- Ageing can push immune cells into a chronic inflammatory mode, which may worsen severe infections like sepsis
- Researchers found older macrophages produce GDF3, a signal that feeds back on the same cells and locks inflammation in place
- Blocking this GDF3 pathway reduced harmful inflammation and improved survival in older preclinical models
Ageing changes the immune system in ways that are not always obvious from the outside.
One of the most damaging shifts is a tendency towards persistent, misdirected inflammation – the kind of background immune activation that can turn infections into life-threatening crises, particularly sepsis.
Researchers at the University of Minnesota report evidence for a self-reinforcing loop inside a key immune cell type: macrophages.
These cells are central to inflammation – they help detect threats, recruit other immune players and shape how strongly the body responds.
The problem, the researchers suggest, is that in older age macrophages may struggle to switch off.
In preclinical models, the team found that ageing macrophages produce a protein called GDF3. Crucially, GDF3 does not just act elsewhere – it signals back to the macrophages that make it, reinforcing the inflammatory programme.
This feedback loop acts like a stuck accelerator, keeping the cells in an activated state and worsening the body’s response when infection strikes.
The signal appears to act through a pathway involving SMAD2/3, leading to longer-lasting changes in gene regulation.
The end result is that macrophages release higher levels of inflammatory cytokines – molecules that can help fight infection but can also damage tissues and organs when produced in excess.
The team then tested what happens when the loop is interrupted.
When the GDF3 gene was deleted, inflammatory responses to bacterial toxins were reduced.
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They also reported that medicines blocking the GDF3 – SMAD2/3 signalling pathway altered inflammatory macrophage behaviour in fat tissue and improved survival in older models exposed to severe infection.
They also looked for signs that the same biology might matter in people.
Using data from a large cohort study of older adults, the researchers found that GDF3 levels were linked with inflammatory signalling, supporting the idea that this pathway could be relevant beyond the lab.
This is not a ready-made treatment, but it is a clearer target. If future work can map the pathway precisely – and confirm which parts can be safely blocked – it could support therapies designed to reduce harmful immune overreactions in older adults without leaving people defenceless against infections.
