Researchers publishing in Aging Cell have discovered how older organisms’ susceptibility to pneumonia is related to inflammatory factors.
Short-lived infection fighters
Polymorphonuclear leukocytes, more commonly known as neutrophils, are part of the first line of defense against lung infections. Illnesses cause these immune cells to be recruited from the bone marrow in a process called emergency granulopoiesis [1].
Unfortunately, with aging, it takes longer for these cells to be recruited and they become overactive once they join the fight [2], leading to tissue damage that may make the condition worse [3]. A previous experiment that involved transferring young neutrophils to old mice reversed their susceptibility to pneumonia [4].
These researchers pinned this age-related decline on two well-known facets of aging: inflammaging, the well-known increase in general inflammation even in the absence of infection, and cellular senescence, which occurs when cells become unable to continue dividing and behave in idiosyncratic ways. Because neutrophils are fully differentiated cells that do not normally last very long after creation, these cells have not been thoroughly investigated in the context of senescence; however, inflammation causes them to stick around for longer [5], and they can exhibit a senescence-like phenotype that has negative effects, including in the context of cancer [6]. This work, therefore, sought to determine how aging drives these changes and if they can be intervened against.
Immature but senescent cells
In their first experiment, the researchers compared the gene expression of neutrophils from young and old mice that had been infected with Streptococcus pneumoniae. While there were few differences at 12 hours after infection, by 24 hours, there were a wide variety of differentially expressed genes. The young mice had stronger immune responses, but the older mice’s neutrophils had enrichment in terms relating to differentiation; this suggests that, in older animals, neutrophils are being released before they fully mature. Meanwhile, these older neutrophils had reduced activation and reduced amounts of phagocytosis, which is required for neutrophils to dispose of bacteria.
The older neutrophils also had alterations in metabolism. Neutrophils in younger mice exhibit more aerobic glycolysis, while older ones have more of the citric acid cycle and less metabolic activity overall. Further work found that this is directly related to these cells’ ability to get rid of bacteria; halting glycolysis through other means, in both murine and human cells, almost completely destroyed younger neutrophils’ phagocytosis.
Despite being immature upon release, the older neutrophils were enriched in genes relating to cellular senescence. In fact, the expression of the senescence biomarker SA-β-gal was directly correlated with cellular immaturity. Older cells also failed to die off as younger neutrophils naturally do. During an infection, the neutrophils in young mice experience more acute oxidative stress, but the older mice consistently exhibit oxidative stress even when not infected, preventing an acute response.
The role of inflammation
Not all of the senescent-like differences appear immediately. The researchers found that, upon release from the bone marrow, older neutrophils exhibit more DNA damage and less proliferation, but it is not until they migrate that they exhibit further signs of senescence.
Many of these differences were found to be due to tumor necrosis factor alpha (TNFα), which is both inflammatory and secreted by senescent cells. Older mice that were treated with antibodies to block TNFα had less SA-β-gal and more neutrophils that died off when they were supposed to. They also had far better responses to infection; the treated older mice had a tenth of the bacterial burden in the lungs that the untreated older mice had.
Therefore, the researchers concluded that the constant inflammatory environment found in older organisms is a strong contributor to older neutrophils’ inability to properly fight infection and that focusing on these senescent-like neutrophils may provide an avenue for new clinical treatments. Of course, this was not a human study, and futher work needs to be done to determine if these particular findings persist in people.
Literature
[1] Manz, M. G., & Boettcher, S. (2014). Emergency granulopoiesis. Nature Reviews Immunology, 14(5), 302-314.
[2] Simmons, S. R., Herring, S. E., Tchalla, E. Y., Lenhard, A. P., Bhalla, M., & Bou Ghanem, E. N. (2024). Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection. Immunity & Ageing, 21(1), 34.
[3] Taenaka, H., Fang, X., Maishan, M., Trivedi, A., Wick, K. D., Gotts, J. E., … & Matthay, M. A. (2024). Neutrophil reduction attenuates the severity of lung injury in the early phase of pneumococcal pneumonia in mice. American Journal of Physiology-Lung Cellular and Molecular Physiology.
[4] Bhalla, M., Simmons, S. R., Abamonte, A., Herring, S. E., Roggensack, S. E., & Bou Ghanem, E. N. (2020). Extracellular adenosine signaling reverses the age‐driven decline in the ability of neutrophils to kill Streptococcus pneumoniae. Aging cell, 19(10), e13218.
[5] Ovadia, S., Özcan, A., & Hidalgo, A. (2023). The circadian neutrophil, inside-out. Journal of leukocyte biology, 113(6), 555-566.
[6] Rys, R. N., & Calcinotto, A. (2025). Senescent neutrophils: a hidden role in cancer progression. Trends in Cell Biology, 35(5), 399-411.
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