Mitochondrial Oxidative Stress in Aging and Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 24785

Special Issue Editors

Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: mtDNA damage and deletions; mitochondrial oxidative stress and antioxidant defense; mitochondrial biogenesis and dynamics; mitochondrial quality control; mitochondrial dysfunction in aging and age-related degenerative disorders; nutritional anti-aging interventions
Special Issues, Collections and Topics in MDPI journals
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: aging; mitochondrial biogenesis in aging; mitochondrial pathologies; pathologies with mitochondrial oxidative stress (age-related diseases, autoimmune and inflammatory pathologies, neurodegenerative diseases); calorie restriction and nutritional anti-aging interventions; mtDNA–TFAM relationships
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mitochondria are the body’s main metabolic hubs, since they house cellular respiration and other crucial processes such as biomolecules synthesis, apoptosis, and calcium regulation. Mitochondria are also involved in signaling pathways entailed in health and disease conditions through changes in metabolites concentrations and in enzyme activities. Mitochondrial respiration is a major source of reactive oxygen species (ROS), which can act both as signaling and damaging molecules. Mitochondrial oxidative stress, resulting from the prevalence of oxidants above antioxidants, is present in physiological processes, such as aging, and in pathological ones, where it can lead to neurotoxicity, genomic instability, pro-inflammatory gene transcription and cytokine release. Mitochondrial oxidative stress is always associated with dysfunction of the organelle, driving to a decreased ATP production and to several different responses that may impinge also out of mitochondria and synergistically cooperate with other pathways to the onset of overt pathologies.  Mitochondria are nowadays emerging as central players in neurodegeneration, age-related and metabolic diseases because alterations in their elaborate maintenance pathways, including also redox regulation, have increasingly been assessed as relevant in different diseases. Therefore, the ongoing trials of several kinds of antioxidants in various experimental and clinical settings aim to preserve mitochondrial redox homeostasis to maintain good health and provide a feasible therapeutical approach.

This Special Issue’s goal is to provide a broad and updated overview of the involvement of “Mitochondrial oxidative stress in aging and disease” that might shed light on model systems, patho-physiological mechanisms and novel therapeutic approaches through contributions by experts of the field in the form of research papers and critical reviews.

Prof. Dr. Vito Pesce
Dr. Angela Maria Serena Lezza
Guest Editors

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Keywords

•    mitochondrial oxidative stress in aging
•    mitochondrial oxidative stress in age-related diseases
•    mitochondrial oxidative stress in metabolic diseases
•    mitochondrial signaling via ROS in diseases
•    mitochondrial oxidative stress and genomic instability
•    mitochondrial oxidative stress and inflammation
•    antioxidants as novel therapeutic approaches
•    mitochondrial pathologies
•    mitochondrial oxidative stress
•    neurodegenerative diseases

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Published Papers (10 papers)

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Research

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18 pages, 2560 KiB  
Article
Therapeutic Dosage of Antipsychotic Drug Aripiprazole Induces Persistent Mitochondrial Hyperpolarisation, Moderate Oxidative Stress in Liver Cells, and Haemolysis
by Tinkara Pirc Marolt, Barbara Kramar, Andrej Vovk, Helena Podgornik, Dušan Šuput and Irina Milisav
Antioxidants 2023, 12(11), 1930; https://doi.org/10.3390/antiox12111930 - 30 Oct 2023
Viewed by 980
Abstract
Aripiprazole has fewer metabolic side effects than other antipsychotics; however, there are some severe ones in the liver, leading to drug-induced liver injury. Repeated treatment with aripiprazole affects cell division. Since this process requires a lot of energy, we decided to investigate the [...] Read more.
Aripiprazole has fewer metabolic side effects than other antipsychotics; however, there are some severe ones in the liver, leading to drug-induced liver injury. Repeated treatment with aripiprazole affects cell division. Since this process requires a lot of energy, we decided to investigate the impact of aripiprazole on rat liver cells and mitochondria as the main source of cellular energy production by measuring the mitochondrial membrane potential, respiration, adenosine triphosphate (ATP) production, oxidative stress, antioxidative response, and human blood haemolysis. Here, we report that mitochondrial hyperpolarisation from aripiprazole treatment is accompanied by higher reactive oxygen species (ROS) production and increased antioxidative response. Lower mitochondrial and increased glycolytic ATP synthesis demand more glucose through glycolysis for equal ATP production and may change the partition between the glycolysis and pentose phosphate pathway in the liver. The uniform low amounts of the haemolysis of erythrocytes in the presence of aripiprazole in 25 individuals indicate lower quantities of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH+H+), which is in accordance with a decreased activity of glucose 6-phosphate dehydrogenase and the lower dehydrogenase activity upon aripiprazole treatment. The lower activity of glucose 6-phosphate dehydrogenase supports a shift to glycolysis, thus rescuing the decreased mitochondrial ATP synthesis. The putative reduction in NADPH+H+ did not seem to affect the oxidised-to-reduced glutathione ratio, as it remained equal to that in the untreated cells. The effect of aripiprazole on glutathione reduction is likely through direct binding, thus reducing its total amount. As a consequence, the low haemolysis of human erythrocytes was observed. Aripiprazole causes moderate perturbations in metabolism, possibly with one defect rescuing the other. The result of the increased antioxidant enzyme activity upon treatment with aripiprazole is increased resilience to oxidative stress, which makes it an effective drug for schizophrenia in which oxidative stress is constantly present because of disease and treatment. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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28 pages, 8787 KiB  
Article
NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3
by Belén Cuevas-López, Edgar Ignacio Romero-Ramirez, Fernando E. García-Arroyo, Edilia Tapia, Juan Carlos León-Contreras, Alejandro Silva-Palacios, Francisco-Javier Roldán, Omar Noel Medina Campos, Luz Hernandez-Esquivel, Alvaro Marín-Hernández, José Guillermo Gonzaga-Sánchez, Rogelio Hernández-Pando, José Pedraza-Chaverri, Laura Gabriela Sánchez-Lozada and Omar Emiliano Aparicio-Trejo
Antioxidants 2023, 12(8), 1592; https://doi.org/10.3390/antiox12081592 - 10 Aug 2023
Cited by 1 | Viewed by 1286
Abstract
The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a [...] Read more.
The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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13 pages, 2116 KiB  
Article
Intraoperative Hemi-Diaphragm Electrical Stimulation Demonstrates Attenuated Mitochondrial Function without Change in Oxidative Stress in Cardiothoracic Surgery Patients
by Robert T. Mankowski, Stephanie E. Wohlgemuth, Guilherme Bresciani, A. Daniel Martin, George Arnaoutakis, Tomas Martin, Eric Jeng, Leonardo Ferreira, Tiago Machuca, Mindaugas Rackauskas, Ashley J. Smuder, Thomas Beaver, Christiaan Leeuwenburgh and Barbara K. Smith
Antioxidants 2023, 12(5), 1009; https://doi.org/10.3390/antiox12051009 - 27 Apr 2023
Cited by 1 | Viewed by 1450
Abstract
Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function [...] Read more.
Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries (n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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34 pages, 11393 KiB  
Article
Dibenzylideneacetone Induces Apoptosis in Cervical Cancer Cells through Ros-Mediated Mitochondrial Damage
by Aline Pinto Zani, Caroline Pinto Zani, Zia Ud Din, Edson Rodrigues-Filho, Tânia Ueda-Nakamura, Francielle Pelegrin Garcia, Sueli de Oliveira Silva and Celso Vataru Nakamura
Antioxidants 2023, 12(2), 317; https://doi.org/10.3390/antiox12020317 - 30 Jan 2023
Cited by 5 | Viewed by 2472
Abstract
Cervical cancer is a health problem among women worldwide. Considering the limitations of prevention and antineoplastic chemotherapy against cervical cancer, research is needed to discover new, more effective, and safe antitumor agents. In the present study, we investigated the in vitro cytotoxicity of [...] Read more.
Cervical cancer is a health problem among women worldwide. Considering the limitations of prevention and antineoplastic chemotherapy against cervical cancer, research is needed to discover new, more effective, and safe antitumor agents. In the present study, we investigated the in vitro cytotoxicity of a new synthetic dibenzylideneacetone derived from 1,5-diaryl-3-oxo-1,4-pentadienyl (A3K2A3) against cervical cancer cells immortalized by HPV 16 (SiHa), and 18 (HeLa) by MTT assay. Furthermore, we performed spectrofluorimetry, flow cytometry, and Western blot analyzes to explore the inhibitory mechanism of A3K2A3 in cervical cancer cells. A3K2A3 showed cytotoxic activity against both cell lines. Mitochondrial depolarization and reduction in intracellular ATP levels were observed, which may be dependent on the redox imbalance between increased ROS and reduced levels of the antioxidant defense. In addition, damage to the cell membrane and DNA, and effective blocking of cell division in the G2/M phase were detected, which possibly led to the induction of apoptosis. This result was further confirmed by the upregulation of apoptosis-related proteins Bax, cytochrome C, and caspases 9 and 3. Our results provided the first evidence that A3K2A3 contributes to the suppression of cervical cancer in vitro, showing promise as a possible alternative for the treatment of this cancer. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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31 pages, 1801 KiB  
Review
Redox-Mediated Rewiring of Signalling Pathways: The Role of a Cellular Clock in Brain Health and Disease
by Filip Vujovic, Claire E. Shepherd, Paul K. Witting, Neil Hunter and Ramin M. Farahani
Antioxidants 2023, 12(10), 1873; https://doi.org/10.3390/antiox12101873 - 17 Oct 2023
Viewed by 1476
Abstract
Metazoan signalling pathways can be rewired to dampen or amplify the rate of events, such as those that occur in development and aging. Given that a linear network topology restricts the capacity to rewire signalling pathways, such scalability of the pace of biological [...] Read more.
Metazoan signalling pathways can be rewired to dampen or amplify the rate of events, such as those that occur in development and aging. Given that a linear network topology restricts the capacity to rewire signalling pathways, such scalability of the pace of biological events suggests the existence of programmable non-linear elements in the underlying signalling pathways. Here, we review the network topology of key signalling pathways with a focus on redox-sensitive proteins, including PTEN and Ras GTPase, that reshape the connectivity profile of signalling pathways in response to an altered redox state. While this network-level impact of redox is achieved by the modulation of individual redox-sensitive proteins, it is the population by these proteins of critical nodes in a network topology of signal transduction pathways that amplifies the impact of redox-mediated reprogramming. We propose that redox-mediated rewiring is essential to regulate the rate of transmission of biological signals, giving rise to a programmable cellular clock that orchestrates the pace of biological phenomena such as development and aging. We further review the evidence that an aberrant redox-mediated modulation of output of the cellular clock contributes to the emergence of pathological conditions affecting the human brain. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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11 pages, 1015 KiB  
Review
Complex II Biology in Aging, Health, and Disease
by Eric Goetzman, Zhenwei Gong, Bob Zhang and Radhika Muzumdar
Antioxidants 2023, 12(7), 1477; https://doi.org/10.3390/antiox12071477 - 24 Jul 2023
Cited by 2 | Viewed by 1625
Abstract
Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate [...] Read more.
Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate and plays an essential role in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). The dysfunction of Complex II not only limits mitochondrial energy production; it may also promote oxidative stress, contributing, over time, to cellular damage, aging, and disease. Intriguingly, succinate, the substrate for Complex II which accumulates during mitochondrial dysfunction, has been shown to have widespread effects as a signaling molecule. Here, we review recent advances related to understanding the function of Complex II, succinate signaling, and their combined roles in aging and aging-related diseases. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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23 pages, 2458 KiB  
Review
Escalating Bi-Directional Feedback Loops between Proinflammatory Microglia and Mitochondria in Ageing and Post-Diagnosis of Parkinson’s Disease
by Shane Michael Ravenhill, Andrew Howard Evans and Sheila Gillard Crewther
Antioxidants 2023, 12(5), 1117; https://doi.org/10.3390/antiox12051117 - 18 May 2023
Cited by 1 | Viewed by 2493
Abstract
Parkinson’s disease (PD) is a chronic and progressive age-related neurodegenerative disease affecting up to 3% of the global population over 65 years of age. Currently, the underlying physiological aetiology of PD is unknown. However, the diagnosed disorder shares many common non-motor symptoms associated [...] Read more.
Parkinson’s disease (PD) is a chronic and progressive age-related neurodegenerative disease affecting up to 3% of the global population over 65 years of age. Currently, the underlying physiological aetiology of PD is unknown. However, the diagnosed disorder shares many common non-motor symptoms associated with ageing-related neurodegenerative disease progression, such as neuroinflammation, microglial activation, neuronal mitochondrial impairment, and chronic autonomic nervous system dysfunction. Clinical PD has been linked to many interrelated biological and molecular processes, such as escalating proinflammatory immune responses, mitochondrial impairment, lower adenosine triphosphate (ATP) availability, increasing release of neurotoxic reactive oxygen species (ROS), impaired blood brain barrier integrity, chronic activation of microglia, and damage to dopaminergic neurons consistently associated with motor and cognitive decline. Prodromal PD has also been associated with orthostatic hypotension and many other age-related impairments, such as sleep disruption, impaired gut microbiome, and constipation. Thus, this review aimed to present evidence linking mitochondrial dysfunction, including elevated oxidative stress, ROS, and impaired cellular energy production, with the overactivation and escalation of a microglial-mediated proinflammatory immune response as naturally occurring and damaging interlinked bidirectional and self-perpetuating cycles that share common pathological processes in ageing and PD. We propose that both chronic inflammation, microglial activation, and neuronal mitochondrial impairment should be considered as concurrently influencing each other along a continuum rather than as separate and isolated linear metabolic events that affect specific aspects of neural processing and brain function. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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21 pages, 3078 KiB  
Review
Targeting Mitochondrial Oxidative Stress as a Strategy to Treat Aging and Age-Related Diseases
by Yun Haeng Lee, Myeong Uk Kuk, Moon Kyoung So, Eun Seon Song, Haneur Lee, Soon Kil Ahn, Hyung Wook Kwon, Joon Tae Park and Sang Chul Park
Antioxidants 2023, 12(4), 934; https://doi.org/10.3390/antiox12040934 - 15 Apr 2023
Cited by 5 | Viewed by 2869
Abstract
Mitochondria are one of the organelles undergoing rapid alteration during the senescence process. Senescent cells show an increase in mitochondrial size, which is attributed to the accumulation of defective mitochondria, which causes mitochondrial oxidative stress. Defective mitochondria are also targets of mitochondrial oxidative [...] Read more.
Mitochondria are one of the organelles undergoing rapid alteration during the senescence process. Senescent cells show an increase in mitochondrial size, which is attributed to the accumulation of defective mitochondria, which causes mitochondrial oxidative stress. Defective mitochondria are also targets of mitochondrial oxidative stress, and the vicious cycle between defective mitochondria and mitochondrial oxidative stress contributes to the onset and development of aging and age-related diseases. Based on the findings, strategies to reduce mitochondrial oxidative stress have been suggested for the effective treatment of aging and age-related diseases. In this article, we discuss mitochondrial alterations and the consequent increase in mitochondrial oxidative stress. Then, the causal role of mitochondrial oxidative stress on aging is investigated by examining how aging and age-related diseases are exacerbated by induced stress. Furthermore, we assess the importance of targeting mitochondrial oxidative stress for the regulation of aging and suggest different therapeutic strategies to reduce mitochondrial oxidative stress. Therefore, this review will not only shed light on a new perspective on the role of mitochondrial oxidative stress in aging but also provide effective therapeutic strategies for the treatment of aging and age-related diseases through the regulation of mitochondrial oxidative stress. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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13 pages, 1384 KiB  
Review
Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases
by Vishal Chavda and Bingwei Lu
Antioxidants 2023, 12(4), 895; https://doi.org/10.3390/antiox12040895 - 06 Apr 2023
Cited by 5 | Viewed by 3360
Abstract
Stroke is one of the leading causes of morbidity and mortality worldwide. A main cause of brain damage by stroke is ischemia-reperfusion (IR) injury due to the increased production of reactive oxygen species (ROS) and energy failure caused by changes in mitochondrial metabolism. [...] Read more.
Stroke is one of the leading causes of morbidity and mortality worldwide. A main cause of brain damage by stroke is ischemia-reperfusion (IR) injury due to the increased production of reactive oxygen species (ROS) and energy failure caused by changes in mitochondrial metabolism. Ischemia causes a build-up of succinate in tissues and changes in the mitochondrial NADH: ubiquinone oxidoreductase (complex I) activity that promote reverse electron transfer (RET), in which a portion of the electrons derived from succinate are redirected from ubiquinol along complex I to reach the NADH dehydrogenase module of complex I, where matrix NAD+ is converted to NADH and excessive ROS is produced. RET has been shown to play a role in macrophage activation in response to bacterial infection, electron transport chain reorganization in response to changes in the energy supply, and carotid body adaptation to changes in the oxygen levels. In addition to stroke, deregulated RET and RET-generated ROS (RET-ROS) have been implicated in tissue damage during organ transplantation, whereas an RET-induced NAD+/NADH ratio decrease has been implicated in aging, age-related neurodegeneration, and cancer. In this review, we provide a historical account of the roles of ROS and oxidative damage in the pathogenesis of ischemic stroke, summarize the latest developments in our understanding of RET biology and RET-associated pathological conditions, and discuss new ways to target ischemic stroke, cancer, aging, and age-related neurodegenerative diseases by modulating RET. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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Other

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15 pages, 2506 KiB  
Perspective
Bio-Hacking Better Health—Leveraging Metabolic Biochemistry to Maximise Healthspan
by Isabella D. Cooper, Yvoni Kyriakidou, Lucy Petagine, Kurtis Edwards and Bradley T. Elliott
Antioxidants 2023, 12(9), 1749; https://doi.org/10.3390/antiox12091749 - 11 Sep 2023
Cited by 2 | Viewed by 5769
Abstract
In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and [...] Read more.
In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD+ to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD+ availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity. Full article
(This article belongs to the Special Issue Mitochondrial Oxidative Stress in Aging and Disease)
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