bims-kimdis 2024-08-25 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–08–25
fiveteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

β-Hydroxybutyrate dehydrogenase functionalized two-dimensional photonic crystals for quantitative and visual sensing of ketone bodies.
Ketone monoester plus high-dose glucose supplementation before exercise does not affect immediate post-exercise erythropoietin concentrations versus glucose alone.
Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.
Transcriptional cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription.
Unlocking peak performance: The role of Nrf2 in enhancing exercise outcomes and training adaptation in humans.
Inner membrane turns inside out to exit mitochondrial organelles.
Consuming Whey Protein with Added Essential Amino Acids, not Carbohydrate, Maintains Post-Exercise Anabolism while Underfed.
shRNA-mediated down-regulation of Acsl1 reverses skeletal muscle insulin resistance in obese C57BL6/J mice.
Time-restricted eating, the clock ticking behind the scenes.
Skeletal muscle adaptations following eccentric contractions are not mediated by keratin 18.
Research progress on the role and inhibitors of Keap1 signaling pathway in inflammation.
Unlocking mitochondrial dysfunction-associated senescence (MiDAS) with NAD+ - A Boolean model of mitochondrial dynamics and cell cycle control.
Diet and physical exercise in elderly people with obesity: The state of the art.
Low-fat yogurt consumption maintains biomarkers of immune function relative to nondairy control food in women with elevated BMI: A randomized controlled crossover trial.
Cardioprotective effects of aerobic training in diabetic rats: Reducing cardiac apoptotic indices and oxidative stress for a healthier heart.

Biosens Bioelectron. 2024 Aug 08. pii: S0956-5663(24)00653-5. [Epub ahead of print]264 116647

β-Hydroxybutyrate dehydrogenase functionalized two-dimensional photonic crystals for quantitative and visual sensing of ketone bodies.

Yuji Zhou, Irfan Muhammad, Lili Qiu, Yifei Wang, Yu Qiao, Zihui Meng.

  β-Hydroxybutyrate (BHB) is a substantial physiological ketone body. Its elevated concentration causes ketoacidosis, which is a disorder with a high mortality rate. Therefore, there is an urgent need to develop a simple method for the in-situ monitoring of BHB in urine. In this study, a photonic crystal hydrogel (PCH) sensing material for the detection of urinary ketones was prepared by embedding a two-dimensional polystyrene photonic crystal array (PCA) in a hydrogel functionalized with β-hydroxybutyrate dehydrogenase (BHBDH). BHBDH catalyzes the interconversion between β-hydroxybutyrate and acetoacetic acid and relies on the cofactor nicotinamide adenine dinucleotide (NAD+) to participate in the reaction process. The catalytic cycle of converting β-hydroxybutyrate to acetoacetate generates H+, which reduces the electrostatic repulsion between the carboxyl groups in the hydrogel network, ultimately leading to the shrinkage of the hydrogel volume. The hydrogel volume change was detected by measuring the diameter of the Debye diffraction ring, thus reflecting the concentration of BHB. When the concentration of BHB was increased from 0 to 10 mM, the reflection spectrum of PCH shifted for 117 nm within 60 min, consequently, the structural color of PCH changed from red to green and finally to blue. The material was used for quantitative detection of BHB with a detection limit of 48.94 μM. Then it was used for detection in artificial urine samples. While, this smart and reusable sensing material could provide a more convenient and efficient strategy for the ketone body detection in clinical diagnosis and point-of-care monitoring.

Keywords:  Ketone bodies; Photonic crystal sensors; β-hydroxybutyrate; β-hydroxybutyrate dehydrogenase

DOI:  https://doi.org/10.1016/j.bios.2024.116647
Physiol Rep. 2024 Aug;12(16): e70009

Ketone monoester plus high-dose glucose supplementation before exercise does not affect immediate post-exercise erythropoietin concentrations versus glucose alone.

Emily E Howard, Jillian T Allen, Julie L McNiff, Stephanie D Small, Kevin S O'Fallon, Lee M Margolis.

  The objective of this study was to examine the effect of consuming ketone monoester plus a high dose of carbohydrate from glucose (KE + CHO) on the change in erythropoietin (EPO) concentrations during load carriage exercise compared with carbohydrate (CHO) alone. Using a randomized, crossover design, 12 males consumed KE + CHO (573 mg KE/kg body mass, 110 g glucose) or CHO (110 g glucose) 30 min before 4 miles of self-paced treadmill exercise (KE + CHO:51 ± 13%, CHO: 52 ± 12% V̇O2peak) wearing a weighted vest (30% body mass; 25 ± 3 kg). Blood samples for analysis were obtained under resting fasted conditions before (Baseline) consuming the KE + CHO or CHO supplement and immediately after exercise (Post). βHB increased (p < 0.05) from Baseline to Post in KE + CHO, with no change in CHO. Glucose and glycerol increased (p < 0.05) from Baseline to Post in CHO, with no effect of time in KE + CHO. Insulin and lactate increased (p < 0.05) from Baseline to Post independent of treatment. EPO increased (p < 0.05) from Baseline to Post in KE + CHO and CHO with no difference between treatments. Although KE + CHO altered βHB, glucose, and glycerol concentrations, results from this study suggest that KE + CHO supplementation before load carriage exercise does not enhance immediate post-exercise increases in EPO compared with CHO alone.

Keywords:  erythropoiesis; exogenous ketones; ketosis; time trial; β‐Hydroxybutyrate

DOI:  https://doi.org/10.14814/phy2.70009
Circulation. 2024 Aug 20.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

Nigopan Gopalasingam, Kristoffer Berg-Hansen, Kristian Hylleberg Christensen, Bertil T Ladefoged, Steen Hvitfeldt Poulsen, Mads Jønsson Andersen, Barry Borlaug, Roni Nielsen, Niels Møller, Henrik Wiggers.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown.
METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period.
RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs.
CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Keywords:  3-hydroxybutyrate; cardiac output; exercise hemodynamics; heart failure with preserved ejection fraction; invasive hemodynamics; ketone ester; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.069732
Liver Int. 2024 Aug 20.

Transcriptional cascades during fasting amplify gluconeogenesis and instigate a secondary wave of ketogenic gene transcription.

Dana Goldberg, Nufar Buchshtab, Meital Charni-Natan, Ido Goldstein.

   BACKGROUND AND AIMS: During fasting, bodily homeostasis is maintained due to hepatic production of glucose (gluconeogenesis) and ketone bodies (ketogenesis). The main hormones governing hepatic fuel production are glucagon and glucocorticoids that initiate transcriptional programs aimed at supporting gluconeogenesis and ketogenesis.
METHODS: Using primary mouse hepatocytes as an ex vivo model, we employed transcriptomic analysis (RNA-seq), genome-wide profiling of enhancer dynamics (ChIP-seq), perturbation experiments (inhibitors, shRNA), hepatic glucose production measurements and computational analyses.
RESULTS: We found that in addition to the known metabolic genes transcriptionally induced by glucagon and glucocorticoids, these hormones induce a set of genes encoding transcription factors (TFs) thereby initiating transcriptional cascades. Upon activation by glucocorticoids, the glucocorticoid receptor (GR) induced the genes encoding two TFs: CCAAT/enhancer-binding protein beta (C/EBPβ) and peroxisome proliferator-activated receptor alpha (PPARα). We found that the GR-C/EBPβ cascade mainly serves as a secondary amplifier of primary hormone-induced gene programs. C/EBPβ augmented gluconeogenic gene expression and hepatic glucose production. Conversely, the GR-PPARα cascade initiated a secondary transcriptional wave of genes supporting ketogenesis. The cascade led to synergistic induction of ketogenic genes which is dependent on protein synthesis. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers were proximal to ketogenic genes, enriched for the PPARα response element and showed increased PPARα binding.
CONCLUSION: This study reveals abundant transcriptional cascades occurring during fasting. These cascades serve two separated purposes: the amplification of the gluconeogenic transcriptional program and the induction of a gene program aimed at enhancing ketogenesis.

Keywords:  chromatin; enhancers; fasting; liver; transcription

DOI:  https://doi.org/10.1111/liv.16077
Free Radic Biol Med. 2024 Aug 14. pii: S0891-5849(24)00597-5. [Epub ahead of print]

Unlocking peak performance: The role of Nrf2 in enhancing exercise outcomes and training adaptation in humans.

Miriam Martinez-Canton, Victor Galvan-Alvarez, Marcos Martin-Rincon, Jose A L Calbet, Angel Gallego-Selles.

  Since the discovery of the nuclear factor erythroid-derived 2-like 2 (Nrf2) transcription factor thirty years ago, it has been shown that it regulates more than 250 genes involved in a multitude of biological processes, including redox balance, mitochondrial biogenesis, metabolism, detoxification, cytoprotection, inflammation, immunity, autophagy, cell differentiation, and xenobiotic metabolism. In skeletal muscle, Nrf2 signalling is primarily activated in response to perturbation of redox balance by reactive oxygen species or electrophiles. Initial investigations into human skeletal muscle Nrf2 responses to exercise, dating back roughly a decade, have consistently indicated that exercise-induced ROS production stimulates Nrf2 signalling. Notably, recent studies employing Nrf2 knockout mice have revealed impaired skeletal muscle contractile function characterised by reduced force output and increased fatigue susceptibility compared to wild-type counterparts. These deficiencies partially stem from diminished basal mitochondrial respiratory capacity and an impaired capacity to upregulate specific mitochondrial proteins in response to training, findings corroborated by inducible muscle-specific Nrf2 knockout models. In humans, baseline Nrf2 expression in skeletal muscle correlates with maximal oxygen uptake and high-intensity exercise performance. This manuscript delves into the mechanisms underpinning Nrf2 signalling in response to acute exercise in human skeletal muscle, highlighting the involvement of ROS, antioxidants and Keap1/Nrf2 signalling in exercise performance. Furthermore, it explores Nrf2's role in mediating adaptations to chronic exercise and its impact on overall exercise performance. Additionally, the influence of diet and certain supplements on basal Nrf2 expression and its role in modulating acute and chronic exercise responses are briefly addressed.

Keywords:  Nrf2 signalling; ROS; exercise; free radicals; keap1; performance; polyphenols

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.011
Nature. 2024 Aug;632(8027): 987-988

Inner membrane turns inside out to exit mitochondrial organelles.

David Pla-Martín, Andreas S Reichert.



Keywords:  Biochemistry; Cell biology

DOI:  https://doi.org/10.1038/d41586-024-02528-w
Med Sci Sports Exerc. 2024 Aug 23.

Consuming Whey Protein with Added Essential Amino Acids, not Carbohydrate, Maintains Post-Exercise Anabolism while Underfed.

Jess A Gwin, David D Church, Jillian T Allen, Marques A Wilson, Christopher T Carrigan, Nancy E Murphy, Alyssa N Varanoske, Lee M Margolis, Robert R Wolfe, Arny A Ferrando, Stefan M Pasiakos.

PURPOSE: Energy deficiency decreases muscle protein synthesis (MPS), possibly due to greater whole-body essential amino acid (EAA) requirements and reliance on energy stores. Whether energy deficit-induced anabolic resistance is overcome with non-nitrogenous supplemental energy or if increased energy as EAA is needed is unclear. We tested the effects of energy as EAA or carbohydrate, combined with an EAA-enriched whey protein, on post-exercise MPS (%/h) and whole-body protein turnover (g protein/240 min).
METHODS: 17 adults (mean ± SD; age: 26 ± 6 y, BMI: 25 ± 3 kg/m 2 ) completed a randomized, parallel study including two 5-d energy conditions (BAL, energy balance; DEF, -30 ± 3% energy requirements) separated by ≥7 d. Volunteers consumed EAA-enriched whey with added EAA (+EAA; 304 kcal, 56 g protein, 48 g EAA, 17 g carbohydrate, 2 g fat; n = 8) or added carbohydrate (+CHO; 311 kcal, 34 g protein, 24 g EAA, 40 g carbohydrate, 2 g fat; n = 9) following exercise. MPS and whole-body protein synthesis (PS), breakdown (PB), and net balance (NET; PS-PB) were estimated postexercise with isotope kinetics.
RESULTS: MPS rates were greater in +EAA (0.083 ± 0.02) than +CHO (0.059 ± 0.01; P = 0.015) during DEF, but similar during BAL ( P = 0.45) and across energy conditions within treatments ( P = 0.056). PS rates were greater for +EAA (BAL, 117.9 ± 16.5; DEF, 110.3 ± 14.8) than +CHO (BAL, 81.6 ± 8.0; DEF, 83.8 ± 5.9 g protein/240 min; both P < 0.001), and greater during BAL than DEF in +EAA ( P = 0.045). PB rates were less in +EAA (8.0 ± 16.5) than +CHO (37.8 ± 7.6 g protein/240 min; P < 0.001), and NET was greater in +EAA (106.1 ± 6.3) than +CHO (44.8 ± 8.5 g protein/240 min; P < 0.001).
CONCLUSIONS: These data suggest that supplementing EAA-enriched whey protein with more energy as EAA, not carbohydrate, maintains postexercise MPS during energy deficit at rates comparable to those observed during energy balance.

DOI: https://doi.org/10.1249/MSS.0000000000003541
PLoS One. 2024 ;19(8): e0307802

shRNA-mediated down-regulation of Acsl1 reverses skeletal muscle insulin resistance in obese C57BL6/J mice.

Kamila Roszczyc-Owsiejczuk, Monika Imierska, Emilia Sokołowska, Mariusz Kuźmicki, Karolina Pogodzińska, Agnieszka Błachnio-Zabielska, Piotr Zabielski.

Prolonged consumption of diet rich in fats is regarded as the major factor leading to the insulin resistance (IR) and type 2 diabetes (T2D). Emerging evidence link excessive accumulation of bioactive lipids such as diacylglycerol (DAG) and ceramide (Cer), with impairment of insulin signaling in skeletal muscle. Until recently, little has been known about the involvement of long-chain acyl-CoAs synthetases in the above mechanism. To examine possible role of long-chain acyl-coenzyme A synthetase 1 (Acsl1) (a major muscular ACSL isoform) in mediating HFD-induced IR we locally silenced Acsl1 in gastrocnemius of high-fat diet (HFD)-fed C57BL/6J mice through electroporation-delivered shRNA and compared it to non-silenced tissue within the same animal. Acsl1 down-regulation decreased the content of muscular long-chain acyl-CoA (LCACoA) and both the Cer (C18:1-Cer and C24:1-Cer) and DAG (C16:0/18:0-DAG, C16:0/18:2-DAG, C18:0/18:0-DAG) and simultaneously improved insulin sensitivity and glucose uptake as compared with non-silenced tissue. Acsl1 down-regulation decreased expression of mitochondrial β-oxidation enzymes, and the content of both the short-chain acylcarnitine (SCA-Car) and short-chain acyl-CoA (SCACoA) in muscle, pointing towards reduction of mitochondrial FA oxidation. The results indicate, that beneficial effects of Acsl1 partial ablation on muscular insulin sensitivity are connected with inhibition of Cer and DAG accumulation, and outweigh detrimental impact of decreased mitochondrial fatty acids metabolism in skeletal muscle of obese HFD-fed mice.

DOI: https://doi.org/10.1371/journal.pone.0307802
Front Pharmacol. 2024 ;15 1428601

Time-restricted eating, the clock ticking behind the scenes.

Aleix Ribas-Latre, Sonia Fernández-Veledo, Joan Vendrell.

   Introduction: Maintaining metabolic balance relies on accumulating nutrients during feeding periods and their subsequent release during fasting. In obesity and metabolic disorders, strategies aimed at reducing food intake while simulating fasting have garnered significant attention for weight loss. Caloric restriction (CR) diets and intermittent fasting (IF) interventions have emerged as effective approaches to improving cardiometabolic health. Although the comparative metabolic benefits of CR versus IF remain inconclusive, this review focuses on various forms of IF, particularly time-restricted eating (TRE).
Methods: This study employs a narrative review methodology, systematically collecting, synthesizing, and interpreting the existing literature on TRE and its metabolic effects. A comprehensive and unbiased search of relevant databases was conducted to identify pertinent studies, including pre-clinical animal studies and clinical trials in humans. Keywords such as "Obesity," "Intermittent Fasting," "Time-restricted eating," "Chronotype," and "Circadian rhythms" guided the search. The selected studies were critically appraised based on predefined inclusion and exclusion criteria, allowing for a thorough exploration and synthesis of current knowledge.
Results: This article synthesizes pre-clinical and clinical studies on TRE and its metabolic effects, providing a comprehensive overview of the current knowledge and identifying gaps for future research. It explores the metabolic outcomes of recent clinical trials employing different TRE protocols in individuals with overweight, obesity, or type II diabetes, emphasizing the significance of individual chronotype, which is often overlooked in practice. In contrast to human studies, animal models underscore the role of the circadian clock in mitigating metabolic disturbances induced by obesity through time-restricted feeding (TRF) interventions. Consequently, we examine pre-clinical evidence supporting the interplay between the circadian clock and TRF interventions. Additionally, we provide insights into the role of the microbiota, which TRE can modulate and its influence on circadian rhythms.

Keywords:  chronotype; circadian rhythms; intermittent fasting; obesity; time-restricted eating

DOI:  https://doi.org/10.3389/fphar.2024.1428601
J Appl Physiol (1985). 2024 Aug 22.

Skeletal muscle adaptations following eccentric contractions are not mediated by keratin 18.

Muni Swamy Ganjayi, Samuel W Frank, Thomas A Krauss, Michael L York, Robert J Bloch, Cory W Baumann.

  The molecular mechanisms that drive muscle adaptations after eccentric exercise training are multifaceted and likely impacted by age. Previous studies have reported that many genes and proteins respond differently in young and older muscles following training. Keratin 18 (Krt18), a cytoskeletal protein involved in force transduction and organization, was found to be upregulated after muscles performed repeated bouts of eccentric contractions, with higher levels observed in young muscle compared to older muscle. Therefore, the purpose of this study was to determine if Krt18 mediates skeletal muscle adaptations following eccentric exercise training. The anterior crural muscles of Krt18 knockout (KO) and wild-type (WT) mice were subjected to either a single bout or repeated bouts of eccentric contractions, with isometric torque assessed across the initial and final bouts. Functionally, Krt18 KO and WT mice did not differ prior to performing any eccentric contractions (p≥0.100). Muscle strength (tetanic isometric torques) and the ability to adapt to eccentric exercise training were also consistent across strains at all time points (p≥0.169). Stated differently, immediate strength deficits and the recovery of strength following a single or multiple bouts of eccentric contractions were similar between Krt18 KO and WT mice. In summary, the absence of Krt18 does not impede the muscle's ability to adapt to repeated eccentric contractions, suggesting it is not essential for exercise-induced remodeling.

Keywords:  damage; exercise; injury; intermediate filaments; strength

DOI:  https://doi.org/10.1152/japplphysiol.00496.2024
Int Immunopharmacol. 2024 Aug 18. pii: S1567-5769(24)01374-2. [Epub ahead of print]141 112853

Research progress on the role and inhibitors of Keap1 signaling pathway in inflammation.

Chao Ding, Ying Wu, Chaochao Zhan, Anam Naseem, Lixia Chen, Hua Li, Bingyou Yang, Yan Liu.

  Inflammation is a protective mechanism against endogenous and exogenous pathogens. It is a typical feature of numerous chronic diseases and their complications. Keap1 is an essential target in oxidative stress and inflammatory diseases. Among them, the Keap1-Nrf2-ARE pathway (including Keap1-Nrf2-HO-1) is the most significant pathway of Keap1 targets, which participates in the control of inflammation in multiple organs (including renal inflammation, lung inflammation, liver inflammation, neuroinflammation, etc.). Identifying new Keap1 inhibitors is crucial for new drug discovery. However, most drugs have specificity issues as they covalently bind to cysteine residues of Keap1, causing off-target effects. Therefore, direct inhibition of Keap1-Nrf2 PPIs is a new research idea. Through non-electrophilic and non-covalent binding, its inhibitors have better specificity and ability to activate Nrf2, and targeting therapy against Keap1-Nrf2 PPIs has become a new method for drug development in chronic diseases. This review summarizes the members and downstream genes of the Keap1-related pathway and their roles in inflammatory disease models. In addition, we summarize all the research progress of anti-inflammatory drugs targeting Keap1 from 2010 to 2024, mainly describing their biological functions, molecular mechanisms of action, and therapeutic roles in inflammatory diseases.

Keywords:  Inflammation; Keap1; Keap1 inhibitors; Natural products; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.intimp.2024.112853
Transl Oncol. 2024 Aug 19. pii: S1936-5233(24)00211-0. [Epub ahead of print]49 102084

Unlocking mitochondrial dysfunction-associated senescence (MiDAS) with NAD+ - A Boolean model of mitochondrial dynamics and cell cycle control.

Herbert Sizek, Dávid Deritei, Katherine Fleig, Marlayna Harris, Peter L Regan, Kimberly Glass, Erzsébet Ravasz Regan.

  The steady accumulation of senescent cells with aging creates tissue environments that aid cancer evolution. Aging cell states are highly heterogeneous. 'Deep senescent' cells rely on healthy mitochondria to fuel a strong proinflammatory secretome, including cytokines, growth and transforming signals. Yet, the physiological triggers of senescence such as reactive oxygen species (ROS) can also trigger mitochondrial dysfunction, and sufficient energy deficit to alter their secretome and cause chronic oxidative stress - a state termed Mitochondrial Dysfunction-Associated Senescence (MiDAS). Here, we offer a mechanistic hypothesis for the molecular processes leading to MiDAS, along with testable predictions. To do this we have built a Boolean regulatory network model that qualitatively captures key aspects of mitochondrial dynamics during cell cycle progression (hyper-fusion at the G1/S boundary, fission in mitosis), apoptosis (fission and dysfunction) and glucose starvation (reversible hyper-fusion), as well as MiDAS in response to SIRT3 knockdown or oxidative stress. Our model reaffirms the protective role of NAD+ and external pyruvate. We offer testable predictions about the growth factor- and glucose-dependence of MiDAS and its reversibility at different stages of reactive oxygen species (ROS)-induced senescence. Our model provides mechanistic insights into the distinct stages of DNA-damage induced senescence, the relationship between senescence and epithelial-to-mesenchymal transition in cancer and offers a foundation for building multiscale models of tissue aging.

Keywords:  Boolean network model; Cell cycle; MiDAS; Mitochondrial ROS; Mitochondrial fusion/fission; NAD(+)

DOI:  https://doi.org/10.1016/j.tranon.2024.102084
Eur J Intern Med. 2024 Aug 17. pii: S0953-6205(24)00345-5. [Epub ahead of print]

Diet and physical exercise in elderly people with obesity: The state of the art.

Francesca Battista, Silvia Bettini, Ludovica Verde, Luca Busetto, Luigi Barrea, Giovanna Muscogiuri.

  Obesity is a disease that is assuming pandemic proportions in recent decades. With the advancement of medicine and increased access to care, average survival has increased, resulting in a larger number of elderly people. As a result, the amount of elderly people living with obesity is increasing, and the morbidity and impact of obesity on ageing implies severe limitations for these people. The link between obesity and ageing is not only epidemiological, but also strictly pathophysiological. Obesity accelerates the ageing process and ageing is characterised by pathophysiological mechanisms shared by obesity itself. Some examples of alterations shared by ageing and obesity are metabolic changes, sarcopenia and reduced functional capacity related to both loss of muscle strength and reduced cardiorespiratory fitness, as well as a general reduction in the perception of quality of life. The specific ability to antagonize these mechanisms through non-pharmacological treatment based on nutrition and exercise has always been one of the focal points of the international literature. Therefore, this review provides the state of the art on scientific knowledge regarding the main effects of an adequate nutritional plan and an individualised exercise prescription on the general health of elderly with obesity. In particular, this paper addresses the effect of nutrition and physical exercise on pathophysiological changes peculiar of ageing and obesity, providing also the scientific rational for nutritional and exercise prescription in the population.

Keywords:  Aging; Body composition; Exercise prescription; Functional capacity; Nutrition; Protein intake

DOI:  https://doi.org/10.1016/j.ejim.2024.08.007
Nutr Res. 2024 Jul 24. pii: S0271-5317(24)00096-4. [Epub ahead of print]129 1-13

Low-fat yogurt consumption maintains biomarkers of immune function relative to nondairy control food in women with elevated BMI: A randomized controlled crossover trial.

Yu Hasegawa, Andrea L Noll, David J Lang, Elizabeth M Akfaly, Zhenhua Liu, Bradley W Bolling.

  Yogurt consumption may help reduce chronic inflammation associated with obesity. However, the underlying mechanism(s) by which yogurt consumption modulates the immune system have not been validated in human intervention studies. We hypothesized that 4-week yogurt consumption (12 oz/day) attenuates systemic inflammation by modulating the proportion of circulating T helper (Th) 17 and regulatory T (Treg) cells in adult women with elevated body mass index (BMI). To test the hypothesis, we conducted a randomized crossover dietary intervention study consisted of a 4-week dietary intervention in which participants consumed 12 oz of either low-fat dairy yogurt or a soy pudding control snack per day, with a 4-week washout between treatments. Thirty-nine healthy adult women with a BMI between 25 and 40 kg/m2 were enrolled and 20 completed the study. Changes in the biometrics, circulating T cells, and markers of systemic and colonic inflammation were assessed between the 2 treatment groups, as well as 24-hour diet recalls were conducted at baseline and following each treatment. The primary study outcome, the change in the proportion of circulating Th17 cells, was unaffected by the treatments. Secondary outcome measures, circulating Treg, Th17, and markers of chronic inflammation, were maintained by yogurt treatment, whereas circulating Treg was increased and interleukin-10 was reduced by control snack treatment. However, circulating Treg changes were not associated with changes to other biomarkers of inflammation, implying other immune cells and/or tissues may mediate circulating biomarkers of chronic inflammation. This study was approved by the University of Wisconsin-Madison institutional review board and registered at ClinicalTrials.gov NCT04149418.

Keywords:  IL-10; Inflammation; Obesity; Th17; Treg; Yogurt

DOI:  https://doi.org/10.1016/j.nutres.2024.07.005
ARYA Atheroscler. 2024 Mar-Apr;20(2):20(2): 50-60

Cardioprotective effects of aerobic training in diabetic rats: Reducing cardiac apoptotic indices and oxidative stress for a healthier heart.

Mohammad Ali Gharaat, Hamid Reza Choobdari, Mohsen Sheykhlouvand.

   BACKGROUND: The present study evaluated the effects of aerobic training with variable intensities on apoptotic indices of cardiac tissue in fatty diabetic rats.
METHODS: Twenty-four male Wistar rats were randomly divided into non-diabetic (ND, n=8), trained diabetic (TD, n=8), and control diabetic (CD, n=8) groups. Following a high-fat dietary regimen, type 2 diabetes was induced by streptozotocin, with blood glucose levels above 300 mg/dL considered indicative of diabetes. The TD group underwent aerobic exercise five times a week for six weeks. Subsequently, measurements were taken for left ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV), ejection fraction (EF%), catalase, caspase-9, P53, glucose, insulin, and HOMA-IR.
RESULTS: Aerobic training led to a significant decrease in blood glucose levels (P < 0.01), caspase-9 (P < 0.05), HOMA-IR (P < 0.05), and P53 expression (P < 0.001) compared with the CD group. LVEDV and LVESV decreased significantly (P < 0.05 for both), while LVEF increased significantly (P < 0.05). Catalase activation showed an insignificant increase in the TD group pre- to post-training compared to CD.
CONCLUSION: Incremental aerobic exercise training (6 weeks) may exert a cardioprotective effect in diabetic rats by reducing apoptosis and oxidative stress indices, while simultaneously increasing aerobic fitness and reducing body weight.

Keywords:  Apoptosis; Diabetes; Oxygen Consumption; Physical Activity; Rat

DOI:  https://doi.org/10.48305/arya.2024.41976.2911