Article

β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

β-hydroxybutyrate (β-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether β-HB alters the senescence pathway in vascular cells remains unknown. Here we report that β-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of β-HB. β-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of β-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that β-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The main component of ketone bodies, β-hydroxybutyrate (BHB), has been recently characterised as a biologically active molecule with multiple beneficial roles [18]. Besides supplying energy, BHB has various cardiovascular protective effects that are especially strong in endothelial cells [19][20][21]. We have published a series of studies in rat models of diabetes, demonstrating that BHB treatment elevated the expression of vascular endothelial growth factor to alleviate aortic endothelial injury, and promoted the generation of matrix metalloproteinase-2 to antagonise glomerulosclerosis [22,23]. ...
... A broad spectrum of targets has been proposed for the protective effects of BHB [18]. BHB has been reported to bind to a membrane receptor, interact with key functional proteins or inhibit the nucleotide-binding domain leucinerich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome [20,24,25]. Notably, BHB enters the nucleus and inhibits type 1 HDACs to elevate histone acetylation and activate the expression of protective genes [26]. ...
... BHB, which can be produced via the practice of intermittent fasting or administrated directly, is believed to improve cardiovascular function and extend healthspan [16,[38][39][40]. Besides being an energy source, BHB prevents endothelial cell senescence [20,21]. Even in diabetes, the administration of BHB is reported to alleviate retinopathy and nephropathy [41,42]. ...
Article
Full-text available
Aims/hypothesis Microvascular endothelial hyperpermeability, mainly caused by claudin-5 deficiency, is the initial pathological change that occurs in diabetes-associated cardiovascular disease. The ketone body β-hydroxybutyrate (BHB) exerts unique beneficial effects on the cardiovascular system, but the involvement of BHB in promoting the generation of claudin-5 to attenuate cardiac microvascular hyperpermeability in diabetes is poorly understood. Methods The effects of BHB on cardiac microvascular endothelial hyperpermeability and claudin-5 generation were evaluated in rats with streptozotocin-induced diabetes and in high glucose (HG)-stimulated human cardiac microvascular endothelial cells (HCMECs). To explore the underlying mechanisms, we also measured β-catenin nuclear translocation, binding of β-catenin, histone deacetylase (HDAC)1, HDAC3 and p300 to the Claudin-5 (also known as CLDN5) promoter, interaction between HDAC3 and β-catenin, and histone acetylation in the Claudin-5 promoter. Results We found that 10 weeks of BHB treatment promoted claudin-5 generation and antagonised cardiac microvascular endothelial hyperpermeability in rat models of diabetes. Meanwhile, BHB promoted claudin-5 generation and inhibited paracellular permeability in HG-stimulated HCMECs. Specifically, BHB (2 mmol/l) inhibited HG-induced HDAC3 from binding to the Claudin-5 promoter, although nuclear translocation or promoter binding of β-catenin did not change with BHB treatment. In addition, BHB prevented the binding and co-localisation of HDAC3 to β-catenin in HG-stimulated HCMECs. Furthermore, using mass spectrometry, acetylated H3K14 (H3K14ac) in the Claudin-5 promoter following BHB treatment was identified, regardless of whether cells were stimulated by HG or not. Although reduced levels of acetylated H3K9 in the Claudin-5 promoter were found following HG stimulation, increased H3K14ac was specifically associated with BHB treatment. Conclusions/interpretation BHB inhibited HDAC3 and caused acetylation of H3K14 in the Claudin-5 promoter, thereby promoting claudin-5 generation and antagonising diabetes-associated cardiac microvascular hyperpermeability. Graphical abstract
... It has been also demonstrated that βHB can modulate gene expression through promotion of histone and non-histone acetylation by HATs [266,269]. Moreover, βHB is able to directly bind to an RNA-binding protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1), which protein regulates, for example, RNA processing and function, as well as stabilization of mRNA [59,270,271]. ...
... Indeed, it was demonstrated that βHB can alleviate cellular senescence through increased autophagy and decreased plasma insulin level and inflammatory processes in male rats [303], likely through AMPK/SIRT1 pathways (Figure 1). It has also been demonstrated that increased level of blood βHB can delay the age-related processes, for example, by inhibition of SASP, thereby senescence, likely through βHB/hnRNP A1-binding-evoked increase in binding of hnRNP A1 and Oct4 (embryonic stem cell regulator octamer-binding transcriptional factor 4) leading to stabilization of Oct4 mRNA (complex formation with Oct4 mRNA and upregulation of Oct4 expression) and SIRT1 mRNAs [59,304]. βHB-evoked activation of Oct4 not only triggers (maintains) quiescent state of cells (e.g., AMPK activation and mTOR inhibition), but also decreases induction of senescent state of cells (e.g., reduction of the blood level of a pro-senescence marker IL-1α and SASP expression) leading to protection of cells against senescence, and likely, induction of autophagy [59]. These results above suggest that, indeed, EKSs(βHB)-evoked ketosis can alleviate aging-processes (aging hallmarks), at least theoretically, through βHB-evoked activation of AMPK/SIRT1 or SIRT3 downstream signaling pathways (e.g., βHB/HCAR2/AMPK/SIRT1/NF-κB pathway), inhibition of mTOR-(e.g., βHB/HCAR2/AMPK/mTOR pathway) and NLRP3/IL-1R-generated effects, HDAC inhibition, β-hydroxybutyrylation and hnRNP A1-binding (Figures 1 and 2) leading to improved healthspan, delayed aging, thereby extended lifespan. ...
... It has also been demonstrated that increased level of blood βHB can delay the age-related processes, for example, by inhibition of SASP, thereby senescence, likely through βHB/hnRNP A1-binding-evoked increase in binding of hnRNP A1 and Oct4 (embryonic stem cell regulator octamer-binding transcriptional factor 4) leading to stabilization of Oct4 mRNA (complex formation with Oct4 mRNA and upregulation of Oct4 expression) and SIRT1 mRNAs [59,304]. βHB-evoked activation of Oct4 not only triggers (maintains) quiescent state of cells (e.g., AMPK activation and mTOR inhibition), but also decreases induction of senescent state of cells (e.g., reduction of the blood level of a pro-senescence marker IL-1α and SASP expression) leading to protection of cells against senescence, and likely, induction of autophagy [59]. These results above suggest that, indeed, EKSs(βHB)-evoked ketosis can alleviate aging-processes (aging hallmarks), at least theoretically, through βHB-evoked activation of AMPK/SIRT1 or SIRT3 downstream signaling pathways (e.g., βHB/HCAR2/AMPK/SIRT1/NF-κB pathway), inhibition of mTOR-(e.g., βHB/HCAR2/AMPK/mTOR pathway) and NLRP3/IL-1R-generated effects, HDAC inhibition, β-hydroxybutyrylation and hnRNP A1-binding (Figures 1 and 2) leading to improved healthspan, delayed aging, thereby extended lifespan. ...
Article
Full-text available
Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.
... Accumulating evidence indicates that the ketone body β-hydroxybutyrate (β-OHB) has many important physiological functions extending beyond its traditional role as an energy source during periods of fasting or low carbohydrate availability (1). β-OHB is now a recognized signaling molecule that can influence metabolic control, inflammation, oxidative stress, and cardiovascular function (2)(3)(4)(5). β-OHB has direct anti-inflammatory effects through inhibition of the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) inflammasome and reduced production of interleukin (IL)-1β and IL-18 (3). In cell culture and rodent models, β-OHB has also been shown to reduce vascular cell senescence and is hypothesized to improve endothelial and smooth muscle cell function (4,5). ...
... β-OHB has direct anti-inflammatory effects through inhibition of the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) inflammasome and reduced production of interleukin (IL)-1β and IL-18 (3). In cell culture and rodent models, β-OHB has also been shown to reduce vascular cell senescence and is hypothesized to improve endothelial and smooth muscle cell function (4,5). These recent discoveries have generated substantial interest in exploring the role of ketogenic diets and fasting as therapies for cardiometabolic disease (6,7). ...
... The observed improvements in FMD may have also been facilitated by the direct action of β-OHB on the vascular endothelium (4,5). In a rat model of diabetes, the provision of 200 mg/kg/day β-OHB for 10 weeks prevented aortic endothelial cell injury and increased serum NO through the β-hydroxybutyrylation of histone H3K9 (5). ...
Article
Background Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing β-hydroxybutyrate (β-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia. We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity. Methods In a randomized crossover design, 14 participants with obesity (age = 56±12 yrs; BMI = 32.8±7.7 kg/m 2) consumed KME (12 g β-OHB) or placebo 15-minutes prior to each meal for 14-days with all meals provided and matched between conditions. Postprandial glycemia was assessed by continuous glucose monitoring. Vascular function and inflammation were assessed before and after treatment periods. Results Postprandial glucose was 8.0% lower in KME versus placebo (g=0.735; p=0.011) and 24-hour average glucose reduced by 7.8% (g=0.686; p=0.0001). Brachial artery flow-mediated dilation increased from 6.2±1.5% to 8.9±3.3% in KME (g=1.05; p=0.0004) with no changes in placebo (condition X time interaction, p=0.004). There were no changes in plasma cytokines; however, LPS-stimulated monocyte caspase-1 activation was lower following KME supplementation versus placebo (stimulation x condition x time interaction; p=0.004). The KME supplement was well tolerated by participants and adherence to the supplementation regimen was very high. Conclusions In adults with obesity, 14-days of pre-meal KME supplementation improves glucose control, enhances vascular function, and may reduce cellular inflammation. KME supplementation may be a viable, non-pharmacological approach to improving and protecting vascular health in people with heightened cardiometabolic risk.
... Calcification was induced by adding inorganic phosphate (Na 2 HPO 4 , Sigma, USA) to normal medium at a concentration of 2.6 mM (calcification medium). To evaluate the impact of BHB on calcification, BHB (Sigma, USA) was administrated into a calcification medium at a concentration of 4.0 mM (BHB intervention medium) (24). The arterial rings were cultured for 14 days, while VSMCs were cultured for 7 days, with the medium for both refreshed every 2 to 3 days (23). ...
... CR upregulates the production of ketone bodies, in which BHB accounted for more than 70%, a multifunctional metabolic substance which could be physiologically elevated under glucose deprivation. Recent studies suggested that BHB played an important role in delaying aging and improving metabolic conditions (18,24,29,36). ...
Article
Full-text available
Background: Vascular calcification (VC) is a landmark of aging, while β-hydroxybutyric acid (BHB) induced by calorie restriction has been identified as a promising factor to extend the lifespan. However, the effect of BHB on VC and the potential mechanism remain unknown. Methods: A total of 160 subjects with or without metabolic abnormalities (MAs) were assigned to four groups according to different calcification severities. The association between BHB, MAs, and VC was investigated via mediation analysis. Then, with high phosphate-induced calcification models, the effect of BHB on arterial ring calcification and osteogenic phenotypic differentiation of vascular smooth muscle cells (VSMCs) was investigated. Hereafter the expressions of autophagy biomarkers, autophagy flux, and effects of autophagy inhibitors on VC were detected. Results: Severe VC was observed in the elderly, accompanied with a higher proportion of hypertension, chronic kidney disease, and lower estimated glomerular filtration rate. The serum BHB level was an independent influencing factor of VC severities. With mediation analysis, BHB was determined as a significant mediator in the effects of MAs on VC, and the indirect effect of BHB accounted for 23% of the total effect. Furthermore, BHB directly inhibited arterial ring calcification and osteogenic phenotypic differentiation in VSMCs, accompanied with autophagy enhancement in VSMCs. In accordance, the inhibition of autophagy counteracted the protective effect of BHB on VC. Conclusion: The present study demonstrated that BHB mediated the effects of MAs on VC; then, it further elucidated that BHB could inhibit arterial and VSMC calcification via autophagy enhancement.
... BHB extends the lifespan of C. elegans through inhibiting HDACs and the DAF16/FOXO and SKN-1/Nrf pathways (Edwards et al., 2014). Han et al. (2018) found that BHB prevents p53 independent and octamer-binding transcriptional factor (Oct) four dependent senescence in mouse vascular cells. BHB upregulates Oct4 expression via interacting with heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), inducing cell quiescence. ...
... BHB upregulates Oct4 expression via interacting with heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), inducing cell quiescence. Intraperitoneal injection of BHB alleviates vascular aging in mice (Han et al., 2018). Because of the BHB roles, it can be considered as a potential mediator of the anti-aging effects of CR and exercise. ...
Article
Full-text available
Regular exercise has a myriad of health benefits. An increase in circulating exercise factors following exercise is a critical physiological response. Numerous studies have shown that exercise factors released from tissues during physical activity may contribute to health benefits via autocrine, paracrine, and endocrine mechanisms. Myokines, classified as proteins secreted from skeletal muscle, are representative exercise factors. The roles of myokines have been demonstrated in a variety of exercise-related functions linked to health benefits. In addition to myokines, metabolites are also exercise factors. Exercise changes the levels of various metabolites via metabolic reactions. Several studies have identified exercise-induced metabolites that positively influence organ functions. Here, we provide an overview of selected metabolites secreted into the circulation upon exercise.
... H 2 O 2 and high glucose are factors contributing to ECs senescence as oxidative stresses 9,10 . Ming-Hui Zou showed that H 2 O 2 could trigger HUVECs and human aortic smooth muscle cells senescence through Oct4A upregulation 11 . H 2 O 2 -induced EC senescence provokes a DNA-damage response, which results in activation of p53 and p16, the important cell cycle regulatory pathways 12 . ...
... MSC-sEV mitigated senescence in HUVECs in vitro H 2 O 2 has been reported to trigger premature senescence by increasing oxidative stress 11 . To investigate the effect of MSC-sEV on senescence, we first established a proper H 2 O 2 -induced HUVEC senescence model. ...
Article
Full-text available
Senescent endothelial cells (ECs) could impair the integrity of the blood vessel endothelium, leading to vascular aging and a series of diseases, such as atherosclerosis, diabetes. Preventing or mitigating EC senescence might serve as a promising therapeutic paradigm for these diseases. Recent studies showed that small extracellular vesicles (sEV) have the potential to transfer bioactive molecules into recipient cells and induce phenotypic changes. Since mesenchymal stem cells (MSCs) have long been postulated as an important source cell in regenerative medicine, herein we investigated the role and mechanism of MSC-derived sEV (MSC-sEV) on EC senescence. In vitro results showed that MSC-sEV reduced senescent biomarkers, decreased senescence-associated secretory phenotype (SASP), rescued angiogenesis, migration and other dysfunctions in senescent EC induced by oxidative stress. In the In vivo natural aging and type-2 diabetes mouse wound-healing models (both of which have senescent ECs), MSC-sEV promoted wound closure and new blood vessel formation. Mechanically, miRNA microarray showed that miR-146a was highly expressed in MSC-sEV and also upregulated in EC after MSC-sEV treatment. miR-146a inhibitors abolished the stimulatory effects of MSC-sEV on senescence. Moreover, we found miR-146a could suppress Src phosphorylation and downstream targets VE-cadherin and Caveolin-1. Collectively, our data indicate that MSC-sEV mitigated endothelial cell senescence and stimulate angiogenesis through miR-146a/Src.
... In addition to the hormonal and metabolic changes that accompany nutrient deprivation, fasting is characterized by a dramatic elevation in blood ketone levels (Han et al., 2018). Here we show that the administration of ketone bodies themselves, absent any other feature of nutrient deprivation, is sufficient to elicit DQ of MuSCs. ...
... Evolutionarily, elevated ketone bodies in the blood may be a rapid way to signal to cell types throughout the body to allocate resources to survival mechanisms, like increased resilience, during a time of nutrient deprivation. Consistent with our findings in MuSCs, this role of exogenous ketone bodies in promoting a quiescent state was recently elucidated in vascular cells (Han et al., 2018). The authors showed that BHB was sufficient to promote quiescence while simultaneously preventing senescence of these cells. ...
Preprint
Full-text available
Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in muscle stem cells(MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically b hydroxybutyrate, directly promote MuSC deep quiescence via a non-metabolic mechanism. We show that b-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
... Moreover, the supplementation of β-HB could extend the lifespan of C. elegans and regulate aging and longevity [73]. β-HB diminishes senescence-associated secretory phenotype as well as senescent vascular cells in mammals [74]. Although a variety of studies verify the therapeutic effects of KD in regenerative medicine including aging and neurodegenerative diseases, the exact molecular mechanism of β-HB has not been fully explored. ...
Article
Full-text available
The ketone bodies, especially β-hydroxybutyrate (β-HB), derive from fatty acid oxidation and alternatively serve as a fuel source for peripheral tissues including the brain, heart, and skeletal muscle. β-HB is currently considered not solely an energy substrate for maintaining metabolic homeostasis but also acts as a signaling molecule of modulating lipolysis, oxidative stress, and neuroprotection. Besides, it serves as an epigenetic regulator in terms of histone methylation, acetylation, β-hydroxybutyrylation to delay various age-related diseases. In addition, studies support endogenous β-HB administration or exogenous supplementation as effective strategies to induce a metabolic state of nutritional ketosis. The purpose of this review article is to provide an overview of β-HB metabolism and its relationship and application in age-related diseases. Future studies are needed to reveal whether β-HB has the potential to serve as adjunctive nutritional therapy for aging.
... Ketone bodies, including β-hydroxybutyrate (β-HB), acetoacetate and acetone, are primarily produced by β-oxidation of fatty acids (FA) in the mitochondria of hepatocytes, even though enterocytes, astrocytes and kidney epithelial cells may produce them as well [24,26]. Interestingly, it has been shown that β-HB decreases the senescence of vascular cells [27], and that ketones abolish the generation of mitochondrial ROS [28]. This review focuses on the participation of mitochondrial ROS (mitROS) and Ca 2+ signaling in the inflammatory process leading to PH development, as well as their mutual interactions, and the possible role of ketone bodies on mitochondrial Ca 2+ and/or ROS signaling. ...
Article
Full-text available
Mitochondria are important organelles that act as a primary site to produce reactive oxygen species (ROS). Additionally, mitochondria play a pivotal role in the regulation of Ca2+ signaling, fatty acid oxidation, and ketone synthesis. Dysfunction of these signaling molecules leads to the development of pulmonary hypertension (PH), atherosclerosis, and other vascular diseases. Features of PH include vasoconstriction and pulmonary artery (PA) remodeling, which can result from abnormal proliferation, apoptosis, and migration of PA smooth muscle cells (PASMCs). These responses are mediated by increased Rieske iron–sulfur protein (RISP)-dependent mitochondrial ROS production and increased mitochondrial Ca2+ levels. Mitochondrial ROS and Ca2+ can both synergistically activate nuclear factor κB (NF-κB) to trigger inflammatory responses leading to PH, right ventricular failure, and death. Evidence suggests that increased mitochondrial ROS and Ca2+ signaling leads to abnormal synthesis of ketones, which play a critical role in the development of PH. In this review, we discuss some of the recent findings on the important interactive role and molecular mechanisms of mitochondrial ROS and Ca2+ in the development and progression of PH. We also address the contributions of NF-κB-dependent inflammatory responses and ketone-mediated oxidative stress due to abnormal regulation of mitochondrial ROS and Ca2+ signaling in PH.
... Some recent results suggest that bHB may delay vascular aging by exerting antisenescence effects in vascular cells. Indeed, bHB suppress the expression of markers of senescence-associated phenotype (IL-6 and IL-1a) and increase the expression of Oct4, a regulator of pluripotency, in embryonic stem cells in human aortic SM cells exposed to a senescence-generating stimulus and in middleaged mice (50). ...
Article
In the past decade, ketogenic diet (KD) has gained some popularity as a potential treatment for a wide range of diseases, including neurological and metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat and carbohydrate-restricted regimen causes changes in the metabolism, leading, through the b-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), which are used by many extrahepatic tissues as energy fuels. Once synthetized, KBs are delivered through the systemic circulation to all the tissues of the organism, where they play pleiotropic roles acting directly and indirectly on various targets, and among them ion channels and neurotransmitters. Moreover, they can operate as signaling metabolites and epigenetic modulators. Therefore, it is inappropriate to consider that the KD regimen can improve the patients' clinical condition simply by means of specific and localized effects; rather, it is more correct to think that KBs affect the organism as a whole. In this review, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention on the excitable ones, namely the nervous system, heart, and muscles. b-hydroxybutyrate; diet therapy; excitable tissues; ketogenic diet; low carbohydrate high fat diet
... 29 Our data revealed that Notch activation upregulates miR-218-1, likely by transactivating the Slit2 promoter, in ECs. It has been well established that characteristic metabolic patterns determine EC quiescence, 3,12,43,44 and that MYC critically regulates EC metabolism in different contexts. [13][14][15] Our results demonstrate that miR-218 mediates the effects of Notch activation on EC quiescence by repressing MYC ( Figure 7G). ...
Article
Full-text available
After angiogenesis-activated embryonic and early postnatal vascularization, endothelial cells (ECs) in most tissues enter a quiescent state necessary for proper tissue perfusion and EC functions. Notch signaling is essential for maintaining EC quiescence, but the mechanisms of action remain elusive. Here, we show that microRNA-218 (miR-218) is a downstream effector of Notch in quiescent ECs. Notch activation upregulated, while Notch blockade downregulated, miR-218 and its host gene Slit2, likely via transactivation of the Slit2 promoter. Overexpressing miR-218 in human umbilical vein ECs (HUVECs) significantly repressed cell proliferation and sprouting in vitro. Transcriptomics showed that miR-218 overexpression attenuated the MYC proto-oncogene, bHLH transcription factor (MYC, also known as c-myc) signature. MYC overexpression rescued miR-218-mediated proliferation and sprouting defects in HUVECs. MYC was repressed by miR-218 via multiple mechanisms, including reduction of MYC mRNA, repression of MYC translation by targeting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), and promoting MYC degradation by targeting EYA3. Inhibition of miR-218 partially reversed Notch-induced repression of HUVEC proliferation and sprouting. In vivo, intravitreal injection of miR-218 reduced retinal EC proliferation accompanied by MYC repression, attenuated pathological choroidal neovascularization, and rescued retinal EC hyper-sprouting induced by Notch blockade. In summary, miR-218 mediates the effect of Notch activation of EC quiescence via MYC and is a potential treatment for angiogenesis-related diseases.
... BHB also significantly inhibits stress-induced premature ageing and replicative senescence through the p53-independent pathway. Furthermore, BHB indirectly increases lamin B1 level by enhancing the expression of the transcription factor octamer-binding transcriptional factor (OCT) 4, which is important for preventing senescence induced by DNA damage (Han et al., 2018;Mendelsohn and Larrick, 2018). Therefore, the protective effect of BHB on hypertension is possibly mediated by delaying vascular stiffness associated with endothelial cell senescence (Figure 5). ...
Article
Full-text available
Hypertension is a significant risk factor for cardiovascular and cerebrovascular diseases, and its development involves multiple mechanisms. Gut microbiota has been reported to be closely linked to hypertension. Short-chain fatty acids (SCFAs)—the metabolites of gut microbiota—participate in hypertension development through various pathways, including specific receptors, immune system, autonomic nervous system, metabolic regulation and gene transcription. This article reviews the possible mechanisms of SCFAs in regulating blood pressure and the prospects of SCFAs as a target to prevent and treat hypertension.
... These cytokines and chemokines stimulated classical senescence proteins activities locking the ECs cells into permanent senescence [70]. However, treatment with β-hydroxybutyrate enhanced octamer-binding transcriptional factor-4 and lamin B1, DNA damage-induced senescence antagonists, terminated VECs SASP formation and inflammation in mice [71], suggesting that DNA damage promotes senescence and SASP formation both in vitro and in vivo. ...
... Metabolomics has already produced results that are leading to frailty interventions, such as ketogenic compounds, for which clinical trials are about to start (85,86). There are at least 20 proteins or peptides in mice related to frailty where preliminary human trials are being considered (87,88). Also with newer techniques, proteins can be measured in very small quantities of sample (e.g., 10 microlitres). ...
Article
The Canadian Frailty Network (CFN), a pan-Canadian not-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program, is dedicated to improving the care of older Canadians living with frailty. The CFN has partnered with the Canadian Longitudinal Study on Aging (CLSA) to measure potential frailty biomarkers in biological samples (whole blood, plasma, urine) collected in over 30,000 CLSA participants. CFN hosted a workshop in Toronto on January 15 2018, bringing together experts in the field of biomarkers, aging and frailty. The overall objectives of the workshop were to start building a consensus on potential frailty biomarker domains and identify specific frailty biomarkers to be measured in the CLSA biological samples. The workshop was structured with presentations in the morning to frame the discussions for the afternoon session, which was organized as a free-flowing discussion to benefit from the expertise of the participants. Participants and speakers were from Canada, Italy, Spain, United Kingdom and the United States. Herein we provide pertinent background information, a summary of all the presentations with key figures and tables, and the distillation of the discussions. In addition, moving forward, the principles CFN will use to approach frailty biomarker research and development are outlined. Findings from the workshop are helping CFN and CLSA plan and conduct the analysis of biomarkers in the CLSA samples and which will inform a follow-up data access competition.
... These interventions include methionine restriction 179 and ketogenic diets 180,181 . Methionine restriction lowers markers of senescence and the SASP 182 , while injection of mice with β-hydroxybutyrate, a major ketone body produced by ketogenic diets, lowers markers of senescence in vascular smooth muscle and endothelial cells 183 . These results indicate that dietary interventions that create a favorable metabolic state that can limit the accumulation of senescent cells. ...
Article
Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence. Wiley and Campisi discuss metabolic inducers of senescence and alterations in cellular metabolism associated with senescence, while pointing out interventions that target metabolic processes to mitigate senescence.
... In endovascular cells, the mRNA stability test showed that hnRNPA1, in the presence of β-HB, can enhance the stability of Oct4 mRNA and enable the normal expression of Oct4 and its downstream LaminB1, which is one of the key factors to resist senescence induced by DNA damage [43]. Therefore, β-HB can maintain the self-renewal of endovascular cells and delay senescence by up-regulating hnRNPA1 and inducing Oct4-mediated LaminB1 pathway [44]. ...
Article
Full-text available
The self-renewal, pluripotency and differentiation of stem cells are regulated by various genetic and epigenetic factors. As a kind of RNA binding protein (RBP), the heterogeneous nuclear ribonucleoproteins (hnRNPs) can act as “RNA scaffold” and recruit mRNA, lncRNA, microRNA and circRNA to affect mRNA splicing and processing, regulate gene transcription and post-transcriptional translation, change genome structure, and ultimately play crucial roles in the biological processes of cells. Recent researches have demonstrated that hnRNPs are irreplaceable for self-renewal and differentiation of stem cells. hnRNPs function in stem cells by multiple mechanisms, which include regulating mRNA stability, inducing alternative splicing of mRNA, epigenetically regulate gene expression, and maintaining telomerase activity and telomere length. The functions and the underlying mechanisms of hnRNPs in stem cells deserve further investigation.
... In mammals, βHB attenuated the SASP phenotype (SASP) and the senescence of vascular cells [547]. An anti-inflammatory action of β-hydroxybutyrate was recently reported in aging kidneys and this effect was attributed to increased interaction between FoxO1 and PGC-1α induced by βHB [548]. ...
Article
The epidemic of obesity is a major challenge for health policymakers due to its far-reaching effects on population health and potentially overwhelming financial burden on healthcare systems. Obesity is associated with an increased risk of developing acute and chronic diseases, including hypertension, stroke, myocardial infarction, cardiovascular disease, diabetes, and cancer. Interestingly, the metabolic dysregulation associated with obesity is similar to that observed in normal aging, and substantial evidence suggests the potential of obesity to accelerate aging. Therefore, understanding the mechanism of fat tissue dysfunction in obesity could provide insights into the processes that contribute to the metabolic dysfunction associated with the aging process. Here, we review the molecular and cellular mechanisms underlying both obesity and aging, and how obesity and aging can predispose individuals to chronic health complications. The potential of lifestyle and pharmacological interventions to counter obesity and obesity-related pathologies, as well as aging, is also addressed.
... However, levels can reach 1-8 mM after KD consumption, prolonged exercise, or deep fasting and can be as high as 25 mM under pathological conditions, such as diabetic ketoacidosis. 7-10 β-OHB accounts for 70% of ketone bodies and has been suggested to be beneficial because it not only serves as a vital alternative metabolic fuel source in the fed, fasted, and starved states 11 , but also exerts antioxidative, 12 antiaging, 13 and antiinflammatory effects. 14 Although numerous reports have acknowledged the beneficial effects of β-OHB, its safety has been challenged by certain clinical lines of evidence related to its effects on cardiovascular health. ...
Article
Full-text available
In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.
... As low as 0.5 mM β-OHB can improve cardiac cell excitationcontraction coupling under hypoxia, providing evidence that β-OHB can exert cardioprotective benefits under stress (Klos et al., 2019). β-OHB can also reduce oxidative stress and induce anti-aging effects through binding to hnRNP A1 to upregulate Oct4 expression at the concentration of 4 mM in the vascular system (Han et al., 2018). Besides enhancing gene expression by inhibiting HDACs, β-OHB can also promote protein hyperacetylation via increasing cellular acetyl-CoA levels to maintain metabolic balance (Newman and Verdin, 2014). ...
Article
Full-text available
One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart’s energy metabolism as an alternative “fuel source.” Utilization of β-OHB in the failing heart increases, and this serves as a “fuel switch” that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative “fuel,” β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes’ expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.
... The ketogenic diet was reported to increase β-hydroxybutyrate (β-HB) level, which may prevent or alleviate symptoms of age-related diseases, exert antiaging effect [28] , and prolong the lifespan [29][30] . In mammals, β-HB may down-regulate senescence-associated secretory phenotype (SASP) and retard the senescence of vascular cells [31] . The ketogenic diet may also alleviate symptoms of Alzheimers disease, an age-related neurodegenerative disease [32][33] . ...
Preprint
Full-text available
Purpose To estimate the prevalence of age-related macular generation (AMD) among people who underwent health examination in Hunan, China and to determine the relationship between dietary pattern and the risk of AMD. Methods The Questionnaire was used to collect dietary data from 56,775 subjects of ≥ 50 years old who underwent health examination at the Department of Health Management, the Third Xiangya Hospital of Central South University between January 2017 and December 2019. The diagnosis of AMD was based on the results of fundus examination and medical history taking. After excluding subjects with incomplete records or other oculopathies that may affect the results of fundus examination, a total of 43,672 subjects were included. The univariate and multivariate logistic regression analyses were used to determine the relationship between dietary pattern and the prevalence of AMD. Results Among the 43,672 subjects, 1080 (2.5%) had early AMD: the prevalences were 2.6% (n = 674) in males and 2.3% (n = 406) in females; the prevalences were 1.0% (n = 289), 3.6% (n = 401), 9.1% (n = 390) in 50–59, 60–69, ≥ 70 years old, respectively. The high-salt intake increased the risk of early AMD [odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.53–1.67], whereas the intake of meat decreased the risk (OR = 0.89, 95% CI = 0.80–0.99). Conclusion Our data indicate that high-salt intake increases the risk of early AMD, whereas intake of meat decreases the risk. Modulating the dietary pattern as an AMD prevention strategy warrants further study.
... More particularly, calorie-restricted mice were shown to have lower telomereassociated DNA damage foci (TAF) in hepatocyte cells (Ogrodnik et al., 2017). Caloric restriction also elevated β-HB, a type of ketone body, which resulted in the reduced aging-related neurodegeneration (Paoli et al., 2014) and a recent study also reported that inducing cellular quiescence with β-HB has an inhibitory effect on replicative senescence and stress-induced premature senescence (Han et al., 2018). Another research investigated the effect of exercise and diet on senescent cells and showed that fast-food diet led to the increased expression of senescence markers (SASP, SA-β-gal, p16 and EGFP) in the adipose tissue of mice. ...
Article
Full-text available
Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.
... In mammals, BHB decreases the secretory phenotype associated with senescence and vascular cell senescence [25] . In addition, the ketogenic diet (KD) significantly extended the median lifespan of mice and preserved the physical function of older mice [26] . Treatment of human umbilical vein ECs (HUVEC) and human aortic smooth muscle cells treated with BHB suppressed oxidant-induced elevation of senescence markers. ...
Article
Ketone bodies have emerged as central mediators of metabolic health, and multiple beneficial effects of a ketogenic diet, impacting metabolism, neuronal pathologies and, to a certain extent, tumorigenesis, have been reported both in animal models and clinical research. Ketone bodies, endogenously produced by the liver, act pleiotropically as metabolic intermediates, signaling molecules, and epigenetic modifiers. The endothelium and the vascular system are central regulators of the organism's metabolic state and become dysfunctional in cardiovascular disease, atherosclerosis, and diabetic micro- and macrovascular complications. As physiological circulating ketone bodies can attain millimolar concentrations, the endothelium is the first-line cell lineage exposed to them. While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature, recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell (EC) functioning by modulating the EC inflammatory status, senescence, and metabolism. Here, we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies-at lower concentrations-on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms. We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects. At low concentration, endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies (or their precursors) may prove beneficial to ameliorate endothelial function and, consequently, pathologies in which endothelial damage occurs.
... It is an energy contributor for cellular activities [25,[29][30][31][32]. 3HB utilization is increased in atrophic cardiomyocyte [33,34], and exogenous 3HB exerts the obvious hemodynamic effects for patients with chronic heart failure (HF) [35,36]. The conventional ketogenic diet (KD) body supplement and 3HB supplemented to foods or drinks gradually have found applications for treating neurodegenerative disease such as epilepsy [37,38], Alzheimer's disease [39,40], cancer [41,42], aging [43], atherosclerosis [44], colonic inflammation and carcinogenesis [45], NLRP3-mediated inflammation [46], osteoporosis [47] and enhanced exercise performance [48]. ...
Article
Full-text available
Background Muscle atrophy is an increasingly global health problem affecting millions, there is a lack of clinical drugs or effective therapy. Excessive loss of muscle mass is the typical characteristic of muscle atrophy, manifesting as muscle weakness accompanied by impaired metabolism of protein and nucleotide. (D)-3-hydroxybutyrate (3HB), one of the main components of the ketone body, has been reported to be effective for the obvious hemodynamic effects in atrophic cardiomyocytes and exerts beneficial metabolic reprogramming effects in healthy muscle. This study aims to exploit how the 3HB exerts therapeutic effects for treating muscle atrophy induced by hindlimb unloaded mice. Results Anabolism/catabolism balance of muscle protein was maintained with 3HB via the Akt/FoxO3a and the mTOR/4E-BP1 pathways; protein homeostasis of 3HB regulation includes pathways of ubiquitin–proteasomal, autophagic-lysosomal, responses of unfolded-proteins, heat shock and anti-oxidation. Metabolomic analysis revealed the effect of 3HB decreased purine degradation and reduced the uric acid in atrophied muscles; enhanced utilization from glutamine to glutamate also provides evidence for the promotion of 3HB during the synthesis of proteins and nucleotides. Conclusions 3HB significantly inhibits the loss of muscle weights, myofiber sizes and myofiber diameters in hindlimb unloaded mouse model; it facilitates positive balance of proteins and nucleotides with enhanced accumulation of glutamate and decreased uric acid in wasting muscles, revealing effectiveness for treating muscle atrophy. Graphical Abstract
... 90 Recently, Oct4 has been shown to mediate the anti-senescence effect of the ketone body b-hydroxybutyrate (b-HB) in vascular tissues by promoting cellular quiescence via a TP53-independent mechanism. 91 Circulating levels of b-HB are increased in response to caloric restriction and direct binding of b-HB to hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) enhances the affinity of hnRNP A1 for Oct4 mRNA. This stabilizes Oct4 mRNA and enables increased expression of Oct4, which in turn up-regulates quiescence markers, including lamin B1 involved in DNA repair, and down-regulates senescence markers, such as cH2AX. ...
Article
Open in new tabDownload slide Open in new tabDownload slide This review seeks to provide an update of the mechanisms of vascular cell senescence, from newly identified molecules to arterial ageing phenotypes, and finally to present a computational approach to connect these selected proteins in biological networks. We will discuss current key signalling and gene expression pathways by which these focus proteins and networks drive normal and accelerated vascular ageing. We also review the possibility that senolytic drugs, designed to restore normal cell differentiation and function, could effectively treat multiple age-related vascular diseases. Finally, we discuss how cell senescence is both a cause and a consequence of vascular ageing because of the possible feedback controls between identified networks.
... β-hydroxybutyrate generated by KD decreased the level of senescence biomarkers in endothelial cells and vascular smooth muscle. 215 In comparison, methionine restriction reduced senescent biomarkers by enhancing methylation and promoting one-carbon metabolism. 216 Studies have demonstrated that appropriate nutritional treatments can deplete senescent cells to shape a supporting metabolic state. ...
Article
Full-text available
Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.
... The ketogenic diet was reported to increase β-hydroxybutyrate (β-HB) level, which may prevent or alleviate symptoms of age-related diseases, exert antiaging effect [33], and prolong the lifespan [34,35]. In mammals, β-HB may down-regulate senescence-associated secretory phenotype (SASP) and retard the senescence of vascular cells [36]. The ketogenic diet may also alleviate symptoms of Alzheimer disease, an age-related neurodegenerative disease [37,38]. ...
Article
Full-text available
Purpose To estimate the frequency of age-related macular degeneration (AMD) among people who underwent health examination in Hunan, China and to determine the relationship between dietary pattern and the risk of AMD. Methods The Questionnaire was used to collect dietary data from 56,775 study participants of ≥ 50 years old who underwent health examination at the Department of Health Management, the Third Xiangya Hospital of Central South University between January 2017 and December 2019. The diagnosis of AMD was based on the results of color fundus photography (CFP), spectral-domain optical coherence tomography (OCT) and multispectral imaging (MSI). After excluding participants with incomplete records or other ocular disease that may affect the results of fundus examination, a total of 43,672 study participants were included. The univariate and multivariate logistic regression analyses were used to determine the relationship between dietary pattern and the frequency of AMD. Results Among the 43,672 study participants, 1080 (2.5%) had early AMD: the frequencies were 2.6% (n = 674) in men and 2.3% (n = 406) in women; the frequencies were 1.0% (n = 289), 3.6% (n = 401), 9.1% (n = 390) in 50–59, 60–69, ≥ 70 years old, respectively. And the age-standard frequency was 6.6% over the 60 years old in Hunan China. The high-salt intake increased the risk of early AMD [odds ratio (OR) = 1.61, 95% confidence interval (CI) = 1.54–1.68], whereas the intake of meat decreased the risk (OR = 0.90, 95% CI = 0.81–0.99). Conclusion In Hunan China, there was a high frequency of early AMD detected through health examination over the 60 years old. And high-salt intake increases the risk of early AMD, whereas intake of meat decreases the risk. Modulating the dietary pattern and reducing the salt intake as an AMD prevention strategy warrant further study.
... These epigenetic effects result in up-regulation of the stress-response genes Nrf2, Foxo3, and Mt2, resulting in cytoprotection from oxidative stress in several model systems [40][41][42][43][44][45]. BHB directly interacts with the RNA binding protein hnRNPA1, thereby enhancing stabilization of the Yamanaka factor Oct4 mRNA, and leading to reduced senescence in mouse vascular endothelial cells [46]. BHB also binds to at least two cell-surface receptors, HCAR2 and FFAR3 (reviewed in [2]). ...
Article
Full-text available
Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, and other cellular processes. While these energy and signaling mechanisms of ketone bodies are currently being studied in a variety of aging-related diseases such as Alzheimer's disease and type 2 diabetes mellitus, they may also be relevant to military service members undergoing stressors that mimic or accelerate aging pathways, particularly traumatic brain injury and muscle rehabilitation and recovery. Here we summarize the biology of ketone bodies relevant to resilience and rehabilitation, strategies for translational use of ketone bodies, and current clinical investigations in this area.
... BHB is also the substrate moiety for histone b-hydroxybutyrylation, a novel protein post-translational modification (PTM) -taking place on histone and non-histone proteins -associated to gene expression [8,9]. The participation of BHB in the regulation of gene transcription and inflammation, together with its capability to prevent senescence of vascular cells [10] and enhance their proliferative potential [11] may contribute to its positive effects on metabolism. Somehow paradoxically, feeding on an energy-dense ketogenic diet is akin to starving or caloric restriction, two other nutritional states relying on the mobilization of stored fat depots once carbohydrate availability becomes scarce: in both cases, BHB will serve as a fat-derived fuel molecule substitute for glucose [12]. ...
Article
Full-text available
Objective The ketogenic diet (KD), characterized by very limited dietary carbohydrate intake and used as nutritional treatment for GLUT1-deficiency syndromes and pharmacologically refractory epilepsy, may promote weight loss and improve metabolic fitness, potentially alleviating the symptoms of osteoarthritis. Here, we have studied the effects of administration of a ketogenic diet in mice previously rendered obese by feeding a high fat diet (HFD) and submitted to surgical destabilization of the medial meniscus to mimic osteoarthritis. Methods 6-weeks old mice were fed an HFD for 10 weeks and then switched to a chow diet (CD), KD or maintained on a HFD for 8 weeks. Glycemia, β-hydroxybutyrate (BHB), body weight and fat mass were compared among groups. In liver and kidney, protein expression and histone post-translational modifications were assessed by Western blot, and gene expression by quantitative Real-Time PCR. Results After a 10 weeks HDF feeding, administration for 8 weeks of a KD or CD induced a comparable weight loss and decrease in fat mass, with better glycemic normalization in the KD group. Histone β-hydroxybutyrylation, but not histone acetylation, was increased in the liver and kidney of mice fed the KD and the rate-limiting ketogenic enzyme HMGCS2 was upregulated – at the gene and protein level – in liver and, to an even greater extent, in kidney. KD-induced HMGCS2 overexpression may be dependent on FGF21, whose gene expression was increased by KD in liver. Conclusions Over a period of 8 weeks, KD is more effective than a chow diet to induce metabolic normalization. Besides acting as a fuel molecule, BHB may exert its metabolic effects through modulation of the epigenome - via histone β-hydroxybutyrylation - and extensive transcriptional modulation in liver and kidney.
... Since aging is a CVD risk factor, delaying or preventing it can play a main role in cardiovascular dysfunction. Caloric restriction with the production of ketones can prevent the aging of vascular cells [48]. Improvement in progressive dilation of the heart and cardiac contractile function was observed in a study following KD in mice [39]. ...
Article
Full-text available
Cardiovascular disease (CVD) and cancer are the first and second leading causes of death worldwide, respectively. Epidemiological evidence has demonstrated that the incidence of cancer is elevated in patients with CVD and vice versa. However, these conditions are usually regarded as separate events despite the presence of shared risk factors between both conditions, such as metabolic abnormalities and lifestyle. Cohort studies suggested that controlling for CVD risk factors may have an impact on cancer incidence. Therefore, it could be concluded that interventions that improve CVD and cancer shared risk factors may potentially be effective in preventing and treating both diseases. The ketogenic diet (KD), a low-carbohydrate and high-fat diet, has been widely prescribed in weight loss programs for metabolic abnormalities. Furthermore, recent research has investigated the effects of KD on the treatment of numerous diseases, including CVD and cancer, due to its role in promoting ketolysis, ketogenesis, and modifying many other metabolic pathways with potential favorable health effects. However, there is still great debate regarding prescribing KD in patients either with CVD or cancer. Considering the number of studies on this topic, there is a clear need to summarize potential mechanisms through which KD can improve cardiovascular health and control cell proliferation. In this review, we explained the history of KD, its types, and physiological effects and discussed how it could play a role in CVD and cancer treatment and prevention.
... In addition to NR, rapamycin and D+Q, there are other compounds that can be used to attenuate cellular senescence. Among them are resveratrol (Kim E. N. et al., 2018;Breuss et al., 2019), metformin (Bharath et al., 2020;Kulkarni et al., 2020), an inhibitor of glutaminase 1 that inhibits glutaminolysis (Johmura et al., 2021), and β-hydroxybutyrate (Han et al., 2018. These senotherapeutics target all types of senescent cells with less or more efficacy, and they are not EC-specific. ...
Article
Full-text available
Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.
Article
In the last decade Ketogenic Diet (KD) came to light as a potential treatment for a wide range of diseases, from neurological to metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat, carbohydrate-restricted regimen causes changes in the metabolism leading, through the β-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), used by many extrahepatic tissues as energy fuels. Once synthetized, KBs move through the systemic circulation and reach all the tissues of the organism, affecting their functions and playing pleiotropic roles acting directly and indirectly on various targets as ion channels and neurotransmitters. Moreover, they can operate as signalling metabolites and epigenetic modulators. Therefore, it is limiting to consider that the clinical condition of each single patient could improve after a KD regimen based on its localized effects; rather it is more complete to think about how KBs might affect the organism as a whole. In this minireview, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention to the excitable ones, namely the nervous system, heart and muscles.
Article
Accumulation of collagen 4 (COL4) and thickened basement membrane are features of diabetic cardiac microvascular fibrosis that may be induced by oxidative stress. The ketone body β-hydroxybutyrate exhibits various cardiovascular protective effects, however its mechanism remains to be clarified. In the current study, the effects of β-hydroxybutyrate on cardiac microvascular fibrosis and COL4 accumulation were evaluated in streptozotocin-induced diabetic rats and in high glucose (HG) treated human cardiac microvascular endothelial cells (HCMECs). Generations of inducible nitric oxide synthase (iNOS) and copper-zinc superoxide dismutase (Cu/Zn-SOD), and the amount of nitrotyrosine (NT) were measured in vivo and in vitro. Ten weeks of β-hydroxybutyrate treatment (160, 200 and 240 mg/kg/d) attenuated cardiac microvascular fibrosis and inhibited cardiac COL4 generation and microvascular distribution in diabetic rats. Furthermore, β-hydroxybutyrate promoted cardiac Cu/Zn-SOD generation and reduced NT content, without reducing iNOS generation in diabetic rats. In HCMECs, stimulation with HG induced excess generation of COL4 via peroxynitrite. β-Hydroxybutyrate treatment (2, 4, 6 mM) attenuated HG-stimulated COL4 accumulation in a concentration-dependent manner. Similarly, 4 mM β-hydroxybutyrate promoted Cu/Zn-SOD generation and reduced NT content, without affecting excess iNOS generation in HG-stimulated HCMECs. In conclusion, this study showed that β-hydroxybutyrate promoted Cu/Zn-SOD generation, reduced peroxynitrite and inhibited cardiac microvascular COL4 accumulation in diabetes.
Article
The liver plays a central role that influences cardiovascular disease outcomes through regulation of glucose and lipid metabolism. It is recognized that the local liver molecular clock regulates some liver-derived metabolites. However, it is unknown whether the liver clock may impact cardiovascular function. Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue surrounding blood vessels. Importantly, crosstalk between the endothelium and PVAT via vasoactive factors is critical for vascular function. Therefore, we designed studies to test the hypothesis that cardiovascular function, including PVAT function, is impaired in mice with liver-specific circadian clock disruption. Bmal1 is a core circadian clock gene, thus studies were undertaken in male hepatocyte-specific Bmal1 knockout (HBK) mice and littermate controls (i.e., flox mice). HBK mice showed significantly elevated plasma levels of β-hydroxybutyrate, non-esterified fatty acids/free fatty acids, triglycerides and insulin-like growth factor 1 compared to flox mice. Thoracic aorta PVAT in HBK mice had increased mRNA expression of several key regulatory and metabolic genes, Ppargc1a, Pparg, Adipoq, Lpl and Ucp1, suggesting altered PVAT energy metabolism and thermogenesis. Sensitivity to acetylcholine-induced vasorelaxation was significantly decreased in aortae of HBK mice with PVAT attached compared to aortae of HBK mice with PVAT removed, however, aortic vasorelaxation in flox mice showed no differences with or without attached PVAT. HBK mice had a significantly lower systolic blood pressure during the inactive period of the day. These new findings establish a novel role of the liver circadian clock in regulating PVAT metabolic gene expression and PVAT-mediated aortic vascular function.
Article
Aging is a complex biological process characterized by a progressive loss of physiological integrity and increased vulnerability to age-related diseases. Adipose tissue plays central roles in the maintenance of whole-body metabolism homeostasis and has recently attracted significant attention as a biological driver of aging and age-related diseases. Here, we review the most recent advances in our understanding of the molecular and cellular mechanisms underlying age-related decline in adipose tissue function. In particular, we focus on the complex inter-relationship between metabolism, immune, and sympathetic nervous system within adipose tissue during aging. Moreover, we discuss the rejuvenation strategies to delay aging and extend lifespan, including senescent cell ablation (senolytics), dietary intervention, physical exercise, and heterochronic parabiosis. Understanding the pathological mechanisms that underlie adipose tissue aging will be critical for the development of new intervention strategies to slow or reverse aging and age-related diseases.
Article
Diabetic kidney disease (DKD) is one of the most common complications of diabetes and clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence. Burgeoning evidence suggests that ketosis, in particular β-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, β-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of γH2AX foci, reduced staining for senescence-associated-β-galactosidase activity, diminished expression of key mediators of senescence signaling like p16INK4A and p21, and preserved expression of synaptopodin. This beneficial action of β-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, β-hydroxybutyrate inhibition of glycogen synthase kinase 3β (GSK3β), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3β abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of β-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that β-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3β and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, β-hydroxybutyrate therapy inhibited GSK3β and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a β-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.
Article
Metabolic intermediates serve as precursors for bioactive molecule synthesis, the energy source for life activities, and signals for environmental adaptation. Ketone bodies are important metabolic intermediates produced in the liver by the degradation of fatty acids, acting as an alternative energy source for extrahepatic tissues when glucose is short in supply (especially during starvation). β-hydroxybutyric acid, with its conjugate base β-hydroxybutyrate, constitutes approximately 70% of ketone bodies. A growing number of studies have demonstrated the beneficial effects of β-hydroxybutyrate, especially in delaying aging, intervening in aging-related disease, and promoting longevity. This review systematically reviews the role of β-hydroxybutyrate in aging hallmarks, shedding light on the possible molecular mechanism by which β-hydroxybutyrate supports healthy aging. Higher circulating β-hydroxybutyrate can be achieved by lifestyle modification (ketogenic diet or caloric restriction) or exogenous β-hydroxybutyrate (or β-hydroxybutyrate precursors, derivates and agonists) supplementation. We will also discuss the pros and cons of different ways to upregulate β-hydroxybutyrate, emphasizing the promising future clinical use of poly-β-hydroxybutyrate, the polymers of β-hydroxybutyrate, which can be easily produced via a microbial platform and synthetic biology.
Article
Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo-controlled double-blind, cross-over design, 14 adults with obesity (10 females; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m-2 ) consumed 30 mL (12 g) of β-OHB or placebo thrice-daily for 14 days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme-linked immunosorbent assay. Cognition was assessed by the digit-symbol substitution (DSST), Stroop and task-switching tests. Following 14 days of ketone supplementation, we observed significant improvements in cerebrovascular outcomes including QCCA (+12%), QVA (+11%), VACVC (+12%) and VA shear rate (+10%). DSST performance significantly improved following ketone supplementation (+2.7 correct responses) and improved DSST performance was positively associated improvements in cerebrovascular outcomes including QCCA , CCACVC , QVA and VACVC . By contrast to one hypothesis, β-OHB did not impact fasting serum and plasma BDNF. β-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. β-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB in a population at risk of neurocognitive impairment. KEY POINTS: People with obesity are at increased risk of neurocognitive dysfunction, partly as a result of -induced reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14 days of thrice-daily β-OHB supplementation improves aspects of cognition and increases cerebrovascular flow, conductance and shear rate in the extracranial arteries of adults with obesity. Our preliminary data indicate a significant positive relationship between elevated CBF and improved cognition following β-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of β-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.
Article
Ketone bodies play significant roles in organismal energy homeostasis, serving as oxidative fuels, modulators of redox potential, lipogenic precursors, and signals, primarily during states of low carbohydrate availability. Efforts to enhance wellness and ameliorate disease via nutritional, chronobiological, and pharmacological interventions have markedly intensified interest in ketone body metabolism. The two ketone body redox partners, acetoacetate and D-β-hydroxybutyrate, serve distinct metabolic and signaling roles in biological systems. We discuss the pleiotropic roles played by both of these ketones in health and disease. While enthusiasm is warranted, prudent procession through therapeutic applications of ketogenic and ketone therapies is also advised, as a range of metabolic and signaling consequences continue to emerge. Organ-specific and cell-type-specific effects of ketone bodies are important to consider as prospective therapeutic and wellness applications increase.
Chapter
Die Kardiologie ist das erste medizinische Fachgebiet, das mit Inauguration der bekannten Framingham-Studie (Kannel et al. 1961) belegen konnte, dass es Risikofaktoren gibt, die kausal Krankheit zur Folge haben. Dies konnte nur durch solch eine longitudinale Kohortenstudie erfolgen. Die Risikofaktoren addieren sich nicht nur in Ihrer prädiktiven Aussage, sondern potenzieren sich. Um dem klinisch relevant Rechnung zu tragen, wurden kardiovaskuläre Risiko-Scores entwickelt. Neben dem ursprünglichen Framingham Risk Score (FRS), der aktuell im griffigen „ASCVD PLUS“ Score (► http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/) im Internet kalkuliert werden kann und vergleichsweise gute Prädiktion gestattet (Grammer et al. 2019), folgten der deutsche PROCAM-Score (Assmann et al. 2002) mit dem Vorteil der Kalibrierung in Deutschland und dem Kohorten-Nachteil der ursprünglichen Fokussierung nur auf das männliche Geschlecht. Der ESC HEART SCORE der europäischen Fachgesellschaft (Piepoli et al. 2016; s. ◘ Abb. 14.1) beruht auf der Zusammenfassung zwölf großer europäischer Kohorten mit Rekalibrierungsmöglichkeiten entsprechend der Risikoträchtigkeit der Regionen (Deutschland mit insbesondere südeuropäischen Ländern rangiert eher im low risk-Bereich, dagegen insbesondere die osteuropäischen Länder im high risk-Bereich). Wir hatten vor einigen Jahren eine vergleichende Bewertung der Pros und Cons der verschiedenen Scores vorgenommen und auch die Limitationen benannt (Mureddu et al. 2013). Eine wesentliche Limitation ist das Alter, da dieses im höheren Bereich – der aber nota bene bereits > 65 Jahren beginnt – die anderen traditionellen Risikofaktoren wie arterielle Hypertonie, Dyslipidämie etc. so massiv superimponiert, dass sich der prädiktive Wert der Einzelfaktoren nivelliert. ◘ Abb. 14.1 zeigt dies deutlich, wie nämlich durch die von unten nach oben zunehmende Alterung eine nahezu durchgehend Rotfärbung der Risikofelder eintritt und das höhere Alter für sich den high risk determiniert. Derzeit wird vom Inaugurator Ian Graham, Dublin, eine Extrapolierung der Tafeln bis zum 75. Lebensjahr statistisch kalkuliert (noch unpubliziert), aber erste Mitteilungen bleiben pessimistisch dazu. Es zeichnet sich aus der Sicht der kardiovaskulären Risikostratifikation tatsächlich ab, dass Alterung eine Krankheit darstellt, wie es seit Jahren in der Anti-Aging-Medizin postuliert wird.
Article
Aims: Until recently, the pluripotency factor OCT4 was believed to be dispensable in adult somatic cells. However, our recent studies provided clear evidence that OCT4 has a critical atheroprotective role in smooth muscle cells (SMC). Here, we asked if OCT4 might play a functional role in regulating endothelial cell (EC) phenotypic modulations in atherosclerosis. Methods and results: Specifically, we show that EC-specific Oct4 knockout resulted in increased lipid, LGALS3+ cell accumulation, and altered plaque characteristics consistent with decreased plaque stability. A combination of single-cell RNA sequencing and EC-lineage-tracing studies revealed increased EC activation, endothelial-to-mesenchymal transitions, plaque neovascularization, and mitochondrial dysfunction in the absence of OCT4. Further, we show that the ATP transporter, ABCG2, is a direct target of OCT4 in EC and establish for the first time that the OCT4/ABCG2 axis maintains EC metabolic homeostasis by regulating intracellular heme accumulation and related reactive oxygen species production, which, in turn, contributes to atherogenesis. Conclusions: These results provide the first direct evidence that OCT4 has a protective metabolic function in EC and identifies vascular OCT4 and its signaling axis as a potential target for novel therapeutics.
Article
Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here, we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet or exogenously administered, promotes a deep quiescent state in muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Furthermore, we show that ketone bodies, specifically β-hydroxybutyrate, directly promote MuSC deep quiescence via a nonmetabolic mechanism. We show that β-hydroxybutyrate functions as an HDAC inhibitor within MuSCs, leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
Article
Background: IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification. Methods: We generated global apoE (apolipoprotein E) and IDO1 double knockout mice, and apoE knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model. Results: Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/- Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification. Conclusions: Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.
Article
Full-text available
Despite recent advances in therapies, cardiovascular diseases ( CVDs ) are still the leading cause of mortality worldwide. Previous studies have shown that metabolic perturbations in cardiac energy metabolism are closely associated with the progression of CVDs. As expected, metabolic interventions can be applied to alleviate metabolic impairments and, therefore, can be used to develop therapeutic strategies for CVDs. β-hydroxybutyrate (β-HB) was once known to be a harmful and toxic metabolite leading to ketoacidosis in diabetes. However, the minor metabolite is increasingly recognized as a multifunctional molecular marker in CVDs. Although the protective role of β-HB in cardiovascular disease is controversial, increasing evidence from experimental and clinical research has shown that β-HB can be a “super fuel” and a signaling metabolite with beneficial effects on vascular and cardiac dysfunction. The tremendous potential of β-HB in the treatment of CVDs has attracted many interests of researchers. This study reviews the research progress of β-HB in CVDs and aims to provide a theoretical basis for exploiting the potential of β-HB in cardiovascular therapies.
Chapter
This chapter discusses the regulation of cerebral metabolism and fuel utilization at rest and during dynamic whole-body exercise in humans. The relative contributions of cerebral metabolic rates of key substrates (oxygen, glucose, lactate, ketone bodies) are outlined with respect to rest and exercise. A brief overview of the current gold-standard techniques to assess cerebral metabolism during dynamic exercise in humans is also provided, and future research areas are highlighted throughout.KeywordsCerebral metabolismCerebral blood flowExerciseGlucoseLactateGlycogenKetone bodies
Article
Vascular calcification is an actively regulated process resembling bone formation and contributes to the cardiovascular morbidity and mortality of chronic kidney disease (CKD). However, effective therapy for vascular calcification is still lacking. The ketone body β‐hydroxybutyrate (BHB) has been demonstrated to have health‐promoting effects including anti‐inflammation and cardiovascular protective effects. However, whether BHB protects against vascular calcification in CKD remains unclear. In this study, Alizarin Red staining and calcium content assay showed that BHB reduced calcification of vascular smooth muscle cells (VSMCs) and arterial rings. Of note, compared with CKD patients without thoracic calcification, serum BHB levels were lower in CKD patients with thoracic calcification. Supplementation with 1,3‐butanediol (1,3‐B), the precursor of BHB, attenuated aortic calcification in CKD rats and VitD3‐overloaded mice. Furthermore, RNA‐Seq analysis revealed that BHB downregulated HDAC9, which was further confirmed by RT‐qPCR and western blot analysis. Both pharmacological inhibition and knockdown of HDAC9 attenuated calcification of human VSMCs, while overexpression of HDAC9 exacerbated calcification of VSMCs and aortic rings, indicating that HDAC9 promotes vascular calcification under CKD conditions. Of note, BHB treatment antagonized HDAC9‐induced vascular calcification. In addition, HDAC9 overexpression activated NF‐κB signaling pathway and inhibition of NF‐κB attenuated HDAC9‐induced VSMC calcification, suggesting that HDAC9 promotes vascular calcification via activation of NF‐κB. In conclusion, our study demonstrates that BHB supplementation inhibits vascular calcification in CKD via modulation of the HDAC9‐dependent NF‐κB signaling pathway. Moreover, we unveil a crucial mechanistic role of HDAC9 in vascular calcification under CKD conditions, thus nutritional intervention or pharmacological approaches to enhance BHB levels could act as promising therapeutic strategies to target HDAC9 for the treatment of vascular calcification in CKD. This article is protected by copyright. All rights reserved.
Article
Cisplatin, as a commonly used anticancer drug, can easily lead to acute kidney injury (AKI), and has received more and more attention in clinical practice. β-hydroxybutyric acid (BHB) is a metabolite in the body and acts as an inhibitor of oxidative stress and NLRP3 inflammasome, reducing inflammatory responses and apoptosis. However, the role of BHB in cisplatin-induced AKI is currently not fully elucidated. In this study, C57BL/6 male mice were randomly divided into normal control group, cisplatin-induced AKI group and AKI with BHB treatment group. Compared to the control, cisplatin-treated mice exhibited high level of serum creatinine, blood urea nitrogen and severe tubular injury, which accompanied with significantly increased expression level of NLRP3, IL-1β, IL-18, BAX, cleaved-caspase 3, as well as aggravated oxidative stress and renal tubular cell apoptosis. However, these changes were significantly improved in that of BHB treatment. In vitro, our study showed that the expression of cleaved-caspase3, IL-1β and IL-18 were significantly increased in human proximal tubular epithelial cell line (HK-2) treated with cisplatin compared with the control group, while decreased in cells treated with BHB. Furthermore, a significantly increased expression of cGAS and STING in HK-2 cells treated with cisplatin were found, whereas notably decreased in cells treated with BHB. This data indicates that BHB protects against cisplatin-induced AKI and renal tubular damage mediated by NLRP3 inflammasome and cGAS-STING pathway.
Article
Cardiovascular diseases (CVDs) constitute the prime cause of global mortality with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and non-ischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions is being increasingly explored, giving rise to the field of senotherapeutics. Therefore, we additionally attempt to clarifythe current state of this field with a focus on cardiac senescence, and discuss the potential of implementing senolytics as atreatment option in heart disease.
Article
Full-text available
Metaflammation is a primary inflammatory complication of metabolic disorders characterized by altered production of many inflammatory cytokines, adipokines and lipid mediators. While multiple inflammation networks have been identified, the mechanisms by which metaflammation is initiated have long been controversial. As mevalonate pathway (MVA) produces abundant bioactive isoprenoids and abnormal MVA has a phenotypic association with inflammation/immunity, we speculate that isoprenoids from the MVA may provide a causal link between metaflammation and metabolic disorders. Using a line with the MVA isoprenoids producer geranygeranyldiphosphate synthase (GGPPS) deleted, we find that GGPP depletion causes an apparent metaflammation as evidenced by abnormal accumulation of fatty acids, eicosanoid intermediates and proinflammatory cytokines. We also find that GGPP prenylate cytochrome b5 reductase 3 (CYB5R3) and the prenylated CYB5R3 then translocate from the mitochondrial to ER pool. As CYB5R3 is a critical NADH-dependent reductase necessary for eicosanoids metabolism in ER, we thus suggests that GGPP-mediated CYB5R3 prenylation is necessary for eicosanoid metabolism. In addition, we observe that pharmacological inhibition of MVA pathway by simvastatin is sufficient to inhibit CYB5R3 translocation and induces smooth muscle death. Therefore, we conclude that the dysregulation of MVA intermediates is an essential mechanism for metaflammation initiation, in which the imbalanced production of eicosanoid intermediates in ER serve as an important pathogenic factor. Moreover, the interplay of MVA and eicosanoids metabolism as we reported here illustrates a model for the coordinating regulation among metabolite pathways.
Article
Full-text available
Our closest living relatives, chimpanzees and bonobos, have a complex demographic history. We analyzed the high-coverage whole genomes of 75 wild-born chimpanzees and bonobos from 10 countries in Africa. We found that chimpanzee population substructure makes genetic information a good predictor of geographic origin at country and regional scales. Multiple lines of evidence suggest that gene flow occurred from bonobos into the ancestors of central and eastern chimpanzees between 200,000 and 550,000 years ago, probably with subsequent spread into Nigeria-Cameroon chimpanzees. Together with another, possibly more recent contact (after 200,000 years ago), bonobos contributed less than 1% to the central chimpanzee genomes. Admixture thus appears to have been widespread during hominid evolution.
Article
Full-text available
During infection in mammals, the protozoan parasite Trypanosoma brucei transforms from a proliferative bloodstream form to a quiescent form that is pre-adapted to host transition. AMP analogs are known to induce quiescence and also inhibit TbTOR4. To examine the role of AMP-activated kinase (AMPK) in the regulation of this developmental transition, we characterized trypanosome TbAMPK complexes. Expression of a constitutively active AMPKα1 induces quiescence of the infective form, and TbAMPKα1 phosphorylation occurs during differentiation of wild-type pleomorphic trypanosomes to the quiescent stumpy form in vivo. Compound C, a well-known AMPK inhibitor, inhibits parasite differentiation in mice. We also provide evidence linking oxidative stress to TbAMPKα1 activation and quiescent differentiation, suggesting that TbAMPKα1 activation balances quiescence, proliferation, and differentiation.
Article
Full-text available
Although somatic cell activation of the embryonic stem cell (ESC) pluripotency factor OCT4 has been reported, this previous work has been controversial and has not demonstrated a functional role for OCT4 in somatic cells. Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe(-/-) mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage. Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration. The reactivation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was hypoxia inducible factor-1α (HIF-1α, encoded by HIF1A) and Krüppel-like factor-4 (KLF4)-dependent. These results provide the first direct evidence that OCT4 has a functional role in somatic cells, and they highlight the potential role of OCT4 in normal and diseased somatic cells.
Article
Full-text available
Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes; depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive, cell-based, prosenescence screen with detailed validation assays. We have characterized the screen using a focused tool compound kinase inhibitor library. We have identified a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses showed that all those compounds that induced tetraploid senescence, inhibited Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint (SAC), and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed only in a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target. © 2015 by The American Society for Cell Biology.
Article
Full-text available
Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK), an energy gauge and redox sensor, controls the cell cycle and protects against DNA damage. However, the molecular mechanisms by which AMPKα isoform regulates DNA damage remain largely unknown. The aim of this study was to determine if AMPKα deletion contributes to cellular hyperproliferation by reducing p21(WAF1/Cip1) (p21) expression thereby leading to accumulated DNA damage. The markers for DNA damage, cell cycle proteins, and apoptosis were monitored in cultured mouse embryonic fibroblasts (MEFs) isolated from wild type (WT, C57BL/6J), AMPKα1, or AMPKα2 homozygous deficient (AMPKα1(-/-), AMPKα2(-/-)) mice by Western blot, flow cytometry, and cellular immunofluorescence staining. Deletion of AMPKα1, the predominant AMPKα isoform, but not AMPKα2 in immortalized MEFs led to spontaneous DNA double-strand breaks (DSB) which corresponded to repair protein p53-binding protein1 (53BP1) foci formation and subsequent apoptosis. Furthermore, AMPKα1 localizes to chromatin and AMPKα1 deletion down-regulates cyclin-dependent kinase inhibitor, p21, an important protein that plays a role in decreasing the incidence of spontaneous DSB via inhibition of cell proliferation. In addition, AMPKα1 null cells exhibited enhanced cell proliferation. Finally, p21 overexpression partially blocked the cellular hyperproliferation of AMPKα1-deleted MEFs via the inhibition of cyclin-dependent kinase 2 (CDK2). Taken together, our results suggest that AMPKα1 plays a fundamental role in controlling the cell cycle thereby affecting DNA damage and cellular apoptosis.
Article
Full-text available
Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.
Article
Full-text available
In response to starvation, cells undergo increased levels of autophagy and cell cycle arrest but the role of autophagy in starvation-induced cell cycle arrest is not fully understood. Here we show that autophagy genes regulate cell cycle arrest in the budding yeast Saccharomyces cerevisiae during nitrogen starvation. While exponentially growing wild-type yeasts preferentially arrest in G 1/G 0 in response to starvation, yeasts carrying null mutations in autophagy genes show a significantly higher percentage of cells in G 2/M. In these autophagy-deficient yeast strains, starvation elicits physiological properties associated with quiescence, such as Snf1 activation, glycogen and trehalose accumulation as well as heat-shock resistance. However, while nutrient-starved wild-type yeasts finish the G 2/M transition and arrest in G 1/G 0, autophagy-deficient yeasts arrest in telophase. Our results suggest that autophagy is crucial for mitotic exit during starvation and appropriate entry into a G 1/G 0 quiescent state.
Article
Full-text available
An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.
Article
Full-text available
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) shuttles between the cytoplasm and nucleus and plays important roles in RNA metabolism. Whereas nuclear hnRNP A1 has been shown to bind intronic sequences and modulate splicing, cytoplasmic hnRNP A1 is associated with poly(A)+ RNA, indicating different RNA ligand specificity. Previous studies indicated that cytoplasmic hnRNP A1 is capable of high-affinity binding of reiterated AUUUA sequences (ARE) that have been shown to modulate mRNA turnover and translation. Through a combination of two-dimensional gel and proteolysis studies, we establish hnRNP A1 (or structurally related proteins that are post-translationally regulated in an identical manner) as the dominant cytoplasmic protein in human T lymphocytes capable of interacting with the ARE contained within the context of full-length granulocyte-macrophage colony-stimulating factor mRNA. We additionally demonstrate that cytoplasmic hnRNP A1 preferentially binds ARE relative to pre-mRNAs in both cross-linking and mobility shift experiments. RNA polymerase II inhibition increased the binding of ARE (AUBP activity) and poly(U)-Sepharose by cytoplasmic hnRNP A1, while nuclear hnRNP A1 binding was unaffected. Nuclear and cytoplasmic hnRNP A1 could be distinguished by the differential sensitivity of their RNA binding to diamide and N-ethylmaleimide. The increase in AUBP activity of cytoplasmic hnRNP A1 following RNA polymerase II inhibition correlated with serine-threonine dephosphorylation, as determined by inhibitor and metabolic labeling studies. Thus, cytoplasmic and nuclear hnRNP A1 exhibit different RNA binding profiles, perhaps transduced through serine-threonine phosphorylation. These findings are relevant to the specific ability of hnRNP A1 to serve distinct roles in post-transcriptional regulation of gene expression in both the nucleus and cytoplasm.
Article
Full-text available
Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR's effects in primates. Here we show that CR significantly improves age-related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood. These data contrast with observations in the 2012 NIA intramural study report, where a difference in survival was not detected between control-fed and CR monkeys. A comparison of body weight of control animals from both studies with each other, and against data collected in a multi-centred relational database of primate ageing, suggests that the NIA control monkeys were effectively undergoing CR. Our data indicate that the benefits of CR on ageing are conserved in primates.
Article
Full-text available
Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies.
Article
Full-text available
Conversion of somatic cells to pluripotency by defined factors is a long and complex process that yields embryonic-stem-cell-like cells that vary in their developmental potential. To improve the quality of resulting induced pluripotent stem cells (iPSCs), which is important for potential therapeutic applications, and to address fundamental questions about control of cell identity, molecular mechanisms of the reprogramming process must be understood. Here we discuss recent discoveries regarding the role of reprogramming factors in remodelling the genome, including new insights into the function of MYC, and describe the different phases, markers and emerging models of reprogramming.
Article
Full-text available
How hematopoietic stem cells (HSCs) coordinate the regulation of opposing cellular mechanisms such as self-renewal and differentiation commitment remains unclear. Here we identified the transcription factor and chromatin remodeler Satb1 as a critical regulator of HSC fate. HSCs lacking Satb1 had defective self-renewal, were less quiescent and showed accelerated lineage commitment, which resulted in progressive depletion of functional HSCs. The enhanced commitment was caused by less symmetric self-renewal and more symmetric differentiation divisions of Satb1-deficient HSCs. Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc, which encode two key factors for the specification of stem-cell fate. Thus, Satb1 is a regulator that promotes HSC quiescence and represses lineage commitment.
Article
Full-text available
Liver fibrosis occurs as a wound-healing response to chronic hepatic injuries irrespective of the underlying etiology and may progress to life-threatening cirrhosis. Here we show that CCN1, a matricellular protein of the CCN (CYR61/CTGF/NOV) family, is accumulated in hepatocytes of human cirrhotic livers. CCN1 is not required for liver development or regeneration, since these processes are normal in mice with hepatocyte-specific Ccn1 deletion. However, Ccn1 expression is upregulated upon liver injuries and functions to inhibit liver fibrogenesis induced by either carbon tetrachloride intoxication or bile duct ligation and promote fibrosis regression. CCN1 acts by triggering cellular senescence in activated hepatic stellate cells and portal fibroblasts by engaging integrin α6β1 to induce reactive oxygen species accumulation through the RAC1-NADPH oxidase 1 enzyme complex, whereupon the senescent cells express an antifibrosis genetic program. Mice with hepatocyte-specific Ccn1 deletion suffer exacerbated fibrosis with a concomitant deficit in cellular senescence, whereas overexpression of hepatic Ccn1 reduces liver fibrosis with enhanced senescence. Furthermore, tail vein delivery of purified CCN1 protein accelerates fibrosis regression in mice with established fibrosis. These findings reveal a novel integrin-dependent mechanism of fibrosis resolution in chronic liver injury and identify the CCN1 signaling pathway as a potential target for therapeutic intervention.
Article
Full-text available
Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions.
Article
Full-text available
Nuclear lamin B1 (LB1) is a major structural component of the nucleus that appears to be involved in the regulation of many nuclear functions. The results of this study demonstrate that LB1 expression in WI-38 cells decreases during cellular senescence. Premature senescence induced by oncogenic Ras also decreases LB1 expression through a retinoblastoma protein (pRb)-dependent mechanism. Silencing the expression of LB1 slows cell proliferation and induces premature senescence in WI-38 cells. The effects of LB1 silencing on proliferation require the activation of p53, but not pRb. However, the induction of premature senescence requires both p53 and pRb. The proliferation defects induced by silencing LB1 are accompanied by a p53-dependent reduction in mitochondrial reactive oxygen species (ROS), which can be rescued by growth under hypoxic conditions. In contrast to the effects of LB1 silencing, overexpression of LB1 increases the proliferation rate and delays the onset of senescence of WI-38 cells. This overexpression eventually leads to cell cycle arrest at the G1/S boundary. These results demonstrate the importance of LB1 in regulating the proliferation and senescence of human diploid cells through a ROS signaling pathway.
Article
Full-text available
The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently fail as remedies, underscoring the need for the development of alternative interventions to successfully treat metabolic disorders and enhance life span and health span. Using calorie restriction (CR)—which is well known to improve both health and longevity in controlled studies—as their benchmark, gerontologists are coming closer to identifying dietary and pharmacological therapies that may be applicable to aging humans. This review covers some of the more promising interventions targeted to affect pathways implicated in the aging process as well as variations on classical CR that may be better suited to human adaptation.
Article
Full-text available
There is no consensus regarding the safety and efficacy of drug-eluting stents, as compared with bare-metal stents, in patients with ST-segment elevation myocardial infarction who are undergoing primary percutaneous coronary intervention (PCI). We randomly assigned, in a 3:1 ratio, 3006 patients presenting with ST-segment elevation myocardial infarction to receive paclitaxel-eluting stents (2257 patients) or otherwise identical bare-metal stents (749 patients). The two primary end points of the study were the 12-month rates of target-lesion revascularization for ischemia (analysis powered for superiority) and a composite safety outcome measure of death, reinfarction, stroke, or stent thrombosis (powered for noninferiority with a 3.0% margin). The major secondary end point was angiographic evidence of restenosis at 13 months. Patients who received paclitaxel-eluting stents, as compared with those who received bare-metal stents, had significantly lower 12-month rates of ischemia-driven target-lesion revascularization (4.5% vs. 7.5%; hazard ratio, 0.59; 95% confidence interval [CI], 0.43 to 0.83; P=0.002) and target-vessel revascularization (5.8% vs. 8.7%; hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P=0.006), with noninferior rates of the composite safety end point (8.1% vs. 8.0%; hazard ratio, 1.02; 95% CI, 0.76 to 1.36; absolute difference, 0.1 percentage point; 95% CI, -2.1 to 2.4; P=0.01 for noninferiority; P=0.92 for superiority). Patients treated with paclitaxel-eluting stents and those treated with bare-metal stents had similar 12-month rates of death (3.5% and 3.5%, respectively; P=0.98) and stent thrombosis (3.2% and 3.4%, respectively; P=0.77). The 13-month rate of binary restenosis was significantly lower with paclitaxel-eluting stents than with bare-metal stents (10.0% vs. 22.9%; hazard ratio, 0.44; 95% CI, 0.33 to 0.57; P<0.001). In patients with ST-segment elevation myocardial infarction who were undergoing primary PCI, implantation of paclitaxel-eluting stents, as compared with bare-metal stents, significantly reduced angiographic evidence of restenosis and recurrent ischemia necessitating repeat revascularization procedures. No safety concerns were apparent at 1 year. (ClinicalTrials.gov number, NCT00433966.)
Article
Full-text available
The MLA 144 gibbon T cell line is infected with a type C retrovirus and constitutively expresses interleukin-2 (IL-2) and granulocyte macrophage colony-stimulating factor (GM-CSF). IL-2 mRNA levels are 10-fold more abundant than GM-CSF in these cells. Comparable transcriptional rates for these lymphokines suggested the involvement of post-transcriptional mechanisms in selective IL-2 mRNA accumulation. IL-2 mRNA is exceptionally stable in MLA cells with a t1/2 of more than 8 h. The presence of reiterated AUUUA sequences in the 3'-untranslated region (UTR) has been shown to confer mRNA lability. The provirally altered MLA IL-2 allele encodes an mRNA in which three AUUUA motifs have been deleted. Six major cytoplasmic proteins bound in vitro transcribed RNA probes containing sequences from the 3'-UTR of normal human IL-2 (3'-IL-2), GM-CSF (delta 2R1), and the virally altered MLA IL-2 (3'-IL-2 PV) mRNA. Increased binding of these proteins to 3'-IL-2 PV was observed relative to 3'-IL-2 or delta 2R1. Northwestern blotting demonstrated similar differential ability of a 36- and 43-kDa protein to bind, as well as showed that these proteins colocalized by immunoblotting as hnRNP A1 and C, respectively. These findings suggest a direct correlation between differential binding of cytoplasmic proteins to AU-rich 3'-UTRs in vitro and lymphokine mRNA stability in vivo.
Article
Full-text available
The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a BRCT domain-a motif that is found in many proteins that are implicated in DNA damage response and in genome stability. Phosphorylation of BRCA1 by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in response to DNA damage and at replication-block checkpoints. Although cells that lack BRCA1 have an abnormal response to DNA damage, the exact role of BRCA1 in this process has remained unclear. Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest. Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition. We show that BRCA1 regulates the expression of both Wee1 kinase, an inhibitor of Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm. We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis.
Article
Full-text available
Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of the nigrostriatal dopaminergic neurons accompanied by a deficit in mitochondrial respiration. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes dopaminergic neurodegeneration and a mitochondrial deficit reminiscent of PD. Here we show that the infusion of the ketone body d-beta-hydroxybutyrate (DbetaHB) in mice confers partial protection against dopaminergic neurodegeneration and motor deficits induced by MPTP. These effects appear to be mediated by a complex II-dependent mechanism that leads to improved mitochondrial respiration and ATP production. Because of the safety record of ketone bodies in the treatment of epilepsy and their ability to penetrate the blood-brain barrier, DbetaHB may be a novel neuroprotective therapy for PD.
Article
Full-text available
hnRNP A1 is a nucleocytoplasmic shuttling protein that is involved in many aspects of mRNA metabolism. We have previously shown that activation of the p38 stress-signaling pathway in mammalian cells results in both hyperphosphorylation and cytoplasmic accumulation of hnRNP A1, affecting alternative splicing regulation in vivo. Here we show that the stress-induced cytoplasmic accumulation of hnRNP A1 occurs in discrete phase-dense particles, the cytoplasmic stress granules (SGs). Interestingly, mRNA-binding activity is required for both phosphorylation of hnRNP A1 and localization to SGs. We also show that these effects are mediated by the Mnk1/2 protein kinases that act downstream of p38. Finally, depletion of hnRNP A1 affects the recovery of cells from stress, suggesting a physiologically significant role for hnRNP A1 in the stress response. Our data are consistent with a model whereby hnRNP A1 recruitment to SGs involves Mnk1/2-dependent phosphorylation of mRNA-bound hnRNP A1.
Article
95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures No relevant conflicts of interest to declare.
Article
During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
Article
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.
Article
The cells in the human body are continuously challenged by a variety of genotoxic attacks. Erroneous repair of the DNA can lead to mutations and chromosomal aberrations that can alter the functions of tumor suppressor genes or oncogenes, thus causing cancer development. As a central tumor suppressor, p53 guards the genome by orchestrating a variety of DNA-damage-response (DDR) mechanisms. Already early in metazoan evolution, p53 started controlling the apoptotic demise of genomically compromised cells. p53 plays a prominent role as a facilitator of DNA repair by halting the cell cycle to allow time for the repair machineries to restore genome stability. In addition, p53 took on diverse roles to also directly impact the activity of various DNA-repair systems. It thus appears as if p53 is multitasking in providing protection from cancer development by maintaining genome stability.
Article
During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.