Caloric restriction delays early phases of carcinogenesis via effects on the tissue microenvironment

Abstract

Caloric restriction (CR) is an effective and consistent means to delay aging and the incidence of chronic diseases related to old age, including cancer. However, the precise mechanisms responsible for the beneficial effect of CR on carcinogenic process are yet to be identified.In the present studies the hypothesis was tested that the CR might delay carcinogenesis via modulatory effects exerted on the age-associated, neoplastic-prone tissue microenvironment. Using a well characterized, orthotopic cell transplantation (Tx) system in the rat, preneoplastic hepatocytes isolated from liver nodules were injected into either old syngeneic rats fed ad libitum (AL) or animals of the same age given a CR diet (70% of AL feeding). Analysis of donor-derived cell clusters performed at 10 weeks post-Tx revealed a significant shift towards smaller class sizes in the group receiving CR diet. Clusters comprising more than 50 cells, including large hepatic nodules, were thrice more frequent in AL vs. CR animals. Incidence of spontaneous endogenous nodules was also decreased by CR. Markers of cell senescence were equally expressed in the liver of AL and CR groups. However, higher levels of SIRT1 and FOXO1 proteins were detected in CR-exposed livers, while expression of HDAC1 and C/EBPβ were decreased. These results are interpreted to indicate that CR delays the emergence of age-associated neoplastic disease through effects exerted, at least in part, on the tissue microenvironment. Nutrient-sensing pathways might mediate such modulatory effect.

Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota

“…For example, we have obtained evidence indicating that CR is able to modulate the age-associated, neoplastic prone tissue landscape in rat liver, thereby decreasing the growth of transplanted pre-neoplastic cells. 24 Even short term CR protects from metabolic heart disease, reduces the rate of renal senescence, proteinuria and triglyceridemia. [25][26][27] However, while the effects of HFD have been well characterized after short and long term exposure, the timing of the microbiota changes induced by CR has not been carefully evaluated so far.…”

Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver

“…Likely, the beneficial effects of CR rely on multiple, highly connected intraand inter-cellular pathways. These include the modulation of genomic stability [43], counteraction of age-related epigenetic alterations [44], promotion of autophagy and of the optimal balance between protein synthesis and degradation [45], maintenance of the stem cells niche [46], regulation of tissue microenvironment [47] and of gut microbiota [48], amongst others.…”

Effects of Dietary Restriction on Cancer Development and Progression

“…It has been observed that aging promotes neoplastic cell growth and proliferation through surrounding microenvironment alterations. This process, named "adaptive oncogenesis," is determined by tissue decline caused by age and oncogenic cell alterations (Cadoni et al 2017). Changes in age-associated tissue microenvironment seem to play an important role in cancer and cancer-related diseases.…”

“…Although the mechanisms responsible for delays in aging and carcinogenesis have not been fully identified, CR is today the only known nongenetic approach able to extend organism life. Nutrient-sensing pathways play a pivotal role in cellular response to CR probably because these regulatory processes are responsible for maintaining a microenvironment that promotes aging and carcinogenicity (Cadoni et al 2017).…”