Ketogenic diet helps muscle stem cells in mice survive stress, Stanford study finds | Information Center

Fasting sends muscle stem cells into a deep resting state that slows muscle repair but also makes them more resistant to stress, according to a Stanford Medicine study in lab mice.

The protective effect can also be achieved by feeding the mice high-fat, low-carb foods – also known as the ketogenic diet – that mimic how the body responds to fasting, or by giving the animals bodies ketones, the byproducts that occur when the body uses fat for energy.

Research explores how the body responds in times of deprivation and abundance and provides clues to the effect of aging on the ability to regenerate and repair damaged tissue. Although the study focused on muscle stem cells, the researchers believe the findings are applicable to other tissue types throughout the body.

“As we age, we experience slower and less complete healing of our tissues,” said Thomas Rando, MD, PhD, professor of neurology and neuroscience. “We wanted to understand what controls this ability to regenerate and how fasting affects this process. We found that fasting induces the resilience of muscle stem cells so that they survive during deprivation and are available to repair muscles when nutrients are available again.

Rando, who recently accepted a position as director of the Broad Stem Cell Research Center at UCLA, is the lead author of the study, which was published online June 7 in Cell metabolism. Instructor Daniel Benjamin, PhD, and graduate student Pieter Both are the lead authors of the study.

calorie restriction

Long-term calorie restriction has been well documented to prolong lifespan and promote overall health in laboratory animals, but it is difficult for people to maintain a very low calorie diet for months or years. Periodic fasting has been explored as another way to achieve the health benefits of calorie restriction, but the effects of intermittent fasting on the body and its ability to regenerate damaged or aging tissues have not been well studied.

Fasting or, alternatively, following a high-fat, low-carb ketogenic diet — a popular weight loss technique — puts the body into a state called ketosis, in which fat is the primary source of energy. Ketone bodies are the by-products of fat metabolism.

The researchers found that mice that had been fasted for between 1 and 2.5 days were less able than non-fasted animals to regenerate new muscle in their hind legs in response to injury. This reduced regenerative capacity persisted for up to three days after the mice resumed feeding and returned to normal body weight; it returned to normal within a week of ending the fast.

Further research showed that muscle stem cells from fasted animals were smaller and divided more slowly than those from non-fasted animals. But they were also tougher: they survived better when grown on a lab dish under harsh conditions, including nutrient deprivation, exposure to cell-damaging chemicals, and radiation. They also survived transplantation into animals better than those from non-fasted animals.

“Usually most muscle stem cells grown in the lab die when they are transplanted,” Rando said. “But these cells are in a deep state of rest that we call deep ketone-induced quiescence that allows them to resist many kinds of stress.”

Muscle stem cells isolated from non-fasted animals and then treated with a ketone body called beta-hydroxybutyrate (BHB) showed similar resilience to fasted animals, the researchers found. Moreover, muscle stem cells isolated from mice fed a ketogenic diet, or a normal diet coupled with injections of ketone bodies, exhibited the same characteristics as deeply quiescent stem cells from fasted animals.

Finally, the researchers isolated muscle stem cells from aged mice treated with ketone bodies for a week. Previous research in Rando’s lab has shown that these older muscle stem cells grow worse in the lab than muscle stem cells from younger animals. But treatment with ketone bodies allowed older muscle stem cells to survive as well as their younger counterparts.

Potential applications

Although more research is needed, the results are intriguing, the researchers said.

“Cells have evolved to exist in times of abundance and in times of deprivation,” Rando said. “They had to be able to survive when food was not readily available. Ketone bodies arise when the body uses fat for energy, but they also push stem cells into a resting state that protects them during deprivation. In this state, they are protected from environmental stress, but they are also less able to regenerate damaged tissue.

Balancing these findings could one day help combat normal aging and improve stem cell function throughout the body, the researchers speculated.

“It would be beneficial if the stem cell effects of fasting could be achieved through ketone bodies, supplanting the need for fasting or following a ketogenic diet,” Rando said. “Maybe it’s possible to eat normally and still get that increased resilience.”

The research was supported by the National Institutes of Health (grants T32GM119995-1A1, PO1AG036695, R37AG023806, and RO1AR073248), the Buck Institute for Research on Aging, and the Department of Veterans Affairs.

UC Berkeley researchers; the Palo Alto Veterans Health System and the Mondor Institute for Biomedical Research in France are co-authors of the study.

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