Researchers at the Salk Institute have found that age plays a significant role in how organisms tolerate and survive sepsis, a severe and often fatal response to infection. The study, led by Janelle Ayres, PhD, and published in Nature on January 14, 2026, compared younger and older mice exposed to sepsis. The findings indicate that the biological mechanisms which help young mice survive can actually be harmful to older mice.
The research focused on disease tolerance—the body's ability to limit damage from its own immune response during infection. According to Ayres' team, "the genes and proteins that protected young survivors from sepsis-induced multi-organ damage and death had the opposite effect in older survivors." This suggests that treatments for sepsis may need to be tailored according to patient age.
Sepsis is a major global health concern, accounting for about 20 percent of deaths worldwide. Standard treatment involves antibiotics, but these do not address the damaging immune response itself. Anti-inflammatory drugs are sometimes used as well but can suppress the immune system too broadly or arrive too late to prevent harm. The increasing threat of antibiotic resistance further complicates current approaches.
Karina Sanchez, co-first author and research scientist in Ayres' lab, said: "While host disease tolerance mechanisms are a great alternative to treating bacterial infections, they are difficult to identify. Thankfully, Ayres' lab developed a novel model to help with that identification, which we could pair with a sepsis model in mice to explore age-related differences in disease tolerance mechanisms."
The researchers used two groups of mice—one young and one old—and applied an LD50 dosing strategy developed by Ayres’ lab in 2018. They observed different patterns of survival: younger mice died more quickly than older ones when they did not survive sepsis.
In surviving young mice, protection was linked to higher activity of Foxo1—a protein—and its regulated gene Trim63. This pathway produced MuRF1 protein, which helped break down large molecules into energy within muscle cells and protected against organ damage. However, this same mechanism had negative effects in older survivors; deleting Foxo1 improved survival rates among older mice but decreased them among younger ones.
Co-first author Justin McCarville noted: "Our findings reveal that young and aged hosts can have distinct disease trajectories when exposed to the same pathogens. Despite this difference, we show that involvement of the same molecular pathway determines survival, but it leads to opposite outcomes depending on age. This raises broader questions about how disease may manifest differently across age groups and underscores the potential need for therapies that are tailored to the unique physiology of different ages."
Ayres added: "We aren't doomed though—this doesn't mean as we get older our bodies completely betray us. Our work demonstrates that aged mice are capable of mounting the appropriate disease tolerance response, and we have initiated lines of investigation in our lab to figure those mechanisms out."
The study's authors include Justin McCarville, Sarah Stengel, April Williams (all from Salk), and Jessica Snyder (University of Washington). Funding came from organizations such as the Howard Hughes Medical Institute, National Institutes of Health (DP1 AI144249, R01AI114929, P30 014915), Keck Foundation, Canadian Institutes of Health Research, NOMIS Foundation, and Helmsley Trust.
These results could inform new approaches for treating sepsis based on patient age by targeting specific tolerance pathways rather than relying solely on antibiotics or general anti-inflammatories—a shift made urgent by rising antibiotic resistance worldwide.
