How age alters sepsis outcomes
March 3, 2026
How age alters sepsis outcomes
At a Glance
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Researchers found a biological pathway that helps young mice survive severe infections but has the opposite effect in older mice.
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The results point to new therapeutic targets and suggest that treatments for sepsis may need to be tailored to a patient’s age.
Scientists have long known that as people age, they become more susceptible to severe disease. Part of the reason is that the immune system becomes less effective at fighting off microbes. Another factor is lower disease tolerance—the protective defense response that blunts the tissue and organ damage caused by infectious microbes.
An NIH-funded research team led by Dr. Janelle S. Ayres of the Salk Institute aimed to learn more about how aging can affect the body’s response to infection. The researchers used a mouse model of a serious type of infection known as sepsis. Sepsis occurs when the body’s immune response to an infection severely damages the body itself.
The team studied the differing responses of young mice (roughly equivalent to human ages 20 to 30 years) and aged mice (about human ages 56 to 69 years). Their findings were published on January 14, 2026, in Nature.
The researchers found that the same dose of bacteria was equally lethal in both young and aged mice. However, the infection had different effects in the body. For example, it took longer to kill older mice. It also damaged the kidneys more in older mice but damaged the heart and liver more in younger mice. Notably, young mice that died from sepsis showed a problematic enlargement of the heart called cardiomegaly. In contrast, the hearts of dying aged mice shrank.
To understand why genetically identical mice respond to sepsis differently at different ages, the researchers examined genetic activity in the heart. They found the most significant differences related to the gene Foxo1. Foxo1 codes for a transcription factor, a type of protein that boosts the activity of other genes. One of its target genes, called Trim63, was also strongly tied to the differences in sepsis response.
Deleting the Foxo1 gene in heart cells or inhibiting the FoxO1 protein led to heart enlargement in both young and aged infected mice. This reduced the odds of surviving sepsis for younger mice but improved it for aged mice. The same effects on survival and heart size were seen when deleting Trim63 or inhibiting the activity of the MuRF1 protein, which is encoded by the Trim63 gene.
These and further experiments suggest that Foxo1 and its target gene Trim63 protect young mice in part by preventing their hearts from becoming too enlarged. However, this same activity can allow the hearts of older mice to shrink dangerously and make the mice more likely to die.
If future studies find the same process at work in humans, it might be possible to tailor treatments by age to help people survive life-threatening infections.
“It’s not just the pathogen that can hurt us; it’s our own responses to those pathogens,” Ayres says. “The focus of my lab has been to elucidate the disease tolerance strategies our bodies use to manage that self-inflicted damage. Dissecting those strategies may lead us to more effective therapies and a way around the antimicrobial resistance crisis.”
—by Brandon Levy
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References
Disease tolerance and infection pathogenesis age-related tradeoffs in mice. Sanchez KK, McCarville JL, Stengel SJ, Snyder JM, Williams AE, Ayres JS. Nature. 2026 Jan 14. doi: 10.1038/s41586-025-09923-x. Epub ahead of print. PMID: 41535469.
Funding
NIH’s National Institute of Allergy and Infectious Diseases (NIAID); Howard Hughes Medical Institute; Keck Foundation; Canadian Institutes of Health; NOMIS Foundation; Helmsley Trust.
