Age-associated changes in a protein called KLF4 upset the normal daily fluctuations in immune system activity in mice, according to an NIA-supported study at Stanford University and the University of Pennsylvania. This loss of daily variation in the immune response may lower the body's ability to fight infections. The findings, published in Nature Immunology, help scientists better understand the declining function of the immune system in older adults.
The research team sought to find a connection between aging and the immune system by investigating the effects of the body’s biological clocks — called circadian rhythms — on the immune response. These internal clocks, which govern our daily cycles of sleep and activity, influence the activities of the immune system.
First, the team showed that circadian rhythms are involved in the immune response in young mice, but not in older mice. In response to an infection, young mice were more likely to survive when they were infected during the day than when they were infected at night, while for older mice, survival declined no matter whether they were infected during the day or night.
The researchers then looked for the immune cells that may explain this age-related difference. They found that circadian rhythms influenced the normal migration of immune cells into the bloodstream to fight infections in young mice, but not in older mice. The researchers also found that certain immune cells from younger mice are more effective at destroying bacteria during the day than they are at night, while the immune cells from older mice did not show any difference in activity according to the time of day.
To find an explanation for the age-related changes, the researchers focused on a specific protein called KLF4, which is important for many diverse functions in the body, including stimulating immune cell proliferation. Because circadian rhythms influence whether KLF4 from the immune cells is active or inactive, its activity normally fluctuates over the course of the day. However, in immune cells from older mice, KLF4 levels did not change throughout the day.
In the immune cells from young mice, KLF4 controls the normal daily fluctuations of the immune cell function. In mice engineered to lack KLF4, circadian rhythms no longer controlled the immune cell activity. This lack of variation over a 24-hour period in immune cells from young mice that lacked KLF4 resembled what researchers observed previously in immune cells from older mice.
To find out whether KLF4 also plays the same role in humans, the researchers looked at medical data collected from nearly 500,000 people in the UK Biobank. When they compared the full study population to older adults with mutations in the KLF4 gene, they confirmed the connection between KLF4 and the aging-related decline in immune function: The loss of KLF4 function increased the likelihood of those adults developing and dying from an infection.
Immune responses that are disrupted, such as by the KLF4 mechanism described in this study, contribute to not only infections but other diseases associated with aging. By identifying the many pathways that control the complex responses of the immune system, researchers can provide clues that may lead to new prevention and treatment approaches for aging-related conditions.
This research was supported in part by NIA grants RO1AG048232, RF1AG058047, P30AG066515, and DP2AG067492.
These activities relate to NIA’s AD+ADRD Research Implementation Milestone 2.F: “Create new research programs aimed at understanding the integrative physiology of circadian rhythms and sleep and its impact on brain aging.”
Reference: Blacher E, et al. Aging disrupts circadian gene regulation and function in macrophages. Nature Immunology. 2022;23(2):229–236. Epub 2021 Dec 23. doi: 10.1038/s41590-021-01083-0.