The Chemistry of Ageing: Free Radicals and Oxidative Stress

Why do we age? It’s one of biology’s oldest questions, and there’s no single answer. But chemistry has contributed one of the most influential ideas: that the oxygen we need to live slowly damages us. The free radical theory of ageing, proposed by Denham Harman in 1956, suggested that reactive by-products of oxygen metabolism accumulate damage in cells over a lifetime. Research since then has shown the picture is more complicated than he imagined — but the chemistry of free radicals remains central to understanding how cells wear out.

What is a free radical?

Most stable molecules have their electrons in pairs. A free radical is an atom or molecule with at least one unpaired electron. Chemists mark it with a dot, as in the hydroxyl radical, HO•.

An unpaired electron makes a species very reactive: it tends to grab an electron from a neighbouring molecule, or pull a hydrogen atom from it, to pair up. But when it does, the neighbour is often left with an unpaired electron itself, becoming a new radical. This sets off a chain reaction, in exactly the same way as the free-radical substitution you meet in organic chemistry when chlorine reacts with methane in UV light:

• Initiation: a radical is formed.
• Propagation: radicals react with molecules to make new radicals.
• Termination: two radicals meet and pair up, ending the chain.

Where do radicals come from in the body?

The main source is oxygen. Molecular oxygen, O₂, is itself unusual: its two outermost electrons are unpaired (it’s a diradical), which is why it can be reduced one electron at a time. In the electron transport chain, oxygen normally accepts four electrons at once at the final enzyme, becoming water safely. But a small fraction of electrons leak out earlier and reduce O₂ by just one electron, forming superoxide:

O₂ + e⁻ → O₂•⁻

Superoxide and the species it leads to are called reactive oxygen species (ROS):

Species	Formula	Notes
Superoxide	O₂•⁻	Formed by electron leakage; moderately reactive
Hydrogen peroxide	H₂O₂	Not a radical, but can cross membranes and form HO•
Hydroxyl radical	HO•	Extremely reactive; attacks almost anything nearby

Hydrogen peroxide turns into the dangerous hydroxyl radical when it meets iron(II) ions, in the Fenton reaction:

Fe²⁺ + H₂O₂ → Fe³⁺ + HO• + OH⁻

This is one reason the body keeps free iron tightly locked away in proteins such as ferritin and transferrin (see iron in the body).

Other sources of radicals include ultraviolet light, ionising radiation, cigarette smoke, air pollution, some drugs, and inflammation — immune cells deliberately make ROS to kill bacteria (see the immune system as chemistry).

What radicals damage

The hydroxyl radical reacts almost as soon as it forms, so it damages whatever is closest. Three targets matter most.

Lipids: chain reactions in membranes

Cell membranes are rich in polyunsaturated fatty acids (see fatty acids). The C–H bonds next to their C=C double bonds are relatively weak, so a radical can pull off a hydrogen atom easily, creating a lipid radical. This reacts with O₂ to form a lipid peroxyl radical, which steals a hydrogen from the next fatty acid, and so on. This lipid peroxidation chain can damage many molecules from a single starting event, making membranes leaky and producing reactive breakdown products such as aldehydes. It’s the same chemistry that makes oils go rancid.

Proteins

Radicals oxidise amino acid side chains — especially cysteine, methionine, tyrosine and tryptophan — and can break protein chains or cross-link them. Oxidised proteins may fold wrongly, lose enzyme activity and clump together. Damaged proteins tend to accumulate in ageing cells.

DNA

Radicals damage both the bases and the sugar–phosphate backbone of DNA. A well-studied product is 8-oxoguanine, an oxidised form of guanine that can pair with adenine instead of cytosine during replication, causing mutations (see DNA structure). Cells have repair enzymes that cut out damaged bases, but repair isn’t perfect, and mitochondrial DNA — which sits close to the main source of ROS — is especially exposed.

The body’s defences

Cells have a layered antioxidant defence system (see antioxidants: what they really do):

1. Enzymes:
   • Superoxide dismutase (SOD) converts superoxide to hydrogen peroxide and oxygen: 2O₂•⁻ + 2H⁺ → H₂O₂ + O₂. Different forms contain copper and zinc, or manganese, at the active site.
   • Catalase breaks down hydrogen peroxide: 2H₂O₂ → 2H₂O + O₂. It’s one of the fastest enzymes known — which is why a drop of hydrogen peroxide on a cut fizzes.
   • Glutathione peroxidase, which contains selenium, reduces peroxides using glutathione.
2. Small-molecule antioxidants: glutathione (made in the body), vitamin C in watery parts of the cell, vitamin E in membranes.
3. Repair and replacement: DNA repair enzymes, and systems that break down damaged proteins and even whole damaged mitochondria.

Oxidative stress is what happens when radical production outpaces these defences.

Did the theory hold up?

Evidence for Harman’s idea:

• Oxidative damage to DNA, proteins and lipids does increase with age in many tissues.
• Many age-related diseases — heart disease, cataracts, neurodegenerative diseases — involve oxidative damage.

Evidence that complicates it:

• In many animal experiments, boosting antioxidant enzymes hasn’t reliably extended lifespan, and some long-lived animals, such as the naked mole rat, show high levels of oxidative damage.
• Large human trials of antioxidant supplements (vitamin E, β-carotene and others) haven’t shown longer lives. Some even found harm, such as a higher lung cancer rate among smokers given high-dose β-carotene.
• ROS turn out to be important signalling molecules. Low levels help cells respond to exercise, fight infection and trigger their own protective defences. Mopping them all up can blunt some benefits of exercise.

The modern view is that oxidative damage is one contributor to ageing, not the whole story.

Other chemical faces of ageing

• Glycation: sugars react slowly with amino groups on proteins, eventually forming advanced glycation end-products (AGEs) that cross-link long-lived proteins such as collagen and lens proteins. This stiffens tissues and contributes to cataracts. It’s the same family of reactions (the Maillard reaction) that browns toast.
• Telomere shortening: the protective caps at chromosome ends shorten with each cell division in many cells.
• DNA damage and mutations accumulating over time.
• Loss of protein quality control, leading to misfolded protein clumps (see protein folding).
• Mitochondrial decline, reducing energy supply.

What actually helps

The strongest evidence for healthy ageing points to lifestyle rather than pills: not smoking, regular exercise, a diet rich in fruit and vegetables, limiting alcohol, protecting skin from excessive UV, and sleep. These reduce radical production, strengthen the body’s own antioxidant enzymes, and work on several ageing mechanisms at once.

Key takeaways

• A free radical has an unpaired electron and reacts in chain reactions.
• Mitochondria leak electrons to O₂, forming superoxide, H₂O₂ and the very reactive hydroxyl radical (via the Fenton reaction).
• ROS damage lipids (peroxidation), proteins and DNA (e.g. 8-oxoguanine).
• SOD, catalase and glutathione peroxidase, plus vitamins C and E, provide defence.
• Oxidative stress contributes to ageing, but antioxidant supplements haven’t extended human lifespan; ROS are also useful signals.