Bruss MD, Khambatta CF, Ruby MA, Aggarwal I, Hellerstein MK. Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates. Am J Physiol Endocrinol Metab 298: E108-E116, 2010. First published November 3, 2009 zdoi:10.1152/ajpendo.00524.2009.-Calorie restriction (CR) increases longevity and retards the development of many chronic diseases, but the underlying metabolic signals are poorly understood. Increased fatty acid (FA) oxidation and reduced FA synthesis have been hypothesized to be important metabolic adaptations to CR. However, at metabolic steady state, FA oxidation must match FA intake plus synthesis; moreover, FA intake is low, not high, during CR. Therefore, it is not clear how FA dynamics are altered during CR. Accordingly, we measured food intake patterns, whole body fuel selection, endogenous FA synthesis, and gene expression in mice on CR. Within 2 days of CR being started, a shift to a cyclic, diurnal pattern of whole body FA metabolism occurred, with an initial phase of elevated endogenous FA synthesis [respiratory exchange ratio (RER) Ͼ1.10, lasting 4 -6 h after food provision], followed by a prolonged phase of FA oxidation (RER ϭ 0.70, lasting 18 -20 h). CR mice oxidized four times as much fat per day as ad libitum (AL)-fed controls (367 Ϯ 19 vs. 97 Ϯ 14 mg/day, P Ͻ O.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a threefold increase in adipose tissue FA synthesis compared with AL. Expression of FA synthase and acetyl-CoA carboxylase mRNA were increased in adipose and liver in a timedependent manner. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for oxidative damage and disease risk. fat synthesis; lipogenesis; palmitoleate; heavy water CALORIE RESTRICTION (CR) delays the development of chronic disease and prolongs lifespan in mice (1,17,27,34). These effects correlate with a rapid induction in the expression of certain genes that persist as long as animals remain on CR (10, 36) even after energy balance is restored. These observations suggest the presence of a chronic signal of reduced energy availability that persists after energy balance has been reestablished. However, the underlying metabolic signals and adaptations responsible are not fully understood.Mice on CR regimens have been reported to exhibit increased expression of genes for fatty acid (FA) oxidation and decreased expression of genes for FA synthesis compared with ad libitum (AL)-fed controls (6,7,30,38). Due to differential entry points into the electron transport chain, a metabolic shift from carbohydrate to FA oxidation may reduce the production of reactive oxygen species (ROS) (15). A shift to FA oxidation thereby represents a potential mechanism for reduced oxidative damage, which has been proposed as a potential explanation for the health benefits of CR (14,15,29,35). It has also be...

Introduction/objectives: Pneumocystis jirovecii pneumonia (PJP) is a rare but potentially fatal opportunistic infection; however, consensus varies around which conditions or medications confer a level of risk sufficient to justify antibiotic prophylaxis for PJP. We used electronic health record (EHR) data to assess the current patterns of PJP prophylaxis, PJP outcomes, and prophylaxisrelated adverse events among patients with rheumatic diseases who were receiving high-risk immunosuppressant drugs.Methods: Data derive from the EHR of a large health system. We included new immunosuppressant users with diagnoses of vasculitis, myositis, or systemic lupus erythematosus. We calculated the proportion of patients who received PJP prophylaxis for each diagnosis and drug combination. We also calculated the number of PJP infections and the number of antibiotic adverse drug events (ADEs) per patient-year of exposure. Results:We followed 316 patients for 23.2 +/− 14.2 months. Overall, 124 (39%) of patients received prophylactic antibiotics for PJP. At least 25% of patients with the highest risk conditions

Bruss MD, Thompson AC, Aggarwal I, Khambatta CF, Hellerstein MK. The effects of physiological adaptations to calorie restriction on global cell proliferation rates. Am J Physiol Endocrinol Metab 300: E735-E745, 2011. First published February 1, 2011 doi:10.1152/ajpendo.00661.2010 reduces the rate of cell proliferation in mitotic tissues. It has been suggested that this reduction in cell proliferation may mediate CR-induced increases in longevity. However, the mechanisms that lead to CRinduced reductions in cell proliferation rates remain unclear. To evaluate the CR-induced physiological adaptations that may mediate reductions in cell proliferation rates, we altered housing temperature and access to voluntary running wheels to determine the effects of food intake, energy expenditure, percent body fat, and body weight on proliferation rates of keratinocytes, liver cells, mammary epithelial cells, and splenic T-cells in C57BL/6 mice. We found that ϳ20% CR led to a reduction in cell proliferation rates in all cell types. However, lower cell proliferation rates were not observed with reductions in 1) food intake and energy expenditure in female mice housed at 27°C, 2) percent body fat in female mice provided running wheels, or 3) body weight in male mice provided running wheels compared with ad libitum-fed controls. In contrast, reductions in insulin-like growth factor I were associated with decreased cell proliferation rates. Taken together, these data suggest that CR-induced reductions in food intake, energy expenditure, percent body fat, and body weight do not account for the reductions in global cell proliferation rates observed in CR. In addition, these data are consistent with the hypothesis that reduced cell proliferation rates could be useful as a biomarker of interventions that increase longevity. food intake; energy expenditure; percent body fat; body weight CALORIE RESTRICTION (CR), defined as a reduction in caloric intake without malnutrition, increases lifespan, delays the onset of age-related diseases, and slows the functional decline of various organs (42). Although the mechanisms mediating these effects are unclear, one of the most rapid and robust effects of CR is a reduction in the rate of cell proliferation in mitotic tissues (25,28,38). The turnover rates of keratinocytes, liver cells, mammary epithelial cells (MECs), splenic T cells, and prostate cells are decreased by 30 -50% following several weeks of CR, and the effects persist throughout the intervention period (25). It has been suggested that this reduction in cell proliferation could mediate many of the longevity and anticancer effects of CR by delaying replicative senescence and reducing the promotional phase of carcinogenesis (11,42). Considering that the rate of cell proliferation is an integrated response that comprises many genetic and hormonal signals and appears to be mechanistically linked to aging, this cellular process represents a potential target for monitoring therapeutic interventions aimed at delaying the onset of age-relate...

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The ROC AUC and predictive accuracy are stable diagnostic characteristics, whereas positive predictive value is greatly influenced by disease prevalence.