# Host Aging Induces a Senescent‐Like Phenotype in Neutrophils and Altered Transcriptional Responses to Streptococcus pneumoniae

## TL;DR

Aging causes neutrophils to adopt a senescent-like state, reducing their ability to fight pneumococcal infections in older individuals.

## Contribution

The study identifies a senescent-like phenotype in aged neutrophils and shows that blocking TNFα can restore antibacterial function.

## Key findings

- Aged neutrophils fail to upregulate glycolysis and ROS production needed for bacterial killing.
- Aged neutrophils show increased SASP factors like IL-10 and TNFα, and reduced apoptosis.
- Blocking TNFα improves antibacterial activity and host resistance to pneumococcal infection in aged mice.

## Abstract

Aging drives increased susceptibility to respiratory infections by
Streptococcus pneumoniae
(pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimicrobial function declines with age. To identify mechanisms underlying this decline, we performed RNA sequencing on PMNs in the lungs of young and old mice following pulmonary infection with
S. pneumoniae
. We observed significant transcriptomic differences across host age. Transcriptional analysis followed by functional validation revealed that in infected mice, PMNs from aged hosts failed to upregulate several effector activities including glycolysis and subsequent mitochondrial reactive oxygen species (ROS) production, which are necessary for bacterial killing by PMNs. Conversely, PMNs in aged mice displayed a higher senescence‐associated secretory phenotype (SASP) score and upregulated pathways involved in cellular senescence. Follow‐up functional characterization found that in uninfected hosts, PMNs in aged mice expressed higher levels of SASP factors IL‐10, TNFα, and ROS, had a lower incidence of apoptosis, and had a higher proportion of cells positive for senescence‐associated β‐galactosidase, features of a senescent‐like phenotype. Importantly, blocking TNFα, one of the SASP factors, altered the senescent‐like phenotype and boosted the antibacterial activity of PMNs from aged hosts and increased host resistance to
S. pneumoniae
pulmonary infection. In conclusion, host aging is associated with altered PMN phenotype, including a shift toward senescent‐like energy‐deficient cells, which contribute to impaired host defense and represent potential targets for improved interventions against infection in older adults.

Aging is associated with a senescent‐like phenotype in neutrophils that emerges in bone marrow cells; however, many facets of this phenotype are only fully acquired upon entry into peripheral tissues. This neutrophil senescent‐like phenotype is in part driven by TNFα and impairs resistance of aged hosts to
S. pneumoniae. Created in BioRender. Boughanem (2026). https://BioRender.com/sbef1sl.