Benefits of Metformin in Attenuating the Hallmarks of Aging

Cell Metabolism, Journal Year: 2020, Volume and Issue: 32(1), P. 15 - 30

Published: April 24, 2020

Language: Английский

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Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways

Frontiers in Genetics, Journal Year: 2019, Volume and Issue: 10

Published: May 14, 2019

Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play key role energy homeostasis and metabolism reactive oxygen species (ROS), require lifetime control constant renewal. This explains recently peaked interest processes mitochondrial biogenesis mitophagy. The principal event regulation DNA (mtDNA) transcription translation, complex coordinated that involves at least two systems factors. It commonly believed its major regulatory protein PGC-1α, acts as factor connecting several regulator cascades involved metabolism. In recent years, number publications on essential Nrf2/ARE signaling has grown exponentially. Nrf2 induced by various xenobiotics antioxidants oxidize some negative regulators. Thus, ROS, particular H2O2, were found be strong activators. At present, there are concepts biogenesis. Some authors suggest direct involvement this process. Others believe regulates expression antioxidant genes, while only PGC-1α. Several studies have demonstrated existence loop involving both PGC-1α Nrf2. review, we summarized data mutual promising targets for drug application other therapies aimed increase active longevity.

Language: Английский

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The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease

Molecular Neurobiology, Journal Year: 2020, Volume and Issue: 57(7), P. 2959 - 2980

Published: May 22, 2020

Language: Английский

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Impact of the Natural Compound Urolithin A on Health, Disease, and Aging

Trends in Molecular Medicine, Journal Year: 2021, Volume and Issue: 27(7), P. 687 - 699

Published: May 21, 2021

Urolithin A (UA) is a gut microbiome-derived natural compound that only 40% of people can naturally convert from dietary precursors at meaningful levels.Positive effects direct UA administration in health, aging, and age-related conditions have been identified several recent studies.Experimental models consistently show increases mitophagy mitochondrial function blunts excessive inflammatory responses.UA increased biomarkers preclinical aging healthy elderly people.UA promising strategy to target health disease especially those linked muscle dysfunction. produced by bacteria ingested ellagitannins (ETs) ellagic acid (EA), complex polyphenols abundant foods such as pomegranate, berries, nuts. was discovered 40 years ago, but recently has its impact on explored. enhances cellular increasing reducing detrimental inflammation. Several studies how protects against affecting muscle, brain, joints, other organs. In humans, benefits supplementation the are supported clinical trials people. Here, we review state art UA's biology translational potential nutritional intervention humans. belongs family urolithins, characterized chemical structure containing an α-benzo-coumarin scaffold (Figure 1). Urolithins colon following microbiome-mediated transformation ETs EA, which contained products, pomegranates, strawberries, raspberries, walnuts [1.Espín J.C. et al.Biological significance microbial acid-derived metabolites: evidence so far.Evid. Based Complement. Alternat. Med. 2013; 2013: 270418Crossref PubMed Scopus (277) Google Scholar, 2.Tomás-Barberán F.A. al.Urolithins, rescue "old" metabolites understand "new" concept: metabotypes nexus among phenolic metabolism, microbiota dysbiosis, host status.Mol. Nutr. Food Res. 2017; 61: 1500901Crossref (198) 3.González-Barrio R. al.Bioavailability anthocyanins consumption raspberries humans subjects with ileostomy.J. Agric. Chem. 2010; 58: 3933-3939Crossref (180) Scholar]. 1 Box 1).Box 1Conversion Ellagitannins Metabolism UAThe EA present variety plant products main UA. very low bioavailability either directly eliminated stool or converted into more bioavailable derivates [2.Tomás-Barberán hydrolyzed bacterial enzymes called tannases. Further enzymatic reactions transform urolithins 1) urolithin B (UB) most final conserved widely studied across species Scholar].Ingesting ET-rich not always enough expose UA, formation depends having appropriate microbiome [10.Cortés-Martín A. al.Where look puzzle health? The postbiotics associated human metabotypes.Mol. 2020; 64: 1900952Crossref (39) Of note, efforts made identify bacterium, bacteria, responsible for conversion. Although some proposed based ex vivo feces [60.Selma M.V. al.Gordonibacter urolithinfaciens sp. nov., urolithin-producing bacterium isolated gut.Int. J. Syst. Evol. Microbiol. 2014; 2346-2352Crossref (69) Scholar,61.Selma al.Description production capacity two intestinal Gordonibacter species.Food Funct. 5: 1779-1784Crossref Scholar], UA-producing still unknown Scholar].After absorption blood circulation, undergoes phase 2 metabolism form conjugates, mainly UA-glucuronide UA-sulfate. detected plasma biological role conjugates clear. vitro experiments suggest lower no activity compared Scholar,70.Bobowska al.Comparative their II macrophage neutrophil functions.European Journal Nutrition. 2021; 60: 1957-1972Crossref (9) Ingesting After First metabolite rats 1980 [4.Doyle B. Griffiths L.A. rat.Xenobiotica Fate Foreign Compd. Biol. 1980; 10: 247-256Crossref (86) similar (see Glossary) conversion later demonstrated many species, including flies mice Scholar] . pioneering study also showed [5.Cerdá al.Identification microflora related compounds.J. 2005; 53: 5571-5576Crossref (191) making common nature. Two then measured after pomegranate [6.Cerdá al.The potent antioxidant juice metabolised poor hydroxy-6H-dibenzopyran-6-one derivatives colonic humans.Eur. 2004; 43: 205-220Crossref (325) nuts [7.Cerdá al.Metabolism chemopreventive walnuts, oak-aged wine humans: identification individual variability.J. 227-235Crossref (318) Interestingly, does occur all individuals. process variable [8.Tomás-Barberán al.Ellagic microbiota: consistent observation three phenotypes trials, independent food source, age, status.J. 62: 6535-6538Crossref (184) takes place approximately population [9.Cortés-Martín revisited: determined aging.Food 2018; 9: 4100-4106Crossref Being 'UA producer' requires varies status, intake Backed growing interest interventions address ever-increasing problems [11.Domingues-Faria C. al.Skeletal regeneration nutrition.Ageing Rev. 2016; 26: 22-36Crossref (50) Scholar,12.Kehoe L. al.Nutritional challenges older adults Europe: current status future directions.Proc. Soc. 2019; 78: 221-233Crossref (21) research groups started relevance instead precursors. This outlines relevant positive impacts due progressive diseases aging. It describes molecular mechanisms explain counter hallmarks Finally, this explores applications effect improvement observed cells, worms, mice, benefit driven clearing recycling dysfunctional mitochondria, selective autophagy [13.Palikaras K. al.Mechanisms homeostasis, physiology pathology.Nat. Cell 20: 1013-1022Crossref (338) Mitophagy impaired age Scholar,69.Diot al.Mitophagy plays central ageing.Mamm. Genome. 27: 381-395Crossref (68) Restoring correct levels counteract decline organ [14.Ryu D. al.Urolithin induces prolongs lifespan elegans rodents.Nat. 22: 879-888Crossref (368) Scholar,16.Fang E.F. inhibits amyloid-β tau pathology reverses cognitive deficits Alzheimer's disease.Nat. Neurosci. 401-412Crossref (396) occurs when mitochondria damaged exposure external inducers 2). proceeds via pathways activate. PTEN-induced kinase (PINK1)/Parkin-dependent starts stabilization PINK1, recruits phosphorylates ubiquitin-conjugating protein Parkin. Parkin turn promotes ubiquitination proteins, phosphorylated PINK1 serve docking sites adaptor microtubule-associated LC3, phagosome membranes. Once engulfed phagophore membrane, they merge lysosomes organelle clearance 2) Other PINK1–Parkin-independent activate BNIP3, NIX, FUNDC1, recruit LC3 promote autophagosome nematode Caenorhabditis elegans, expression genes lgg-1 pink-1, pdr-1 [15.Luan P. improves inducing muscular dystrophy.Sci. Transl. 13eabb0319Crossref worm homologs mammalian encoding LC-3B, vesicle formation. ablation pink-1 dct-1, ortholog abolished beneficial [16.Fang phospho-ubiquitin accumulation prominent C2C12 mouse myoblasts treated vivo, higher ubiquitinated phospho-ubiquitinated proteins were tissues administering wild-type rodents mdx model Duchenne dystrophy (DMD) reported neuroblastoma SH-SY5Y cells hippocampal neurons (AD) Consistently, events AD brains. PINK1/Parkin activation pancreatic diabetic [17.Tuohetaerbaike al.Pancreas protective type induced high fat streptozotocin regulating AKT/mTOR signaling pathway.J. Ethnopharmacol. 250: 112479Crossref (15) nucleus pulposus [18.Lin A-induced suppresses apoptosis attenuates intervertebral disc degeneration AMPK pathway.Free Radic. 150: 109-119Crossref (23) less explored mammals; however, data Bnip3 mRNA mild BNIP3 UA-treated quality pool tightly generation new organelles, leading improved respiratory [19.Ploumi al.Mitochondrial biogenesis clearance: balancing act.FEBS 284: 183-195Crossref (154) Mitochondrial abundance reduced upon short-term treatment worms Conversely, content unchanged mildly liver [20.Toney A.M. A, metabolite, insulin sensitivity through augmentation biogenesis.Obesity. 612-620Crossref (26) longer exposure. suggests first, activates thereafter favors biogenesis. Consistent this, oxidative phosphorylation (OXPHOS) tissue Scholar,15.Luan kidney subjected acute injury [21.Zou al.Oral delivery nanoparticle normalizes stress survival cisplatin-induced AKI.Am. Physiol.-Ren. Physiol. 317: F1255-F1264Crossref (11) gene sets upregulated transcriptomic HT29 [22.Singh al.Enhancement barrier integrity Nrf2 pathway.Nat. Commun. 89Crossref (169) functional readouts skeletal where elevated Complex I- II-mediated respiration shown regulate systemically muscle. Data first-in-human Phase I trial decrease acylcarnitines [23.Andreux P.A. activator safe signature humans.Nat. Metab. 1: 595-603Crossref (108) markers reflect efficacy fatty oxidation level entire body [24.Schooneman M.G. al.Acylcarnitines.Diabetes. 1-8Crossref increase shared between exposed attenuation responses. particularly clinically because chronic, low-grade process, named inflamm-aging [25.Franceschi al.Inflammaging: immune–metabolic viewpoint diseases.Nat. Endocrinol. 14: 576-590Crossref (603) contributes organismal function. anti-inflammatory first time marker cyclooxygenase (COX2) dextran sulphate sodium (DSS)-induced rat colitis [26.Larrosa M. al.Anti-inflammatory properties extract urolithin-A inflammation metabolism.J. Biochem. 21: 717-725Crossref (309) reduction proinflammatory cytokines interleukin beta (IL-1β), 6 (IL-6), tumor necrosis factor alpha (TNFα) both acute, trinitrobenzenesulfonic (TNBS)-induced DSS-induced same streptozotocin-induced IL-10, noted IL-1β livers high-fat diet (HFD)-fed obese kidneys nephrotoxic [27.Guada mitigates nephrotoxicity inhibiting renal experimental model.J. Pharmacol. Exp. Ther. 363: 58-65Crossref (20) Lower fractalkine, cytokine influences myocardial [28.Taube al.Fractalkine depresses cardiomyocyte contractility.PLoS ONE. 8e69832Crossref cardiomyopathy (DCM) [29.Savi al.In prevents occurrence cardiac dysfunction rats.Cardiovasc. Diabetol. 16: 80Crossref (55) neuronal tissues, IL-1β, IL-6, TNFα brains amyloid precursor protein/presenilin (APP/PS1) Scholar,30.Gong Z. memory impairment neuroinflammation APP/PS1 mice.J. Neuroinflammation. 1-13Crossref (49) These suggested promotion phagocytic microglia, crucial clean up debris nervous system (CNS) control responses, protection Notably, knockdown Pink1 microglia ablated UA-mediated IL-10 secretion, indicating reduces induction cell infiltration analyzing white matter autoimmune encephalomyelitis (EAE) [31.Shen P.-X.

Language: Английский

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TNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging

Blood, Journal Year: 2019, Volume and Issue: 134(9), P. 727 - 740

Published: July 17, 2019

Language: Английский

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Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 28, 2021

Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that decline of physical function often initiates by cell senescence organ ageing. Epigenetic dynamics immunometabolic reprogramming link to alterations cellular response intrinsic extrinsic stimuli, representing current hotspots as they not only (re-)shape individual identity, but also involve fate decision. This review focuses on present findings emerging concepts epigenetic, inflammatory, metabolic regulations consequences process. Potential therapeutic interventions targeting regulatory mechanisms, using state-of-the-art techniques are discussed.

Language: Английский

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Cardiovascular Aging and Heart Failure

Journal of the American College of Cardiology, Journal Year: 2019, Volume and Issue: 74(6), P. 804 - 813

Published: Aug. 1, 2019

Language: Английский

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Biological aging processes underlying cognitive decline and neurodegenerative disease

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(10)

Published: May 15, 2022

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability mortality in later life. As with many chronic conditions, aging is single most influential factor development of ADRD. Even older adults who remain free dementia throughout their lives, cognitive decline neurodegenerative changes appreciable advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview cognition, brain morphology, neuropathological protein accumulation across lifespan humans, complementary mechanistic evidence from animal models. Next, highlight selected processes that differentially regulated disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular inflammation, lipid dysregulation. We summarize research clinical translational studies link biological underlying ADRD pathogenesis. Targeting fundamental may represent a yet relatively unexplored avenue attenuate both age-related Collaboration fields geroscience neuroscience, coupled new models more closely align human processes, necessary advance novel therapeutic discovery realm.

Language: Английский

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Mitophagy, Mitochondrial Dynamics, and Homeostasis in Cardiovascular Aging

Oxidative Medicine and Cellular Longevity, Journal Year: 2019, Volume and Issue: 2019, P. 1 - 15

Published: Nov. 4, 2019

Biological aging is an inevitable and independent risk factor for a wide array of chronic diseases including cardiovascular metabolic diseases. Ample evidence has established pivotal role interrupted mitochondrial homeostasis in the onset development aging-related anomalies. A number culprit factors have been suggested aging-associated anomalies oxidative stress, lipid toxicity, telomere shortening, disturbance, DNA damage, with recent findings revealing likely compromised dynamics quality control machinery such as autophagy. Mitochondria undergo consistent fusion fission, which are crucial energy adaptation. Autophagy, particular, mitochondria-selective autophagy, namely, mitophagy, refers to highly conservative cellular process degrade clear long-lived or damaged organelles mitochondria, function gradually deteriorates increased age. Mitochondrial could be achieved through cascade but closely related processes fusion, biogenesis. With improved health care human longevity, ever-rising society imposed high disease prevalence. It thus imperative understand regulation lifespan healthspan. Targeting should offer promising novel therapeutic strategies against complications, particularly

Language: Английский

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Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

Oxidative Medicine and Cellular Longevity, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 11

Published: March 27, 2020

Mitochondrial DNA (mtDNA) damage is associated with the development of cardiovascular diseases. Cardiac aging plays a central role in There accumulating evidence linking cardiac to mtDNA damage, including mutation and decreased copy number. Current wisdom indicates that susceptible by mitochondrial reactive oxygen species (mtROS). This review presents cellular molecular mechanisms aging, autophagy, chronic inflammation, mtROS, effects biogenesis oxidative stress on mtDNA. The importance nucleoid-associated proteins (Pol γ ), nuclear respiratory factors (NRF1 NRF2), cGAS-STING pathway, pathway concerning during discussed. Thus, repair damaged provides potential clinical target for preventing aging.

Language: Английский

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