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Aging Cell 21 e13662. 1007 s13539-011-0032-8ArticlePubMedPubMed CentralGoogle Scholar Marcangeli V, Youssef L, Dulac M, Carvalho LP, Hajj-Boutros G, Reynaud O, Guegan B, Buckinx F, Gaudreau P, Morais JA, Mauriège P, Noirez P, Aubertin-Leheudre M, Gouspillou G 2022 Impact of high-intensity interval training with or without l -citrulline on physical performance, skeletal muscle, and adipose tissue in obese older adults. Muscle tissue collection and blood sampling for biological markers of mitochondrial function were performed at the baseline visit and after four weeks following the last UA dose.slairT lacinilC dezimodnaR namuH ni AU .62 ,52 ,31 ,21 ygahpotim hguorht htlaeh lairdnohcotim evorpmi ot si tceffe tnetsisnoc tsom s AU taht dewohs snamuh dna ,ecim ,smrow ,sllec ni ataD . Such improvements of mitochondrial health by UA supplementation have been associated with better health span in worms and rodent models Fig. Specific genes related to mitophagy activity, such as PARK2GABARAPL1and Ulk1were also positively impacted by UA in the muscle. UA is a member of the urolithin family, characterized by an alpha-benzo-coumarin scaffold in its chemical structure. The findings of this first clinical trial confirmed results observed in pre-clinical studies, demonstrating UA s safety, bioavailability, and positive effect on muscle mitochondria. Cell Rep Med 3 100633. Authors and Affiliations. Skeletal muscle aging is associated with progressive muscle mass and strength decline. Aging Cell 7 2 12. 112479ArticleCASPubMedGoogle Scholar D Amico D, Olmer M, Fouassier AM, Valdés P, Andreux PA, Rinsch C, Lotz M 2022 Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. J Cachexia Sarcopenia Muscle 13 1526 1540. The best-described regulatory pathway currently involves Parkin, an E3 ubiquitin ligase-like protein, in collaboration with PINK1. 1038 s41598-020-76564-7ArticleCASPubMedPubMed CentralGoogle Scholar Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktäschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA 2019 Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer s disease. The molecular components that perform these activities, such as enzymatic activities, protein transport and complexes, and Fe buffering, among others, defined in Monzel et al. 675ArticlePubMedGoogle Scholar Hepple RT, Baker DJ, McConkey M, Murynka T, Norris R 2006 Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles. 2001ArticleCASPubMedGoogle Scholar Chabi B, Ljubicic V, Menzies KJ, Huang JH, Saleem A, Hood DA 2008 Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Antioxid Redox Signal 8 517 528. The latter is recognized by an autophagic marker such as the microtubule-associated protein LC3 and recruit lysosomes containing hydrolytic enzymes, to form an autophagosome and degrade damaged mitochondria 21. Julie Faitg. It ensures that only healthy mitochondria are preserved and can effectively contribute to cellular energy production and other essential functions. Enhancement in muscle strength, endurance and tetanic force were observed with UA also in the mdx dystrophic mice model and UA significantly increased the survival rate in the more severe DKO mice model of DMD 27. 100633ArticleCASPubMedPubMed CentralGoogle Scholar Liu S, D Amico D, Shankland E, Bhayana S, Garcia JM, Aebischer P, Rinsch C, Singh A, Marcinek DJ 2022 Effect of urolithin a supplementation on muscle endurance and mitochondrial health in older adults a randomized clinical trial. Several ongoing studies are further investigating the impact of mitophagy activation via UA in additional clinical settings. J Cell Biol 189 211 221. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. J Cachexia Sarcopenia Muscle 2 75 80. This makes direct supplementation of UA a relevant strategy for everyone to benefit from this active molecule. 2020104705 Singh A, D Amico D, Andreux PA, Dunngalvin G, Kern T, Blanco-Bose W, Auwerx J, Aebischer P, Rinsch C 2022 Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population.

elegans , UA led to an improvement of pharyngeal pumping measured by counting the contraction of the pharynx during 30 s and nematode motilities. Beneficial effects of Urolithin A. UA exhibited a very safe profile, showed a dose-dependent linear increase in bioavailability up to the 1000 mg dose and did not accumulate in the plasma over time.elcsum lateleks tar ni segnahc detaler-ega gnitneverp ni noitcirtser cirolac fo ssenevitceffE 8991 O onobleD ,M nahtanagneR ,M wehyaM ralohcS elgooGdeMbuPSACelcitrA715 . Subjects were selected based on low mitochondrial function in their hand skeletal muscle first dorsal interosseus muscle strength assessed via magnetic resonance spectroscopy and low-average physical performance assessed via the 6-min walk test 13. Having the right microbiome is required for Urolithin A s natural conversion from dietary precursors. Author information. elegans and increases muscle function in rodents. Also, complex I and II-mediated respiration in muscle tissues from mdx mice have been enhanced after UA supplementation 27. Nat Metab 5 546 562. These pre-clinical data have shown that UA can activate mitophagy through either PINK1-Parkin dependent or independent mitophagy 33 and indicate a combined effect of UA on the skeletal-muscle system to protect against age-related decline in mobility, sarcopenia, and to support healthy mobility Table 1. In plasma, UA administration of up to 1000 mg daily led to a decrease in several plasma acylcarnitines, which are markers that reflect the efficacy of mitochondrial fatty acid oxidation 26. Future Perspectives.Mitophagy Activation by Urolithin A to Target Muscle Aging. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Avoid common mistakes on your manuscript. Nat Metab 1 595 603.gniega ni rotcaf elbissop noitcnuf niahc yrotaripser lairdnohcotim elcsum lateleks ni enilceD 9891 S ikuzraM ,E enryB ,I ecnuorT ralohcS elgooGlartneC deMbuPdeMbuPelcitrA97244 . 200910140ArticleCASPubMedPubMed CentralGoogle Scholar Palikaras K, Lionaki E, Tavernarakis N 2018 Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. One cause of the loss of mitochondrial homeostasis during aging is the accumulation of dysfunctional mitochondria. Exercise and CR are two strategies to improve mitochondrial health 11. Currently, the most efficient preventive and non-pharmacological strategies to attenuate sarcopenia are physical activity 1, 2 and caloric restriction CR 3,4,5,6. 4132ArticleCASPubMedGoogle Scholar Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C 2019 The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. It would be interesting for future trials to investigate the association between ability to naturally produce UA from diet and muscle function with aging. 13-242750ArticleCASPubMedGoogle Scholar Dirks A, Leeuwenburgh C 2002 Apoptosis in skeletal muscle with aging. These findings have paved the way for investigating the role of UA in different human clinical settings. This is, in turn, derived from the impaired ability of cells to remove faulty organelles, a process called mitophagy 19. Interestingly clinical data showed UA to increase by 20 the resistance to fatigue of both hand first dorsal interosseus and leg tibialis anterior skeletal muscles, after 2 months, compared to the placebo group, The positive effect of UA on resistance to fatigue was maintained after 4-months of supplementation. 1038 s41598-018-26944-xArticleCASPubMedPubMed CentralGoogle Scholar Kurz J, Parnham MJ, Geisslinger G, Schiffmann S 2019 Ceramides as novel disease biomarkers. 9438ArticleCASPubMedGoogle Scholar Baker DJ, Betik AC, Krause DJ, Hepple RT 2006 No decline in skeletal muscle oxidative capacity with aging in long-term calorically restricted rats effects are independent of mitochondrial DNA integrity. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies.

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During aging, mitophagy levels decline and negatively impact skeletal muscle performance. J Gerontol A Biol Sci Med Sci 61 675 684. UA oral intake also reduced plasma biomarkers of inflammation, such as ceramides 35 , and C-reactive protein 36 compared to placebo 13. PLoS Biol 8 e1000298. Coggan AR, Spina RJ, King DS, Rogers MA, Brown M, Nemeth PM, Holloszy JO 1992 Histochemical and enzymatic comparison of the gastrocnemius muscle of young and elderly men and women. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. In old mice UA administration promoted a 9 increase in muscle strength measured as grip test and a 57 increase of spontaneous activity endurance measured using the running wheel as compared with vehicle 25. Role of Mitophagy to Improve Mitochondrial Health in Sarcopenia. Free Radic Biol Med 150 109 119. 1000298ArticleCASPubMedPubMed CentralGoogle Scholar Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou Y-S, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K 2010 PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. , 2018 and Onishi et al. Urolithin A Intervention Mediated Mitophagy to Address Muscle Aging. , the effect of UA is mediated also by skn-1 Nrf2 homolog , which encodes for a transcription factor regulating mitochondrial biogenesis and mitophagy gene expression 25. A key secondary outcome was the change in muscle endurance resistance to fatigue via single muscle function tests in hand and leg muscles. At biomarker levels, these clinical effects were associated with a significant decrease in circulating plasma acylcarnitine levels, consistent with data observed from the first-in-human study. Mitophagy is a selective autophagy process involving the clearing and recycling of dysfunctional mitochondria that are impaired with aging and in several age-related diseases. 1007 s00335-016-9651-xArticleCASPubMedPubMed CentralGoogle Scholar Narendra DP, Jin SM, Tanaka A, Suen D-F, Gautier CA, Shen J, Cookson MR, Youle RJ 2010 PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. Front Physiol 10 420. 1038 s41430-021-00950-1ArticleCASPubMedGoogle Scholar Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J 2016 Urolithin A induces mitophagy and prolongs lifespan in C. It is a postbiotic metabolite derived from microflora conversion of ingested ellagitannins and ellagic acid, precursor molecules in foods like pomegranates, strawberries, raspberries, and walnuts. UA-mediated mitophagy activation has been confirmed in several other tissues and experimental conditions 29,30,31. Rejuvenation Res 9 219 222. Finally, UA-induced mitophagy and protected against cartilage degradation in a rat osteoarthritis OA disease model 32 and in human chondrocytes obtained from OA patients. An ongoing RCT will examine the impact of UA supplementation on muscle performance and recovery parameters in high-performance athletes undergoing a controlled exercise training program NCT04783207. In the vastus lateralis skeletal muscle, UA enhanced the expression of several mitochondrial function-related gene sets in dose dependent manner 26. 1038 s41593-018-0332-9ArticleCASPubMedPubMed CentralGoogle Scholar Lin J, Zhuge J, Zheng X, Wu Y, Zhang Z, Xu T, Meftah Z, Xu H, Wu Y, Tian N, Gao W, Zhou Y, Zhang X, Wang X 2020 Urolithin A-induced mitophagy suppresses apoptosis and attenuates intervertebral disc degeneration via the AMPK signaling pathway. 219ArticleCASPubMedGoogle Scholar Faitg J, Leduc-Gaudet J-P, Reynaud O, Ferland G, Gaudreau P, Gouspillou G 2019 Effects of aging and caloric restriction on fiber type composition, mitochondrial morphology and dynamics in rat oxidative and glycolytic muscles. abb0319 Ghosh N, Das A, Biswas N, Gnyawali S, Singh K, Gorain M, Polcyn C, Khanna S, Roy S, Sen CK 2020 Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD and SIRT1. Pharmacological interventions, such as myostatin inhibitors 7 , and nutritional strategies, including high-protein or amino acid supplementation 8, 9 , have focused on boosting muscle mass rather than muscle strength to circumvent the declining muscle function associated with aging. J Ethnopharmacol 250 112479. 3390 cells11010030ArticleCASPubMedPubMed CentralGoogle Scholar.

Biochem Biophys Res Commun 251 95 99. 3390 cells9122657ArticleCASPubMedPubMed CentralGoogle Scholar Dioguardi FS 2011 Clinical use of amino acids as dietary supplement pros and cons. 024ArticleCASPubMedGoogle Scholar Tuohetaerbaike B, Zhang Y, Tian Y, Zhang NN, Kang J, Mao X, Zhang Y, Li X 2020 Pancreas protective effects of Urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT mTOR signaling pathway. Mitochondrial health is crucial for cellular energy production, and it depends on several integrated processes that require multiple activities. 12955ArticlePubMedPubMed CentralGoogle Scholar Monzel AS, Enríquez JA, Picard M 2023 Multifaceted mitochondria moving mitochondrial science beyond function and dysfunction. This first-in-human study was followed by two efficacy studies with UA supplemented for a longer duration 2 4 months in which subjects were tested, for the first time for, a battery of muscle function and physical performance outcomes The first efficacy study investigated UA s benefits on muscle endurance in healthy older adults aged 65 90 years, mean age 72 years after daily administration of UA 1000 mg for 4 months ClinicalTrials. 004ArticleCASPubMedGoogle Scholar Gouspillou G, Sgarioto N, Kapchinsky S, Purves-Smith F, Norris B, Pion CH, Barbat-Artigas S, Lemieux F, Taivassalo T, Morais JA, Aubertin-Leheudre M, Hepple RT 2014 Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. Notably, UA significantly increased aerobic endurance in young rats undergoing voluntary running activity, indicating that addition of UA to an exercise regimen further improves muscle health benefits in this pre-clinical model. The primary outcome of the study was the change in six-minute walking distance from the baseline after 4-months of UA supplementation. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. 1016 s0140-6736 89 92143-0ArticleCASPubMedGoogle Scholar Gouspillou G, Bourdel-Marchasson I, Rouland R, Calmettes G, Franconi J-M, Deschodt-Arsac V, Diolez P 2010 Alteration of mitochondrial oxidative phosphorylation in aged skeletal muscle involves modification of adenine nucleotide translocator. J Gerontol A Biol Sci Med Sci 74 195 203. Subjects were administered either placebo, UA 500 mg, or UA 1000 mg either with single ascending doses or in multiple dosing for 4 weeks. Other PINK1 Parkin-independent mitophagy pathways activate other mitochondrial proteins, such as BNIP3, FUNDC1, and NIX, directly recruit LC3 to promote autophagosome formation and mitochondrial degradation. The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. It is well established that mitochondria play a central role in skeletal muscle wasting during aging. The PINK1-Parkin-dependent mitophagy process is initiated by stabilizing the kinase PINK1, which stimulates Parkin s recruitment and activation from the cytosol, unblocking its enzymatic activity and leading to the ubiquitination of outer membrane mitochondrial proteins 20. Nat Med 22 879 888. Sci Rep 10 20184.81,71,61 sisotpopa yb htaed llec detaidem-lairdnohcotim desaercni dna 61,51,41 ygrene lairdnohcotim deriapmi htiw detaicossa neeb sah stluda redlo dna slamina dlo htob ni ssam elcsum dna htgnerts fo ssol ehT . 1038 s42255-019-0073-4ArticleCASPubMedGoogle Scholar Luan P, D Amico D, Andreux PA, Laurila P-P, Wohlwend M, Li H, Imamura de Lima T, Place N, Rinsch C, Zanou N, Auwerx J 2021 Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy. 004ArticleCASPubMedGoogle Scholar Singh A, D Amico D, Andreux PA, Fouassier AM, Blanco-Bose W, Evans M, Aebischer P, Auwerx J, Rinsch C 2022 Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. 009ArticleCASPubMedGoogle Scholar Andreux PA, van Diemen MPJ, Heezen MR, Auwerx J, Rinsch C, Groeneveld GJ, Singh A 2018 Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly. Mamm Genome 27 381 395. Interestingly, the same gene sets were lower in the muscles of pre-frail older adults compared with healthy older adults who practiced regular physical activity 34. The first-in-human trial NCT02655393 enrolled healthy older adults, males and females, aged 61 85 years mean age 70 years. Nat Neurosci 22 401 412. Given that these are two functional and anatomically different muscles, UA was likely to have a global impact on skeletal muscle mitochondria. Sci Transl Med 13 eabb0319. These processes include Oxphos, protein import, and calcium uptake etc.3361 1261 82 J BESAF .

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009ArticleCASPubMedGoogle Scholar Lassale C, Batty GD, Steptoe A, Cadar D, Akbaraly TN, Kivimäki M, Zaninotto P 2019 Association of 10-year C-reactive protein trajectories with markers of healthy aging findings from the English longitudinal study of aging. b71ArticleCASPubMedGoogle Scholar Song W, Kwak H-B, Lawler JM 2006 Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Improving and maintaining mitochondrial health are considered potential strategies to enhance the health span, meaning how many of those years we remain healthy and disease-free. Another trial is investigating the impact of UA on the mitochondrial health of immune cells and overall immune function in a healthy, middle-aged population NCT05735886 and yet another is investigating the impact of combining UA with high-protein supplementation in an immobilization setting that rapidly induces muscle atrophy NCT05814705. Cells 9 2657. , to enhance mitochondrial health via targeted interventions. This study confirmed that UA was safe and bioavailable following long-term supplementation. The effect of oral administration of UA has been investigated in multiple double-blind, randomized, placebo-controlled clinical trials. Amazentis SA, EPFL Innovation Park, 1024, Ecublens, Switzerland Julie Faitg, Davide D Amico, Chris Rinsch Anurag Singh. As a result of damage to mitochondria or exposure to mitophagy inducers, mitochondria undergo mitophagy. Notably, the improvement in fatigue resistance with UA occurred without any changes to participants exercise routine and dietary habits. Am J Physiol Regul Integr Comp Physiol 282 R519-527. Mitochondrial health refers to the well-being and proper functioning of mitochondria, the organelles in most eukaryotic cells responsible for producing energy through adenosine triphosphate ATP. Nat Cell Biol 20 1013 1022. 1038 s42255-023-00783-1ArticlePubMedGoogle Scholar Gouspillou G, Hepple RT 2013 Facts and controversies in our understanding of how caloric restriction impacts the mitochondrion. The improvement in fatigue resistance occurred without any changes to participants exercise routine and dietary habits and indicated the efficacy of UA to counteract muscle aging decline in older adults. 016ArticleCASPubMedGoogle Scholar Iorio R, Celenza G, Petricca S 2021 Mitophagy molecular mechanisms, new concepts on parkin activation and the emerging role of AMPK ULK1 axis. Table 1 Summary of pre-clinical and clinicals studies on UA and muscle health. gov Identifier NCT03283462. Walking distance was greater in the UA group, but compared to the placebo group these changes were not-significant, suggesting that intervention longer than 4-months with a higher sample size would be needed in future studies. 00420ArticlePubMedPubMed CentralGoogle Scholar Rybalka E, Timpani CA, Debruin DA, Bagaric RM, Campelj DG, Hayes A 2020 The failed clinical story of myostatin inhibitors against duchenne muscular dystrophy exploring the biology behind the battle. However, both might suffer from poor compliance with exercise regimens and adherence to tedious caloric restriction protocols. First, this study investigated UA s safety, tolerability and pharmacokinetic profile in older adults. Sci Rep 8 8548. Urolithin A Induced Mitophagy and Improves Muscle Function Pre-clinically. Extensive descriptions of mitophagy monitoring procedures, and their advantages and limitations, have been reviewed by Palikras et al. According to Ryu et al. xArticleCASPubMedGoogle Scholar Diot A, Morten K, Poulton J 2016 Mitophagy plays a central role in mitochondrial ageing. Reducing muscle function below critical thresholds results in a clinical condition known as sarcopenia, significantly impacting quality of life by reducing the ability to perform daily tasks. Mitophagy leads to improved mitochondrial respiratory capacity by improving the quality of cellular mitochondria pools. .

Following intake, UA peaked in plasma between six and eight hours and exhibited a relatively long half-life t 1 2 17 22 h , probably because it was actively recirculated through the liver. There was also no food-effect on UA bioavailability. 1038 s41556-018-0176-2ArticleCASPubMedGoogle Scholar Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K 2021 Molecular mechanisms and physiological functions of mitophagy. Eur J Clin Nutr 76 297 308. Altogether, these clinical studies 12, 13, 26 consistently indicate that oral UA, in the range of 500 1000 mg, increases mitophagy and mitochondrial metabolism in skeletal muscle, and report positive effects on a range of muscle function outcomes, including skeletal muscle resistance to fatigue, improved muscle strength, and exercise performance measures Fig. JAMA Netw Open 5 e2144279. Curent studies and the growing research on UA indicate how supplementing with UA is an effective nutritional intervention to counter age-related muscle decline, by targeting mitophagy Table 1. Furthermore, human studies should be designed to study the impact of UA on other organs impacted by aging and that could contribute to disability during sarcopenia. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline. Trends Mol Med 25 20 32. Lancet 1 637 639.snamuh ni seiduts morf degreme ytivegnol dna gniga no evitcepsrep cimetsys a gnigammalfni-itna dna gnigammalfnI 7002 S iloivlaS ,CG inalletsaC ,E inineveC ,M itrucS ,L inaleC ,L aidivnI ,PM aigruonaP ,F iniveS ,F ireivilO ,S atnuiG ,D itnoM ,M irpaC ,C ihcsecnarF ralohcS elgooGdeMbuPelcitrA820ylg anoreg 3901 . Mech Ageing Dev 128 92 105. This occurs in approximately 30 40 of people 24 at variable levels, with only a small percentage deriving UA from natural exposure at substantial levels able to confer a health benefit. We will summarize recent pre-clinical evidence and clinical studies that have shown the potential of the postbiotic a gut microbiome-derived compound Urolithin A UA to improve muscle function in different study populations such as overweight middle-aged and healthy older adults 12, 13 via its ability to activate mitophagy. In the multiple ascending dosing part of the study, different cohorts received either a placebo or two doses 500 and 1000 mg of UA daily for four weeks. An effective strategy to improve muscle strength and function is via targeting muscle bioenergetics i. For instance, joint and heart muscle tissues for which promising preclinical data on a beneficial impact of UA are already available. In humans, UA was shown to regulate mitochondrial function systemically and in skeletal muscle. Exp Gerontol 48 1075 1084.gniga dna ,esaesid ,htlaeh no A nihtilorU dnuopmoc larutan eht fo tcapmI 1202 J xrewuA ,C hcsniR ,A hgniS ,P sédlaV ,AP xuerdnA ,D ocimA D ralohcS elgooGlartneC deMbuPdeMbuPSACelcitrA26631 . Finally, when administered intragastrically to middle-aged mice for 16 weeks, UA increased markers of angiogenesis in the skeletal muscle, activated the SIRT1-PGC-1α pathway, and elevated ATP and NAD levels 28. In wild-type rodents 25 and in the mdx mouse model of Duchenne muscular dystrophy DMD 27 , higher levels of mitophagy markers such as mitochondrial Parkin, ubiquitinated and phospho-ubiquitinated mitochondrial proteins were observed in skeletal muscle tissues after UA supplementation. Altogether, the data gathered herein support the health-promoting activity of UA. In worms, UA enhanced the expression of mitophagy genes lgg-1 25 , pink-1 , and pdr-1 27 and exhibited a similar health span-promoting signature as CR. J Gerontol 47 B71-76. EMBO J 40 e104705. These biomarkers are known to be elevated with chronic inflammation observed during aging, a process known as inflamm-aging 37. Biochim Biophys Acta 1797 143 151. Trends Mol Med 27 687 699. Mitophagy serves as a quality control mechanism to maintain mitochondrial health by selectively removing dysfunctional or superfluous mitochondria from the cell.

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