The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Effects of Intermittent Fasting on Health and Aging Evidence is accumulating that eating in a 6-hour period and fasting for 18 hours can trigger a metabolic switch from glucose-based to ketone-base...

https://www.nejm.org/doi/pdf/10.1056/NEJMra1905136

Effects of Intermittent Fasting on Health, Aging, and Disease

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.

/pdf/gut-microbiome-profound-implications-for-diet-and-disease-2lv5nkm7m0.pdf

Gut Microbiome: Profound Implications for Diet and Disease

The Ah receptor (AHR) is a ligand-activated transcription factor that mediates a pleiotropic response to environmental contaminants such as benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. In an effort to gain in- sight into the physiological role of the AHR and to develop models useful in risk assessment, gene targeting was used to inactivate the murine Ahr gene by homologous recombination. Ahr 2/2 mice are viable and fertile but show a spectrum of hepatic defects that indicate a role for the AHR in normal liver growth and development. The Ahr 2/2 phenotype is most severe between 0-3 weeks of age and involves slowed early growth and hepatic defects, including reduced liver weight, transient microvesicular fatty metamorphosis, prolonged extramedul- lary hematopoiesis, and portal hypercellularity with thicken- ing and fibrosis.

Characterization of a murine Ahr null allele: Involvement of the Ah receptor in hepatic growth and development (dioxiny2,3,7,8-tetrachlorodibenzo-p-dioxinygene targetingyliver)

Conceptual scientific and medical advances have led to a recent realization that there may be no single, one-size-fits-all diet and that differential human responses to dietary inputs may rather be driven by unique and quantifiable host and microbiome features. Integration of these person-specific host and microbiome readouts into actionable modules may complement traditional food measurement approaches in devising diets that are of benefit to the individual. Although many host-derived factors are hardwired and difficult to modulate, the microbiome may be more readily reshaped by environmental factors such as dietary exposures and is increasingly recognized to potentially impact human physiology by participating in digestion, the absorption of nutrients, shaping of the mucosal immune response and the synthesis or modulation of a plethora of potentially bioactive compounds. Thus, diet-induced microbiota alterations may be harnessed in order to induce changes in host physiology, including disease development and progression. However, major limitations in ‘big-data’ processing and analysis still limit our interpretive and translational capabilities concerning these person-specific host, microbiome and diet interactions. In this Review, we describe the latest advances in understanding diet–microbiota interactions, the individuality of gut microbiota composition and how this knowledge could be harnessed for personalized nutrition strategies to improve human health. In this Review, Kolodziejczyk, Zheng and Elinav describe the latest advances in understanding diet–microbiota interactions, the individuality of gut microbiota composition and how this knowledge could be harnessed for personalized nutrition strategies to improve human health.

Diet–microbiota interactions and personalized nutrition

Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

https://digital.csic.es/bitstream/10261/180389/1/Aryl%20Hydrocarbon_MorenoMarin.pdf

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, inflammation, altered lipid metabolism, and profibrotic growth factors in the kidney, which collectively contribute to age-related kidney disease. With increasing population of older individuals and the increasing incidence of acute kidney injury and chronic kidney disease, identifying preventable or treatable aspects of age-related nephropathy becomes of critical importance. In this regard we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs), whose expression levels are decreased in aging human and mouse kidneys. Our studies have identified the estrogen related receptors ERR, ERR{beta}, and ERR{gamma} as important modulators of age-related mitochondrial dysfunction, cellular senescence, and inflammation. Significantly these pathways are also regulated by lifelong caloric restriction (CR), which is known to prevent several age-related complications including kidney disease. ERR, ERR{beta}, and ERR{gamma} expression levels are decreased in the aging kidney, and CR and pharmacological treatment with a pan ERR agonist results in increases in expression of ERR, ERR{beta}, and ERR{gamma} in the kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related mitochondrial dysfunction, the cellular senescence marker p21, and inflammatory cytokines, including the STAT3 and STING signaling pathways.

/pdf/err-agonism-reverses-mitochondrial-dysfunction-and-31wcwo5r79.pdf

ERR agonism reverses mitochondrial dysfunction and inflammation in aging

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Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota

Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

ERR agonism reverses mitochondrial dysfunction and inflammation in aging