How Damaged Mitochondria May Drive Chronic Inflammation as We Age

Healthy cells continuously inspect their mitochondria.

Minor damage may be managed by repairing or removing individual proteins. More serious damage may lead to the removal of an entire mitochondrion through mitophagy.

When this quality control becomes less effective, poorly functioning mitochondria may accumulate inside cells. They may produce more reactive oxygen species-unstable molecules that can damage proteins, cell membranes and DNA.

Damaged mitochondria may also release some of their contents into the surrounding cell or circulation.

These released molecules are known as damage-associated molecular patterns, or DAMPs. They include mitochondrial DNA, ATP, cardiolipin and other substances that would normally remain contained within mitochondria.

Mitochondria developed from ancient bacteria. Because of this evolutionary history, some mitochondrial molecules resemble material associated with microorganisms.

When these molecules appear in the wrong part of the cell or outside the cell, the immune system may interpret them as evidence of infection or injury.

They can activate several immune pathways, including Toll-like receptors, the NLRP3 inflammasome and the cGAS-STING system.

The names are technical, but their shared purpose is easier to understand: they detect potential danger and initiate an inflammatory response.

When inflammation develops without infection, it is known as sterile inflammation.

The review proposes that repeated release of mitochondrial danger signals may help keep this response active. Over time, this could contribute to the chronic inflammatory environment associated with ageing.

The authors also describe a possible self-reinforcing cycle. Mitochondrial damage may promote inflammation, while persistent inflammation and oxidative stress may cause further mitochondrial damage.

The paper reports that circulating mitochondrial DNA tends to increase after approximately the age of 50 and has been associated with higher levels of several inflammatory signals. However, these observations do not prove that mitochondrial DNA alone causes inflammaging.

The review shows that mitochondria may influence ageing in at least two connected ways.

First, damaged mitochondria may produce energy less efficiently, affecting tissues with high energy demands, including the muscles, heart and brain.

Second, they may release danger signals that contribute to persistent immune activation.

This connection may help explain why mitochondrial dysfunction, reduced physical capacity and chronic inflammation frequently appear together in ageing and age-related disease.

Maintaining mitochondrial quality may therefore be important not only for energy production, but also for preserving metabolic balance, tissue function and appropriate immune regulation.

The mechanisms discussed may be relevant to frailty, muscle loss, cardiovascular disease, metabolic dysfunction and neurodegenerative disorders.

However, this review does not demonstrate that one mitochondrial pathway causes these conditions in an individual patient. It brings together mechanistic and mainly preclinical evidence to explain a biologically plausible connection.

There is no routine clinical test that measures mitochondrial quality control or mitophagy throughout the human body.

Inflammatory markers such as C-reactive protein are not specific to mitochondrial dysfunction. Their levels may also be affected by infection, excess body fat, autoimmune disease, dental inflammation and many other conditions.

The review discusses possible approaches involving exercise, calorie restriction, mitochondrial renewal, mitophagy and experimental medicines.

However, it does not prove that antioxidant supplements or products marketed as "mitochondrial boosters" prevent inflammaging or extend human life.

Physical activity remains the most established practical strategy associated with better mitochondrial function, muscle health and lower inflammatory risk.

Not smoking, obtaining adequate sleep and controlling blood glucose, body weight, blood pressure and other cardiovascular risks may also reduce long-term stress on mitochondria and tissues.

Medicines intended to stimulate mitophagy or block mitochondrial inflammatory signals remain experimental and require stronger evidence from human clinical studies.