Low-certainty evidence was found that a reduction in unprocessed red meat intake of 3 servings per week is associated with a very small reduction in risk for cardiovascular mortality, stroke, myocardial infarction (MI), and type 2 diabetes. Likewise, low-certainty evidence was found that a reduction in processed meat intake of 3 servings per week is associated with a very small decrease in risk for all-cause mortality, cardiovascular mortality, stroke, MI, and type 2 diabetes. LIMITATION: Inadequate adjustment for known confounders, residual confounding due to observational design, and recall bias associated with dietary measurement. CONCLUSION: The magnitude of association between red and processed meat consumption and all-cause mortality and adverse cardiometabolic outcomes is very small, and the evidence is of low certainty.
We report that BHB, but neither acetoacetate nor structurally-related short chain fatty acids, butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to several structurally unrelated NLRP3 activators, without impacting NLRC4, AIM2 or non-canonical caspase-11 inflammasome activation. Mechanistically, BHB inhibitsNLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 were not dependent on chirality or classical starvation regulated mechanisms like AMPK, reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blockedNLRP3 inflammasome without undergoing oxidation in TCA cycle, independently of uncoupling protein-2 (UCP2), Sirt2, receptor Gpr109a and inhibition of NLRP3 did not correlate with magnitude of histone acetylation in macrophages. BHB reduced the NLRP3 inflammasome mediated IL-1β and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediateddiseases like Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS) and urate crystal induce body cavity inflammation. Taken together, these findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diet may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions that elevate circulating BHB against NLRP3-mediated proinflammatory diseases.
Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health
. Furthermore, the ketone β-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signalinginduces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.
We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mousethymus tissue under starvation conditions, which result in increasedconcentration of serum BHB, and in response to genotoxic stresscaused by γ-irradiation to activatep53. Our findings thus show that BHB-mediatedp53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.
Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging.
Consistent with the hypothesis that systemic low-grade inflammationpromotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improvedglycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lowerNlrp3 activity to delay multiple age-related chronic diseases. Although, it remains unknown whether reduction in Nlrp3 activation can extend lifespan, our data demonstrate unequivocally that deletion of Nlrp3 inflammasome enhances healthspan and prevents functional decline in multiple organs, including protection against thymic demise, cataract development, glucose intolerance and also enhances cortical and trabecular bone mass.
These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer innovative therapeutic strategy to lowerNlrp3 activity to delay multiple age-related chronic diseases.
Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation.
Histone Kbhb marks are dramatically induced in response to elevated β-hydroxybutyrate levels in cultured cells and in liver from mice subjected to prolonged fasting or streptozotocin-induced diabetic ketoacidosis. In total, we identified 44 histone Kbhb sites, a figure comparable to the known number of histone acetylation sites. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbhb is a mark enriched in active gene promoters and that the increased H3K9bhb levels that occur during starvation are associated with genes upregulated in starvation-responsive metabolicpathways. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression, offering a new avenue to study chromatin regulation and diverse functions of β-hydroxybutyrate in the context of important human pathophysiological states, including diabetes, epilepsy, and neoplasia.
Caffeine intake increases plasma ketones: an acute metabolic study in humans.
«Brainglucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketonesare the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brainglucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantlystimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.»
The Ketone Metabolite β-Hydroxybutyrate Attenuates Oxidative Stress in Spinal Cord Injury by Suppression of Class I Histone Deacetylases.
The ketone metabolite β-hydroxybutyrate (βOHB), is reported to be neuroprotective after spinal cord injury (SCI) in rats. Our results indicate that the ketone metabolite βOHB attenuates oxidative stress in SCI by inhibition of class I HDACs, and selected suppression of HDAC1 or HDAC2 regulates FOXO3a, NOX2, and NOX4 expression. Therefore, the ketone metabolite βOHB may be a novel promising therapeutic agent for SCI.
A Ketone Ester Drink Lowers Human Ghrelin and Appetite.
«RESULTS: KE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP-1, and PYY levels were significantlylower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantlysuppressed 1.5 hours after consumption of KE, compared with consumption of DEXT.
CONCLUSIONS: Increased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat.»