They sleep well, eat healthily, and avoid bad habits — yet they still feel fatigued, their skin looks dull, and they are plagued by random aches and minor chronic complaints. It’s as if there’s a persistent “fire” smoldering within their bodies.
This mysterious phenomenon might be linked to a hidden process called “inflammaging” — a form of aging driven by chronic, low-grade inflammation. Unlike a cold or fever that comes on suddenly, inflammaging works silently over time, depleting our health reserves and accelerating aging.
But in this long-lasting battle between inflammation and the body, who’s secretly adding fuel to the fire?
A recent study published in Nature Aging [1] identified a key culprit behind chronic inflammation and aging: a special type of T cell in the immune system that “goes rogue” as we age. These cells, which normally suppress inflammation and maintain immune balance, can transform into ticking time bombs of chronic inflammation as they accumulate in the body over time.
Even the Immune System’s “Good Guys” Aren’t Immune to Aging
Our bodies are made up of trillions of cells, each with potential instability. In youth, the immune system keeps misbehaving cells in check. But as we age, even our immune cells themselves can fall victim to aging and inadvertently fuel chronic inflammation.
Among the immune army are regulatory T cells (Tregs), whose job is to calm excessive immune reactions and maintain balance. Think of them as peacekeepers preventing the immune system from attacking the body itself.
📖 In the anime “Cells at Work!”, Tregs are portrayed as secretaries assisting helper T cells in keeping the immune response under control.
Normally, Tregs suppress inflammation by releasing inhibitory cytokines and directly restraining overactive immune cells. But could these “anti-inflammatory” cells themselves be transformed by aging, turning from protectors into accelerators of inflammaging?
To investigate, researchers used single-cell RNA sequencing to read the RNA inside cells and reveal their functional states. Comparing CD4+ T cells from young and old mice, they discovered that certain types of T cells accumulated with age. Among them, some Tregs showed abnormal activation.
📊 Figure: Distribution of CD4+ T cells in the spleens of young (left) and aged (right) mice
The Emergence of “Rogue” Tregs
To pinpoint these cells, researchers turned to flow cytometry, a technique that tags and distinguishes cell types by surface markers. One marker stood out: KLRG1, a receptor associated with T cell maturation and immune aging.
They found that Tregs expressing KLRG1 (dubbed kTregs) significantly increased in older mice and humans. These kTregs accumulated in the blood, spleen, bone marrow, liver, and especially in immune structures of the gut mucosa.
📊 Figure: KLRG1+ Tregs increase in human blood with aging
Worse still, these kTregs weren’t harmless. Instead of suppressing inflammation, they appeared to fan its flames, acting like time bombs for chronic inflammation and aging.
Evidence of Aging and Dysfunction in kTregs
1️⃣ Mitochondrial Damage
Using fluorescent markers to assess mitochondrial activity, researchers observed reduced fluorescence in many CD4+ T cells from aged mice, indicating impaired mitochondrial function.
📊 Figure: Reduced mitochondrial activity in CD4+ T cells from aged mice
Electron microscopy revealed kTreg mitochondria to be small, round, and structurally degraded — their energy production machinery essentially collapsed. Among all CD4+ T cell subsets, kTregs had some of the worst mitochondrial dysfunction.
2️⃣ Signs of Cellular Senescence
kTregs expressed high levels of cell cycle inhibitors P16 and P21, hallmarks of senescence. They also showed elevated γH2AX, a marker of DNA damage.
📊 Figure: P16, P21, and γH2AX expression levels in Treg subsets
3️⃣ Loss of Anti-Inflammatory Function, Gain of Pro-Inflammatory Traits
In animal models, kTregs were less effective at suppressing effector T cells and preventing inflammation.
📊 Figure: Mice receiving kTregs failed to maintain body weight due to ineffective inflammation suppression
Even worse, these cells secreted pro-inflammatory SASP factors (e.g., IL-1β, IL-6, IL-13, IFN-γ, GM-CSF, CXCL2), perpetuating inflammaging.
📊 Figure: SASP cytokine levels in kTregs
Who’s Pulling the Strings? The IL-33/ST2 Pathway
Digging deeper, researchers identified a signaling pathway behind the transformation of normal Tregs into rogue kTregs: the IL-33/ST2 axis.
IL-33 is released during tissue damage or stress, acting like an alarm to mobilize immune cells. ST2, a receptor on Tregs, receives IL-33’s signals.
kTregs were found to express high levels of ST2. When young mice were injected with IL-33, their kTreg numbers surged, and these cells adopted the same pro-inflammatory, senescent traits seen in naturally aged mice.
📊 Figure: IL-33 drives Treg transformation into pro-inflammatory kTregs
A Vicious Cycle of Inflammaging
As we age, IL-33 levels rise in certain tissues, promoting the conversion of normal Tregs into dysfunctional kTregs. These rogue cells accumulate, releasing inflammatory molecules and creating a vicious cycle of chronic inflammation and aging.
In short, the very cells designed to maintain immune balance have “gone dark” — turning into accomplices of inflammaging.
A Future Without “Rogue” Tregs?
If we can find ways to prevent the transformation of Tregs into kTregs or selectively eliminate these rogue cells, we might be able to break the cycle of inflammaging and reduce chronic inflammation at its source.
This breakthrough offers a tantalizing glimpse of a future where chronic inflammation — a driver of cardiovascular disease, diabetes, Alzheimer’s, and other age-related conditions — can finally be brought under control.
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