Eating fewer calories has repeatedly been linked to longer life in laboratory animals. New research suggests one possible reason may be that it slows some of the changes that build up in DNA with age.
In a study published in Cell, mice fed 30% fewer calories than they would normally eat accumulated fewer DNA mutations in several parts of the body. Mutations are small changes in DNA that naturally build up over time. Most do no harm, but some can interfere with how cells work and contribute to diseases including cancer.
The finding does not mean people should start cutting their calorie intake by 30%. The study was done in mice, and the researchers say this level of restriction would be difficult for people to maintain. Instead, the work may help scientists better understand why calorie restriction has been tied to healthier aging in animals.
“While links between diet and lifespan have been established in animals, our results show that diet and mutations across the genome are also linked,” said co-corresponding author Gilad D. Evrony of NYU Langone Health and NYU Grossman School of Medicine.
Researchers compared mice allowed to eat freely with mice receiving substantially fewer calories. They then looked for DNA changes that had accumulated in several tissues as the animals aged.
The mice eating fewer calories had fewer mutations overall, although the effect was not the same throughout the body. The reduction was greatest in the liver and smaller in the kidney and brain.
That difference is important because it suggests calorie restriction does not affect every part of the body in exactly the same way.
“Mice on a calorie-restricted diet are healthier for longer, but this diet is too challenging for humans,” Evrony said. “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.”
Scientists have studied calorie restriction and aging for decades. In a variety of animal studies, substantially reducing calorie intake without causing malnutrition has been associated with longer lifespan and slower development of some age-related problems.
But researchers are still trying to understand why.
The new study suggests the slower buildup of DNA mutations could be one piece of that puzzle. It does not show, however, that having fewer mutations was responsible for the animals living longer or staying healthier.
It also does not show that calorie restriction prevents cancer. Although some DNA mutations can contribute to cancer, this study looked at changes in DNA rather than whether the animals ultimately developed the disease.
The researchers found another unexpected difference: in liver and kidney cells, calorie restriction appeared to have its biggest effect in parts of DNA that were less active.
“We didn’t expect to find this asymmetry across the genome,” said co-corresponding author Jonathan Shoag of University Hospitals Cleveland and Case Western Reserve University School of Medicine.
Researchers have ideas about why that may happen, but the answer is not yet clear. Future studies will look at other diets, tissues and cell types to better understand what connects calorie intake with the buildup of DNA changes.
That may ultimately be the most useful part of the discovery.
Scientists are not necessarily trying to convince people to follow an extreme calorie-restricted diet. Instead, understanding what happens inside the body when calories are reduced could help researchers identify other ways to produce some of the same effects without requiring people to dramatically cut how much they eat.
“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 author Marta Grońska-Pęski of NYU Langone Health.
For now, the findings provide another clue about how diet and aging may be connected.
Eating substantially fewer calories was associated with fewer age-related DNA changes in mice. Whether the same thing happens in people, whether it meaningfully affects human health or lifespan and whether those effects could someday be achieved without severe calorie restriction remain unanswered questions.
The research was supported by the National Institutes of Health, 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.