Could changing how immune and lung cells use energy control chronic inflammation?

Research Signal – Source date 2023-12-18

A cell can stop dividing without becoming biologically quiet. It may remain metabolically active, accumulate internal damage and release signals that alter the surrounding tissue. In chronic inflammatory lung disease, that combination raises a difficult treatment question: could changing how immune and structural lung cells use energy reduce damaging inflammation, or would it interfere with useful forms of cellular aging and repair?

An EAACI position paper from the Task Force for Immunopharmacology, published on December 18, 2023, brings these questions together. It examines immune senescence, the metabolic changes that accompany it, and observations from asthma and chronic obstructive pulmonary disease. It also discusses experimental treatments and selected registered trials. The paper is not a new treatment trial. Its contribution is to connect several areas of research that are often considered separately and show why the same metabolic pathway may behave differently in different cells and diseases.

Aging is not the only route to senescence

Cellular senescence is commonly associated with aging, but chronological age is only one route into the state. Replicative senescence develops as part of the normal aging process. Accelerated senescence can arise at any age when cells experience acute or chronic stress, including inflammatory or environmental stress.

The distinction matters for lung disease. The paper describes signs of senescence in severe and late-onset asthma and COPD, while also noting that features of immune senescence can appear in childhood allergies and asthma. This does not mean that every affected cell has the same cause or metabolic profile. It means that disease-related stress may push cells toward senescence before the changes associated with old age would otherwise be expected.

Senescence also has a useful side. A stable halt in cell division can help with cancer surveillance, tissue development and wound healing. The problem arises when senescent cells accumulate or remain in a damaging inflammatory environment. Instead of acting as a temporary protective response, their altered behavior can contribute to chronic disease and multimorbidity.

A cell can stop dividing and still send inflammatory signals

The apparent contradiction becomes clearer when cell division is separated from cellular activity. Senescent cells have a stable, nonreversible arrest of proliferation, but they are still alive and metabolically active. The paper describes four linked features: cell-cycle arrest, macromolecular damage, dysregulated metabolism and a senescence-associated secretory phenotype, often shortened to SASP. In ordinary language, SASP means that a senescent cell releases a changed mixture of signaling molecules that can influence nearby cells.

Mitochondria are part of the cell’s energy machinery. They help convert available nutrients into usable energy, but they also respond to stress and can become a source of damaging reactive oxygen species. Under healthy conditions, cells remove worn-out mitochondria through a recycling process called mitophagy. The paper describes reduced mitochondrial autophagy in senescence. Damaged mitochondria can therefore accumulate, increasing oxidative stress and reinforcing the senescent state.

The consequences can spread beyond the original cell. Impaired mitochondria may release molecular signs of damage, including oxidized mitochondrial DNA and cardiolipin, into the cell. These signals can activate inflammatory pathways such as the NLRP3 inflammasome, cGAS-STING and NF-kB. Senescence-associated secretions also interact with interleukin-1 signaling and can change NAD+ metabolism through increased expression of CD38, an enzyme that consumes NAD+. The result is a feedback pattern in which mitochondrial dysfunction, altered energy handling and inflammatory signaling can strengthen one another.

Metabolism here does not mean one universal switch. Healthy cells shift nutrients among glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation and fatty-acid oxidation as their energy and growth demands change. Senescence can disrupt these adjustments, but the direction is not identical in every cell. Some senescent states show increased glycolysis and reduced oxidative phosphorylation; others can retain or increase mitochondrial activity. A treatment aimed at “normalizing metabolism” would therefore need to identify which cell, pathway and disease context it is actually changing.

Asthma and COPD leave different metabolic fingerprints

The paper’s asthma examples center on both tissue markers and fuel use. In lung tissue from elderly people with asthma, the authors describe increased expression of senescence-associated markers such as phosphorylated p53 and p21, together with greater airway fibrosis than in age-matched people without asthma and younger controls. In patients with stable asthma, urinary metabolic patterns included reduced carnitine, and severe asthma was associated with changes involving SLC22A5, a carnitine transporter.

Carnitine helps move fatty acids into mitochondria, where they can be used for energy. The airway smooth-muscle cells described in the paper showed increased mitochondrial respiration and beta oxidation, consistent with greater fatty-acid consumption. Changes in LDL-receptor and CPT2 expression were linked to fatty-acid entry into cells and mitochondria. These observations point to a disease-associated metabolic pattern in particular tissues and patient groups. They do not establish that the pattern causes an individual’s asthma or provide a validated test for selecting treatment.

COPD presents a different cellular problem. The paper describes lung macrophages with senescence-like features, including reduced phagocytosis, weaker bactericidal capacity and impaired efferocytosis, the clearance of dead or dying cells. Reduced autophagy and mitophagy, mitochondrial dysfunction and increased SASP can coexist with persistent inflammatory activity. A macrophage may therefore contribute to inflammation while becoming less effective at removing debris or helping defend the lower airways against bacteria.

COPD macrophages can also show different activation patterns, including predominantly pro-inflammatory cells and cells expressing features associated with both inflammatory and more anti-inflammatory states. The paper reports that activating the energy sensor AMPK can decrease glycolysis and production of inflammatory cytokines such as interleukin-6. COPD airway smooth-muscle cells add another layer, with abnormal mitochondrial function, increased oxidant release and changes in lactate, glutamine, fatty-acid and amino-acid metabolism alongside altered growth and morphology.

These findings should not be compressed into one “senescent lung cell” defect. Asthma tissue markers, airway smooth-muscle fuel use and COPD macrophage clearance failure describe different compartments and functional consequences. They provide reasons to investigate metabolism, but they do not by themselves prove that one metabolic alteration drives the whole disease or that changing it will improve patient outcomes.

From a plausible target to a treatment claim

The position paper separates two broad therapeutic ideas. One is to change the metabolic conditions that help maintain harmful senescence or inflammation. The other is to remove selected senescent cells with senolytic drugs. Both ideas are biologically plausible, but plausibility is not the same as demonstrated benefit in asthma or COPD.

Metformin illustrates the difference between types of evidence. In animal models, the paper reports that metformin activated AMPK and reduced lung inflammation, airspace enlargement and small-airway remodeling. In the COPD Gene cohort, metformin use over five years was associated with reduced progression of pulmonary emphysema. The animal findings involve an intervention under experimental conditions; the cohort finding is an association observed in people. Together they justify further study, but they do not establish that metformin causes a treatment benefit for people with COPD.

The paper also lists the dasatinib-quercetin combination as a senolytic approach. In vitro, it reduced senescent human cells. In mice, it was associated with lower SASP, greater exercise capacity and longer lifespan in the settings summarized by the paper. The table also includes reduced physical dysfunction in people with idiopathic pulmonary fibrosis. That human finding belongs to a different lung disease and cannot be used as evidence that the combination works for asthma or COPD.

A registered clinical trial supplies a narrower kind of information. The paper lists NCT01708278, a phase 1 study of quercetin in COPD, with a status of completed. That entry establishes the listed phase and completion status. It does not, by itself, establish a positive efficacy result, a suitable dose for routine care or a proven senescence-targeting strategy for people with COPD.

The therapeutic challenge is selective change

The strongest idea in this research area is not simply to eliminate senescent cells or suppress metabolism. It is to separate harmful, persistent senescence from the protective functions that senescence can serve. A therapy that broadly removes cells could interfere with cancer surveillance or wound healing. A therapy that broadly suppresses a metabolic pathway could affect healthy immune activation or cells that need the same pathway for another purpose.

Cell-specific variation makes the problem harder. A macrophage with impaired bacterial killing is not equivalent to an airway smooth-muscle cell with altered fatty-acid use. Even within one cell type, the metabolic signature may differ with disease phenotype, inflammatory history and the surrounding tissue environment. The paper therefore identifies disease-specific metabolic profiles as an important research need, along with better understanding of how biologics, immunotherapy and corticosteroid treatment may affect senescence-related metabolism.

That interaction with existing treatment is especially important. A metabolic intervention might eventually work as an addition to established anti-inflammatory therapy, but the paper does not establish which combinations are beneficial or how long their effects would last. Researchers would need to show that a proposed target is active in the relevant patients, that changing it improves meaningful lung outcomes and that useful immune and repair functions remain intact.

What this could change

A better understanding of cell-specific metabolism could eventually give people with asthma or COPD another way to control persistent inflammation and limit continuing injury to lung tissue. The possible benefit is not a promise of reversing aging or eliminating every senescent cell. It is the prospect of matching a carefully selected metabolic or senescence-directed treatment to the cells and disease processes that are actually driving harm.

That future depends on several links holding together: actionable disease-specific targets must be identified; experimental signals must translate into sustained benefit for patients; and treatment must preserve senescence’s useful roles in immune protection and tissue repair. If those conditions are met, metabolic therapies could become partners to existing treatments rather than replacements for them. The December 2023 position paper presents that possibility as an emerging research direction, with the central task still being to learn which changes are harmful, which are protective and which can be modified safely.

Key Sources

• Primary source: Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.
  DOI or Journal Page · Peer-Reviewed Paper · 2023-12-18