Caloric restriction reduces genetic mutations across the mouse genome
· News-MedicalMutations are changes in the molecular "letters" that make up DNA, the genetic blueprint for cells. Mutations build up with age in every cell when DNA is damaged or when cells make mistakes in fixing or copying it. Most mutations are harmless, but when they disrupt genes, they can cause cancer and other diseases.
Past studies in animals have shown that a large reduction in the number of calories they consume, called caloric restriction, extends their lifespans and slows aspects of aging. But whether caloric restriction also slows the rate at which mutations occur with age had not been investigated across the genome, the complete set of genetic material present in every cell.
Now a new study, published online September 9 in Cell, showed that caloric restriction reduced the level of mutations across several tissues in mice that were fed 30 percent fewer calories than they would have ingested if allowed to eat freely. While prior studies have looked at how such caloric restriction changes mutations in single genes, the new work determined for the first time its impact on mutation patterns across a large portion of the genome.
Led by researchers at NYU Langone Health and University Hospitals Cleveland, in collaboration with researchers at the University of Texas Southwestern Medical Center and the National Institutes of Health, the study analyzed the effect of caloric restriction on different types of genetic changes. They found that, to varying degrees across tissues, it dialed down the level of substitution mutations, in which one DNA letter is swapped for another, and insertion and deletion mutations, in which one or more DNA letters are added to or missing from the genome. The authors reached these conclusions using advanced DNA sequencing technology, which detects mutations in DNA with great accuracy.
Gilad D. Evrony, MD, PhD, co-corresponding study author, a core member of the Center for Human Genetics and Genomics at NYU Langone and the Jacob D. Goldfield Associate Professor of Pediatrics and Neuroscience, NYU Grossman School of MedicineWhile links between diet and lifespan have been established in animals, our results show that diet and mutations across the genome are also linked. Mice on a calorie-restricted diet are healthier for longer, but this diet is too challenging for humans. Nevertheless, considering the role mutations play in cancer and many other diseases, it's exciting to have found a way to decrease mutations, which we can now work to understand."
Caloric restriction's effect strongest in least active genomic regions
The study results also showed that the impact of caloric restriction varies across tissues and cell types as well as across the genome, providing further insight into how diet is linked to the genome. For example, liver cells showed a greater reduction in mutation burdens with caloric restriction than kidney or brain cells. This makes sense, said the authors, because of the vast diversity of cell types, and the differences in the ways DNA is damaged and repaired in each.
Surprisingly, in liver and kidney cells, the reduction in the number of mutations from caloric restriction was greatest in the least active regions of the genome, which contain either no genes or genes not being used by a given cell. The authors said one possible explanation is that if caloric restriction reduces DNA damage across the genome, active regions of the genome would not benefit as much because those regions already repair DNA damage frequently.
"We didn't expect to find this asymmetry across the genome," said co-corresponding author Jonathan Shoag, MD, an associate professor in the Department of Urology at University Hospitals Cleveland and Case Western Reserve University School of Medicine. "By profiling more dietary interventions and mutations in additional tissues and cell types, we hope to learn what drives the connection between diet and mutations."
"Understanding these mechanisms could eventually reveal new ways to reduce mutations – without the challenges and risks of an extreme diet-to counter diseases of aging," said first study author Marta Grońska-Pęski, PhD, a postdoctoral fellow in Dr. Evrony's lab.
Other authors were Victoria Acosta-Rodríguez and Amanda Garrido of the Translational Gerontology Branch of the National Institute on Aging; Shany Picciotto at University Hospitals Cleveland; and Carla Green and Joseph Takahashi in the Department of Neuroscience and the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center.
"We were fortunate to have collaborated with Dr. Victoria Acosta-Rodríguez, Dr. Joseph Takahashi, and Dr. Carla Green, who established this mouse caloric restriction cohort," said Dr. Evrony. Another study author from NYU Langone's Center for Human Genetics and Genomics was Amoolya Srinivasa.
This work was supported by National Institutes of Health grants T32AG052909, F32AG076287, and UH3NS132024, the Pew Charitable Trusts, the Jacob Goldfield Foundation, the Damon Runyon Cancer Research Foundation, the Smythe Family Impact Fund, the Vail family, and the Howard Hughes Medical Institute.
Source:
Journal reference: