Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway.

We recently reported that macrophages from aged mice produced less tumor necrosis factor (TNF)-alpha following lipopolysaccharide (LPS) stimulation than macrophages from young animals. This correlated with decreased levels of phosphorylated and total p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs). Here, we went on to determine if age affects other Toll-like (TLR) and non-TLR signaling pathways.

The aging innate immune system.

Advanced age is associated with a breakdown of the epithelial barriers of the skin, lung and gastrointestinal tract, which enables invasion of delicate mucosal tissues by pathogenic organisms. Thus, there is an increased challenge for the innate immune system in aged subjects, as the portal of pathogen entry becomes more readily disturbed. Because of the number of aging baby boomers and the added environmental stresses that bombard the immune system on a daily basis, gaining an understanding of the functional integrity of the innate immune system in aged subjects is of paramount importance.

Aging and innate immune cells.

The innate immune system serves an important role in preventing microbial invasion. However, it experiences significant changes with advancing age. Among the age-associated changes are: Aged macrophages and neutrophils have impaired respiratory burst and reactive nitrogen intermediates as a result of altered intracellular signaling, rendering them less able to destroy bacteria.

Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression.

Age-related changes in immunity render elderly individuals more susceptible to infections than the young. Previous work by our laboratory and others showed that macrophages from aged mice are functionally impaired. Macrophages produce proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6, when stimulated with lipopolysaccharide (LPS), which signals through Toll-like receptor-4 (TLR4) and requires activation of mitogen-activated protein kinases (MAPKs).