Ketogenic diet extends healthy lifespan in mice – and, perhaps, in humans

SUBSCRIBE to our fortnightly e-newsletter to receive more stories like this. Dr Jon Ramsey at the UC Davis School of Veterinary Medicine, holding a mouse. A recent study helmed by Ramsey found that mice fed high-fat, low-carb, low-protein 'ketogenic' diets live longer, healthier lives.

Two recent Californian studies, both published in the September 2017 issue of Cell Metabolism, have shown that mice fed ‘ketogenic’ diets – very high in fats but low in carbs and protein – stay healthier for longer and show improved strength, coordination, curiosity and memory function.

Their independent but similar findings are potential game-changers that could form the basis of new drugs, therapies and dietary interventions to combat later-life decline, including major age-related diseases, physical degeneration and cognitive impairment.

The UC Davis study: Longer lifespans, greater strength

A group of researchers at University of California, Davis’s School of Veterinary Medicine, cognisant of the fact that increasing numbers of people are now living well into their 80s and 90s, decided to test the hypothesis that high-fat (‘ketogenic’) diets can increase longevity and improve physical performance in lab mice.

They found that older mice fed diets very high in fats but low in carbs and protein live longer and show greater strength and motor coordination than those fed high-carb or ‘conventional’ diets with equal caloric loads.

Nutritionist Jon Ramsey, senior author of the resulting paper, was pleasantly surprised by his team’s findings.

“We expected some differences, but I was impressed by the magnitude we observed – a 13 percent increase in median lifespan for the mice on a high-fat versus high-carb diet,” Ramsey told UC Davis News post-publication. “In humans, that would be seven to 10 years.

“But equally important, those mice retained quality of health in later life,” he said.

The study

Ramsey, who has spent the past two decades studying the mechanics of ageing, notes that ageing itself is a contributing factor to many major diseases affecting both rodents and humans.

Previous studies have shown that, in several animal species, restricting kilojoule intake slows ageing. Ramsey was keen to explore whether the ketogenic diet also impacts the ageing process and if so, how.

With funding from the US’s National Institutes of Health (NIH) and the university’s Mouse Metabolic Phenotyping Center, he designed a study to test that hypothesis.

Ramsey and his team divided middle-aged lab mice into three test groups.

  • Group 1 (the control) was fed a regular rodent high-carb diet;
  • Group 2 was put on a low-carb, high-fat diet; and
  • Group 3 was fed a ketogenic diet in which 89 to 90 percent of each mouse’s total intake of kilojoules came from fats.

Concerned that the high-fat diet given to the mice in Groups 2 and 3 could lead to increases in weight and reductions in lifespan, they ensured the daily kilojoule counts of all three groups’ diets were equivalent.

“We designed the diet not to focus on weight loss, but to look at metabolism,” Ramsey told UC Davis News. “What does that do to ageing?”

The results

As well as an increased median lifespan, the Group 3 mice – those fed the ketogenic diet – showed improvements in memory, strength and some motor functions, notably coordination.

It appeared that the ketonic diet fed to mice in Group 3 prevented increases in age-related markers of inflammation. It also appeared to reduce the incidence of tumours in the Group 3 rodents.

The implications

The results have potentially game-changing implications for how we treat ageing.

“In this case, many of the things we’re looking at aren’t much different from humans,” Ramsey told UC Davis News. “At a fundamental level, humans follow similar changes and experience a decrease in overall function of organs during ageing.

“This study indicates that a ketogenic diet can have a major impact on life and health span without major weight loss or restriction of intake,” he said.

“It also opens a new avenue for possible dietary interventions that have an impact on ageing.”

Read the original report

Roberts et al.: “A ketogenic diet extends longevity and healthspan in adult mice.” in Cell Metabolism, 05 September 2017. DOI: 10.1016/j.cmet.2017.08.005

Gloved hand holds lab mouse: scientists at California's Buck Institute for Research on Aging study found that mice fed ketogenic diets were less likely to die in middle age and had better memory function than those kept on normal rodent rations.
Gloved hand holds lab mouse: scientists at California's Buck Institute for Research on Aging study found that mice fed ketogenic diets were less likely to die in middle age and had better memory function than those kept on normal rodent rations.
Rama, Global Panorama, Flickr CC

The Buck Institute study: extending healthspan, boosting memory

In a companion study at California’s Buck Institute for Research on Aging, published in the same issue of Cell Metabolism, a team of medical researchers found that feeding middle-aged lab mice a ketogenic diet extended their healthy lifespans and improved their memory function.

The study

Previous, albeit small studies in people with cognitive impairment have indicated that BHB could improve memory.

The researchers, helmed by senior scientist and Buck Institute CEO and president Eric Verdin MD, conjectured that feeding lab mice a high-fat, low-protein, low-carb diet should boost their production of ketone bodies known as beta-hydroxybutyrate acid (BHB).

Dr Verdin and his team fed middle-aged mice a ketogenic diet, then looked at their mortality risk in later life. The team also tested each mouse’s memory function.

The findings

The Buck Institute researchers found that the mice on ketogenic diets had a reduced risk of mortality as they moved from middle to older age. While the maximum lifespans of the mice fed a ketogenic diet remained unchanged, they were less likely to die as they aged from one to two years old.

When they memory-tested another group of mice, first in middle age (at one year old), then again in old age (at two years old), they found that the mice fed a ketogenic diet performed at least as well on memory tests in old age as they did in middle age, while mice that had been consuming a typical rodent diet displayed the expected age-associated degeneration. The mice on the ketogenic diet explored their environs more. 

A memory test conducted on the same mice a few months later, after they’d returned to typical rodent diets and had no BHB in their bloodstreams, confirmed their continued improved memory function.

Mice allowed to stay on the ketogenic diet eventually become obese.

“We were careful to have all of the mice eating a normal diet during the actual memory testing, which suggests the effects of the ketogenic diet were lasting,” said Dr Verdin.

"Something changed in the brains of these mice to make them more resilient to the effects of age. Determining what this is, is the next step in the work.”

The implications

The study’s findings could lead to new therapies to combat cognitive problems linked with ageing, Dr Verdin said. “As we gain a deeper understanding of what BHB does in our body and our brain, we can intelligently design therapies to capture individual benefits while minimising harms,” he said.

According to Dr Verdin, this is the first study in ageing mammals that shows in detail the positive effects of BHB on memory and lifespan.

“This opens up a new field in ageing research,” he said. “We think the health benefits of BHB may go beyond memory and could affect tissues and organ systems.”

The findings also support Dr Verdin’s efforts to move from laboratory findings to clinical studies. “We’re looking for drug targets,” he said. “The ultimate goal is to find a way for humans to benefit from BHBs without having to go on a restrictive diet.”

The Verdin lab at Buck Institute is now investigating potential beneficial effects of a similar ketogenic diet in a mouse model of Alzheimer’s disease.

Results of the study from Eric Verdin’s lab at the Buck Institute for Research on Aging are published in the 5 September 2017 issue of Cell Metabolism.

Read the original report

Newman et al.: “Ketogenic diet reduces mid-life mortality and improves memory in aging mice.” In Cell Metabolism, 05 September 2017. DOI: 10.1016/j.cmet.2017.08.004 

For more information on the Buck Institute paper, contact Kris Rebillot on krebillot@buckinstitute.org.

Big breakfast, hold the carbs? While studies link ketogenic diet with an array of potential health benefits, nutritionists warn that eating a high-fat, low-carb, low-protein diet longterm leads to obesity and other health risks.
Big breakfast, hold the carbs? While studies link ketogenic diet with an array of potential health benefits, nutritionists warn that eating a high-fat, low-carb, low-protein diet longterm leads to obesity and other health risks.
Bob Walker, Flickr CC

The ketogenic diet: NCBI review of potential health benefits

According to the US’s National Center for Biotechnology Information (NCBI), this almost-all-fat diet was developed almost a century ago in the 1920s “in response to the observation that fasting had anti-seizure properties”.

During fasting, the NCBI explains, the body metabolises fat stores via lipolysis, then the fatty acids undergo beta-oxidation, turning them into acetoacetate, β-hydroxybutyrate and acetone – ketone bodies that cells can then use as precursors to generate adenosine triphosphate (ATP).

“The ketogenic diet, which is very high in fat and low in carbohydrates, is thought to simulate the metabolic effects of starvation by forcing the body to use primarily fat as a fuel source,” the NCBI states.

With the development of new anticonvulsant agents in the late 1930s, the ketogenic diet fell by the wayside but in the past two decades, it’s resurfaced, primarily as a treatment for refractory epilepsy.

With renewed interest in the diet has come “heightened interest in its potential use for other conditions [and, more recently,] an explosion in speculation about the diet’s potential applications in a variety of metabolic, oncologic, neurodegenerative, and psychiatric disorders”, the NCBI states.

Read the NCBI review

To read the NCBI’s recent review of the literature on the proven and potential health and medical benefits of ketogenic diets, click here

Further reading

For more information on the ketogenic diet, read this recent article in The Conversation. 

Check out other articles on the subject at Medical Xpress

Or read the 5 September 2017 issue of Cell Metabolism, which includes reports from the UC Davis and Buck Institute studies as well as a discussion of high-fat diets. 

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