Caloric restriction modulates genome-wide somatic mutation in mice

Marta Grońska-Pęski and colleagues tested whether caloric restriction changes the accumulation of somatic DNA mutations, a core feature of biological aging. Using high-fidelity duplex sequencing, they measured mutations in bulk liver, bulk kidney, hepatocytes, and cerebellar neurons from mice exposed to caloric restriction. Caloric restriction reduced substitution and insertion/deletion burdens across several tissues and cell types. The size of the reduction varied by tissue. The intervention also reduced activity of SBS5, a mutational process that accounts for many mammalian mutations. The largest reduction occurred in transcriptionally inactive regions, an unexpected pattern that may help clarify how nutrition affects genome maintenance. The paper strengthens a mechanism for caloric restriction in a mammalian model. It does not show that the same mutation changes occur in humans, nor that a particular calorie target is safe or effective for people. It does not test a supplement, time-restricted eating, or a human longevity outcome. Energy restriction can cause nutrient deficiencies and loss of lean mass if poorly designed. The finding is mechanistic and preclinical. Human trials with validated genomic and functional endpoints are needed before claims about mutation prevention or lifespan extension.

This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.