Effects of Calorie Restriction on Health Span and Insulin Resistance: Classic Calorie Restriction Diet vs. Ketosis-Inducing Diet

Abstract

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.

Keywords: calorie restriction; chronic non-communicable diseases; diet; fasting; health span; insulin resistance; ketosis; lifespan; low-calorie; low-carb; metabolic syndrome.

Figure 1

Illustration of the terms used to describe different types of fasting. ADF: Alternate Day Fasting; IF: Intermittent Fasting; ADMF: Alternate Day Modified Fasting; PF: Periodic Fasting; TRF: Time Restricted Feeding.

Figure 2

Circadian clock and effects of eating behaviors. CNCD: Chronic Non-communicable Diseases. CR: Calorie Restriction; CVD: Cardiovascular Diseases.

Figure 3

Cellular metabolic pathways activated during feeding and calorie restriction and fasting. During feeding, insulin and IGF1 lead to the activation of the insulin-pAKT-mTOR pathway, that drives downstream gene activities that promote anabolic processes, cell growth and cell survival. This pathway, although crucial for the organism, also favor the Warburg effect (aerobic glycolysis in cancer cells). In contrast, CR or a few hours of fasting activate AMPK, which triggers repair and catabolic processes, as well as autophagy. CR and fasting have an anti-Warburg effect by counteracting the insulin and IGF1 pathways. AKT: Protein Kinase B; AMPK: AMP-activated protein Kinase; CR: Calorie Restriction; IGF1: Insulin-like Growth Factor 1; IRS: Insulin Receptor Substrates; MAP: Mitogen-Activated Protein; mTOR: mechanistic Target OF Rapamycin; PI3K: Phosphoinositide 3-Kinase; PIP2: Phosphatidylinositol biphosphate; PIP3: Phosphatidylinositol triphosphate; ULK1: Serine/threonine-protein kinase 1.