There is an accumulation of fascinating scientific evidence that intermittent calorie restriction (ICR) offers a number of advantages over continuous calorie restriction (CCR) for successful long term weight loss and the ‘turning on’ of genes that favor longevity. Consider a study published recently in the International Journal of Obesity in which the investigators compared ICR and CCR for weight loss and metabolic disease risk markers in overweight women. The authors state:

“Excess weight and weight gain during adult life increases the risk of several diseases including diabetes, cardiovascular disease (CVD), dementia, certain forms of cancer including breast cancer, and can contribute to premature death. Observational and some randomised trials indicate that modest weight reduction (>5% of body weight) reduces the incidence and progression of many of these diseases. Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known.”

Moreover…

“Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation. Sustainable and effective energy restriction strategies are thus required.”

In other words, a method that can be comfortable enough to be accepted into daily life for the long that also avoids loss of improvements due to adaption is required.

“One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction.”

So the authors set out to…

“…compare the feasibility and effectiveness of IER with CER for weight loss, insulin sensitivity and other metabolic disease risk markers…This is the largest randomised comparison of an isocalorific intermittent vs. continuous energy restriction to date in free living humans..”

They designed a randomised comparison of a 25% energy restriction as IER (~2266 kJ/day which equals 541 calories per day for 2 days/week) or CER (~6276 kJ/day equaling 1499 calories each day for 7 days/week) in 107 overweight or obese premenopausal women for a 6 month study period. They measured an extensive list of biomarkers at baseline and after 1, 3 and 6 months: weight, anthropometry (size, weight and proportions), biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, IGF-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain derived neurotrophic factor. What did the data show?

“Last observation carried forward analysis showed IER and CER are equally effective for weight loss, mean weight change for IER was −6.4 kg vs. −5.6 kg for CER. Both groups experienced comparable reductions in leptin, free androgen index, high sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than CER; difference between groups for fasting insulin −1.2 μU/ml, and insulin resistance −1.2 μU/mmol/L.”

Regarding concerns about tolerance…

“A recent blinded trial of a 2 day VLCD [very low calorie diet] (1311 kJ/day [313 calories per day!]) reported no adverse effects on cognition, energy levels, sleep or mood, suggesting symptoms are expected with VLCD and therefore experienced and could potentially be overcome with appropriate counselling. Importantly IER did not lead to overeating on non-VLCD days.”

The authors briefly summarize the results of their comparison of IER and CER by concluding:

“IER is as effective as CER in regards to weight loss, insulin sensitivity and other health biomarkers and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.”

That’s not all though. The authors additionally note an extremely interesting observation with profound implications and potential for benefit regarding additional benefits of an intermittent very low calorie method:

“Recent reviews speculate that IER may be associated with greater disease prevention than CER due to increased cellular stress resistance, in particular increased resistance to oxidative stress. This is thought to be mediated by ‘hormesis’ whereby the moderate stress of energy restriction increases the production of cytoprotective, restorative proteins, antioxidant enzymes and protein chaperones. Alternate day fasting has been linked to increased SIRT-1 gene expression in muscle, and to greater neuronal resistance to injury compared to CER in C57BL/6 mice. The tendency for greater improvements in oxidative stress markers in our IER than in the CER group may support these assertions. Declines in long term protein oxidation product aggregates suggest IER as a possible activator of catabolism and autophagy.”

In other words, intermittent calorie restriction can be as effective as continuous calorie restriction for weight loss, but have the added advantage of ‘turning on’ genes beneficial for health and longevity and preventing adaptation that would result in regaining weight.

Other investigators also have compared intermittent with continuous calorie (daily) calorie restriction as in a study published recently in the journal Obesity Reviews. The authors set out to…

“…evaluate and compare the effects of daily CR versus intermittent CR on weight loss, fat mass loss, lean mass retention and visceral fat mass reduction, in overweight and obese adults.”

They undertook a review of studies that were randomized control trials, had a primary endpoint of weight loss and/or body composition changes, used daily CR or intermittent CR as the primary focus of the intervention; had a study duration of 4–24 weeks, and involved adult populations who were overweight or obese subjects but not diabetic. These included 11 daily continuous calorie restriction trials and five intermittent CR trials published between 2000 and 2010, along with two unpublished trials of intermittent CR from their own lab. What did all these studies add up to?

“Results reveal similar weight loss and fat mass loss with 3 to 12 weeks’ intermittent CR (4–8%, 11–16%, respectively) and daily CR (5–8%, 10–20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR.”

This is a significant advantage of ICR over CCR (continuous = daily calorie restriction). The authors conclude by stating:

“In sum, intermittent CR and daily CR diets appear to be equally as effective in decreasing body weight, fat mass, and potentially, visceral fat mass. However, intermittent restriction regimens may be superior to daily restriction regimens in that they help conserve lean mass at the expense of fat mass. These findings add to the growing body of evidence showing that intermittent CR may be implemented as another viable option for weight loss in overweight and obese populations.”

Numerous other studies have examined the distinctive benefits of intermittent calorie restriction. A paper published recently in the journal Oncogene investigates the positive effects of brief ICR compared to CCR for cancer patients. The authors state:

“The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.”

They point out that cancer cells are unable to respond to the positive stimuli of calorie restriction:

“Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells.”

Moreover…

“Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans.”

They go on to review studies on fasting, cellular protection and chemotherapy resistance, and futher compare them to those on continuous calorie restriction and cancer treatment. The authors conclude:

“Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.”

A study published in the Journal of Molecular and Cellular Cardiology offers evidence that intermittent calorie restriction activates genes that help in the recovery from heart damage. The authors state:

“Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI).“

Two weeks after myocardial ischemia was induced in their study animals, they were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks the authors evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival. The results were truly striking:

“Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4 ± 0.17 versus 3.9 ± 0.18. Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group. Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-α (3010 ± 350% versus 650 ± 151%), BDNF (523 ± 32% versus 110 ± 12%), and VEGF (450 ± 21% versus 170 ± 30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone.”

This is a dramatic indication that intermittent calorie restriction can be used to protect and repair heart tissue. The authors conclude:

“Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.”

Another fascinating study published recently in the journal Cancer Prevention Research demonstrates that intermittent calorie restriction is clearly superior to both continuous calorie restriction and an unrestricted diet for breast cancer prevention. Specifically, the authors studied…

“The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels…in relation to mammary tumorigenesis.”

Their subjects were assigned to ad libitum fed, ICR (3-week 50% caloric restriction followed by 3-wks 100% AL consumption), and CCR groups.

“Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad.”

This amounts to an impressive ‘turning on’ of genes that protect against breast cancer for ICR. In conclusion…

“…we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.”

A paper published in the journal Nutrition and Cancer demonstrates that ICR offers a greater protective effect than CCR for prostate cancer. The authors state:

“Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development.”

Their animal models for prostate cancer were assigned to ad libitum (AL), ICR, and CCR groups. There were distinctive differences according to the manner of calorie restriction that dramatically favored the ICR over both the AL and CCR cohorts:

“ICR mice were older at tumor detection than AL and CCR mice. There was no difference for age of tumor detection between AL and CCR mice. Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups.”

Not only did the subjects on CCR live longer with healthier biomarkers than the ones on either the free diet or CCR, there was no difference between the AL and CCR groups for age of tumor detection or survival. The implication is exciting: the benefits were due not to the weight loss component but to the way in which ICR affects gene expression. The authors conclude:

“These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.”

A paper published in the The Journal of Nutritional Biochemistry also offers evidence that intermittent calorie restriction protects heart tissue:

“It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats.”

The authors showed by echocardiographic analysis of heart structur and function that intermittent fasting attenuates the disease related increase in heart thickness, end systolic and diastolic volumes, and ejection fraction. Additionally…

“The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI.”

There is now a large body of evidence showing that ICR increases the protective hormone adiponectin much more than CCR. The authors conclude:

“Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.”

A paper published in the journal Ageing Research Reviews discusses how IFR and CCR can protect the brain from accelerated neurodegeneration associated with aging. The authors note:

“The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span.”

As we’ve seen regarding cardioprotection and tumorigenesis…

“CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease.”

These studies comprise the first post that illustrates the scientific basis for the Lapis Light Weight Loss & Gene Modulation Program that customizes intermittent calorie restriction according to the individual’s weight management and other health needs. Subsequent posts will offer additional scientific evidence important for other aspects of the program.