Mice on ketogenic diets live longer and healthier in old age

Mice on ketogenic diets live longer and healthier in old age

So-called "keto" diets have been gaining public attention for an array of weight loss and health benefit claims. But scientists are still uncovering what exactly happens in ketosis, when carbohydrate intake is so low that the body shifts to producing ketones to help fuel organs.

Two independent mouse studies provide evidence that a ketogenic diet improves memory in older animals, as well as the chances that an animal lives to old age. The findings, published in the journal Cell Metabolism, raise hopes that ketogenic diets can improve both longevity and health span, or the time someone lives in good health, but further testing in humans is needed.

"The fact that we had such an effect on memory and preservation of brain function is really exciting," says senior author of one of the papers. "The older mice on the ketogenic diet had a better memory than the younger mice. That's really remarkable."

Mice in both studies were fed one of three diets starting in mid-life: a ketogenic diet, a control diet, or a low-carb, high-fat diet. The researchers tested the mice at various ages in tasks such as mazes, balance beams, and running wheels. Further testing checked for heart function and gene regulation changes through RNA sequencing analysis, which revealed that the diets influenced insulin signaling and gene expression patterns typically found in fasting.

While both studies showed improvements in mid-life lifespan and memory tests, one study also found that a ketogenic diet preserved physical fitness, such as grip strength, in old age.

"The magnitude of the changes surprised me," said a senior author on the second paper, which found the improved physical strength in mice. "We've had the hypothesis that the shift in metabolism induced by a ketogenic diet would have beneficial effects on aging, but I was impressed by the changes we observed."

The ketogenic diet owes its origins to fasting. People have long recognized that the practice of fasting had the effect of reducing seizures. Starting in the 1920s, doctors found they could mimic the benefits of fasting for epilepsy patients by cutting out carbs, thereby creating a ketogenic diet. When carbohydrate intake is low enough, the liver will produce ketone bodies to provide energy for organs, especially the brain. Both fasting and exercise can kick off this process of ketosis. For a diet to produce ketosis, it must be extremely low carb, or no carb. Both recent studies used diets in which fat made up 89%-90% of total calorie intake.

"When you do a ketogenic diet, you are essentially reorganizing all of metabolism," said the senior author on the first paper. This shock to the system can come with health risks. For example, mice allowed to eat a ketogenic diet at will eventually become obese. To prevent this, researchers alternated between a ketogenic diet and a regular diet. Authors in the second paper limited the calories given to mice on ketogenic diets to maintain their weight. The difference in approach may explain why mice in one study, but not the other, retained physical capabilities in old age.

In December 2012, researchers in the first  published a paper in the journal Science  that showed that the ketone body β-hydroxybutyrate (BHB) not only functioned as fuel, but also produced cell signaling. BHB cell signaling could induce a state in an animal that made it resistant to oxidative stress, which is one of the pathways of aging.

They are now exploring a molecule that can be used as a precursor to BHB to see if simply taking the molecule as a supplement can induce the same benefits of a ketogenic diet.