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Sirtuins and Epigenetics in Aging and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 67251

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Special Issue Editors

Prof. Dr. Michele Caraglia

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Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
Interests: noncoding RNAs; micro-RNAs; prostate cancer; nanotechnological delivery of anticancer drugs and nucleic acids; diagnostic markers in cancer; urotensin II receptor; next-generation sequencing; predictive markers of response; circulating tumor cells
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Prof. Dr. Maria Luisa Balestrieri

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Department of Biochemistry, Biophysics and General Pathology, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: aging; oxidative stress; nitric oxide; endothelial cells; endothelial progenitor cells; angiogenesis; inflammation; cell senescence; apoptosis; atherosclerosis; diabetes, endothelial dysfunction, sirtuins and cardiovascular disease; natural products; betaines; health; bioactive compounds; free radicals; antioxidants; ergothioneine; cell cycle; cancer-related biochemical pathways; cell proliferation; senescence; cancer cell death; epigenetic regulation; sirtuins and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sirtuins, a family of nicotine adenine dinucleotide (NAD+)-dependent deacetylases that target histone and non-histone proteins, are crucial in the crosstalk between the environment and genome. Other factors contributing to aging and human diseases, including diabetes and cancer, are epigenetic signalings that include both DNA methylation and noncoding RNA interference. In the past few years, basic and translational research has been focused on sirtuins for their central role in the control of cell metabolism and in the regulation of many cellular functions, including DNA repair, inflammatory response, cell cycle and apoptosis. The field of sirtuins and epigenetic regulation of genome integrity and longevity is still capturing the attention of scientists, as well as the identification of novel modulators able to target with high specificity the pathways of chronic-degenerative disease. Moreover, the discovery of non-coding RNAs has disclosed a new scenario for the determination of novel molecular targets in the treatment of chronic degenerative diseases including cancer and metabolic diseases.

This Special Issue of the International Journal of Molecular Sciences will focus on recent advances on “Sirtuins and Epigenetics in Aging and Diseases”, including new insights into the molecular epigenetic mechanisms of aging, cancer, metabolic disorders, and cardiovascular disease. Moreover, emerging data on natural or synthetic epigenetic modulators in relation with new therapeutic options are welcome.

Prof. Dr. Michele Caraglia
Prof. Dr. Maria Luisa Balestrieri
Guest Editors

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Keywords

Epigenetics
Sirtuins
Aging
Cancer
Cardiovascular disease
miRNA
long non-coding RNAs
Inflammation
Therapeutics
Diabetes

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Published Papers (9 papers)

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Research

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24 pages, 6246 KiB

Open AccessArticle

Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer

by Vincenzo Carafa, Angelita Poziello, Laura Della Torre, Pia Giovannelli, Marzia Di Donato, Elham Safadeh, Zhijun Yu, Alfonso Baldi, Gabriella Castoria, Daniela Tomaselli, Antonello Mai, Dante Rotili, Angela Nebbioso and Lucia Altucci

Int. J. Mol. Sci. 2019, 20(22), 5654; https://doi.org/10.3390/ijms20225654 - 12 Nov 2019

Cited by 13 | Viewed by 3016

Abstract

Sirtuins, a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure–activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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17 pages, 1826 KiB

Open AccessArticle

Sorafenib-Induced Apoptosis in Hepatocellular Carcinoma Is Reversed by SIRT1

by Antje Garten, Theresa Grohmann, Katarina Kluckova, Gareth G. Lavery, Wieland Kiess and Melanie Penke

Int. J. Mol. Sci. 2019, 20(16), 4048; https://doi.org/10.3390/ijms20164048 - 19 Aug 2019

Cited by 69 | Viewed by 7073

Abstract

Sorafenib is a multi-kinase inhibitor and one of the few systemic treatment options for patients with advanced hepatocellular carcinomas (HCCs). Resistance to sorafenib develops frequently and could be mediated by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin (SIRT)1. We aimed to test whether sorafenib efficacy is influenced by cellular NAD levels and NAD-dependent SIRT1 function. We analyzed sorafenib effects on apoptosis induction, NAD salvage, mitochondrial function, and related signaling pathways in HCC cell lines (HepG2, Hep3B, und HUH7) overexpressing SIRT1 or supplemented with the NAD metabolite nicotinamide mononucleotide (NMN) compared to controls. Treatment of HCC cell lines with sorafenib dose-dependently induced apoptosis and a significant decrease in cellular NAD concentrations. The SIRT1 protein was downregulated in HUH7 cells but not in Hep3B cells. After sorafenib treatment, mitochondrial respiration in permeabilized cells was lower, citrate synthase activity was attenuated, and cellular adenosine triphosphate (ATP) levels were decreased. Concomitant to increased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), sorafenib treatment led to decreased activity of the mechanistic target of rapamycin (mTOR), indicative of energy deprivation. Transient overexpression of SIRT1, as well as NAD repletion by NMN, decreased sorafenib-induced apoptosis. We can, therefore, conclude that sorafenib influences the NAD/SIRT1/AMPK axis. Overexpression of SIRT1 could be an underlying mechanism of resistance to sorafenib treatment in HCC. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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10 pages, 2021 KiB

Open AccessCommunication

Abdominal Fat SIRT6 Expression and Its Relationship with Inflammatory and Metabolic Pathways in Pre-Diabetic Overweight Patients

by Nunzia D’Onofrio, Gorizio Pieretti, Feliciano Ciccarelli, Antonio Gambardella, Nicola Passariello, Maria Rosaria Rizzo, Michelangela Barbieri, Raffaele Marfella, Gianfranco Nicoletti, Maria Luisa Balestrieri and Celestino Sardu

Int. J. Mol. Sci. 2019, 20(5), 1153; https://doi.org/10.3390/ijms20051153 - 6 Mar 2019

Cited by 33 | Viewed by 4269

Abstract

The role of sirtuin 6 (SIRT6) in adipose abdominal tissue of pre-diabetic (pre-DM) patients is poorly known. Here, we evaluated SIRT6 expression in visceral abdominal fat of obese pre-diabetic patients and the potential effects of metformin therapy. Results indicated that obese pre-DM subjects showed low SIRT6 protein expression and high expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), peroxisome proliferator-activated receptor gamma (PPAR-γ), and sterol regulatory element-binding transcription factor 1 (SREBP-1). Obese pre-DM patients showed high values of glucose, insulin resistance (HOMA-IR), C reactive protein (CRP), nitrotyrosine, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and low values of insulin (p < 0.05). Of note, abdominal fat tissue of obese pre-DM patients treated with metformin therapy presented higher SIRT6 expression and lower NF-κB, PPAR-γ, and SREBP-1 expression levels compared to pre-DM control group. Collectively, results show that SIRT6 is involved in the inflammatory pathway of subcutaneous abdominal fat of obese pre-DM patients and its expression responds to metformin therapy. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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Review

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14 pages, 1200 KiB

Open AccessReview

Proposed Tandem Effect of Physical Activity and Sirtuin 1 and 3 Activation in Regulating Glucose Homeostasis

by Francesca Pacifici, Davide Di Cola, Donatella Pastore, Pasquale Abete, Fiorella Guadagni, Giulia Donadel, Alfonso Bellia, Eleonora Esposito, Chiara Salimei, Paola Sinibaldi Salimei, Camillo Ricordi, Davide Lauro and David Della-Morte

Int. J. Mol. Sci. 2019, 20(19), 4748; https://doi.org/10.3390/ijms20194748 - 25 Sep 2019

Cited by 31 | Viewed by 5658

Abstract

Sirtuins (SIRTs) are seven nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacetylases enzymes (SIRT1–7) that play an important role in maintaining cellular homeostasis. Among those, the most studied are SIRT1 and SIRT3, a nuclear SIRT and a mitochondrial SIRT, respectively, which significantly impact with an increase in mammals’ lifespan by modulating metabolic cellular processes. Particularly, when activated, both SIRT1 and 3 enhance pancreatic β-cells’ insulin release and reduce inflammation and oxidative stress pancreatic damage, maintaining then glucose homeostasis. Therefore, SIRT1 and 3 activators have been proposed to prevent and counteract metabolic age-related diseases, such as type 2 diabetes mellitus (T2DM). Physical activity (PA) has a well-established beneficial effect on phenotypes of aging like β-cell dysfunction and diabetes mellitus. Recent experimental and clinical evidence reports that PA increases the expression levels of both SIRT1 and 3, suggesting that PA may exert its healthy contribute even by activating SIRTs. Therefore, in the present article, we discuss the role of SIRT1, SIRT3, and PA on β-cell function and on diabetes. We also discuss the possible interaction between PA and activation of SIRTs as a possible therapeutic strategy to maintain glucose hemostasis and to prevent T2DM and its complications, especially in the elderly population. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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13 pages, 507 KiB

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The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer

by Débora Kristina Alves-Fernandes and Miriam Galvonas Jasiulionis

Int. J. Mol. Sci. 2019, 20(13), 3153; https://doi.org/10.3390/ijms20133153 - 28 Jun 2019

Cited by 245 | Viewed by 16109

Abstract

Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC), an NAD+-dependent enzyme deeply involved in gene regulation, genome stability maintenance, apoptosis, autophagy, senescence, proliferation, aging, and tumorigenesis. It also has a key role in the epigenetic regulation of tissue homeostasis and many diseases by deacetylating both histone and non-histone targets. Different studies have shown ambiguous implications of SIRT1 as both a tumor suppressor and tumor promoter. However, this contradictory role seems to be determined by the cell type and SIRT1 localization. SIRT1 upregulation has already been demonstrated in some cancer cells, such as acute myeloid leukemia (AML) and primary colon, prostate, melanoma, and non-melanoma skin cancers, while SIRT1 downregulation was described in breast cancer and hepatic cell carcinomas. Even though new functions of SIRT1 have been characterized, the underlying mechanisms that define its precise role on DNA damage and repair and their contribution to cancer development remains underexplored. Here, we discuss the recent findings on the interplay among SIRT1, oxidative stress, and DNA repair machinery and its impact on normal and cancer cells. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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11 pages, 521 KiB

Open AccessReview

Exercise and Sirtuins: A Way to Mitochondrial Health in Skeletal Muscle

by Katya Vargas-Ortiz, Victoriano Pérez-Vázquez and Maciste H. Macías-Cervantes

Int. J. Mol. Sci. 2019, 20(11), 2717; https://doi.org/10.3390/ijms20112717 - 3 Jun 2019

Cited by 91 | Viewed by 8189

Abstract

The sirtuins form a family of evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. Seven sirtuins (SIRT1–SIRT7) have been described in mammals, with specific intracellular localization and biological functions associated with mitochondrial energy homeostasis, antioxidant activity, proliferation and DNA repair. Physical exercise affects the expression of sirtuin in skeletal muscle, regulating changes in mitochondrial biogenesis, oxidative metabolism and the cellular antioxidant system. In this context, sirtuin 1 and sirtuin 3 have been the most studied. This review focuses on the effects of different types of exercise on these sirtuins, the molecular pathways involved and the biological effect that is caused mainly in healthy subjects. The reported findings suggest that an acute load of exercise activates SIRT1, which in turn activates biogenesis and mitochondrial oxidative capacity. Additionally, several sessions of exercise (training) activates SIRT1 and also SIRT3 that, together with the biogenesis and mitochondrial oxidative function, jointly activate ATP production and the mitochondrial antioxidant function. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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20 pages, 271 KiB

Open AccessReview

Controversial Impact of Sirtuins in Chronic Non-Transmissible Diseases and Rehabilitation Medicine

by Alessia Mongelli and Carlo Gaetano

Int. J. Mol. Sci. 2018, 19(10), 3080; https://doi.org/10.3390/ijms19103080 - 9 Oct 2018

Cited by 5 | Viewed by 4048

Abstract

A large body of evidence reports about the positive effects of physical activity in pathophysiological conditions associated with aging. Physical exercise, alone or in combination with other medical therapies, unquestionably causes reduction of symptoms in chronic non-transmissible diseases often leading to significant amelioration or complete healing. The molecular basis of this exciting outcome—however, remain largely obscure. Epigenetics, exploring at the interface between environmental signals and the remodeling of chromatin structure, promises to shed light on this intriguing matter possibly contributing to the identification of novel therapeutic targets. In this review, we shall focalize on the role of sirtuins (Sirts) a class III histone deacetylases (HDACs), which function has been frequently associated, often with a controversial role, to the pathogenesis of aging-associated pathophysiological conditions, including cancer, cardiovascular, muscular, neurodegenerative, bones and respiratory diseases. Numerous studies, in fact, demonstrate that Sirt-dependent pathways are activated upon physical and cognitive exercises linking mitochondrial function, DNA structure remodeling and gene expression regulation to designed medical therapies leading to tangible beneficial outcomes. However, in similar conditions, other studies assign to sirtuins a negative pathophysiological role. In spite of this controversial effect, it is doubtless that studying sirtuins in chronic diseases might lead to an unprecedented improvement of life quality in the elderly. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

21 pages, 928 KiB

Open AccessReview

Sirtuins and Immuno-Metabolism of Sepsis

by Xianfeng Wang, Nancy L. Buechler, Alan G. Woodruff, David L. Long, Manal Zabalawi, Barbara K. Yoza, Charles E. McCall and Vidula Vachharajani

Int. J. Mol. Sci. 2018, 19(9), 2738; https://doi.org/10.3390/ijms19092738 - 13 Sep 2018

Cited by 46 | Viewed by 7443

Abstract

Sepsis and septic shock are the leading causes of death in non-coronary intensive care units worldwide. During sepsis-associated immune dysfunction, the early/hyper-inflammatory phase transitions to a late/hypo-inflammatory phase as sepsis progresses. The majority of sepsis-related deaths occur during the hypo-inflammatory phase. There are no phase-specific therapies currently available for clinical use in sepsis. Metabolic rewiring directs the transition from hyper-inflammatory to hypo-inflammatory immune responses to protect homeostasis during sepsis inflammation, but the mechanisms underlying this immuno-metabolic network are unclear. Here, we review the roles of NAD+ sensing Sirtuin (SIRT) family members in controlling immunometabolic rewiring during the acute systemic inflammatory response associated with sepsis. We discuss individual contributions among family members SIRT 1, 2, 3, 4 and 6 in regulating the metabolic switch between carbohydrate-fueled hyper-inflammation to lipid-fueled hypo-inflammation. We further highlight the role of SIRT1 and SIRT2 as potential “druggable” targets for promoting immunometabolic homeostasis and increasing sepsis survival. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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19 pages, 747 KiB

Open AccessReview

Sirtuins as Mediator of the Anti-Ageing Effects of Calorie Restriction in Skeletal and Cardiac Muscle

by Alberto Zullo, Emanuela Simone, Maddalena Grimaldi, Vincenzina Musto and Francesco Paolo Mancini

Int. J. Mol. Sci. 2018, 19(4), 928; https://doi.org/10.3390/ijms19040928 - 21 Mar 2018

Cited by 48 | Viewed by 10211

Abstract

Fighting diseases and controlling the signs of ageing are the major goals of biomedicine. Sirtuins, enzymes with mainly deacetylating activity, could be pivotal targets of novel preventive and therapeutic strategies to reach such aims. Scientific proofs are accumulating in experimental models, but, to a minor extent, also in humans, that the ancient practice of calorie restriction could prove an effective way to prevent several degenerative diseases and to postpone the detrimental signs of ageing. In the present review, we summarize the evidence about the central role of sirtuins in mediating the beneficial effects of calorie restriction in skeletal and cardiac muscle since these tissues are greatly damaged by diseases and advancing years. Moreover, we entertain the possibility that the identification of sirtuin activators that mimic calorie restriction could provide the benefits without the inconvenience of this dietary style. Full article

(This article belongs to the Special Issue Sirtuins and Epigenetics in Aging and Diseases)

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