From discoveries in ageing research to therapeutics for healthy ageing

Nature, Год журнала: 2019, Номер 571(7764), С. 183 - 192

Опубликована: Июль 10, 2019

Язык: Английский

---

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Signal Transduction and Targeted Therapy, Год журнала: 2020, Номер 5(1)

Опубликована: Окт. 7, 2020

Abstract Nicotinamide adenine dinucleotide (NAD + ) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells adapt environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation xenobiotics. These effects are mainly achieved by driving effect of NAD on metabolic pathways enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple -dependent enzymes involved physiology either post-synthesis chemical modification DNA, RNA proteins, or releasing second messenger cyclic ADP-ribose (cADPR) NAADP . Prolonged disequilibrium metabolism disturbs physiological functions, resulting diseases diseases, cancer, aging neurodegeneration disorder. In this review, we summarize recent advances our understanding molecular mechanisms -regulated responses stresses, contribution deficiency various via manipulating cellular communication networks potential new avenues for therapeutic intervention.

Язык: Английский

---

The sirtuin family in health and disease

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Дек. 29, 2022

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, involved numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles members SIRT family health disease conditions. Notably, this protein plays a variety important cellular biology such as inflammation, metabolism, oxidative stress, apoptosis, etc., thus, it is considered potential therapeutic target for different kinds pathologies including cancer, cardiovascular disease, respiratory other Moreover, identification modulators exploring functions these prompted increased efforts discover new small molecules, which can modify activity. Furthermore, several randomized controlled trials indicated that interventions might affect expression human samples, supplementation diverse impact on physiological function participants. In review, we introduce history structure family, discuss molecular mechanisms elaborate regulatory SIRTs summarize inhibitors activators, review related clinical studies.

Язык: Английский

---

Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress

Circulation Research, Год журнала: 2019, Номер 126(4), С. 439 - 452

Опубликована: Дек. 19, 2019

Rationale: Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 (Sirtuin 3) is critical in regulation metabolic antioxidant functions which associated with cardiovascular disease factors diminish level. Objective: We hypothesized that reduced expression vascular increased protects function decreases hypertension. Methods Results: To test therapeutic potential targeting expression, we developed new transgenic mice global Sirt3OX (Sirt3 overexpression), from endothelial dysfunction, oxidative stress, hypertrophy attenuates Ang II (angiotensin II) deoxycorticosterone acetate–salt induced Global depletion −/− results stress due hyperacetylation superoxide dismutase (SOD2), increases HIF1α (hypoxia-inducible factor-1), reduces cadherin, stimulates hypertrophy, permeability inflammation (p65, caspase 1, VCAM [vascular cell adhesion molecule-1], ICAM [intercellular MCP1 [monocyte chemoattractant protein 1]), inflammatory infiltration kidney, telomerase accelerates senescence age-dependent hypertension; conversely, prevents these deleterious effects. clinical relevance was confirmed arterioles human mediastinal fat patients essential hypertension showing 40% decrease Sirt3, coupled Sirt3-dependent 3-fold SOD2 acetylation, NF-κB (nuclear kappa-light-chain-enhancer activated B cells) activity, VCAM, ICAM, levels hypertensive subjects compared normotensive subjects. Conclusions: suggest promotes inflammation, end-organ damage. Our data support

Язык: Английский

---

The landscape of aging

Science China Life Sciences, Год журнала: 2022, Номер 65(12), С. 2354 - 2454

Опубликована: Сен. 2, 2022

Язык: Английский

---

Role of NAD+ in regulating cellular and metabolic signaling pathways

Molecular Metabolism, Год журнала: 2021, Номер 49, С. 101195 - 101195

Опубликована: Фев. 18, 2021

Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ often studied the context aging, cancer, and neurodegenerative disorders. Cellular depletion compromised adaptive stress responses, impaired neuronal plasticity, DNA repair, senescence. Increasing evidence has shown efficacy boosting levels using precursors various diseases. This review provides comprehensive understanding into role aging other pathologies discusses potential therapeutic targets. An alteration NAD+/NADH ratio or pool size can lead to derailment biological system contribute disorders, tumorigenesis. Due varied distribution different locations within cells, direct NAD+-dependent humans remains unestablished. In regard, longitudinal studies are needed quantify its related metabolites. Future research should focus on measuring fluxes through pathways synthesis degradation.

Язык: Английский

---

Cardiomyocyte Senescence and Cellular Communications Within Myocardial Microenvironments

Frontiers in Endocrinology, Год журнала: 2020, Номер 11

Опубликована: Май 21, 2020

Cardiovascular diseases have become the leading cause of human death. Aging is an independent risk factor for cardiovascular diseases. Cardiac aging associated with maladaptation cellular metabolism, dysfunction (or senescence) cardiomyocytes, a decrease in angiogenesis, and increase tissue scarring (fibrosis). These events eventually lead to cardiac remodeling failure. Senescent cardiomyocytes show hallmarks DNA damage, endoplasmic reticulum stress, mitochondria dysfunction, contractile hypertrophic growth, senescence-associated secreting phenotype (SASP). Metabolism within essential not only fuel pump function heart but also maintain functional homeostasis participate senescence cardiomyocytes. The cardiomyocyte regulated by non-myocytes (endothelial cells, fibroblasts, immune cells) local microenvironment. On other hand, senescent alter their phenotypes subsequently affect microenvironment contribute pathological remodeling. In this review, we first summarized Then, discussed metabolic switch provided discussion communications between dysfunctional We addressed functions regulators modulating myocardial Finally, pointed out some interesting important questions that are needed be further studies.

Язык: Английский

---

Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

Antioxidants, Год журнала: 2022, Номер 11(7), С. 1394 - 1394

Опубликована: Июль 19, 2022

Macrophage polarization refers to the process by which macrophages can produce two distinct functional phenotypes: M1 or M2. The balance between both strongly affects progression of inflammatory disorders. Here, we review how redox signals regulate macrophage and reprogramming during acute inflammation. In M1, augment NADPH oxidase isoform 2 (NOX2), inducible nitric oxide synthase (iNOS), synaptotagmin-binding cytoplasmic RNA interacting protein (SYNCRIP), tumor necrosis factor receptor-associated 6 increase oxygen nitrogen reactive species, triggers response, phagocytosis, cytotoxicity. M2, down-regulate NOX2, iNOS, SYNCRIP, and/or up-regulate arginase superoxide dismutase type 1, counteract oxidative nitrosative stress, favor anti-inflammatory tissue repair responses. M2 exhibit different metabolic profiles, are tightly regulated mechanisms. Oxidative stress sustain phenotype activating glycolysis lipid biosynthesis, but inhibiting tricarboxylic acid cycle phosphorylation. This profile is reversed in because changes state. Therefore, new therapies based on mechanisms have emerged treat inflammation with positive results, highlights relevance signaling as a master regulator reprogramming.

Язык: Английский

---

NAD ⁺ Repletion Reverses Heart Failure With Preserved Ejection Fraction

Circulation Research, Год журнала: 2021, Номер 128(11), С. 1629 - 1641

Опубликована: Апрель 22, 2021

Rationale: Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. We recently demonstrated in mice that combination of metabolic and hypertensive stress recapitulates key features human HFpEF. Objective: Using this novel preclinical HFpEF model, we set out to define manipulate dysregulations occurring myocardium. Methods Results: observed impairment mitochondrial fatty acid oxidation associated hyperacetylation enzymes the pathway. Downregulation sirtuin 3 deficiency NAD + secondary an impaired salvage pathway contribute protein hyperacetylation. Impaired expression genes involved biosynthesis was confirmed cardiac tissue from patients Supplementing nicotinamide riboside or direct activator led improvement function amelioration phenotype. Conclusions: Collectively, these studies demonstrate myocardial dysfunction unveil repletion as promising therapeutic approach syndrome.

Язык: Английский

---

Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation

Frontiers in Pharmacology, Год журнала: 2022, Номер 12

Опубликована: Фев. 22, 2022

Doxorubicin (DOX) is an anthracycline antibiotic that used extensively for the management of carcinoma; however, its clinical application limited due to serious cardiotoxic side effects. Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death has been proven contribute progression DOX-induced cardiomyopathy. Fisetin a natural flavonoid abundantly present in fruits vegetables. It reported exert cardioprotective effects against cardiotoxicity experimental rats. However, underlying mechanisms remain unknown. The study investigated role fisetin molecular mechanism through experiments cardiomyopathy rat H9c2 models. results revealed treatment could markedly abate by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating hypertrophy rats, attenuating ferroptosis cardiomyocytes reversing decline GPX4 level. Mechanistically, exerted antioxidant effect reducing MDA lipid ROS levels increasing glutathione (GSH) Moreover, protective SIRT1 expression Nrf2 mRNA protein nuclear translocation, which resulted activation downstream genes such as HO-1 FTH1. Selective inhibition attenuated cells, turn decreased GSH levels, well Nrf2, HO-1, FTH1 expressions. In conclusion, exerts therapeutic inhibiting via SIRT1/Nrf2 signaling pathway activation.

Язык: Английский

---