Time-restricted feeding delays the emergence of the age-associated, neoplastic-prone tissue landscape

Abstract

Aging increases the risk of cancer partly through alterations in the tissue microenvironment. Time-restricted feeding (TRF) is being proposed as an effective strategy to delay biological aging. In the present studies, we assessed the effect of long-term exposure to TRF on the emergence of the age-associated, neoplastic-prone tissue landscape. Animals were exposed to either ad libitum feeding (ALF) or TRF for 18 months and then transplanted with hepatocytes isolated from pre-neoplastic nodules. Both groups were continued ALF and the growth of transplanted cells was evaluated 3 months later. A significant decrease in frequency of larger size clusters of pre-neoplastic hepatocytes was seen in TRF-exposed group compared to controls. Furthermore, TRF modified several parameters related to both liver and systemic aging towards the persistence of a younger phenotype, including a decrease in liver cell senescence, diminished fat accumulation and up-regulation of SIRT1 in the liver, down-regulation of plasma IGF-1, decreased levels of plasma lipoproteins and up-regulation of hippocampal brain-derived growth factor (BDNF).These results indicate that TRF was able to delay the onset of the neoplastic-prone tissue landscape typical of aging. To our knowledge, this is the first investigation to describe a direct beneficial effect of TRF on early phases of carcinogenesis.

Aging and the Biological Response to Liver Injury

“…To delay biological aging, a time restriction feeding (TRF) was proposed in mice that underwent transplantation of hepatocytes isolated from preneoplastic nodules. 113 The TRF modified several parameters related to both liver and systemic aging, promoting the persistence of a younger phenotype, by decreasing liver cell senescence and reducing fat accumulation. In the same model, upregulation of SIRT1 was detected in the liver, together with downregulation of IGF-1 and decrease in plasma lipoprotein levels.…”

“…In the same model, upregulation of SIRT1 was detected in the liver, together with downregulation of IGF-1 and decrease in plasma lipoprotein levels. 113 Several works have highlighted the correlation between diet, aging, gene expression, and correct functioning of the digestive system. 114 Calorie restriction (CR) may extend longevity by modulating the mechanisms involved in aging.…”

Dietary patterns and the neoplastic‐prone tissue landscape of old age

“…In rodents, TRF was able to decrease the incidence of spontaneous hepatocellular carcinoma 76 and to limit the growth of transplanted preneoplastic cells in the liver. 80 Results with fasting-refeeding in mice subjected to alternate-day fasting had a major reduction in the incidence of lymphomas, 116 whereas fasting for 1 day/week delayed the emergence of spontaneous tumors in p53-deficient mice. 117 In aging mice subjected to FMD starting from 16 months of age, a delay in the emergence and progression of spontaneous lymphomas was observed.…”

“…77 Importantly, under controlled experimental conditions animals exposed to TRF are able to eat ≥90% of the food ration consumed by AL-fed controls, after a short training period of less than 1 week. [78][79][80] Among the best characterized effects of TRF is the prevention of obesity, which is a major risk factor for several diseases, including cardiovascular pathologies, cancer, chronic liver and kidney disease, and diabetes mellitus. 68 The ability of TRF to prevent excess increase in body weight was first shown in Drosophila melanogaster 72 and then confirmed in mice fed either regular or HFDs.…”

“…When one such regimen, namely, TRF, was tested for its ability to impact the emergence of the age-associated, neoplastic-prone tissue landscape, results were very similar to those obtained with CR, that is, long-term exposure to TRF diet reduced the clonal expansion of orthotopically transplanted preneoplastic hepatocytes. 80 Mechanistically, multiomics approaches have pointed to metabolic hubs associated with longevity and improved health conditions, including a decreased incidence of cancer, in experimental animals exposed to either CR or TRF. 122 Specific metabolic pathways involving amino acids glycine, serine, and threonine were implicated in life span extension, whereas short-chain fatty acids (SCFAs) and essential poly unsaturated fatty acids metabolisms were uniquely associated to health-span.…”