflammationâand the fact that something is not rightâgets communicated to the brain, âand we decided to figure out what that was.â
They found that when immune cells called macrophages recognize infections (and gobble up infectious cells), the macrophages release chemicals called cytokines and chemokines. Interleukin-1âor IL-1âis a kind of cytokine and is a pro-inflammatory agent.
When IL-1 is produced in the body, it sends the brain an âI am sickâ message by activating nerves that send signals to the brain, Maier said.
âThe immune system, in addition to its other well-known functions, acts as a sense organ,â Maier said. âWe would argue that your immune system is actually your sixth sense.â
When that signal reaches the brain, glial cells in the brain respond by producing IL-1, which causes neuroinflammation. That inflammation retards the formation of new long-term memories, which require the formation of new proteins and long-lasting structural changes in the brain.
Blocking IL-1 receptors in the brain leaves the animal unaware that it is sick. Injecting IL-1 into the brain, meanwhile, impairs memory, Maier noted.
Thatâs because the formation of memories depends on growth factors that are suppressed by elevated levels of IL-1, Maier noted. In older animals, IL-1 levels remain high for many days after an infection, whereas younger animalsâ IL-1 levels drop quickly.
Brains of older animals, therefore, are âprimedâ to respond adversely to multiple âhitsââsuch as hip surgery and subsequent pneumonia. âIf they have more than one âhit,â memory loss may be semi-permanent,â Maier said.
This byproduct of aging can be mitigated with exercise, Maier said, noting that itâs unclear now how much and what intensity is needed. It is also possible that post-operative cognitive decline could be counteracted with a drug that would target the expression of certain genes in the hippocampus, which is central to the formation of long-term memory.
âIf we can develop drugs that will target the relevant receptors, we believe that when you go into that hip surgery, youâll come out with a healthy hip and a healthy mind,â Maier said.
The audience peppered Maier with questions. Maier seemed impressed. âThese are all good experimental questions. You guys have proposed several lifetimes of experiments.â
Watkins, a renowned leader in pain research, described similar systems implicated in the perception and management of pain.
Leading researchersâ view of pain has been changing, she noted. Pain has long been viewed as primarily a function of neurons that tell the brain when the body is injured or suffering from inflammation.
Pain is perceived when immune cells such as macrophages and lymphocytes devour pathogens and release pro-inflammatory substances like Interleukin-1.
In response to infection, for instance, IL-1 levels rise rapidly in the spinal cord, Watkins noted. âIf you can block these pro-inflammatory cytokines, you block the pain.â
The newer view of pain that has evolved during the past 18 years, Watkins noted, involves glial cells in the brain, which are activated in a range of causes enhanced painâperipheral nerve injury, chemotherapy, bone cancer, multiple sclerosis, spinal-cord injury and herniated discs.
When the brainâs glial cells are activated by pain messages, they get âall hot and bothered,â and respond more actively to subsequent pain messages. When this happens, the animal has a heightened sensitivity to pain.
But if the activation of the glial cells is blocked, pain is blocked, Watkins said. Based on this research, drug trials are now in the works to test pain-blocking mechanisms.
One of those trials involves Interleukin-10 DNA therapy, a strategy born at CU.
IL-10 evolved to target glial cells to calm them down, Watkins said, adding: âWhat weâve developed is gene therapy. Your cells pick it up. Your cells make their own IL-10, and your body takes care of the chronic painâyour body solves chronic pain by making IL-10.â
After only one injection of IL-10 DNA therapy, rats that had nerve-injury-induced chronic pain experienced complete resolution of pain for at least three months, she noted.
After chemotherapy, people have neuropathic pain. Rats treated with Taxol (a chemotherapy drug) experience simple touch as pain. âIf you give them the IL-10 gene therapy, pain goes away,â Watkins said.
This may help cancer patients stay on their chemotherapy to treat their cancer, so that treatment doesnât stop because of neuropathic pain.
In the case of multiple sclerosis, rats with an âanimal modelâ of the degenerative disease make a full recovery after an injection of IL-10, she said. âIt cures the paralysis, and it cures the pain.â
âYou can think of it as Valium for glia.â
Jim Kneser, one of the founders of the Colorado Academy of Lifelong Learning, said the academy aims to offer intellectual stimulation for people who are for the most part retired.
âWeâre trying to provide the highest-quality intellectual experience at the lowest prices,â Kneser said.
âSomething like the CU Science Sampler is just a real five-star opportunity for us,â he said.
The CU Science Sampler is the fruit of collaboration between the university, the CU Foundation and the academy. It benefits all involved, Kneser said.
When Watkins and Maier spoke, the audience included a number of physicians who were very interested in the effects of aging, Kneser said. âI donât think weâve ever had a program that was as well received.â
âThe value of pure research as practiced at the university is recognized by the academy participants,â Kneser stated. âI understand that contributions to the university from academy members impressed with the presentations have already been received.â
The next session of the CU Science Sampler is scheduled to include five presentations in four sessions between April 8 and April 29. For more information, seeÌęÌęor emailInfo@AcademyLL.org. To learn more about CU or to support its cutting-edge work, contact Mary McGee, CU Foundation assistant principal gifts officer for the College of Arts and Sciences and Graduate School, at 303-541-1470 orÌęMary.McGee@cufund.org.
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