NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Ноя. 21, 2019

Abstract Metabolic dysfunction is a primary feature of Werner syndrome (WS), human premature aging disease caused by mutations in the gene encoding (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but underlying mechanisms are not understood, and whether deficit can be targeted for therapeutic intervention has been determined. Here we report impaired mitophagy depletion NAD + , fundamental ubiquitous molecule, patient samples invertebrate models. WRN regulates transcription key biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). repletion restores profiles improves mitochondrial quality through DCT-1 ULK-1-dependent mitophagy. At organismal level, remarkably extends lifespan delays accelerated aging, including stem cell dysfunction, Caenorhabditis elegans Drosophila melanogaster models WS. Our findings suggest that mediated function mitophagy, bolstering cellular levels counteracts phenotypes.

Язык: Английский

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METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA

Nucleic Acids Research, Год журнала: 2020, Номер 48(19), С. 11083 - 11096

Опубликована: Сен. 23, 2020

Abstract N6-Methyladenosine (m6A) messenger RNA methylation is a well-known epitranscriptional regulatory mechanism affecting central biological processes, but its function in human cellular senescence remains uninvestigated. Here, we found that levels of both m6A and the methyltransferase METTL3 were reduced prematurely senescent mesenchymal stem cell (hMSC) models progeroid syndromes. Transcriptional profiling modifications further identified MIS12, for which hMSCs METTL3-deficient hMSCs. Knockout accelerated hMSC whereas overexpression rescued phenotypes. Mechanistically, loss turnover decreased expression MIS12 mRNA while knockout senescence. Furthermore, reader IGF2BP2 was as key player recognizing stabilizing m6A-modified mRNA. Taken together, discovered alleviates through modification-dependent stabilization transcript, representing novel premature

Язык: Английский

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Heterochromatin: an epigenetic point of view in aging

Experimental & Molecular Medicine, Год журнала: 2020, Номер 52(9), С. 1466 - 1474

Опубликована: Сен. 1, 2020

Abstract Aging is an inevitable process of life. Defined by progressive physiological and functional loss tissues organs, aging increases the risk mortality for organism. The affected various factors, including genetic epigenetic ones. Here, we review chromatin-specific changes that occur during normal (chronological) in premature diseases. Taking advantage reversible nature modifications, will also discuss possible lifespan expansion strategies through modulation, which was considered irreversible until recently.

Язык: Английский

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Chemical screen identifies a geroprotective role of quercetin in premature aging

Protein & Cell, Год журнала: 2018, Номер 10(6), С. 417 - 435

Опубликована: Авг. 1, 2018

Aging increases the risk of various diseases. The main goal aging research is to find therapies that attenuate and alleviate aging-related In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), premature model recently established. Ten candidate were identified quercetin was investigated in detail due its leading effects. Mechanistic studies revealed alleviated senescence via enhancement cell proliferation restoration heterochromatin architecture WS hMSCs. RNA-sequencing analysis transcriptional commonalities differences effects by Vitamin C. Besides hMSCs, also attenuated cellular Hutchinson-Gilford progeria (HGPS) physiological-aging Taken together, our study identifies as agent against accelerated providing potential therapeutic intervention treating age-associated disorders.

Язык: Английский

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Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

Protein & Cell, Год журнала: 2018, Номер 9(4), С. 333 - 350

Опубликована: Фев. 23, 2018

Hutchinson-Gilford progeria syndrome (HGPS) and Werner (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting production truncated protein product—progerin. WS mutations WRN encoding loss-of-function RecQ DNA helicase. Here, gene editing we created isogenic embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA biallelic knockout, for modeling pathogenesis, respectively. While ESCs endothelial (ECs) did not present any features premature senescence, HGPS- WS-mesenchymal (MSCs) showed aging-associated phenotypes different kinetics. WS-MSCs had early-onset mild aging while HGPS-MSCs exhibited late-onset acute characterisitcs. Taken together, our study compares contrasts distinct pathologies underpinning disorders, provides reliable stem-cell based models to identify new therapeutic strategies pathological physiological aging.

Язык: Английский

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Vitamin C: A Review on its Role in the Management of Metabolic Syndrome

International Journal of Medical Sciences, Год журнала: 2020, Номер 17(11), С. 1625 - 1638

Опубликована: Янв. 1, 2020

Oxidative stress and inflammation are two interlinked events that exist simultaneously in metabolic syndrome (MetS) its related complications.These pathophysiological processes can be easily triggered by each other.This review summarizes the current evidence from animal human studies on effects of vitamin C managing MetS.In vivo showed promising C, but most interventions used were combination with other compounds.The direct remain to elucidated.In humans, state revealed lower intake circulating concentration found MetS subjects.A negative relationship was observed between / risk MetS.Oral supplementation also improved conditions.It has been postulated positive outcomes may part mediated through anti-oxidative anti-inflammatory properties.These observations suggest importance patients have an adequate food, beverages or supplements order maintain systemic circulation potentially reverse MetS.

Язык: Английский

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Human RecQ Helicases in DNA Double-Strand Break Repair

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Фев. 25, 2021

RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These play important roles multiple cellular functions, including replication, transcription, repair, telomere maintenance. Humans have five helicases: RECQL1, Bloom syndrome (BLM), Werner helicase (WRN), RECQL4, RECQL5. Defects BLM WRN cause autosomal disorders: (BS) (WS), respectively. Mutations RECQL4 associated with three genetic disorders, Rothmund–Thomson (RTS), Baller–Gerold (BGS), RAPADILINO syndrome. Although no disorders been reported due to loss of RECQL1 or RECQL5, dysfunction either gene is tumorigenesis. Multiple genetically independent pathways evolved that mediate the repair double-strand break (DSB), pivotal each them. The importance DSB supported by observations defective can chromosomal aberrations, genomic instability, senescence, cell death, which ultimately lead premature aging, neurodegeneration, In this review, we will introduce human family, describe detail their provide relevance between diseases.

Язык: Английский

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Mitochondrial functions and rare diseases

Molecular Aspects of Medicine, Год журнала: 2020, Номер 71, С. 100842 - 100842

Опубликована: Фев. 1, 2020

Язык: Английский

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Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing

Mechanisms of Ageing and Development, Год журнала: 2020, Номер 186, С. 111208 - 111208

Опубликована: Янв. 15, 2020

Nicotinamide adenine dinucleotide (NAD+) plays a fundamental role in life and health through the regulation of energy biogenesis, redox homeostasis, cell metabolism, arbitration survival via linkages to apoptosis autophagic pathways. The importance NAD+ ageing healthy longevity has been revealed from laboratory animal studies early-stage clinical testing. While basic researchers clinicians have investigated molecular mechanisms translation potential NAD+, there are still major gaps applying science design most effective trials. This mini-review was based on programme discussions 3rd NO-Age Symposium held at Akershus University Hospital, Norway 28th October 2019. symposium brought together leading who or going perform augmentation-related studies. meeting covered talks about synthetic pathways, subcellular homeostasis benefits augmentation maternal milk offspring, current trials precursor nicotinamide riboside (NR) Ataxia-Telangiectasia (A-T), Parkinson's disease (PD), post-sepsis fatigue, as well other NR-based Importantly, consensus is emerging with respect order measure meaningful parameters ensure safety.

Язык: Английский

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Evolutionarily conserved transcription factors as regulators of longevity and targets for geroprotection

Physiological Reviews, Год журнала: 2022, Номер 102(3), С. 1449 - 1494

Опубликована: Март 28, 2022

Aging is the single largest risk factor for many debilitating conditions, including heart diseases, stroke, cancer, diabetes, and neurodegenerative disorders. Although far from understood in its full complexity, it scientifically well established that aging influenced by genetic environmental factors can be modulated various interventions. One of aging's early hallmarks aberrations transcriptional networks, controlling example metabolic homeostasis or response to stress. Evidence different model organisms abounds a number evolutionarily conserved transcription factors, which control such affect life span health across species. These thus potentially represent regulators longevity are emerging as important targets challenging quest develop treatments mitigate age-related possibly even slow itself. This review provides an overview impact diseases at least one multicellular organism (nematodes, flies, mice) and/or tentatively linked human aging. Discussed general evidence regulation disease, followed more detailed look selected families, common pathways involved, targeting strategy geroprotective

Язык: Английский

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