Sepsis—one of the world’s deadliest medical emergencies—may require age-specific treatments to improve survival, according to a groundbreaking study from the Salk Institute. New research reveals that younger and older individuals respond to sepsis through fundamentally different biological mechanisms, suggesting that a “one-size-fits-all” approach to treatment may be limiting patient outcomes.

The study, published in Nature on January 14, 2026, shows that disease tolerance mechanisms—the body’s ability to limit tissue damage during infection—change dramatically with age. Remarkably, the same genes and proteins that protect young individuals from sepsis-induced organ failure can have the opposite effect in older individuals.

Beyond Killing Pathogens: The Importance of Disease Tolerance

Surviving an infection is not solely about eliminating the invading pathogen. The immune system must also carefully regulate its response to avoid damaging the body itself. This protective balancing act is known as disease tolerance, and it plays a crucial role in preventing organ failure during severe infections like sepsis.

“There are many cases where the pathogen is successfully eliminated, but the patient still dies,” said Janelle Ayres, PhD, senior author of the study, Howard Hughes Medical Institute Investigator, and holder of the Salk Institute Legacy Chair. “It’s not just the pathogen that can hurt us—it’s our own immune response. Understanding disease tolerance may help us develop better therapies and avoid the growing problem of antibiotic resistance.”

Sepsis: A Global Health Crisis

Sepsis occurs when the immune system overreacts to infection, triggering widespread inflammation that can lead to multi-organ failure and death. It affects people of all ages and is responsible for approximately 20% of all deaths worldwide.

Current treatments rely heavily on antibiotics, sometimes combined with anti-inflammatory drugs. However, antibiotics do not address immune-mediated tissue damage, and their effectiveness is increasingly threatened by antimicrobial resistance, which the World Health Organization has named one of the top 10 global threats to humanity.

Different Ages, Different Survival Strategies

To understand how disease tolerance changes with age, the Salk researchers studied young and aged mice with sepsis using a specialized LD50 infection model that allows direct comparison between survivors and non-survivors.

They found that:

Young mice and older mice followed distinct disease trajectories

Young mice that did not survive died faster, while older mice declined more slowly

Survivors in each age group relied on different disease tolerance mechanisms

In young mice, survival depended on activation of a protein called Foxo1 and its downstream gene Trim63, which promotes energy production in heart and muscle cells through the protein MuRF1. This pathway protected young mice from cardiac damage and multi-organ failure.

Surprisingly, the same pathway proved harmful in older mice.

One Pathway, Opposite Outcomes

In older mice, blocking Foxo1 actually improved survival, while its presence was linked to cardiac enlargement and reduced recovery. Deleting Foxo1 had the opposite effect in young mice, decreasing survival.

“Our findings show that the same molecular pathway determines survival in both young and aged hosts, but it produces opposite outcomes depending on age,” said Justin McCarville, PhD, co-first author of the study. “This underscores the urgent need for therapies that reflect the unique physiology of different age groups.”

Rethinking Sepsis Treatment

The researchers explain their findings through the concept of antagonistic pleiotropy—an evolutionary principle in which traits that are beneficial early in life can become harmful later on.

“While evolution prioritizes survival in youth, that doesn’t mean we’re doomed as we age,” Ayres said. “Aged individuals can still mount effective disease tolerance responses—we just need to understand and support the right ones.”

Toward Age-Specific Sepsis Therapies

The study points toward a new therapeutic strategy: targeting disease tolerance rather than pathogens, with treatments tailored to a patient’s age. Such therapies could:

Reduce immune-driven organ damage

Improve survival across age groups

Avoid contributing to antimicrobial resistance

Because disease tolerance targets the host rather than the pathogen, it also offers a promising way to stay ahead of drug-resistant infections.

A New Era of Personalized Infection Care

As antibiotic resistance continues to rise and sepsis remains a leading cause of death worldwide, this research highlights the potential of age-tailored therapies to transform how infections are treated.

By recognizing that young and older patients fight disease differently, future treatments could be designed to work with the body’s natural defenses—ushering in a more precise, effective, and sustainable approach to Sepsis Care.

Source: https://www.news-medical.net/news/20260114/Age-tailored-therapies-needed-for-treating-the-young-and-old-with-sepsis.aspx