Short term fasting shows beneficial effects in humans, mice and yeast

A diet designed to mimic fasting over short time scales was shown to reduce health risk factors in a pilot human trial, and increased lifespan in both mice and yeast. The authors of the study, published in Cell Metabolism, suggest their ‘Fasting Mimicking Diet’ which drastically reduces caloric intake for five days per month has high potential to promote human health and longevity. The diet had a positive impact on biomarkers for aging, diabetes, cardiovascular disease and cancer for participants in the trial, while the mice showed improved cognitive performance, increased stem cell count and tissue regeneration, and decreased cancer incidence. 

 
 

Dr. Marc Hellerstein, Robert C. and Veronica Atkins Professor of Human Nutrition, Department of Nutritional Sciences and Toxicology, University of California, Berkeley and Professor of Endocrinology, Metabolism and Nutrition, University of California, San Francisco (webpage):

Expertise: study of metabolic regulation using modern tracer techniques to answer questions concerning the regulation of disease-modifying pathways by diet, genes, drugs and other factors, and to apply these techniques in humans. Dr Hellerstein has studied the effects of calorie restriction, alternate-day fasting and calorie-restriction mimetics onbiomarkers of longevity and cancer progression.

“Two long-standing goals of metabolic researchers have been to mimic the remarkable effects of long-term calorie restriction on longevity and health-span through less burdensome interventions and to translate results observed in rodents to humans. Some important cautions have become clear after more than a half-century of work in this area. Effects on life-span should include non-cancer effects to be translatable (since older mice in captivity die disproportionately from cancer) and should show extension of maximal lifespan, not just compression of early mortality; effects are most relevant and interesting if dissociated from weight loss, since life-long underweight is unlikely to be translatable; and biomarkers chosen should have functional significance and be translatable into humans.

“The report of Brandhorst et al makes many claims but, unfortunately, does not stand us to careful scrutiny. The studies in mice are confounded by the fact of lower body weights; which provides an uninteresting explanation for changes in body fat, glucose, insulin, IGF-1, etc. In addition, several of the molecular biomarkers presented are of completely unknown physiologic significance (e.g., what do changes in muscle transcription factors MyoD, MyoG or Pax7 mean? Are P62 levels the same as autophagic flux? What does Ki67 expression for a few days in liver cells mean? Why are increased numbers of mesenchymal stem cells a sign of rejuvenation if hematopoeitic stem cell numbers increase with normal aging?). Other markers are not significantly changed, but are discussed as though meaningful (e.g., inflammation markers). The effects on cognition and behavior are of some interest, but improvements in the rotarod test of muscle function are not significant after correction for lower body weight and increases in neurogenesis are well known with a variety of non-specific interventions, such as environmental enrichment, exercise, etc.

“Importantly, they show no increase in maximal lifespan, just a delay in median death, and the effect is entirely on cancer (in fact, there is an increase in non-cancer deaths).  Nor is this novel – other intermittent fasting interventions have shown similar results in rodents.

“The clinical study does not meet the criteria for a proper trial and is inadequately described (e.g. why did 20% of subjects drop out?).  Again, there was weight loss (3%), which could explain the modest changes in serum glucose. They do not present insulin or test insulin sensitivity data. The changes in trunk fat are not significant, though discussed as if they were. Indeed, for a high impact journal, the quality of review here was disappointing. Several statements about “rejuvenating effects” are allowed, though completely speculative; non-significant results are discussed as though significant; the authors say that food intake was not different in mice, but they do not show increased expenditure to explain the very reduced body weights; the clinical trial is poorly described; the modest nutritional intervention is inappropriately medicalized (“potent and broad spectrum”- why would any toxic effects be expected after  5 days of 35-55% caloric intake?); and it is allowed to read more like an advertisement than a research article.

“In summary, this study adds to the intriguing area of periodic fasting but has many flaws that make it not close to ready for recommendation as a diet. Many or most of the effects may be explained by modest weight loss; the changes in lifespan do not meet rigorous criteria for relevance (effect is only cancer-related with no increase in maximal life-span); the human study is quite weak and also involves weight loss. The conclusions are very much over-stated and physicians should not use this publication as a basis to recommend the diet.”

 

Dr. Rafael de Cabo, Senior Investigator, Chief, Translational Gerontology Branch, National Institute on Aging (webpage):

Expertise: consequences of dietary interventions and caloric restriction on lifespan, pathology, and behavioral function; physiological and molecular approaches to study effects of nutritional interventions on aging and age-related diseases.

“The study design is elegant and the biomarkers used are appropriate. The results of the study show that periodic feeding of a fasting mimicking diet offers many benefits to yeast, mice and men. Depending on the organism the benefits go from stress resistance, improved biomarkers of some age-related diseases and to increased cognitive performance and lifespan extension in mice. In mice and humans the fasting mimicking diet results in decreased risk factors for chronic diseases like cardiovascular disease and diabetes.

“The feeding strategy used in the study is quite different from caloric restriction, a pretty robust intervention used to delay aging processes and that leads to many long term health benefits. In a caloric restriction experiment, the organism is allowed a limited amount of calories per day (typically a reduction of 40% from compared to the ad libitum controls) throughout its lifespan. In this study the dietary intervention, is periodic cycles of a fasting mimicking diet. This method offers a new tool for researchers to study the underlying mechanisms of this intervention on longevity, aging and age-related diseases.

“Valter Longo and his team have used the understanding that they have gained over the years from his work in yeast, translated it into mice and then humans. This is a great demonstration of how, basic research in the biology of aging is starting to be translated into humans, an excellent example of how to go from the bench to bedside.

“We still need a lot more work about the underlying mechanisms of the benefits evoked by the fasting mimicking diets to provide solid grounds to further develop its applicability to humans in the context of health and disease. It will also be equally important to determine the “if, how, when, for how long, to whom” these diets can be prescribed under the supervision of a physician/nutritionist. Further longer term clinical trials will be able to address these issues.”

 

Dr. Francene M. Steinberg, Professor and Chair, Department of Nutrition, University of California, Davis (webpage):

Expertise: physiologic effects of bioactive food components that reduce risk factors for cardiovascular and obesity-related chronic diseases, characterize metabolic responses that promote health and chronic disease risk reduction.

“Caloric restriction in animal models has been associated with increased longevity for some time. The scientific literature using nematodes or inbred rodent strains usually shows benefits with regard to aging. However, the outcomes of caloric restriction on aging show much more modest effects in primates and the ultimate benefits in humans are somewhat uncertain. This illustrates that caution should be used when generalizing the results of animal studies directly to humans.

“Intermittent fasting has been used by researchers as one strategy for dietary caloric restriction to improve health biomarkers and lifespan in animals. The results of the mouse study in this paper are consistent with that.  The other part of the article, the fasting mimicking diet protocol that was pilot tested in humans, produced some interesting and provocative results. The biomarkers used were mostly markers of diet compliance, which indicate that the fasting mimicking diet was being consumed. C Reactive Protein, a marker of cardiovascular risk, did decrease significantly after the diet. However, it should be noted that the study subjects started out at an average level and were not at high risk to begin with. The measure of stem and progenitor cells did not change; therefore this short pilot does not prove that regeneration was promoted in these individuals after the fasting mimicking diet regimen. Finally, the subjects did lose a small but significant amount of weight at the end of the three month period. 

“The human pilot study did not test all the same outcomes that the mouse study examined (i.e. cognitive performance, lifespan, cancer development, and tissue and organ rejuvenation). This pilot study does not enable a distinction to be made about whether the changes in the metabolic markers in the humans are simply due to the weight loss that occurred or whether they are specifically related to the fasting mimicking diet protocol per se.  A larger study will be needed using more people and comparing the fasting mimicking diet protocol to other diets and to other means of similar weight loss, in order to tease apart what aspect is driving the metabolic changes.

“Healthy aging is not just about lengthening lifespan, but especially about delaying or preventing chronic degenerative diseases. Nutritional interventions to promote healthy aging are much broader than just caloric restriction. Promotion of health includes a variety of lifestyle choices and proven healthy eating patterns, such as the Mediterranean diet, USDA dietary guidelines and the Dietary Approaches to Stop Hypertension (DASH).  At this time, there are too many questions about the long term effectiveness of the fasting mimicking diet protocol, which has not yet been broadly tested in large numbers or in individuals at high risk or who have chronic diseases; therefore fasting mimicking diet should not be recommended as a diet protocol based only on the results of this early human pilot trial.”

 

Dr. Beau Kjerulf Greer, Associate Professor, Exercise Science and Nutrition Sacred Heart University (webpage):

Expertise: exercise and nutritional influences on weight management and chronic disease risk, efficacy of dietary supplements for health or sport.

“The data reported by Brandhorst et al. provide further support of cyclically applied fasting bouts for chronic disease risk reduction in humans, and reduction of chronic disease per se in lower organisms.  Although actual disease endpoints would not expected in a pilot trial, the rodent data provide some degree of support for expected efficacy (beyond simply biomarkers) among free-living humans.  It is also appreciated that researchers have realized investigating long-term caloric restriction in humans is of limited clinical use and have instead turned to investigating strategies with better chances for patient adherence.

“The design methodology and statistical treatment of data are all appropriate.  My sole methodological concern in the human pilot trial is the lack of physical activity monitoring during the fasting mimicking diet period.  As evidence exists that multiple mammals will increase spontaneous physical activity while in a caloric deficit, it is logical that humans may respond similarly and consequently monitoring physical activity via accelerometry would have potentially provided support that none of the benefits of fasting mimicking were influenced by alterations in physical activity.

“A concern among this line of research has been applicability or danger of use with frail or elderly populations, due to expected losses in bone density and/or lean body mass. Although lean mass body actually increased in the human trial, large decreases in Insulin-like Growth Factor (IGF) and a temporary increase in IGF binding protein 1 may extend concerns regarding bone density.  Consequently, the regeneration of bone cells after fasting in rodents (and actual increase in bone density) is perhaps the most unique result of the entire study when compared to similar intermittent fasting trials, and provides support for prolonged clinical trial safety. 

“Additionally, it’s important to note that this investigation only provides evidence for human cardiovascular disease, diabetes, and cancer risk reduction through the use of 1-2 biomarkers each.  C-reactive protein, while arguably a better predictor of cardiovascular disease than total cholesterol (a heavily maligned marker itself), is not of great predictive use when viewed independently of other risk factors.

“Physicians have a notable lack of nutrition education (< 20 hours average in U.S. medical schools), and therefore most should not attempt to prescribe similar fasting mimicking diets without the assistance of a registered dietician.  While the evidence across species is compelling, it may be premature to recommend practitioner use of such a dietary scheme at this point.  After all, the field of dietary restriction and longevity is characterized by diminished effect sizes when applying strategies to the human model. To their credit, authors of the present study use appropriate language when discussing the application and interpretation of results.”

 

Reference:
A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan‘ by Bandhorst et al., published in Cell Metabolism on Wednesday June 18, 2015.

 

Declared interests (see GENeS register of interests policy):

No interests declared

 

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