As we age, our immune systems don’t work as well as they did when we were younger. That phenomenon is called immunosenescence, and it’s not exclusive to humans. The decline of the immune system with age has been found in every organism scientists have tested. But why does it happen? And why do some individuals age more quickly than others? While factors like our diet, exercise level, and the air and water quality where we live play a role in our long-term health, so do our genetics, says UMBC’s Jeff Leips.
With funding from a new National Institutes of Health grant, Leips, professor of biological sciences, is on a mission to identify genes that play a role in the decreasing efficacy of the immune system with age. The fourth-leading cause of hospitalization among the elderly is an infection that their immune system can’t handle on its own, Leips says, and being hospitalized poses its own risks, “so it’s a big problem.”
Leips’s lab uses Drosophila, or fruit flies, to study the genetic basis of aging across a range of traits, from immune system function to walking speed, endurance, and strength. While it may seem strange to use an organism so different from us, “We know many aspects of the innate immune system in Drosophila—a lot of the signaling pathways—are conserved between flies and humans,” he explains. “So the idea would be to identify candidate genes that we could then test for their effects on human immunosenescence.”
The grant will allow Leips and his team of students to compare how quickly 200 different strains of flies, each with a unique genetic makeup, can clear an identical infection. Within each strain, the lab will test at least 20 flies of different ages. All the strains they’ll use have already had their entire genome sequenced, so “we can associate differences at the DNA level with differences in their ability to clear infection,” Leips explains.
With the extensive sequencing and ease of raising flies in the lab, “If you want to know something about basic biology, in an aging context, there’s arguably no species that’s this good.”
Focusing on the first step
Vertebrates, including humans, have a two-stage immune response: innate and adaptive. The adaptive system is the one that “remembers” being infected with a disease, which is what makes vaccines work. Leips is focusing on the innate response, which researchers know less about. The two systems interact in vertebrates, but flies only have an innate system.
“In invertebrates, we can look at effects on the innate system without the complications of the adaptive component feeding back into it,” Leips says. “It’s a simpler system, and maybe more useful.”
The innate immune system also comes in two stages. In the first stage, circulating blood cells engulf bacteria or other invaders and destroy them. If needed, the organism’s innate immune system activates stage two and deploys antimicrobial proteins to tackle the problem. Leips will focus specifically on the first stage, called phagocytosis, “because that’s the first thing that happens,” Leips says. “It’s only if that system is overwhelmed that the antimicrobial proteins respond.”
A tricky technique
Leips and Michelle Starz-Gaiano, associate professor of biological sciences, worked together to develop an imaging technique that allows them to count the number of bacteria swallowed by a fly’s blood cells. Using this method, “We can compare the ability of different genotypes to engulf bacteria across different ages,” Leips explains.
When they found that older flies had more bacteria in their cells, it came as a surprise. But even phagocytosis has multiple stages: the cells must swallow the bacteria, and then digest them. When Leips and Starz-Gaiano injected the flies with microscopic, non-digestible beads, they found that old and young flies had the same number of beads in their cells.
“We think the reason the old cells have many more bacteria in them is because the bacteria are accumulating in the cells, but not being processed,” Leips says. As part of the new grant, they’ll look at genes that might affect how the bacteria are trafficked into the cell and how it digests them.
This work is one of many projects in Leips’s lab. Another involves collaborating with Peter Abadir at Johns Hopkins University to see how flies with different genetic material respond to human medications for high blood pressure.
There’s evidence that some human patients (but, notably, not all) experience improved strength and endurance on these medications in addition to lower blood pressure. Leips and his colleague would like to know if differences in how people respond to these medications are genetically driven. If so, the findings could lead to more precise personalized medicine.
“We’d like to be able to identify genes that would predict if you’re going to respond in a positive, negative, or neutral way to a drug,” Leips says. “We’ve gotten some really cool results.” They found that flies respond to the drug even though they don’t have a circulatory system. They do have the same genes that the drug targets, he says, “which means effects of the drug on these traits might be through some other mechanism.”
With his new NIH grant, Leips says, “Ideally, I want to understand the mechanisms—what goes wrong with age and immunity? Once we know that, the next question is whether we can find ways to try to ameliorate the effects of aging on those traits.”
Leips hopes the research will provide data that will fuel future work on aging and immunity with implications for human health. “Getting sick is one of the worst things that happens to people,” he says. “So if you can minimize that when you’re old, it’s going to improve your quality of life. And that’s really what the lab is all about.”
Banner image: Jeff Leips works in the lab with students at UMBC for summer research through the UMBC STEM BUILD program. From left to right: Moriah Thompson, Anne Arundel Community College; Teiona Sanders, Morgan State University; and Bolutife Baiyewu, Morgan State University.
All photos by Marlayna Demond ’11 for UMBC.