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As the incidence of Chronic Non-Communicable Diseases (CNCDs) increases, preventive approaches become more crucial. In this review, calorie restriction (CR) effects on human beings were evaluated, comparing the benefits and risks of different CR diets: classic CR vs. ketosis-inducing diets, including intermittent fasting (IF), classic ketogenic diet (CKD), fasting mimicking diet (FMD), very-low-calorie ketogenic Diet (VLCKD) and Spanish ketogenic Mediterranean diet (SKMD). Special emphasis on insulin resistance (IR) was placed, as it mediates metabolic syndrome (MS), a known risk factor for CNCD, and is predictive of MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

Concluding, with the data from recent studies about metabolic regulation with CR dietary strategies (from the most classic low-calorie diet to the emerging low-carb ketogenic diet approaches), we are convinced that the paradigm that has guided dietary prescriptions and the work of physicians and scientists in the last decades (based on the food pyramid, 50–60% carbohydrates, and lipid restriction) for the prevention of chronic cardiovascular disease, dyslipidemia and diabetes, will have to change and adapt to the newest evidence. Changes in dietary paradigms have previously happened, such as with the false idea that sardines and eggs caused dyslipidemia, and well-designed robust studies are already challenging the current dietary paradigm. As evidence grows, we believe official guidelines will tend to dramatically reduce the percentages of carbohydrates, especially those derived from grains in the form of refined flours with a high glycemic index, and increase the percentage of unprocessed fat, animal or vegetable, preferably from sources of omega 3, 6 and 9 with appropriate proportions, and a normoproteic ratio as stipulated (0.8–1 gr/kg of weight). Similar proportions were evaluated with great results in the SKMD, based on fish, egg, poultry, and legumes as sources of protein, olive oil as the main source of fat and vegetables as a source of carbohydrates.