Eating less slowed the build-up of DNA mutations in mice

Every time a cell copies its DNA, and every day it is exposed to wear and tear, small errors can slip into its genome. These somatic mutations (mutations in body cells, not passed to children) build up throughout life in every tissue. They are one of the “hallmarks of aging” and the root cause of most cancers. Whether they also cause aging is still debated.

Calorie restriction (eating clearly fewer calories than an animal would if food were unlimited) extends lifespan in yeast, worms, flies, mice, rats and monkeys. A study in Cell asked whether it also changes how fast mutations accumulate.

Counting rare errors

Measuring somatic mutations is hard: each cell carries its own rare errors, scattered over billions of DNA letters, and ordinary sequencing makes too many reading mistakes to tell them apart. The team used duplex sequencing (NanoSeq), which reads both strands of each DNA molecule separately and only counts a change if it appears on both. That makes it accurate enough to count very rare mutations.

They studied 19-month-old male mice (old for a mouse) from an earlier experiment with three diets: normal free feeding, and two versions of 30% fewer calories. In one, the mice got all their food at the start of their active night-time; in the other, food came in small portions spread over the day. Earlier work had found the night-time version extended median lifespan by 35% and the spread-out version by only 10%.

What they found

• Fewer mutations with less food. Compared with freely fed mice, the calorie-restricted mice had 29% fewer single-letter mutations in the liver, 15% fewer in the kidney and 39% fewer in purified liver cells (hepatocytes). Small insertions and deletions of DNA letters were also reduced in the liver. In brain neurons the difference was small and not statistically clear.
• The main source of mutations slowed down. Most mutations in mammals come from a slow, steady process whose cause is still unknown (researchers call its fingerprint “SBS5”). Calorie restriction reduced it in all four types of sample.
• Both diets worked equally well, even though one extended life much more than the other. So the number of mutations can’t be the whole explanation for why calorie restriction prolongs life.
• The quiet parts of the genome were protected most. Genes that are actively used get extra repair while they are being read. Calorie restriction made the biggest difference in regions with no or little gene activity. In non-active gene regions, normally fed liver cells had about 2.5 times as many mutations as restricted ones; in the most active genes there was no difference. One possible explanation the authors give: less food means less DNA damage everywhere, but the benefit only shows where repair is weak.

What to keep in mind

Only male mice of one strain were studied, and only a few tissue types. The method counts small mutations, not large rearrangements of chromosomes. The diet used, 30% fewer calories for most of life, is not practical for people, as the authors note. And because the most-protected regions are the ones cells use least, the effect on cancer risk may be smaller than the overall numbers suggest; the authors found no clear difference in tumours at death between the two restricted diets.

Why it matters

This is the first genome-wide evidence that a diet can slow the build-up of mutations below the normal baseline. It turns “genome stability” from a fixed property into something that can be changed, and it gives researchers a way to test whether drugs that mimic calorie restriction, or weight-loss drugs, do the same. The authors speculate that the reverse may also be true: that overeating and obesity speed up mutations, which could explain part of the higher cancer risk linked to obesity. That idea has not been tested yet.