Should younger and older people receive different treatments for the same infection?

LA JOLLA (January 14, 2025)—Dealing with an infection isn’t as straightforward as simply killing the pathogen. The body also needs to carefully steer and monitor its immune response to prevent collateral damage. This regulation, called disease tolerance, is crucial to protecting our tissues while the immune system tackles the infection head-on.

To survive an infection, your body must activate a tolerance mechanism that is compatible with the specific progression of your disease. So, if your body is changing over the course of your lifetime, does that mean the specific mechanisms it uses to survive an immune onslaught change, too?

Salk scientist Janelle Ayres, PhD, has spent the past two decades studying disease tolerance, and this question is the latest to cross her lab bench. The answer, published in Nature on January 14, 2026, is that younger and older mice with sepsis—a life-threatening exaggerated response to infection—have distinct disease courses and tolerance mechanisms. What’s more, the genes and proteins that protected young survivors from sepsis-induced multi-organ damage and death had the opposite effect in older survivors.

The mechanisms young mice used to survive sepsis were the very same mechanisms that caused older mice to die, suggesting that future therapies may be more effective if tailored to the patient’s age. New sepsis treatments are especially needed as the antibiotic resistance crisis continues to threaten current care strategies.

“There are many cases where a patient’s body successfully kills the infectious pathogen, but the patient still dies—I want to understand why,” says Ayres, senior author of the study, Howard Hughes Medical Institute Investigator, and professor and holder of the Salk Institute Legacy Chair at Salk. “It’s not just the pathogen that can hurt us; it’s our own responses to those pathogens. 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.”

What is sepsis?

The immune system is a powerful ally. Many organs, cells, and molecules combine to form a united front against invaders like the flu or dysfunctions like cancer. Sometimes, however, the immune system focuses too tightly on eliminating the threat and forgets that its attacks have repercussions on the rest of the body as well.

Sepsis is an extreme example of the damage the immune system can do when it overreacts. In this condition, the immune system sets out to attack a bacterial, fungal, viral, or parasitic infection, but that protective response quickly spirals out of control. So out of control, in fact, that sepsis can cause multi-organ failure and death.

The threat of sepsis is enormous—anyone can get it, and sepsis-related deaths make up 20 percent of all global deaths. So, how do we treat it?

Antibiotics are the first medication deployed. However, the patient’s immune response is doing so much more damage than the pathogen those antibiotics are targeting, and the growing threat of antibiotic resistance also adds concern about the overuse of antibiotics as the primary treatment for sepsis.

Anti-inflammatory medications are sometimes used in addition to antibiotics, but they come with their own shortcomings. First is timing, as the damage is usually done by the time they’re administered. Second is lack of specificity, as silencing the entire immune response can immunocompromise the patient and put them at even greater risk.

The search for novel solutions beyond the antibiotics we know is also more urgent than ever, in the face of an escalating antibiotic resistance crisis, which has been named one of the top 10 global threats to humanity by the World Health Organization. Global antibiotic resistance deaths outnumber deaths from HIV, tuberculosis, and malaria combined.

Ayres says disease tolerance mechanisms may be more precise targets for controlling infection-generated damage—offering a powerful alternative to the current antibiotic and anti-inflammatory duo. The challenge is figuring out what those exact disease tolerance mechanisms are, and accounting for the fact that the ones that are important for survival may be changing as an individual ages.

"While host disease tolerance mechanisms are a great alternative to treating bacterial infections, they are difficult to identify,” says co-first author Karina Sanchez, a research scientist in Ayres’ lab. “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.”

Does sepsis affect younger and older people differently?

To determine if and how disease tolerance mechanisms change with age, the researchers started with two groups of mice—one younger, one older. They dosed both groups using the strategy Sanchez mentioned, called LD50, that the lab developed in 2018, which allows the researchers to easily compare mice that do and don’t recover from infection.

When the researchers observed the mice that did not survive, they noticed the younger mice died faster than the older mice, demonstrating two distinct disease trajectories. But for the younger and older mice that survived, did their disease tolerance mechanisms also differ?

The researchers discovered that young survivors were protected by a protein called Foxo1 and a gene it regulates, called Trim63. When Foxo1 turns on Trim63 expression, it stimulates the production of the protein MuRF1, which then promotes the breakdown of larger molecules into usable energy in cardiac and skeletal muscle cells.

In young survivors, increased expression of Foxo1 and Trim63 created a cardioprotective effect, blocking multi-organ damage and preventing the cardiac remodeling seen in their deceased counterparts. Surprisingly, Foxo1, Trim63, and MuRF1 had the opposite effect on older survivors.

The researchers saw that Foxo1 deletion improved survival of older mice and decreased survival of younger mice. And in normal conditions, older survivors recovered with enlarged hearts, showing that the very same mechanism causing younger mice’s demise had enabled their survival.

“Our findings reveal that young and aged hosts can have distinct disease trajectories when exposed to the same pathogens,” says co-first author Justin McCarville, a former postdoctoral researcher in Ayres’ lab. “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.”

Creating age-specific therapies for sepsis

The concept of antagonistic pleiotropy helps make sense of these seemingly surprising findings. Antagonistic pleiotropy is a theory first proposed in evolutionary biology that suggests some traits that are beneficial in youth can incur costs later in life. Getting through the reproductive years of youth is the evolutionary priority, so biology will often optimize those years at the expense of an organism’s health down the line.

“We aren’t doomed, though—this doesn’t mean as we get older our bodies completely betray us,” says Ayres. “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.”

These findings may guide the development of more effective treatments for sepsis, and potentially other infections, diseases, and disorders. Medications could be developed that are age-specific, targeting different disease tolerance mechanisms in younger and older patients. This strategy would improve outcomes for both age groups, ushering in an exciting new era of tailored therapeutics that pathogens will not evolve resistance to, helping to overcome the global crisis of antibiotic resistance.

Other authors and funding

Other authors include Justin McCarville, Sarah Stengel, and April Williams of Salk, and Jessica Snyder of the University of Washington.

The work was supported by the Howard Hughes Medical Institute, National Institutes of Health (DP1 AI144249, R01AI114929, P30 014915), Keck Foundation, Canadian Institutes of Health, NOMIS Foundation, and Helmsley Trust.

About the Salk Institute for Biological Studies

Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology, and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Learn more at www.salk.edu.

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