bims-kimdis 2023-04-02 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒04‒02
thirteen papers selected by
Matías Javier Monsalves Álvarez

Low-Carbohydrate Diet Modulates Glucose-Lipid Utilization in Skeletal Muscle of Diabetic Mice.
Ketones and the Heart: Metabolic Principles and Therapeutic Implications.
Very low calorie ketogenic diet and common rheumatic disorders: A case report.
Serum neurofilament light chain in relapsing multiple sclerosis patients on a ketogenic diet.
Defective Muscle Ketone Body Oxidation Disrupts BCAA Catabolism by Altering Mitochondrial Branched-Chain Aminotransferase.
Protective Potential of β-Hydroxybutyrate against Glucose-Deprivation-Induced Neurotoxicity Involving the Modulation of Autophagic Flux and the Monomeric Aβ Level in Neuro-2a Cells.
In vivo assessment of β-hydroxybutyrate metabolism in mouse brain using deuterium (2 H) MRS.
Circulating ketone bodies as signals for cardiovascular disease and mortality.
Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.
Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet.
The ketone body acetoacetate activates human neutrophils through FFAR2.
Malonylation of Acetyl-CoA carboxylase 1 promotes hepatic steatosis and is attenuated by ketogenic diet in NAFLD.
Aging Hallmarks and the Role of Oxidative Stress.

Nutrients. 2023 Mar 21. pii: 1513. [Epub ahead of print]15(6):

Low-Carbohydrate Diet Modulates Glucose-Lipid Utilization in Skeletal Muscle of Diabetic Mice.

Yan Li, Zi Yang, Yu Wang, Mingcong Fan, Chenzhipeng Nie, Lamei Xue, Li Wang, Haifeng Qian.

  Type 2 diabetes is associated with many complications, including skeletal muscle atrophy. Ketogenic diets and low-carbohydrate diets (LCD) have recently been introduced as dietary interventions in patients with diabetes, but their effects on glucose and lipid metabolism in skeletal muscle have not been studied. In the current study, we compared the effects of LCD and ketogenic diet on glucose and lipid metabolism in skeletal muscle of diabetic mice. C57BL/6J mice with type 2 diabetes, constructed by a high-fat diet combined with streptozotocin, were fed a standard diet, a high-fat diet, an LCD, or a ketogenic diet for 14 weeks, respectively. Here, we found that the LCD, rather than the ketogenic diet, retained skeletal muscle weight and suppressed the expression of atrophy-related genes in diabetic mice. In addition, the LCD had more glycolytic/type IIb myofiber content and inhibited forkhead box O1 and pyruvate dehydrogenase kinase 4 expression, leading to improved glucose utilization. However, the ketogenic diet maintained more oxidative/type I myofibers. Moreover, compared with the ketogenic diet, the LCD decreased intramuscular triglycerides content and muscle lipolysis, suggesting improvement in lipid metabolism. Taken together, these data suggested that the LCD improved glucose utilization, and inhibited lipolysis and atrophy in skeletal muscle of diabetic mice, while the ketogenic diet showed metabolic disorders in skeletal muscle.

Keywords:  glucose utilization; ketogenic diet; low-carbohydrate diet; skeletal muscle; type 2 diabetes

DOI:  https://doi.org/10.3390/nu15061513
Circ Res. 2023 Mar 31. 132(7): 882-898

Ketones and the Heart: Metabolic Principles and Therapeutic Implications.

Timothy R Matsuura, Patrycja Puchalska, Peter A Crawford, Daniel P Kelly.

  The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

Keywords:  3-hydroxybutyric acid; acetoacetate; diet, ketogenic; fatty acid oxidation; heart failure; hypertrophy; ketone bodies

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.321872
World J Clin Cases. 2023 Mar 26. 11(9): 1985-1991

Very low calorie ketogenic diet and common rheumatic disorders: A case report.

Mariangela Rondanelli, Zaira Patelli, Clara Gasparri, Francesca Mansueto, Cinzia Ferraris, Mara Nichetti, Tariq A Alalwan, Ignacio Sajoux, Roberto Maugeri, Simone Perna.

  BACKGROUND: The scientific literature provides evidence that nutritional ketosis can be an important support in the treatment of pathologies in which inflammation is present, as recent studies have shown that ketone bodies have anti-inflammatory activity in numerous diseases, including rheumatic diseases. We report the case of a 22-year-old woman with class I obesity and juvenile idiopathic arthritis who started treatment with a very low calorie ketogenic diet (VLCKD).CASE SUMMARY: The patient was a 22-year-old woman diagnosed with juvenile idiopathic arthritis at age 4 years and with a body mass index (BMI) of 30.8 kg/m2, waist circumference (WC) 80 cm, fat mass (FM) 28.1 kg, free FM 45.7 kg, and visceral adipose tissue (VAT) 3.5 kg, assessed on bioimpedance analysis. She was treated using a commercial VLCKD weight-loss program (PNK® method); this program provides high-biological-value protein preparations and natural foods. Each protein preparation contains 15 g protein, 4 g carbohydrate, 3 g fat, and 50 mg omega-3 docosahexaenoic acid, with an energy content of 90-120 kcal. After four months on the program, the BMI was 28.6 kg/m2, WC 73 cm, FM 23.2 kg, free FM 41.9 kg, and VAT 2.9 kg.
CONCLUSION: VLCKD enabled the patient to reach her target weight and to reduce her joint pain and headaches. Laboratory inflammatory indices also normalized.

Keywords:  Case report; Inflammation; Obesity; PNK® method; Rheumatic disorders; Very low calorie ketogenic diet; Weight loss

DOI:  https://doi.org/10.12998/wjcc.v11.i9.1985
Mult Scler Relat Disord. 2023 Mar 25. pii: S2211-0348(23)00174-8. [Epub ahead of print]73 104670

Serum neurofilament light chain in relapsing multiple sclerosis patients on a ketogenic diet.

Unsong Oh, Emma Woolbright, Diana Lehner-Gulotta, Rachael Coleman, Mark Conaway, Myla D Goldman, J Nicholas Brenton.

  BACKGROUND: Ketogenic diets have anti-inflammatory and neuroprotective properties which make these diets an attractive complimentary treatment approach for patients living with multiple sclerosis (MS). The objective of this study was to assess the impact of ketogenic diets on neurofilament light chain (NfL), a biomarker of neuroaxonal injury.METHODS: Thirty-nine subjects with relapsing MS completed a 6-month ketogenic diet intervention. NfL levels were assayed at both baseline (pre-diet) and 6-months on-diet. In addition, ketogenic diet study participants were compared to a cohort (n = 31) of historical, untreated MS controls.
RESULTS: Baseline (pre-diet) mean NfL was 5.45 pg/ml (95% CI 4.59 - 6.31). After 6 months on ketogenic diet, mean NfL was not significantly changed (5.49 pg/ml; 95% CI 4.82 - 6.19). Compared to untreated MS controls (mean 15.17 pg/ml), NfL levels for the ketogenic diet cohort were relatively low. MS subjects with higher levels of ketosis (as measured by serum beta-hydroxybutyrate) exhibited greater reductions in NfL between baseline and 6-months on ketogenic diet.
CONCLUSIONS: Ketogenic diets do not worsen biomarkers of neurodegeneration in relapsing MS patients, with stable, low levels of NfL observed throughout the diet intervention. Subjects with greater biomarkers of ketosis experienced a higher degree of improvement in serum NfL.
CLINICAL TRIAL IDENTIFIER: NCT03718247 - "Utilization of the Ketogenic Diet in Patients with Relapsing-Remitting MS" https://clinicaltrials.gov/ct2/show/NCT03718247.

Keywords:  Diet; Ketogenic; Multiple sclerosis; Neurodegeneration; Neurofilament light chain

DOI:  https://doi.org/10.1016/j.msard.2023.104670
Am J Physiol Endocrinol Metab. 2023 Mar 29.

Defective Muscle Ketone Body Oxidation Disrupts BCAA Catabolism by Altering Mitochondrial Branched-Chain Aminotransferase.

Hamza Mechchate, Abdualrahman Mohammed Abdualkader, James Bradshaw Bernacchi, Keshav Gopal, S Amirhossein Tabatabaei Dakhili, Kunyan Yang, Amanda A Greenwell, Xingxing Kong, Peter A Crawford, Rami Al Batran.

  Ketone bodies are an endogenous fuel source generated primarily by the liver to provide alternative energy for extrahepatic tissues during prolonged fasting and exercise. Skeletal muscle is an important site of ketone body oxidation which occurs through a series of reactions requiring the enzyme succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1). We have previously shown that deleting SCOT in the skeletal muscle protects against obesity-induced insulin resistance by increasing pyruvate dehydrogenase (PDH) activity, the rate-limiting enzyme of glucose oxidation. However, it remains unclear whether inhibiting muscle ketone body oxidation causes hypoglycemia and affects fuel metabolism in the absence of obesity. Here, we show that lean mice lacking skeletal muscle SCOT (SCOTSkM-/-) exhibited no overt phenotypic differences in glucose and fat metabolism from their human α-skeletal actin-Cre (HSACre) littermates. Of interest, we found that plasma and muscle branched-chain amino acid (BCAA) levels are elevated in SCOTSkM-/- lean mice compared to their HSACre littermates. Interestingly, this alteration in BCAA catabolism was only seen in SCOTSkM-/- mice under low-fat feeding and associated with decreased expression of mitochondrial branched-chain aminotransferases (BCATm/Bcat2), the first enzyme in BCAA catabolic pathway. Loss- and gain-of-function studies in C2C12 myotubes demonstrated that suppressing SCOT markedly diminished BCATm expression, whereas overexpressing SCOT resulted in an opposite effect without influencing BCAA oxidation enzymes. Further, SCOT overexpression in C2C12 myotubes significantly increased luciferase activity driven by a Bcat2 promoter construct. Together, our findings indicate that SCOT regulates the expression of the Bcat2 gene, which, through the abundance of its product BCATm, may influence circulating BCAA concentrations.

Keywords:  BCAAs; BCATm; Ketone body; SCOT; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00206.2022
Biomedicines. 2023 Feb 24. pii: 698. [Epub ahead of print]11(3):

Protective Potential of β-Hydroxybutyrate against Glucose-Deprivation-Induced Neurotoxicity Involving the Modulation of Autophagic Flux and the Monomeric Aβ Level in Neuro-2a Cells.

Yi-Fen Chiang, Ngan Thi Kim Nguyen, Shih-Min Hsia, Hsin-Yuan Chen, Shyh-Hsiang Lin, Ching-I Lin.

  Hypoglycemia has been known as a potential contributory factor to neurodegenerative diseases, such as Alzheimer's disease. There may be shared pathogenic mechanisms underlying both conditions, and the ketone body, β-hydroxybutyrate (BHB), as an alternative substrate for glucose may exert neuroprotection against hypoglycemia-induced injury. To investigate this, Neuro-2a cells were subjected to a 24 h period of glucose deprivation with or without the presence of BHB. Cell viability, reactive oxygen species (ROS) production, apoptosis, autophagy, and adenosine triphosphate (ATP) and beta-amyloid peptide (Aβ) levels were evaluated. The results show that Neuro-2a cells deprived of glucose displayed a significant loss of cell survival with a corresponding decrease in ATP levels, suggesting that glucose deprivation was neurotoxic. This effect was likely attributed to the diverse mechanisms including raised ROS, defective autophagic flux and reduced basal Aβ levels (particularly monomeric Aβ). The presence of BHB could partially protect against the loss of cell survival induced by glucose deprivation. The mechanisms underlying the neuroprotective actions of BHB might be mediated, at least in part, through restoring ATP, and modulating ROS production, autophagy flux efficacy and the monomeric Aβ level. Results imply that a possible link between the basal monomeric Aβ and glucose deprivation neurotoxicity, and treatments designed for the prevention of energy impairment, such as BHB, may be beneficial for rescuing surviving cells in relation to neurodegeneration.

Keywords:  Alzheimer’s disease; autophagic flux; glucose deprivation; monomeric beta-amyloid peptides; neurodegenerative diseases; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/biomedicines11030698
Magn Reson Med. 2023 Mar 27.

In vivo assessment of β-hydroxybutyrate metabolism in mouse brain using deuterium (2 H) MRS.

Narayan Datt Soni, Anshuman Swain, Paul Jacobs, Halvor Juul, Ryan Armbruster, Ravi Prakash Reddy Nanga, Kavindra Nath, Corinde Wiers, John Detre, Ravinder Reddy.

  PURPOSE: To monitor the metabolic turnover of β-hydroxybutyrate (BHB) oxidation using 2 H-MRS in conjunction with intravenous administration of 2 H labeled BHB.METHODS: Nine-month-old mice were infused with [3,4,4,4]-2 H4 -BHB (d4 -BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d4 -BHB was monitored using 2 H-MRS spectra acquired with a home-built 2 H surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses.
RESULTS: Deuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]-2 H2 -Glx (d2 -Glx) over time and reaching a quasi-steady state concentration of ∼0.6 ± 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d4 -BHB also resulted in the formation of semi-heavy water (HDO), with a four-fold (10.1 to ∼42.1 ± 7.3 mM) linear (R2 = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d4 -BHB metabolism was determined to be 0.034 ± 0.004 min-1 .
CONCLUSION: 2 H-MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of 2 H-MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions.

Keywords:  2H-MRS; TCA; brain; d4-BHB; ketone bodies; metabolism

DOI:  https://doi.org/10.1002/mrm.29648
Eur Heart J. 2023 Mar 30. pii: ehad176. [Epub ahead of print]

Circulating ketone bodies as signals for cardiovascular disease and mortality.

Suzanne N Voorrips, B Daan Westenbrink.

DOI: https://doi.org/10.1093/eurheartj/ehad176
Mol Genet Metab Rep. 2023 Jun;35 100968

Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.

Eri Ogawa, Takako Hishiki, Noriyo Hayakawa, Hisato Suzuki, Kenjiro Kosaki, Makoto Suematsu, Toshiki Takenouchi.

  The pyruvate dehydrogenase complex serves as the main connection between cytosolic glycolysis and the tricarboxylic acid cycle within mitochondria. An infant with pyruvate dehydrogenase complex deficiency was treated with vitamin B1 supplementation and a ketogenic diet. These dietary modifications resolved the renal tubular reabsorption, central apnea, and transfusion-dependent anemia. A concurrent metabolome analysis demonstrated the resolution of the amino aciduria and an increased total amount of substrates in the tricarboxylic acid cycle, reflecting the improved mitochondrial energetics. Glutamate was first detected in the cerebrospinal fluid, accompanied by a clinical improvement, after the ketogenic ratio was increased to 3:1; thus, glutamate levels in cerebrospinal fluid may represent a biomarker for neuronal recovery. Metabolomic analyses of body fluids are useful for monitoring therapeutic effects in infants with inborn errors of carbohydrate metabolism.

Keywords:  Ketogenic diet; Metabolome; Pyruvate dehydrogenase deficiency; Whole genome sequencing

DOI:  https://doi.org/10.1016/j.ymgmr.2023.100968
Int J Mol Sci. 2023 Mar 16. pii: 5654. [Epub ahead of print]24(6):

Exercise Induces an Augmented Skeletal Muscle Mitochondrial Unfolded Protein Response in a Mouse Model of Obesity Produced by a High-Fat Diet.

Pía Apablaza, Juan Carlos Bórquez, Rodrigo Mendoza, Mónica Silva, Gladys Tapia, Alejandra Espinosa, Rodrigo Troncoso, Luis A Videla, Nevenka Juretić, Andrea Del Campo.

  Increase in body fat contributes to loss of function and changes in skeletal muscle, accelerating sarcopenia, a phenomenon known as sarco-obesity or sarcopenic obesity. Studies suggest that obesity decreases the skeletal muscle (SM)'s ability to oxidize glucose, increases fatty acid oxidation and reactive oxygen species production, due to mitochondrial dysfunction. Exercise improves mitochondrial dysfunction in obesity; however, it is not known if exercise regulates the mitochondrial unfolded protein response (UPRmt) in the SM. Our study aimed to determine the mito-nuclear UPRmt in response to exercise in a model of obesity, and how this response is associated with the improvement in SM functioning after exercise training. C57BL/6 mice were fed a normal diet and high-fat diet (HFD) for 12 weeks. After 8 weeks, animals were subdivided into sedentary and exercised for the remaining 4 weeks. Grip strength and maximal velocity of mice submitted to HFD improved after training. Our results show an increase in the activation of UPRmt after exercise while in obese mice, proteostasis is basally decreased but shows a more pronounced increase with exercise. These results correlate with improvement in the circulating triglycerides, suggesting mitochondrial proteostasis could be protective and could be related to mitochondrial fuel utilization in SM.

Keywords:  UPRmt; exercise; obesity; skeletal muscle

DOI:  https://doi.org/10.3390/ijms24065654
J Leukoc Biol. 2023 Mar 31. pii: qiad035. [Epub ahead of print]

The ketone body acetoacetate activates human neutrophils through FFAR2.

Jonas Mårtensson, Lena Björkman, Simon Lind, Moa Bjerhem Viklund, Linjie Zhang, Saray Gutierrez, Claes Dahlgren, Martina Sundqvist, Xin Xie, Huamei Forsman.

  Neutrophils express many surface receptors that sense environmental changes. One such sensor is FFAR2 (free fatty acid receptor 2), a receptor that detects gut microbiota-derived short chain fatty acids. As such, FFAR2 has been regarded as a molecular link between metabolism and inflammation. Our recent studies on FFAR2, using its endogenous agonist propionate in combination with allosteric modulators, have identified several novel aspects of FFAR2 regulation. A recent study has also identified the ketone body acetoacetate as an endogenous ligand for mouse FFAR2. Whether human FFAR2 also recognizes acetoacetate and how this recognition modulates human neutrophil functions has not been earlier investigated. In this study, we found that acetoacetate can induce a decrease of cAMP and translocation of β-arrestin in cells overexpressing FFAR2. In addition, we show that similar to propionate, FFAR2 specific allosteric modulators enhance acetoacetate-induced transient rise in cytosolic calcium, production of reactive oxygen species and cell migration in human neutrophils. In summary, we demonstrate that human neutrophils recognize the ketone body acetoacetate through FFAR2. Thus, our data further highlight the key role of FFAR2 in inflammation and metabolism.

Keywords:  FFAR2; G-protein coupled receptor; Neutrophil; acetoacetate; ketone body

DOI:  https://doi.org/10.1093/jleuko/qiad035
Cell Rep. 2023 Mar 31. pii: S2211-1247(23)00330-3. [Epub ahead of print]42(4): 112319

Malonylation of Acetyl-CoA carboxylase 1 promotes hepatic steatosis and is attenuated by ketogenic diet in NAFLD.

Huanyi Cao, Qingxian Cai, Wanrong Guo, Qiao Su, Hancheng Qin, Tian Wang, Yingxin Xian, Longyi Zeng, Mengyin Cai, Haixia Guan, Sifan Chen, Hua Liang, Fen Xu.

  Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-coenzyme A (CoA) carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. A malonylation-mimic mutant of ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.

Keywords:  CP: Metabolism; Lysine malonylation; acetyl-CoA carboxylase 1; hepatic steatosis; ketogenic diet; non-alcoholic fatty liver disease

DOI:  https://doi.org/10.1016/j.celrep.2023.112319
Antioxidants (Basel). 2023 Mar 06. pii: 651. [Epub ahead of print]12(3):

Aging Hallmarks and the Role of Oxidative Stress.

Edio Maldonado, Sebastián Morales-Pison, Fabiola Urbina, Aldo Solari.

  Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production.

Keywords:  ROS; aging; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3390/antiox12030651