Mechanism of age-related accumulation of mtDNA mutations in human blood

Why it matters

Mutations in mitochondrial DNA (mtDNA) build up with age and have long been blamed on oxidative damage from the mitochondria themselves, a cornerstone of the free-radical theory of aging. This study tests that explanation in about 750,000 people, and its answer challenges a common assumption. It also ties together three signs of aging that had been studied separately. Each cell holds hundreds to thousands of mtDNA copies, which copy themselves far more often than nuclear DNA, so even a small error rate per copy adds up.

What they did

The researchers used whole-genome sequences from blood of about 750,000 people in the UK Biobank and All of Us. They called mtDNA sequence, mtDNA amount and heteroplasmic variants (mutations present in only some copies), studied the mutation spectrum and signs of selection, and ran genome-wide and rare-variant searches for inherited factors linked to a person's mtDNA mutation burden.

What they found

Mitochondrial single-letter mutations rose sharply at about age 60, were present at low levels, showed little sign of positive selection and appear mostly neutral. Their pattern did not look like oxidative damage, as is often claimed, but fitted errors made when mtDNA is copied. The genome-wide search found inherited variants near TERT, TCL1A and SMC4, all linked to clonal hematopoiesis, and rare-variant analysis linked high mutation burden to mutations in many clonal-hematopoiesis driver genes. These links held even after excluding people with known driver mutations. The authors propose that mtDNA mutations arise randomly as copying errors, stay hidden in bulk blood, and only become detectable when blood-cell clones expand with age. They suggest mtDNA could be a sensitive blood marker of clonal mosaicism, unifying TERT variants, clonal hematopoiesis and mtDNA mutation build-up.

Limits

The study is of blood only, so it does not show that the same explanation applies in muscle, brain or other tissues where mtDNA mutations may matter more. Mutation spectra point to a likely cause but do not prove it. The authors note further limitations in the full paper. The finding does not mean oxidative damage plays no role in aging; it means that, for these blood mtDNA mutations, the evidence points to copying errors instead.

Key terms

Mitochondrial DNA (mtDNA)

The small, separate genome inside mitochondria, present in many copies per cell.

Heteroplasmy

A mix of normal and mutated mtDNA copies in the same cell or person.

Mutational spectrum

The pattern of letter changes, which can hint at what caused the mutations.

Clonal hematopoiesis

Expansion of blood cells descended from one stem cell.

TERT

The gene for the enzyme part of telomerase, which maintains chromosome ends.