4. Caloric restriction

Caloric restriction (CR) is the most effective and reproducible dietary intervention known to affect aging process and increase the healthy lifespan in various model organisms from unicellular yeast to rodents and primates. There is no agreement on how severe a CR must be in order to confer benefits in different organs and systems. However, CR which in most cases involves a 20–40% reduction of dietary requirement relative to normal intake is a severe intervention that results in both beneficial and detrimental effects [63, 64]. Studies show that CR does not need to be prolonged for a long time to be effective, with the advantage that shortterm CR is easier to include in clinical practice. In this context, a genomic analysis revealed that the results obtained from short- and long-term CR were similar [65]. It is one of the most common and cost-effective interventions used to induce body weight reduction and control CVD risk factors. It is important to note that the induction of negative energy balance is mandatory for achieving the metabolic benefits of weight loss. Benefits on CV risk factors by reducing the daily caloric intake have been widely described in obese subjects [7, 65–67]. CR reduces body weight, waist circumferences (visceral fat), serum lipids, insulin level and improves insulin sensitivity. The decrease in adiposity leads to a reduction of proinflammatory adipokines (e.g. leptin, Il-6, TNF-α, etc.), oxidative stress as well as to an increase in the anti-inflammatory adipokines (e.g. adiponectin, omentin, etc.) [7, 66–68]. Weight loss enhances FMD, which significantly improves endothelial function in vitro [8].

The molecular mechanism of CR is complex. It involves downregulation of insulin (also IGF-1 pathway) and insulin-like signaling, the signaling of mTOR (mammalian target of rapamycin) kinase pathway, a rise in the energy balance modulator sirtuins (particularly sirtuin 1) as well as a decrease in pro-inflammatory mediators, growth factors and ROS production [63]. Especially sirtuins are responsible for some beneficial and longevity-promoting effects of CR in many species of animals—from fruit flies to mammals. They are implicated in many physiological effects as control of circadian clock, mitochondrial biogenesis, aging, apoptosis and inflammation [69].

Large observational data support a detrimental effect of obesity on the risk of several cancers, including breast and colon cancer, two of the most common cancers in North America and Europe [63]. The most important causes predisposing to cancer development in obese people are elevated female sex hormones, hyperinsulinemia and a high level of pro-angiogenic and pro-inflammatory factors. Relatively little data exist on the effects of weight gain or weight loss on the risk of cancers [63]. The lack of data on weight loss is likely a function of the small number of individuals able to achieve a sustained weight loss. It is relatively often emphasized that the risk of colorectal cancer is reduced due to weight loss [70]. The best evidence that weight loss can reduce the risk of cancer comes from recent studies in bariatric surgery patients [71]. Tumors become malignant when they attract new blood vessels. Angiogenic switch could be slowed down when special drugs which can stop a key angiogenic mediator—VEGF are used. This concept of angiogenesis was first described by the pediatric surgeon Folkma [72]. The balance between pro- and anti-angiogenic factors allows neoangiogenesis to occur. Angiogenesis could be inhibited through an action on VEGF, bFGF and MMPs. Additionally, high level of mitogenic insulin resistance (IR) correlates with some angiogenic factors [73]. It is well documented that pro-inflammatory cytokines in obesity are mitogenic and pro-angiogenic. CR can decrease (i) insulin signaling, (ii) angiogenic mediators, (iii) inflammation lowering pro-inflammatory adipokines, NF-κB signaling and COX-2 expression, (iv) pro-angiogenic leptin and (v) increase anti-angiogenic adiponectin [74–76]. This anti-inflammatory effect of CR contributes significantly to crucial endothelial function in regulating angiogenesis, hemostasis, vascular tone and vascular wall integrity. This modified effect of CR exerted on endothelium is not only caused by decreased inflammation and angiogenic factors, but also by regulating fibrinolysis, the integrity of the basement membrane and extracellular matrix proteins [20]. Plasminogen activator inhibitor-1 (PAI-1), t-PA, u-PA and also MMPs are involved in angiogenesis. The circulating levels of PAI-1 and MMPs are consistently decreased in response to CR [4]. Rats fed a diet reduced by 40% showed improved vascular EC function, reduced free radical production, expression of NF-κB and a decreased expression of pro-inflammatory genes such as IL-6, TNF-α, sICAM-1 or iNOS [77]. Furthermore, the positive effect of a reduced caloric intake leads to an increased expression of eNOS and transcriptional factor Nrf2 (nuclear factor erythroid 2-related factor), which produces anti-oxidative stress proteins, and activates the VEGFdependent metabolic pathways [64, 74, 77].
