High-fat, low-carb regimen stresses out cells in heart, kidneys, brain, and liver, but effects may be reversible

Many influencers, athletes, and regular folks swear by ketogenic diets—skimping on carbs and feasting on fats to quickly shed pounds and improve their metabolism. Yet piling on the bacon and skipping the pancakes could come with a dangerous downside, according to a new study. Mice fed a particular type of ketogenic diet accumulated so-called senescent cells in their organs, researchers report today in Science Advances.

The same kind of cells build up in our bodies as we age and can impair the functions of tissues. However, keto aficionados may not need to chuck their low-carb recipe books just yet. The study also found no increase in senescent cells in mice that took regular breaks from the diet.

The results don’t prove that ketogenic diets are harmful in people, stresses W. H. Wilson Tang, a cardiologist at the Cleveland Clinic who wasn’t involved in the work. But, “This paper is an important addition” to the research on their potential side effects, he says. “We need to be more cautious and less cavalier.”

The rationale behind ketogenic diets is that slashing the consumption of carbohydrates—a class of molecules used by cells as fuel—forces the body to burn fat instead. To feed cells that normally subsist on carbs, the liver pumps out molecules called ketones, hence the diet’s name. A doctor at the Mayo Clinic devised the regimen in the 1920s to treat epilepsy in children, and many kids with the neurological condition still follow it today.

But ketogenic diets have also taken off among people looking to lose weight, reduce blood sugar, boost athletic performance, or gain other benefits. Keto dieters typically obtain 70% to 80% of their calories from fat and only 5% to 10% from carbohydrates, whereas the average U.S. resident gets about 36% of their calories from fat and 46% from carbs. Keto dieters can lose weight, and clinical trials suggest possible benefits in illnesses such as Alzheimer’s disease.

Radiation oncologist David Gius wasn’t looking for detrimental outcomes of the ketogenic diet. Instead, he and colleagues at the University of Texas Health Science Center at San Antonio were probing the diet’s effects on p53, a potent cancer-fighting protein.

One of p53’s roles is to orchestrate cellular senescence, telling stressed-out, unruly cells to stop dividing before they cause problems. The immune system usually culls senescent cells. But, “When they persist, they cause havoc,” says Jesús Gil, a cellular senescence expert at Imperial College London who wasn’t connected to the new research. If stem cells undergo senescence, for example, they can undermine tissues’ ability to make repairs. Senescent cells also exude molecules that can trigger inflammation and other deleterious effects.

Gius and his team stumbled on the senescence connection when they put mice on a supercharged ketogenic diet in which about 90% of the calories came from fat—mainly in the form of the shortening Crisco. A control group of rodents dined on food in which fat provided only 17% of the calories. After the mice stayed on these diets for 7 or 21 days, the researchers analyzed tissue samples from their hearts, kidneys, livers, and brains.

Levels of the p53 protein climbed in animals on the ketogenic diet, the team found. The scientists also detected an increase in other molecules that indicate the presence of senescent cells.

The researchers tested whether the cells went away after the mice switched to a normal diet. After a 3-week hiatus, the level of senescent cells had almost returned to normal, they found. Gius and his colleagues also probed the effects of temporarily taking time off from the ketogenic regimen, a so-called intermittent diet. The team put mice on a high-fat food for 4 days, allowed them to eat normal chow for 7 days, and then repeated the cycle twice more. Senescent cells did not build up in these rodents, an analysis of the animals’ organs showed.

Gil says he was surprised that the senescent cells disappeared so quickly when the mice returned to their normal diet. Cells don’t recover from senescence, he says, so it’s possible that the cells in the mice were not senescent; they may have entered a similar inactive state that is reversible.

Senescent cells don’t always mean a tissue is unhealthy, notes cell biologist Yi Zhu of the Mayo Clinic. They help wounds heal, for example. Before anyone could claim keto diets are dangerous, researchers would need to demonstrate that the cells actually harm the mice, she says. “Only showing an increase in senescence is not enough to show that the diet is detrimental.”

Obesity researcher and statistician David Allison of Indiana University adds that ketogenic diets vary in many ways, including in the sources of fat and protein. The new study finds an effect “for this [one] diet that happens to be ketogenic,” he says. “That doesn’t mean it’s true for all ketogenic diets.”

Although the effects haven’t been replicated in humans, Gius notes the results may offer a lesson for people following keto regimens. “We aren’t saying the diet is bad,” he says. “[But] you probably need to take a break.”

Source https://www.science.org/content/article/keto-diet-may-cause-organ-damage-mouse-study-finds