Grant: Project Grant

Our immune system changes as we age. As an example, we begin to produce more of some kinds of white blood cells (monocytes and neutrophils) and less of others (B and T cells). Since monocytes and neutrophils are required to protect us from infection, you might think that this would protect older adults from infections, but what actually happens is that these cells don't mature properly and enter into the bloodstream prematurely. These immature monocytes don't help fight infection but actually make some infections worse. Furthermore, these immature monocytes produce a lot of inflammation which also has a negative impact on our health as we age. The purpose of this proposal is to determine why we start to produce more monocytes as we get older, to determine why these monocytes do not mature properly and to identify ways in which we might be able to restore this process. To do this we will collect blood from young and older adults and assess how maturity decreases with age and determine whether this immaturity correlates with levels of inflammation. Specifically we believe that a molecule called TNF might be involved because when we aged mice that did not have TNF, they did not have any changes in the development or function of their monocytes with age. To determine if this is the case in humans, we have collected samples from humans who are undergoing anti-TNF therapy. We predict that when their TNF is high, their monocytes will be less mature and when their TNF goes down due to their therapy, their monocytes will become normal. We will use our unique colony of old mice (18-22 mo), including old mice that don't make TNF (called TNF knockout mice) to determine which cells make this TNF. The long-term goal of this project is to find novel ways to keep us healthier as we get older. Because monocytes protect us from infections but can also contribute to diseases that increase with age (e.g. cardiovascular disease), we hope these findings will have broad applications.