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EXPERT REACTION: Ketogenic diet helps mice live longer - but can also make them obese

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The 'ketogenic diet' may seem to be just be another in the long string of diet fads offering weight loss, but researchers have tried feeding mice a ketogenic diet and in two separate studies found that it can improve the memory of older mice, and help them live longer. The 'keto' diet is where carbohydrate intake is so low that the body shifts to producing ketones to help fuel organs. The keto diet mimics the effects of fasting but the shock to the body can come with health risks, including obesity, say the authors. The authors say they still don't know enough about the impact of the diet and further testing in humans is needed before it's given the green light.

Journal/conference: Cell Metabolism

DOI: Buck Institute paper: 10.1016/j.cmet.2017.08.004 | UC Davis paper:

Organisation/s: Buck Institute for Research on Aging; University of California, Davis, USA

Funder: These studies were supported by a Program Project Grant from the National Institutes of Health (USA) and the UC Davis mouse metabolic phenotyping center; National Institutes of Health grants, Gladstone Institutes intramural funds, Buck Institute intramural funds, as well as funds from the Larry L. Hillblom Foundation, Glenn Foundation for Medical Research, and the American Federation for Aging Research.

Media Release

From: Cell Press

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 September 5 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 Eric Verdin (@EricVerdin), President and CEO of the Buck Institute for Research on Aging and senior author of one of the papers (Newman et al.). "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.

"The conclusion we draw out of this is that it's a robust effect," said Verdin. "The two studies reinforce each other, because they both show the same global effect on healthspan."

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 Jon Ramsey, PhD, a professor at the University of California Davis and a senior author on the second paper (Roberts et al.), 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 Verdin. 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, Verdin and colleagues alternated between a ketogenic diet and a regular diet. Ramsey and colleagues 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.

"If we have a better idea of the mechanisms by which the ketogenic diet works, it would open a path to develop less-restrictive interventions," said Ramsey.

In December 2012, Verdin and colleagues published a paper in the journal Science (doi: 10.1126/science.1227166) 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.

Verdin and his colleagues 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.

"The ketogenic diet is a complicated, drastic diet to follow; can we reduce all of this beneficial effect to one molecule?" said Verdin. Researchers don't yet know, but this type of research will help further understanding of what is, or isn't, driving the health and aging benefits of the ketogenic diet.

Attachments:

  • Buck Institute for Research on Aging
    Web page
    Paper 1: The URL will go live after the embargo ends
  • University of California, Davis, USA
    Web page
    Paper 2: The URL will go live after the embargo ends

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Dr Alan Barclay is an accredited practicing dietitian and nutritionist, author and academic and a Research Associate at the University of Sydney.

Ketones are a kind of fuel produced from fatty acids (either from our dietary intake or body fat stores), by our liver, when glucose (a sugar) is severely restricted. Dietary regimens that stimulate the production of ketones by the liver are known as 'ketogenic diets'. 

In these new studies, mice in the intervention (ketogenic diet) group were fed diets providing around 90 per cent of energy (kilojoules) from fat and in the control groups were fed more than 65 per cent of energy from carbohydrates (starches and sugars). Those mice fed the ketogenic diet lived longer, and their memory was preserved better with ageing, compared to those fed the high carbohydrate diet. 

Needless to say, mice are not men, and much more research is needed before we know whether ketogenic diets have similar effects in free-living human populations. Short-term studies in humans suggest a small, non-clinically significant improvement in weight loss. There are currently no long-term (i.e. greater than 2 years) studies of ketogenic diets in humans.

Adult Australians consumed an average of 43.5 per cent of energy from carbohydrates in 2011/2 – far less than the >65 per cent of energy fed to the mice in the control diet. Total fat intake averaged 30.9 per cent of energy – far less than the 90 per cent fed to the mice in the intervention diet. It is unlikely that the average Australian would be able to (or would want to) adhere to a ketogenic diet for long periods of time.

Ketogenic diets typically require people to limit total carbohydrate intake to less than 10 per cent of energy (less than 50 g a day for a typical adult), and recommend fat provides around 80% of energy. What this means in real terms is severe restriction of:
*             most fruits, 
*             starchy vegetables (carrots, corn, peas, pumpkin, potatoes, etc...), 
*             cereal-based foods (bread, breakfast cereals, pasta, rice, etc...), 
*             legumes (beans, chickpeas, lentils, etc...),
*             milk and yoghurt.

For a typical adult, 10 per cent of energy, or 50 g of carbohydrate is equal to 1-slice of bread, 1-piece of fruit and 1/3rd cup of pasta or rice for the day. 

Instead of having carbohydrate-containing food, you must therefore eat mostly:
*             Meat, seafood, poultry
*             eggs, 
*             cheese,
*             butter and cream,
*             fats and oils,
*             low-carbohydrate vegetables (greens, onions, peppers, etc...),
*             low-carbohydrate fruits (berries).

Perhaps unsurprisingly, it’s difficult to obtain all of the essential vitamins, minerals and dietary fibres from a ketogenic diet, and supplements are therefore required.

Last updated: 16 Aug 2018 11:52am
Declared conflicts of interest:
None declared.
Professor Lesley Campbell is a Senior Endocrinologist at the University of New South Wales and Laboratory Co-Head at the Garvan Institute of Medical Research

Dietary experiments in mice differ from human studies e.g. high fat feeding has different effects in male and female B6 mice so studies usually report only male mice (as often there is no effect in females). 

The high fat diet is purely  experimental as, unlike humans, mice don't eat much fat naturally.

 So these studies of extreme diet change e.g.  ketosis in a male mouse eating excess fat without carbohydrate may invoke "survival" responses which may not occur in a human (especially a female). While the responses raise interesting questions regarding a beneficial effect   of stimulating fat burning while avoiding excess energy intake  which  usually occurs in high fat diet in a mouse by alternating the diet.

In summary, there is much more experimentation to do to test if the beneficial effects of such diet manipulation are applicable in  humans.

Last updated: 06 Sep 2017 3:05pm
Professor Joseph Proietto is from the School of Medicine, University of Melbourne

Two independent mouse studies published in the same issue of Cell Metabolism conclude that elevated ketones improve longevity and memory in rodents. In both studies the elevated ketones are produced by replacing the carbohydrate content of the diet with fat.

When managing human obesity, it would be inadvisable to prescribe a diet that is high in fat as it could worsen lipids. In any case it is possible to induce ketosis by simply avoiding carbohydrates without an increase in fat intake.

This is because the patients have adequate reserves of fat to burn. The patients simply need to be deprived of carbohydrate for 2-3 days. Studies inducing ketosis without increasing fat intake have not been done and it would be interesting if the effects are even more marked without the high fat intake.

Last updated: 06 Sep 2017 3:00pm
Emeritus Professor Mark Wahlqvist is former Professor and Head of Medicine at Prince Henry’s Hospital and Monash Medical Centre, Associate Dean (International Health and Development) and Director of the Asia Pacific Health and Nutrition Centre

Ketogenesis or the generation of ketones which are types of short chain fatty acids (SCFAs) have been known to serve as body fuels in starvation and prolonged exercise for many years. In these and other extreme situations or some diseases states like certain types of epilepsy they may become impotent fuels for the brain. Ordinarily, the brain uses glucose as its preferred fuel.

Interest has grown that body energy metabolism, especially of the nervous system, might age at a slower rate if SCFAs serve to a greater extent as a fuel. The mice studies reported in 2 recent reports are consistent with this possibility.

This is not to say that the same would be found in people although there are some clues that it might. Much is said about dietary restriction as a way to prolong life, possibly through ketogenesis. But we know that the ability to have about 300 calories per day over and above the sedentary requirements, as long as they come from nutritious foods and are used in physical activity prolongs life.

Moreover, weight loss and underweight in later life are predictors of premature death. So ,while the mice studies raise interesting  possibilities about increasing survival and decreasing neurodegeneration , safer ways to realise these goals in humans will depend on basically healthy diets  and being active for as long as possible.

And, of course, ketogenic diets in childhood to prolong life much later are out of the question as dietary insufficiency, linked to infection, remain the greatest cause of death.

Last updated: 06 Sep 2017 2:54pm
Brian J. Morris is an Emeritus Professor at the School of Medical Sciences and Bosch Institute, in The University of Sydney

Caloric restriction extends lifespan and healthspan in experimental animals, but for humans is arduous, with few people willing to undertake the ordeal of cutting food intake by 30 per cent.

For decades, researchers have sought a means of producing the same outcome with a ‘pill’. Since caloric restriction shifts metabolism from burning carbohydrates to burning fats for energy production, so causing the formation of ketone bodies, it was reasonable to test whether a ketogenic diet might mimic the benefits of caloric restriction.

In a new study published in the prestigious journal Cell, researchers in California found that indeed it did, at least in mice. It is most probable that this approach could improve health outcomes, slow diseases of ageing and increase human lifespan.

Last updated: 05 Sep 2017 5:39pm
Professor Helen Truby is from the Department of Nutrition, Dietetics & Food at Monash University

These well conducted and controlled studies in mice suggest that mice provided with very tiny amounts of carbohydrate benefit in terms of better memory to complete tasks such as mazes, more muscle function, and longevity compared to control mice.
 
There has long been interest in humans to restrict dietary carbohydrate to extremely low levels in order to induce weight loss. In most studies, these diets have been tested in the very short term due to the difficulties that humans have in adhering to extremely low carb diets necessary to maintain ketosis.

This would mean in a human adult only 20-30g of carbohydrates per day - a dietary pattern that would lead to deficiency in vitamins and minerals unless the diet is carefully constructed, and would usually require micro-nutrients and minerals to be provided by supplements.

Feelings of hunger and desire to eat are reduced whilst the body is in the state of ketosis, which may help explain why people eat less. However, in humans who have lost weight using ketosis-inducing diets will re-gain that weight unless the are able to maintain a lower energy intake as appetite returns.* 
 
The results of the memory improvements are intriguing in these mice experiments and provide a clue as to how the brain may operate using ketones rather than glucose as a fuel. The precise mechanisms need to be understood further as they may be helpful to people with severe diseases of the brain, such as epilepsy. 
 
So, should people start ketogenic diets? Answer: not unless there is a medical indication to do so and under the guidance of an accredited practising dietitian who can ensure nutritional adequacy.

In terms of ketosis being the cure for memory loss - I doubt anyone would be able to stick to the sort of strict low carb regimen necessary for long term use and therefore its applicability to humans is currently limited by the unpalatability of the dietary pattern that is required.

Last updated: 05 Sep 2017 5:38pm
Professor Manny Noakes is an Adjunct Research Professor in the School of Health Sciences at UniSA

These studies are interesting in that they provided the dietary changes midlife rather than post-weaning, which is often the case. As such, this would make these studies somewhat more relevant to changing diets during adulthood.

However, as useful as the studies were to understand biological pathways, any extrapolation to humans needs caution. We note that firstly, the mice were lean (unlike most Australians these days), and secondly, that the “control diets” were 65-77% high glycaemic carbohydrates and included a significant amount of sucrose.

So is it that the low carbohydrate/ketogenic diet is relatively effective or is it that the “control diet” is relatively adverse? I might suggest the latter but at least there is an increasing research effort into understanding lower carbohydrate dietary patterns, which have been on the fringes in the scientific literature until now.

Our own work supports the metabolic advantages of less refined carbohydrate diets in humans with a more liberal approach to fat.

Last updated: 05 Sep 2017 5:35pm

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