A short-term caloric restriction diet enhanced a DNA repair process known as non-homologous end joining. These results may partially explain how caloric restriction and similar diets increase lifespan and healthspan in a wide range of organisms.
Eat less, live longer
Caloric restriction – that is, reduced caloric intake without malnutrition – is one of the most reliable methods of increasing lifespan in animals. Experiments in the 1930s showed that caloric restriction increased the lifespan of rats, and work since then has found similar results in other organisms and has demonstrated other health benefits.
In mice, reducing caloric intake by 30-40% leads to a 30-40% increase in lifespan. Though results in humans remain inconclusive, work in model organisms has shown that caloric restriction can reduce the incidence of tumors, cardiovascular disease, diabetes, and other disorders. There is also evidence that it protects against damage to DNA, proteins, and other macromolecules.
A better fix
A team of researchers based at New York’s University of Rochester has now shown that mice kept on a caloric restriction diet have improved DNA repair efficiency . One of the most dangerous forms of DNA damage is a double-stranded break. The severing of both strands can lead to rearrangements or other genomic instability.
Cells have several mechanisms to repair double-strand breaks, including non-homologous end joining (NHEJ). To detect NHEJ, the researchers created a genetic construct in which the GFP gene, which encodes a fluorescent protein, is disrupted by the inclusion of a foreign killer sequence. The killer sequence can be cut out using a specific enzyme, after which NHEJ should reassemble GFP. The researchers could thus quantitatively estimate NHEJ activity and efficiency by measuring fluorescence in cell cultures that had been exposed to the enzyme.
They found that NHEJ efficiency was greater in skin, lung, kidney, and brain cell cultures from mice kept on a caloric restriction diet for four weeks. There was also an increase in the expression of the DNA repair-associated genes DNA-PK and SIRT6. The improvement in DNA repair is likely to lead to lower rates of cell death, mutation, and cancer incidence.
Calorie restriction (CR) improves health, reduces cancer incidence and extends lifespan in multiple organisms including mice. CR was shown to enhance base excision repair and nucleotide excision repair pathways of DNA repair, however, whether CR improves repair of DNA double-strand breaks has not been examined in in vivo system. Here we utilize non-homologous end joining (NHEJ) reporter mice to show that short-term CR strongly enhances DNA repair by NHEJ, which is associated with elevated levels of DNA-PK and SIRT6.
While caloric restriction has proven reliable for life extension in model organisms, the mechanisms behind this have remained unclear. Even if caloric restriction were shown to work in humans, it’s unlikely that most people would be able to maintain such a diet. That makes it important to understand the changes triggered by this diet, which likely involve a wide range of signaling pathways, and figuring out which contribute to increased healthspan and lifespan. Improved DNA repair is an attractive candidate in that regard; now, we are faced with the task of identifying the steps linking reduced caloric intake with changes in DNA repair machinery.
 Ke, Z., Firsanov, D., Spencer, B., Seluanov, A., and Gorbunova, V. (2020) Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice. npj Agiing and Mechanisms of Disease, doi: 10.1038/s41514-020-00047-2