Caloric restriction modulates genome-wide somatic mutation in mice

Why it matters

Somatic mutations accumulate in every cell throughout life, and this genomic instability is one of the hallmarks of aging. Caloric restriction extends lifespan in many species, but whether it slows mutation build-up was unclear. This study links diet directly to the integrity of DNA, a central theme for a nutrition course. Most of what we know about mutations and diet comes from cancer research. Measuring how a diet changes the normal, slow build-up of mutations in healthy tissue only became possible with very accurate sequencing methods, so studies like this are new.

What they did

The researchers put mice on caloric restriction and used high-fidelity duplex DNA sequencing, a method accurate enough to count rare mutations, on bulk liver, bulk kidney, isolated liver cells (hepatocytes) and cerebellar neurons. They compared mutation burdens, the types of mutation, and where in the genome mutations fell.

What they found

Caloric restriction reduced genome-wide somatic mutation burden across several tissues and cell types. It reduced both single-letter substitutions and small insertions and deletions, by amounts that varied between sample types. It also lowered the activity of SBS5, a mutational process of unknown cause that produces most mutations in mammals. Surprisingly, the reduction was greatest in parts of the genome that are not being actively read. The authors conclude that the work links diet, aging and genome integrity and establishes genome integrity as a modifiable axis of aging.

Limits

This is a mouse study, and the abstract does not give the strength of restriction, the ages, or the sexes studied, so it cannot tell us what level of eating would matter for people. Fewer mutations does not by itself show that the mutations were driving aging in these mice. Long-term caloric restriction is hard for people to sustain and is not risk-free. The study also cannot say whether the same benefit would come from other eating patterns, such as time-restricted eating, or from a change in diet quality rather than quantity.

Key terms

Caloric restriction

Eating fewer calories than usual without malnutrition.

Duplex sequencing

A very accurate DNA sequencing method that checks both strands of each molecule to count rare mutations.

SBS5

A common, clock-like mutational signature whose cause is not known.

Indel

A small insertion or deletion of DNA letters.

Genomic instability

The tendency of the genome to gather mutations and damage; a hallmark of aging.

Mutational signature

A typical pattern of DNA letter changes left by a particular cause, numbered like SBS1 or SBS5.

Hepatocyte

The main working cell of the liver.