When Immune Regulation Becomes Inflammatory: A Bioenergetic View of Aging

Aging is often described as a gradual decline in immune function. Older adults respond less effectively to infections and vaccines, recover more slowly from tissue injury, and carry a greater burden of chronic low-grade inflammation. At the same time, immune tolerance becomes less reliable: the immune system may fail to restrain unnecessary inflammation while also becoming less effective at eliminating damaged, infected, or abnormal cells.

A recent study in Nature Aging offers a mechanistic clue to this apparent contradiction. Soto-Heredero and colleagues identified a population of aging-associated regulatory T cells marked by the surface receptor KLRG1. These cells accumulate with age, show substantial mitochondrial abnormalities, acquire features of cellular senescence, and become less effective at suppressing inflammation in living animals. Yet they do not simply lose their regulatory identity. Instead, they retain regulatory markers while simultaneously producing inflammatory signals.

This mixed phenotype may help explain why aging is accompanied not only by immune weakness, but also by chronic immune activation.

Regulatory T cells are supposed to preserve tolerance

Regulatory T cells, or Treg cells, are essential for immune balance. They prevent excessive immune responses, reduce tissue damage, and help maintain tolerance to the body’s own tissues and to harmless environmental or microbial exposures.

In principle, an increase in Treg cells with age might appear protective. More regulatory cells should mean greater control of inflammation. However, the study shows that cell number alone does not reveal functional quality.

The researchers identified a subset of Treg cells expressing KLRG1, referred to as KLRG1-positive Treg cells or kTreg cells. These cells increased progressively with age in mice and were found in the blood, spleen, bone marrow, liver, adipose tissue, intestinal tissues, and Peyer’s patches. They were particularly abundant in the colonic lamina propria, an important site of immune tolerance and interaction with the gut microbiome.

A similar population was also increased in human blood. KLRG1-positive Treg cells accounted for approximately 6.35% of Treg cells in young adults but 14.56% in adults aged 55 years or older.

The central question, therefore, was not whether these cells accumulated, but what kind of cells they had become.

Mitochondrial failure changes more than energy production

The KLRG1-positive Treg cells showed several signs of mitochondrial deterioration:

• reduced mitochondrial mass,

• reduced mitochondrial membrane potential,

• abnormal mitochondrial morphology,

• disrupted or lost cristae,

• and reduced expression of genes related to mitochondrial function.

These findings matter because mitochondria do much more than generate ATP. They regulate redox balance, calcium handling, biosynthesis, inflammatory signalling, cell survival, and the ability of a cell to adapt to stress.

Treg cells are especially dependent on mitochondrial respiration to sustain their suppressive function. When their mitochondrial system becomes impaired, the consequence may not be immediate cell death. Instead, the cell may remain alive but enter a constrained state in which it can preserve only part of its original function.

From a bioenergetic perspective, this is a critical distinction.

Aging may not simply reduce the amount of energy available to cells. It may reduce the capacity to generate, distribute, and use energy at the right time. Cells can continue to survive, but their ability to regulate inflammation, repair damage, restore balance, and return to baseline becomes progressively compromised.

Senescence as an incomplete adaptive state

The same KLRG1-positive Treg cells also showed several features associated with cellular senescence. They expressed higher levels of the cell-cycle regulators P16 and P21, showed activation of p53-related pathways, and accumulated DNA damage marked by increased γH2AX.

Senescence is often described as permanent cell-cycle arrest. But that description is incomplete. Senescent cells remain metabolically active and can release a wide range of signalling molecules. These may include inflammatory cytokines, chemokines, growth factors, and tissue-remodelling signals collectively associated with the senescence-associated secretory phenotype, or SASP.

In this study, the aging-associated Treg cells produced several inflammatory and SASP-related mediators, including IL-1β, IL-6, IL-13, IFN-γ, GM-CSF, CXCL1, CXCL2, CCL1, and CCL3.

The cells therefore did not become silent. They became persistently active in a different way.

This supports a broader interpretation of senescence as a stress-adapted state that may initially preserve survival when normal function can no longer be sustained. When damage is temporary and recovery remains possible, such adaptation may be reversible or useful. When the stress persists and bioenergetic recovery fails, the state can become locked in and increasingly harmful.

A conflicting immune phenotype

Perhaps the most important finding is that the KLRG1-positive Treg cells retained several features of regulatory cells. They continued to express FOXP3 and produced the anti-inflammatory cytokine IL-10.

At the same time, they produced inflammatory mediators and failed to suppress immune activation effectively in vivo.

In laboratory culture, KLRG1-positive and KLRG1-negative Treg cells appeared to have similar suppressive capacity. But when tested in living animals, the difference became clear. KLRG1-negative Treg cells restrained inflammation and protected against weight loss and intestinal pathology. KLRG1-positive Treg cells did not provide the same protection.

Animals receiving these cells showed greater activation of conventional T cells, more colon fibrosis, fecal bleeding, splenomegaly, and increases in circulating neutrophils and basophils.

This reveals a conflicting phenotype:

The cells still look regulatory, but they no longer regulate effectively.

They preserve some elements of their original identity while losing the energetic and functional capacity required to maintain immune tolerance.

This may be one reason aging is associated with both immune suppression and inflammation. The immune system does not simply become overactive or underactive. It becomes poorly coordinated.

Lower immune tolerance may reflect failed recovery

Immune tolerance depends on more than suppressing individual immune reactions. It requires repeated cycles of activation and resolution.

The immune system must recognize a threat, mobilize resources, contain damage, remove the threat, repair tissues, and then return to a resting state. Each stage requires energy, coordination, and time.

A bioenergetically healthy immune cell can respond, adapt, and recover. A bioenergetically constrained cell may still respond and adapt, but fail to complete recovery.

This creates a different trajectory:

Persistent demand → mitochondrial strain → incomplete recovery → senescence-like reprogramming → impaired regulation → chronic inflammatory signalling

Under this model, reduced immune tolerance in aging is not explained only by loss of immune control. It may also reflect the accumulation of regulatory cells that have become trapped in a partially functional, partially inflammatory state.

They remain present, but their ability to restore homeostasis is diminished.

The IL-33 signal: adaptation under persistent tissue stress

The study also found that KLRG1-positive Treg cells expressed high levels of ST2, the receptor for IL-33. IL-33 is an alarmin released during tissue stress and injury. When young mice were treated with IL-2 and IL-33, the number of KLRG1-positive Treg cells increased.

This suggests that persistent tissue danger signalling may help drive the formation of these cells.

Initially, this may be adaptive. Expanding regulatory cells at sites of tissue stress could help limit excessive inflammation. But if the stress signal persists while mitochondrial capacity declines, the same adaptive response may become maladaptive.

The cells continue to accumulate, yet their function deteriorates. What began as an attempt to preserve tolerance may eventually contribute to inflammatory burden.

Aging as a failure of bioenergetic resolution

This study supports a view of aging in which mitochondrial dysfunction is not merely one isolated hallmark among many. It may act as an upstream constraint that changes how cells respond to stress, how long they remain activated, and whether they can return to homeostasis.

When mitochondrial capacity is preserved, immune activation can be followed by resolution.

When mitochondrial capacity is compromised, cells may remain trapped in prolonged adaptation. Senescence, inflammatory secretion, impaired suppression, and loss of immune tolerance may then emerge as interconnected consequences of failed recovery.

This does not mean that mitochondrial dysfunction is the sole cause of immune aging. The study is mainly mechanistic in mice, and the human findings are cross-sectional. It also does not prove that mitochondrial failure begins the entire process.

However, it clearly demonstrates that mitochondrial alteration, senescence-like reprogramming, impaired immune regulation, and inflammatory signalling can coexist within the same aging-associated immune-cell population.

That is an important shift in perspective.

The problem in aging may not simply be that immune cells disappear or stop working. Some cells remain active but operate under bioenergetic constraint. They preserve survival at the expense of flexibility, resolution, and coordinated function.

In this sense, inflammaging may partly reflect not excessive defence alone, but the cumulative failure of stressed immune cells to complete recovery.

Soto-Heredero, G., Gabandé-Rodríguez, E., Carrasco, E., Escrig-Larena, J. I., Gómez de las Heras, M. M., Delgado-Pulido, S., Francos-Quijorna, I., Blanco, E. M., Fernández-Almeida, Á., Abia, D., Rodríguez, M. J., Fernández-Díaz, C. M., Álvarez-Flores, M. B., Ramírez de Molina, A., Jung, S., del Sol, A., Zorita, V., Sánchez-Cabo, F., Torroja, C., & Mittelbrunn, M. (2025). KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging. Nature Aging, 5, 799–815. https://doi.org/10.1038/s43587-025-00855-9