Chronic caloric restriction (CR) without malnutrition is known to affect different cellular processes such as stem cell function, cell senescence, inflammation, and metabolism. Despite the differences in the implementation of CR, the reduction of calories produces a widespread beneficial effect in noncommunicable chronic diseases, which can be explained by improvements in immuno-metabolic adaptation. Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. In this review, we define these modifications and systematically summarize the current evidence related to CR and the epigenome. We then explain the significance of genome-wide epigenetic modifications in the context of disease development. Although substantial evidence exists for the widespread effect of CR on longevity, there is no consensus regarding the epigenetic regulations of the underlying cellular mechanisms that lead to improved health. We provide compelling evidence that CR produces long-lasting epigenetic effects that mediate expression of genes related to immuno-metabolic processes. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Liver is the crucial organ as a hub for metabolic reactions. p16(INK4a) is a well-established cyclin-dependent kinase (CDK) inhibitor that plays important role in the molecular pathways of senescence, which lead to irreversible cell cycle arrest with secretion of proinflammatory cytokines and mitochondrial dysfunction. This study tested the hypothesis that cellular senescence regulated by p16(INK4a) is associated with high-fat diet in adult male rats. Sprague Dawley rats were fed a high-fat (HF) diet or a control (C) diet for 9 weeks after weaning. At 12 weeks of age, liver samples of male rats were collected to investigate the key genes and liver physiological status. Both mRNA and protein expression level of cellular senescence marker, p16(INK4a), was increased significantly in HF group when compared to C group. A decrease of tri-methylated histone H3 lysine 27 (H3K27Me3) in the coding region of p16(INK4a) was observed. On the other hand, mRNA and protein expression of another inhibitor of cyclin-dependent kinase, p21(Cip1), was decreased significantly in HF group; however, no significant chromatin modification was found in this gene. Histological analysis demonstrated hepatic steatosis in HF group as well as severe fat accumulation. Our study demonstrated that HF diet regulated cellular senescence marker p16(INK4a) through chromatin modifications, which may promote hepatic fat accumulation and steatosis.

Ablation of hnRNPI in intestinal epithelia modulates gut microbiota; causing dysbiosis. Increased ratio of fecal Paraclostridium bifermentans to Dubosiella sp. is a signature of inflammation in hnRNPI knockout mice. hnRNPI knockout exacerbated colitis from dextran sodium sulfate challenge in knockout mice. Bacterial metabolites produced by P. bifermentans and Dubosiella newyorkensis could impact colon health in mice. hnRNPI gene ablation exacerbates chemically induced inflammation and colitis; potentially increasing cancer risk.

(1) Background: Knockout (KO) of heterogeneous nuclear ribonucleoprotein I (Hnrnp I) in mouse intestinal epithelial cells (IECs) induced a severe inflammatory response in the colon, followed by hyperproliferation. This study aimed to investigate the epithelial lineage dynamics and cell–cell communications that underlie inflammation and colitis. (2) Methods: Single cells were isolated from the colons of wildtype (WT) and KO mice and used in scRNA-seq. Whole colons were collected for immunofluorescence staining and cytokine assays. (3) Results: from scRNA-seq, the number of DCLK1 + colonic tuft cells was significantly higher in the Hnrnp I KO mice compared to the WT mice. This was confirmed by immunofluorescent staining of DCLK1. The DCLK1 + colonic tuft cells in KO mice developed unique communications with lymphocytes via interactions between surface L1 cell adhesion molecule (L1CAM) and integrins. In the KO mice colons, a significantly elevated level of inflammatory cytokines IL4, IL6, and IL13 were observed, which marks type-2 immune responses directed by group 2 innate lymphoid cells (ILC2s). (4) Conclusions: This study demonstrates one critical cellular function of colonic tuft cells, which facilitates type-2 immune responses by communicating with ILC2s via the L1CAM–integrins interaction. This communication promotes pro-inflammatory signaling pathways in ILC2, leading to the increased secretion of inflammatory cytokines.

The present study identifies that maternal high-fat-diet-induced IL-4 upregulation is associated with DNA hypomethylation at the +6 kb region of the 3’ downstream region of the gene. Furthermore, our results confirm that the induced Il4 expression in the liver of male offspring corresponds to the induced immune cell, especially eosinophil, infiltration.