This visual abstract reflects the finds of Stekovic et al., who show in the clinic that alternate day fasting (ADF) is a simple alternative to calorie restriction and provokes similar improvements on cardiovascular parameters and body composition. ADF was shown to be safe and beneficial in healthy, non-obese humans, not impairing immune function or bone health. [Stekovic et al./Cell Metabolism]

It may be a fairly extreme approach to dieting, but alternate day fasting (ADF) could have some health benefits above that of helping people to lose weight, according to results of a controlled study in healthy human volunteers. The largest study of its kind found that alternating 36 hours of zero calorie intake with 12 hours of unlimited eating for four weeks was associated with significant weight loss and improved fat-to-lean ratio, but also positive changes in cardiovascular disease risk factors, and anti-aging markers. “The elegant thing about strict ADF is that it doesn’t require participants to count their meals and calories: they just don’t eat anything for one day,” said Thomas Pieber, head of endocrinology at the Medical University of Graz, and senior author of the international research team’s study, which is reported in Cell Metabolism, and titled, “Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.”

Restricting how many calories are eaten, or caloric restriction (CR), is known to prolong lifespan and healthspan in animal models, including nonhuman primates, the authors wrote. Trials in humans have been launched to see whether these benefits also translate to humans. However, CR can be hard to maintain, and has also been linked with suppressed immune systems, lower levels of circulating white blood cells and reduced bone density. In contrast, the researchers continued, intermittent fasting (IF) could potentially represent a more “easily manageable alternative to constant CR,” while retaining similar health benefits. “However, there is still some debate about the safety and efficiency of CR and IF, particularly on healthy humans.”

ADF represents one of the more extreme forms of IF. It’s a diet regimen during which the individual eats and drinks nothing that contains any calories for 36 hours (fast days), but then is allowed to eat without restriction for 12 hours (feast days). To investigate the potential safety and effectiveness of ADF directly, the team set up a controlled trial in healthy, non-overweight human volunteers, through which they measured the effects of four weeks of strict ADF on cardiovascular parameters such as heart rate, blood pressure, cholesterol levels, CVD risk, and body composition. The study also evaluated the potential influence of ADF on the immune system, bone mineral density, and bone mass. “This is the first study, to the best of our knowledge, that comprehensively reports the effects of short- and long-term strict ADF on the physiology, cardiovascular system, and body composition in a nonobese cohort,” the investigators stated.

They enrolled 60 healthy, normal weight volunteers into the four week trial. Participants were randomized to either an ADF group, or were assigned to the control group that could continue their normal eating patterns. Participants in the ADF group underwent continuous glucose monitoring to ensure they didn’t take in any calories on their fasting days. They were also asked to fill in diaries documenting their fasting days. They otherwise lived their normal, everyday lives.

The researchers separately studied a group of 30 people who had already practiced more than six months of strict ADF prior to the controlled study enrollment. The team compared these individuals to normal, healthy controls who had no fasting experience, primarily as a way of examining the long-term safety of the ADF.

“Strict ADF is one of the most extreme diet interventions, and it has not been sufficiently investigated within randomized controlled trials,” said Frank Madeo, PhD, a professor at the Institute of Molecular Biosciences at Karl-Franzens University of Graz. “In this study, we aimed to explore a broad range of parameters, from physiological to molecular measures. If ADF and other dietary interventions differ in their physiological and molecular effects, complex studies are needed in humans that compare different diets.”

The results showed that during their 12 hours of normal diet, the ADF participants did compensate for some, but not all of the calories lost from fasting, noted Harald Sourij, PhD, a professor at the Medical University of Graz. “Overall, they reached a mean calorie restriction of about 35% and lost an average of 3.5 kg [7.7 lb] during the four weeks of ADF.”

Results from the four week controlled trial period also showed that ADF group participants had lower levels of cholesterol, and reduced lipotoxic android trunk fat mass (belly fat). “ADF reduced the total body weight, waist-to-hip ratio, fat mass, and fat-free mass in obese individuals and in patients at medium- to high-risk of CVD,” the team noted. The ADF group participants also exhibited reduced levels of sICAM-1, a marker linked with age-associated disease and inflammation, and lower levels of triiodothyronine without impaired thyroid gland function. Reduced levels of this hormone have previously been linked with human longevity. ADF group individuals in addition exhibited continued upregulation of ketone bodies, even on non-fasting days, which has previously been shown to promote health, and demonstrated fluctuating downregulation of amino acids, and particularly methionine, which has been linked with increased lifespan in rodents.

“Given the simple protocol and few guidelines the probands had to follow, ADF seems to be an easy way to achieve high levels of CR in non-obese humans,” the scientists stated. “… Given the general good health conditions and low baseline risk of the groups, the observed improvement suggests short-term ADF as a valid intervention to improve cardiovascular health in the general population.” However, Pieber acknowledged, there are still some unknowns. “Why exactly calorie restriction and fasting induce so many beneficial effects is not fully clear yet.”

Results from the team’s evaluation of individuals who had already undertaken six months of strict ADF found no evidence to suggest that this form of intermittent fasting can lead to compromised immune systems, which contrasts with previous results for CR. “The reason might be due to evolutionary biology,” Madeo explained. “Our physiology is familiar with periods of starvation followed by food excesses. It might also be that continuous low-calorie intake hinders the induction of the age-protective autophagy program, which is switched on during fasting breaks.”

Compared with the control group, the six-month ADF individuals also demonstrated “… lower levels of circulating total cholesterol, low density (LDL), very low-density lipoprotein (VLDL), and triglycerides compared to the control group, while high-density lipoprotein (HDL) was similar in both groups. In line with the effects of four weeks of ADF, we observed lower heart rate in the >6 months of ADF group supporting the hypothesis that ADF may lead to improved cardiovascular health.”

“ADF and CR may share large overlaps in their beneficial effects on the human body, with obvious differences regarding the oscillating nature of ADF,” the researchers concluded. “Whether these additional features of ADF are increasing the beneficial impact on the health status, needs to be studied in future trials.”

Despite these promising findings, the authors advocate caution, as the consequences of a strict ADF diet exceeding the period of six months aren’t known. “Thus, it will be important to compare ADF and CR interventions in humans with matched levels of caloric reduction and to further validate preclinical findings, such as the essential role of the gut microbiome in the beneficial effects of periodic fasting.”

In the meantime, the researchers say it’s probably wise not to think of ADF as a general nutrition scheme for everybody. “We feel that it is a good regime for some months for obese people to cut weight, or it might even be a useful clinical intervention in diseases driven by inflammation,” Madeo said. “However, further research is needed before it can be applied in daily practice. Additionally, we advise people not to fast if they have a viral infection, because the immune system probably requires immediate energy to fight viruses. Hence, it is important to consult a doctor before any harsh dietary regime is undertaken.”

They plan to continue their research and study the effects of strict ADF in different groups of people, including those with obesity and diabetes. They also aim to compare ADF to other dietary interventions and to further explore the molecular mechanisms in animal models.


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