Intermittent and Periodic Fasting, Hormones, and Cancer Prevention

Abstract

The restriction of proteins, amino acids or sugars can have profound effects on the levels of hormones and factors including growth hormone, IGF-1 and insulin. In turn, these can regulate intracellular signaling pathways as well as cellular damage and aging, but also multisystem regeneration. Both intermittent (IF) and periodic fasting (PF) have been shown to have both acute and long-term effects on these hormones. Here, we review the effects of nutrients and fasting on hormones and genes established to affect aging and cancer. We describe the link between dietary interventions and genetic pathways affecting the levels of these hormones and focus on the mechanisms responsible for the cancer preventive effects. We propose that IF and PF can reduce tumor incidence both by delaying aging and preventing DNA damage and immunosenescence and also by killing damaged, pre-cancerous and cancer cells.

Keywords: DNA damage; aging; cancer prevention; fasting; growth hormones.

Figure 2

CONSORT diagram. CONSORT diagram of participants selected for the clinical study described by Brandhorst et al., and Wei et al. [112,140]. In the clinical study, 100 participants were enrolled; 48 subjects were randomized to a control group and were asked to continue their normal diet for 3 months and then were subjected to 3 FMD cycles (16 participants withdrew or were excluded throughout the study). Instead, 52 subjects were randomized to the FMD group; FMD was provided for 5 consecutive days per month, for 3 months (13 subjects withdrew or were excluded throughout the study). [112,140].

Figure 3

A periodic diet that mimics fasting promotes longevity and reduces risk factors involved in age-related diseases. The fasting mimicking diet (FMD) is characterized by low proteins and sugars and relatively high unsaturated fats. This dietary regimen is able to mimic the metabolic changes induced by water-only fasting while lowering the burden and risk for side effects [112,140]. Preclinical studies show that periodic cycles of FMD can significantly reduce blood glucose, IGF-1, leptin and insulin levels in mice, while increasing ketone bodies production and IGFBP-1 levels. These metabolic changes promote immune system regeneration and rejuvenation while reducing neoplasia incidence by 45%, inflammation associated skin lesions by 50% and obesity [112]. Analogously to rodents, also in humans, periodic FMD decreases blood glucose, insulin, IGF-1, and leptin levels while increasing ketone bodies and IGFBP-1, metabolic changes partially maintained even after the refeeding period [112,140]. These FMD-dependent effects are of particular interest given their key role in age-related diseases, especially cancer and metabolic disorders. Taken together, these data indicate that periodic cycles of FMD could prevent obesity and reduce cancer risk in humans, as suggested by results obtained in preclinical trials [112].

Figure 1

Conserved nutrient signaling pathways in yeast, worms, flies and mammals. A schematic model of the conserved nutrient-signaling pathways that regulate stress response mechanisms, DNA damage, longevity and cancer in different model organisms [22]. In Saccharomyces cerevisiae, glucose and amino acids activate Ras/AC/PKA and TOR/Sch9 pathways, respectively. Their activation leads to serine-threonine kinase Rim15 inhibition and consequently to a lowering in Msn2/Msn4 stress resistance transcription factors. These mechanisms promote aging in part by decreasing cell stress response and repair thus increasing DNA damage [20]. In Caenorhabditis elegans, insulin/IGF-1 receptor like (daf-2) signaling, through the activation of AKT/PKB pathway, inactivates the Forkhead FoxO transcription factor daf-16, which is involved in the regulation of genes implicated in the cellular stress response and protection against free radicals. As in yeast, also in worms, amino acids can activate the TOR/S6K pathway, accelerating the aging process [44]. Analogously to worms, in Drosophila melanogaster growth factors and amino acids activate AKT/PKB and TOR/S6K pathways, respectively [47]. The activation of TOR/S6K, PI3K/AKT and Ras/AC/PKA pathways, mediated by glucose, amino acids and IGF-1 like signaling, is also maintained in rodents and other mammals, suggesting that these nutrient-sensing pathways, involved in longevity and stress-response mechanisms, are conserved, in part, from the simplest model organism to humans [22,63].