Free Radical / Oxidative Stress Theory

What it proposes

Aging results from cumulative oxidative damage to DNA, lipids, and proteins by reactive oxygen species (ROS) generated as a by-product of mitochondrial respiration and inflammatory signalling.

Why it was compelling

• ROS damage to macromolecules is measurable and rises with age.
• Tissues with high metabolic rate often show early functional decline.
• Genetic over-expression of antioxidant enzymes extended lifespan in some early invertebrate studies.

Why it’s been substantially revised

• Antioxidant supplementation has failed: large RCTs of vitamin E, β-carotene, vitamin C, and others have shown no longevity benefit and (for β-carotene in smokers) measurable harm.
• Mitohormesis: low-dose ROS act as essential signalling molecules; blunting them entirely is harmful.
• Some long-lived species (naked mole-rat) have higher oxidative damage than short-lived ones — the relationship is not monotonic.
• Direct genetic manipulation of antioxidant systems in mice has not consistently extended lifespan.

What survives

Oxidative damage is real and contributes to aging, but it is one mechanism among many and largely downstream of upstream signalling. The framing has shifted from “antioxidants are good” to “managed oxidative stress signalling is good”.

Related entries

Mitochondrial dysfunction, Hormesis, Mitochondrial theory.