Today I’ll point you to an interesting paper in which the authors investigate one of the contributing factors that cause ever greater levels of chronic inflammation to accompany aging, in this case the factor being detrimental changes in the behavior of monocyte immune cells in older individuals. The researchers demonstrate that monocytes are influenced by rising levels of the inflammatory cytokine TNF, and either removing TNF or the problem monocytes improves the impaired immune response in aged mice.
The immune system is enormously complex, one of the many aspects of our biology in which the high level sketch – information that fills books in and of itself – must still be painted in at the detail level. One measure of what is left to learn is the present lack of understand of the root causes of many autoimmune diseases, intricate failure modes in the regulation of immune activities in which immune cells attack healthy tissue. If the research community understood the immune system completely, the scientists involved would also understand autoimmunity well enough to prevent it and reverse it. As it is, there are only hints and connections made in a growing, ceaseless river of data, while cures are yet to be found. The situation for the aging of the immune system is much the same. A variety of theories backed by differing levels of evidence explain why the immune system in aged individuals becomes both progressively less effective and progressively more active at the same time, chasing its tail to no good end. Greater activity means more inflammation, and sustained inflammation is a source of tissue damage and cellular dysfunction, a potent contribution to the pathology of many age-related diseases. Researchers have given the name “inflammaging” to this unfortunate end stage of the immune system and its detrimental effects on health.
Today we are at a point at which the research community can present a convincing story of immune aging based upon processes such as the atrophied thymus reducing the supply of new immune cells, the limited number of immune cells increasingly consisting of those uselessly devoted to a few persistent pathogens rather than capable of dealing with new threats, and so on and so forth. The relevance and importance of these processes can still be argued, however. Given the pace of progress in biotechnology, I believe that the proof of theories on immune aging will be provided by therapies capable of addressing the causes of immune decline, and this will happen long before proof can be provided via a full mapping of the biochemistry and processes of the immune system. Therapies that work will point the way, and the cost of testing any given hypothesis in mice continues to fall year after year.
Researchers are interested in how the immune system ages. In this study, they focus on monocytes, immune cells that are central to the process of inflammation. Monocytes multiply and mature in the bone marrow and circulate in the blood stream. They are recruited to sites of injury or infection and there turn into macrophages that ingest pathogens, infected cells, or cellular debris. Monocytes are also potent producers of pro-inflammatory cytokines, small molecules that promote an inflammatory immune response.
Comparing younger and older mice, the researchers found that the latter have higher numbers of monocytes both in the bone marrow and in the blood. They also saw higher levels of TNF and IL-6, two pro-inflammatory cytokines, in blood from older mice and blood from older human donors. Studying mouse monocytes in more detail, the researchers found that the increase in TNF levels that occurs with age causes premature release of immature monocytes from the bone marrow into the blood stream. When stimulated with bacterial products, these immature monocytes themselves produce more inflammatory cytokines, thus further increasing levels in the blood.
The researchers then infected younger and older mice with the bacteria Streptococcus pneumoniae, which causes so-called pneumococcal pneumonia. They found that, although the older mice had higher numbers of monocytes in the blood and at the sites of infection, their monocytes were not able to clear the bacteria and successfully fight the infection. However, when the researchers used drugs or mouse mutations that reduced the number of monocytes or removed TNF, they were able to restore antibacterial immunity in aged mice. The researchers conclude that “monocytes both contribute to age-associated inflammation and are impaired by chronic exposure to the inflammatory cytokine TNF, which ultimately impairs their anti-pneumococcal function.” They go on to suggest that “lowering levels of TNF may be an effective strategy in improving host defense against S. pneumoniae in older adults.”
As we age, levels of inflammatory cytokines in the blood and tissues increase. Although this appears to be an inevitable part of aging, it ultimately contributes to declining health. Epidemiological studies indicate that older adults with higher than age-average levels of inflammatory cytokines are at increased risk of acquiring, becoming hospitalized with and dying of pneumonia but how age-associated inflammation increased susceptibility to was not entirely clear. We demonstrate that the increase in the inflammatory cytokine TNF that occurs with age cause monocytes to leave the bone marrow prematurely and these immature monocytes produce more inflammatory cytokines when stimulated with bacterial products, thus further increasing levels of inflammatory cytokines in the blood. Furthermore, although old mice have higher levels of these inflammatory monocytes arriving at the site of S. pneumoniae, they are not able to clear the bacteria. By pharmacologically or genetically removing the inflammatory cytokine TNF or reducing the number of inflammatory monocytes we were able to restore antibacterial immunity in aged mice.
What drives the rise in TNF Alpha as the mouse ages? Obivously the 7 categories of SENS defined damage, but has anyone mapped a molecular pathway from them to rising systemic TNF?
Michael Rae’s reply to my comment:
@Jim: most directly, we know that TNF-α is released by senescent cells as part of the SASP.
Oxidative stress also activates nuclear factor κB, which in turn promotes the expression of TNF-α and several other inflammatory cytokines, so age-related mitochondrial mutations are an obvious candidate.
Immune cells in the atherosclerotic artery may also produce TNF-α, which may even be locally beneficial in the earliest stages of lesion development even if it has deleterious long-term local and systemic effects. As usual, looking for a solution involving up- or downregulating such production is therefore fraught.
And the rising inflammatory tone with aging can certainly be linked with lifelong dysregulation of the immune system, although probably not directlty linked with the accumulation of anergic T-cells (which, indeed, fail to produce TNF-α upon antigenic stimulus, which is part of why they’re called “anergic” in the first place).
These are all really secondary questions, however. The best way to identify the sources and relative priority of cellular and molecular damage of aging driving increased levels of TNF-α or any other alteration in the systemic environment is to clear them out and see what happens.