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Glossary

Reactive Oxygen and Nitrogen Species (RONS) and Aging

What Are RONS?

Reactive Oxygen and Nitrogen Species (RONS) are a broad class of highly reactive molecules generated primarily as byproducts of normal cellular metabolism. They include reactive oxygen species (ROS) such as superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂), and reactive nitrogen species (RNS) such as nitric oxide (NO•) and peroxynitrite (ONOO⁻)¹.

These molecules are not inherently harmful. At controlled levels, they are essential for normal physiology. The key issue in aging biology is not their presence, but the gradual imbalance between their production and the body’s ability to regulate and neutralise them².

Sources of RONS

The primary source of RONS is the mitochondria, particularly the electron transport chain during ATP production. As electrons move through oxidative phosphorylation, a small proportion leak and react with oxygen, forming reactive oxygen species³.

Additional sources include immune cell activity, where RONS are generated to destroy pathogens⁴, enzymatic reactions such as NADPH oxidase activity⁵, and inflammatory signaling pathways that increase RONS production during immune activation⁶.

RONS as Signalling Molecules

RONS are not simply damaging byproducts. At low to moderate levels, they function as signalling molecules in a process known as redox signalling.

In this role, RONS regulate cellular adaptation to stress⁷, support immune defence⁴, influence mitochondrial biogenesis⁸, and contribute to oxygen sensing and vascular tone regulation⁹.

This dual role means that RONS are both necessary and potentially harmful, depending on their regulation.

When Do RONS Become a Problem?

With aging, RONS biology shifts from controlled signalling to chronic imbalance:

Mitochondrial efficiency declines, increasing electron leakage and baseline RONS production¹⁰
Antioxidant systems such as glutathione, superoxide dismutase, and catalase become less effective, reducing the body’s ability to neutralise reactive species¹¹
Chronic inflammation increases RONS production outside mitochondria, further elevating oxidative stress¹²
At the same time, declining NAD⁺ levels impair mitochondrial maintenance and DNA repair systems, indirectly worsening oxidative damage¹³

How RONS Contribute to Aging

When RONS levels exceed the body’s regulatory capacity, they begin to damage key cellular structures:

Oxidative DNA damage contributes to mutations and genomic instability¹⁴
Protein oxidation leads to misfolding and functional loss, affecting enzymes and structural proteins¹⁵
Lipid peroxidation damages cell membranes and mitochondrial integrity, impairing cellular function¹⁶

This damage is not isolated but reinforces other aging processes.

RONS and the Hallmarks of Aging

RONS are not a standalone hallmark of aging but act upstream of multiple key processes:

They contribute to mitochondrial dysfunction, both as a cause and consequence¹⁰
They accelerate DNA damage accumulation and genomic instability¹⁴
They promote cellular senescence, leading to accumulation of dysfunctional cells¹⁷
They drive chronic inflammation, often referred to as inflammaging¹²
They impair autophagy and cellular repair systems, reducing the ability to remove damaged components¹⁸

In this way, RONS function as a central amplification signal linking metabolism to long-term cellular damage¹⁹.

Summary - Why RONS Matter for Longevity

RONS sit at the intersection of metabolism, stress response, and cellular damage.

At controlled levels, they are essential signalling molecules that support adaptation and resilience.

At elevated levels, they contribute to cumulative damage, loss of cellular function, and progression of aging.

Longevity is therefore not about eliminating RONS, but maintaining balance between production and regulation.

Strategies that improve mitochondrial function, reduce chronic inflammation, and support antioxidant systems help maintain this balance and preserve cellular integrity over time.

Footnotes

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