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The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 26304

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Special Issue Editors

Dr. Alessia Grozio

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Guest Editor

The Buck Institute for Research on Aging, Novato, CA, USA
Interests: NAD+ biosynthesis and metabolism; NAD+ consuming enzymes; aging

Dr. Rosalba Perrone

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Co-Guest Editor

The Buck Institute for Research on Aging, Novato, CA, USA
Interests: NAD+ metabolism; NAD+ consuming enzymes; aging; age-related diseases

Dr. Andrea Benzi

E-Mail Website
Co-Guest Editor

Department of Experimental Medicine, University of Genoa, Genoa, Italy
Interests: NAD+ metabolism; age-related diseases; metabolic disorders

Special Issue Information

Dear Colleagues,

Nicotinamide adenine dinucleotide (NAD+) is an important coenzyme for hundreds of different oxidoreductases as well as an essential cofactor for NAD+-dependent enzymes, such as sirtuins, poly(ADP-ribose) polymerases (PARPs) and NAD+ glycohydrolases (CD38, CD157 and SARM1). These enzymes play a fundamental role in many pivotal cellular processes including DNA repair, regulation of gene expression, redox balance and cell metabolism and signaling. The decline in NAD+ levels has been associated with several hallmarks of aging and age-related diseases. In this regard, boosting NAD+ levels by enhancing its biosynthesis or inhibiting its degradation has emerged as a promising therapeutic approach to counteract the aging process and to treat age-associated diseases. This Special Issue aims at providing novel insights into the role of NAD+ metabolism in the context of aging and age-associated diseases. We welcome original research and review articles in which the topics may include (but are not limited to) the following:

Cellular and molecular studies presenting novel pathways linking NAD+metabolism to hallmarks of aging.
Therapeutic strategies aiming to boost intracellular NAD+levels in the context of age-associated diseases.
Review that discusses recent advances and future perspectives in understanding the role of NAD+during aging.

We look forward to receiving your contributions.

Dr. Alessia Grozio
Dr. Rosalba Perrone
Dr. Andrea Benzi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

NAD+ metabolism
NAD+-dependent enzymes
NAD+ booster strategies
hallmarks of aging
aging
age-associated diseases

Published Papers (7 papers)

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Research

Jump to: Review

16 pages, 4475 KiB

Open AccessArticle

Hepatic Nampt Deficiency Aggravates Dyslipidemia and Fatty Liver in High Fat Diet Fed Mice

by Dao-Xin Wang, Sheng-Li Qing, Zhu-Wei Miao, Heng-Yu Luo, Jia-Sheng Tian, Xiu-Ping Zhang, Shu-Na Wang, Tian-Guang Zhang and Chao-Yu Miao

Cells 2023, 12(4), 568; https://doi.org/10.3390/cells12040568 - 10 Feb 2023

Cited by 4 | Viewed by 1789

Abstract

Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt^-/-) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt^-/- mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt^-/- mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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23 pages, 2613 KiB

Open AccessArticle

Nicotinamide Mononucleotide Administration Prevents Doxorubicin-Induced Cardiotoxicity and Loss in Physical Activity in Mice

by Marielle Margier, Chisaka Kuehnemann, Nicolas Hulo, Jazmin Morales, Prasanna Vadhana Ashok Kumaar, Cecile Cros, Helene Cannelle, Julie Charmetant, Eric Verdin, Matthias Canault and Alessia Grozio

Cells 2023, 12(1), 108; https://doi.org/10.3390/cells12010108 - 27 Dec 2022

Cited by 4 | Viewed by 8358

Abstract

Doxorubicin (Doxo) is a widely used antineoplastic drug with limited clinical application due to its deleterious dose-related side effects. We investigated whether nicotinamide mononucleotide (NMN) could protect against Doxo-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic. In the acute study, C57BL6/J (B6) mice were injected intraperitoneally (i.p.) once with Doxo (20 mg/kg) and NMN (180 mg/kg/day, i.p.) was administered daily for five days before and after the Doxo injection. In the chronic study, B6 mice received a cumulative dose of 20 mg/kg Doxo administered in fractionated doses for five days. NMN (500 mg/kg/day) was supplied in the mice’s drinking water beginning five days before the first injection of Doxo and continuing for 60 days after. We found that NMN significantly increased tissue levels of NAD+ and its metabolites and improved survival and bodyweight loss in both experimental models. In addition, NMN protected against Doxo-induced cardiotoxicity and loss of physical function in acute and chronic studies, respectively. In the heart, NMN prevented Doxo-induced transcriptomic changes related to mitochondrial function, apoptosis, oxidative stress, inflammation and p53, and promyelocytic leukemia nuclear body pathways. Overall, our results suggest that NMN could prevent Doxo-induced toxicity in heart and skeletal muscle. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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19 pages, 2334 KiB

Open AccessArticle

Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice

by Andrea Benzi, Sonia Spinelli, Laura Sturla, Markus Heine, Alexander W. Fischer, Friedrich Koch-Nolte, Hans-Willi Mittrücker, Andreas H. Guse, Antonio De Flora, Joerg Heeren and Santina Bruzzone

Cells 2022, 11(23), 3812; https://doi.org/10.3390/cells11233812 - 28 Nov 2022

Cited by 1 | Viewed by 1817

Abstract

Boosting NAD⁺ levels are considered a promising means to promote healthy aging and ameliorate dysfunctional metabolism. The expression of CD38, the major NAD⁺-consuming enzyme, is downregulated during thermogenesis in both brown and white adipose tissues (BAT and WAT). Moreover, BAT activation and WAT “browning” were enhanced in Cd38^−/− mice. In this study, the role of CD38 in the liver during thermogenesis was investigated, with the liver being the central organ controlling systemic energy metabolism. Wild-type mice and Cd38^−/− mice were exposed to cold temperatures, and levels of metabolites and enzymes were measured in the livers and plasma. During cold exposure, CD38 expression was downregulated in the liver, as in BAT and WAT, with a concomitant increase in NAD(H) and a marked decrease in NADPH levels. Glucose-6-phosphate dehydrogenase and the malic enzyme, along with enzymes in the glycolytic pathway, were downregulated, which is in line with glucose-6-P being re-directed towards glucose release. In Cd38^−/− mice, the cross-regulation between glycolysis and glucose release was lost, although this did not impair the glucose release from glycogen. Glycerol levels were decreased in the liver from Cd38^−/− animals upon cold exposure, suggesting that glyceroneogenesis, as gluconeogenesis, was not properly activated in the absence of CD38. SIRT3 activity, regulating mitochondrial metabolism, was enhanced by cold exposure, whereas its activity was already high at a warm temperature in Cd38^−/− mice and was not further increased by the cold. Notably, FGF21 and bile acid release was enhanced in the liver of Cd38^−/− mice, which might contribute to enhanced BAT activation in Cd38^−/− mice. These results demonstrate that CD38 inhibition can be suggested as a strategy to boost NAD⁺ and would not negatively affect hepatic functions during thermogenesis. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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15 pages, 3454 KiB

Open AccessArticle

Low Nephron Number Induced by Maternal Protein Restriction Is Prevented by Nicotinamide Riboside Supplementation Depending on Sirtuin 3 Activation

by Anna Pezzotta, Luca Perico, Marina Morigi, Daniela Corna, Monica Locatelli, Carlamaria Zoja, Ariela Benigni, Giuseppe Remuzzi and Barbara Imberti

Cells 2022, 11(20), 3316; https://doi.org/10.3390/cells11203316 - 21 Oct 2022

Cited by 7 | Viewed by 2351

Abstract

A reduced nephron number at birth, due to critical gestational conditions, including maternal malnutrition, is associated with the risk of developing hypertension and chronic kidney disease in adulthood. No interventions are currently available to augment nephron number. We have recently shown that sirtuin 3 (SIRT3) has an important role in dictating proper nephron endowment. The present study explored whether SIRT3 stimulation, by means of supplementation with nicotinamide riboside (NR), a precursor of the SIRT3 co-substrate nicotinamide adenine dinucleotide (NAD⁺), was able to improve nephron number in a murine model of a low protein (LP) diet. Our findings show that reduced nephron number in newborn mice (day 1) born to mothers fed a LP diet was associated with impaired renal SIRT3 expression, which was restored through supplementation with NR. Glomerular podocyte density, as well as the rarefaction of renal capillaries, also improved through NR administration. In mechanistic terms, the restoration of SIRT3 expression through NR was mediated by the induction of proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α). Moreover, NR restored SIRT3 activity, as shown by the reduction of the acetylation of optic atrophy 1 (OPA1) and superoxide dismutase 2 (SOD2), which resulted in improved mitochondrial morphology and protection against oxidative damage in mice born to mothers fed the LP diet. Our results provide evidence that it is feasible to prevent nephron mass shortage at birth through SIRT3 boosting during nephrogenesis, thus providing a therapeutic option to possibly limit the long-term sequelae of reduced nephron number in adulthood. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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17 pages, 4096 KiB

Open AccessFeature PaperArticle

Nicotinamide Mononucleotide Administration Amends Protein Acetylome of Aged Mouse Liver

by Chengting Luo, Wenxi Ding, Songbiao Zhu, Yuling Chen, Xiaohui Liu and Haiteng Deng

Cells 2022, 11(10), 1654; https://doi.org/10.3390/cells11101654 - 16 May 2022

Cited by 7 | Viewed by 3125

Abstract

It is known that the activities of nicotine adenine dinucleotide (NAD⁺)-dependent deacetylase decline in the aging mouse liver, and nicotinamide mononucleotide (NMN)-mediated activation of deacetylase has been shown to increase healthspans. However, age-induced changes of the acetylomic landscape and effects of NMN treatment on protein acetylation have not been reported. Here, we performed immunoprecipitation coupled with label-free quantitative LC-MS/MS (IPMS) to identify the acetylome and investigate the effects of aging and NMN on liver protein acetylation. In total, 7773 acetylated peptides assigned to 1997 proteins were commonly identified from young and aged livers treated with vehicle or NMN. The major biological processes associated with proteins exhibiting increased acetylation from aged livers were oxidation-reduction and metabolic processes. Proteins with decreased acetylation from aged livers mostly participated in transport and translation processes. Furthermore, NMN treatment inhibited the aging-related increase of acetylation on proteins regulating fatty acid β oxidation, the tricarboxylic acid (TCA) cycle and valine degradation. In particular, NAD (P) transhydrogenase (NNT) was markedly hyperacetylated at K70 in aged livers, and NMN treatment decreased acetylation intensity without altering protein levels. Acetylation at cytochrome 3a25 (Cyp3a25) at K141 was also greatly increased in aged livers, and NMN treatment totally arrested this increase. Our extensive identification and analysis provide novel insight and potential targets to combat aging and aging-related functional decline. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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Review

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22 pages, 1747 KiB

Open AccessReview

The Role of CD38 in the Pathogenesis of Cardiorenal Metabolic Disease and Aging, an Approach from Basic Research

by Munehiro Kitada, Shin-ichi Araki and Daisuke Koya

Cells 2023, 12(4), 595; https://doi.org/10.3390/cells12040595 - 12 Feb 2023

Cited by 3 | Viewed by 2696

Abstract

Aging is a major risk factor for the leading causes of mortality, and the incidence of age-related diseases including cardiovascular disease, kidney disease and metabolic disease increases with age. NAD⁺ is a classic coenzyme that exists in all species, and that plays a crucial role in oxidation–reduction reactions. It is also involved in the regulation of many cellular functions including inflammation, oxidative stress and differentiation. NAD⁺ declines with aging in various organs, and the reduction in NAD⁺ is possibly involved in the development of age-related cellular dysfunction in cardiorenal metabolic organs through the accumulation of inflammation and oxidative stress. Levels of NAD⁺ are regulated by the balance between its synthesis and degradation. CD38 is the main NAD⁺-degrading enzyme, and CD38 is activated in response to inflammation with aging, which is associated with the reduction in NAD⁺ levels. In this review, focusing on CD38, we discuss the role of CD38 in aging and the pathogenesis of age-related diseases, including cardiorenal metabolic disease. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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32 pages, 1256 KiB

Open AccessReview

NAD⁺ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

by Lucie Chanvillard, Alessandra Tammaro and Vincenzo Sorrentino

Cells 2023, 12(1), 21; https://doi.org/10.3390/cells12010021 - 21 Dec 2022

Cited by 5 | Viewed by 3941

Abstract

Premature aging causes morphological and functional changes in the kidney, leading to chronic kidney disease (CKD). CKD is a global public health issue with far-reaching consequences, including cardio-vascular complications, increased frailty, shortened lifespan and a heightened risk of kidney failure. Dialysis or transplantation are lifesaving therapies, but they can also be debilitating. Currently, no cure is available for CKD, despite ongoing efforts to identify clinical biomarkers of premature renal aging and molecular pathways of disease progression. Kidney proximal tubular epithelial cells (PTECs) have high energy demand, and disruption of their energy homeostasis has been linked to the progression of kidney disease. Consequently, metabolic reprogramming of PTECs is gaining interest as a therapeutic tool. Preclinical and clinical evidence is emerging that NAD⁺ homeostasis, crucial for PTECs’ oxidative metabolism, is impaired in CKD, and administration of dietary NAD⁺ precursors could have a prophylactic role against age-related kidney disease. This review describes the biology of NAD⁺ in the kidney, including its precursors and cellular roles, and discusses the importance of NAD⁺ homeostasis for renal health. Furthermore, we provide a comprehensive summary of preclinical and clinical studies aimed at increasing NAD⁺ levels in premature renal aging and CKD. Full article

(This article belongs to the Special Issue The Role of NAD+ Metabolism in Cellular Processes during Aging and Age-Associated Diseases)

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