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.
Highlights
Neoplastic disease is inextricably associated with aging
We explored the fate of normal hepatocytes transplanted into the liver of aged animals exposed to either ad libitum (AL) or Caloric restriction (CR)
This was largely based on our earlier observation indicating that the tissue microenvironment of the aged rat liver supports the clonal expansion of hepatocytes isolated from a normal young donor, while the liver of young recipients was not permissive [13]
Summary
Neoplastic disease is inextricably associated with aging. Five out of six cancer-related deaths occur in patients aged 60 years and older [1]. An important concept emerging from the literature is that aging and cancer do not merely represent two chronologically parallel processes, but they share relevant pathogenetic mechanisms [2,3,4,5]. Along these lines, in a recent study we have provided evidence to indicate that aging promotes the growth of pre-neoplastic cells through alterations imposed on the tissue microenvironment, i.e. by generating an age-associated, neoplastic-prone tissue landscape [3]. Henry et al have reported that aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors [2]; it was proposed that cell competition may drive the emergence of oncogenically altered cells in a background of age-induced decline in tissue fitness, in a process that has been referred to as “adaptive oncogenesis” [4, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
