Suchergebnisse

The evolution of lifespan is a central question in evolutionary biology, begging the question why there is so large variation among taxa. Specifically, a central quest is to unravel proximate causes of ageing. Here, we show that the degree of unsaturation of liver fatty acids predicts maximum lifespan in 107 bird species. In these birds, the degree of fatty acid unsaturation is positively related to maximum lifespan across species. This is due to a positive effect of monounsaturated fatty acid content, while polyunsaturated fatty acid content negatively correlates with maximum lifespan. Furthermore, fatty acid chain length unsuspectedly increases with maximum lifespan independently of degree of unsaturation. These findings tune theories on the proximate causes of ageing while providing evidence that the evolution of lifespan in birds occurs in association with fatty acid profiles. This suggests that studies of proximate and ultimate questions may facilitate our understanding of these central evolutionary questions. ; We acknowledge funding from the Spanish Ministry of Economy and Competitiveness (references BFU2009‐11879/BFI, RD12/0043/0018, PI1300584, and PI1400328), and the Autonomous Government of Catalonia (ref. 2014SGR168) to R.P. I.G. is supported by a Ramón y Cajal Fellowship (ref. RYC‐2012‐10237) from the Spanish Ministry of Economy and Competitiveness.

Aging and age-related diseases are one of the most important health issues that the world will confront during the 21st century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory. ; This study was supported by the European Research Council (ERC Starting Grant to A.S.), the Academy of Finland (Research Academy Fellowship to A.S), the Spanish Ministry of Economy and Competitiveness (BFU2009-11879/BFI; RD12/0043/0018 and PI1400328 to R.P.), and the Autonomous Government of Catalonia (2014SGR168 to R.P).

Mitochondrial reactive oxygen species (ROS) production, specifically at complex I (Cx I), has been widely suggested to be one of the determinants of species longevity. The present study follows a comparative approach to analyse complex I in heart tissue from 8 mammalian species with a longevity ranging from 3.5 to 46 years. Gene expression and protein content of selected Cx I subunits were analysed using droplet digital PCR (ddPCR) and western blot, respectively. Our results demonstrate: 1) the existence of species-specific differences in gene expression and protein content of Cx I in relation to longevity; 2) the achievement of a longevity phenotype is associated with low protein abundance of subunits NDUFV2 and NDUFS4 from the matrix hydrophilic domain of Cx I; and 3) long-lived mammals show also lower levels of VDAC (voltage-dependent anion channel) amount. These differences could be associated with the lower mitochondrial ROS production and slower aging rate of long-lived animals and, unexpectedly, with a low content of the mitochondrial permeability transition pore in these species. ; This work was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (grant number PI14/00328), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250) to R.P, and PR [19] BIO MET 0155 to GB.This study has been co-financed by FEDER funds from the European Union ("A way to build Europe"). IRBLleida is a CERCA Programme/Generalitat of Catalonia.

The fatty acid elongase elongation of very long-chain fatty acids protein 2 (ELOVL2)controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3,docosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn-6)in vivo. Expectedly,Elovl2-ablation drastically reduced the DHA and DPAn-6 in liver mitochondrial membranes. Unex-pectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation.The lipid peroxidation process was not involved in PUFAs reduction since malondialdehyde-lysine(MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrialrespiratory chain proteins remained unchanged. Still, membrane remodeling was associated withthe high voltage-dependent anion channel (VDAC) and adenine nucleotide translocase 2 (ANT2),a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mi-tochondrial function was impaired despite preserved content of the respiratory chain proteins andthe absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coeffi-cients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fattyacid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume andnumber of peroxisomes increased as revealed by transmission electron microscopy. In conclusion,the results imply that endogenous DHA production is vital for the normal function of mouse livermitochondria and could be relevant not only for mice but also for human metabolism. ; This study was supported by grants from the Swedish Science Council (VR-NT 2017-04715and VR-MT 2019-01508). This research was also funded in part by the Spanish Ministry of Science,Innovation, and Universities (grant RTI2018-099200-B-I00), and the Generalitat of Catalonia: Agencyfor Management of University and Research Grants (2017SGR696) to R.P. This study was co-financedby FEDER funds from the European Union ("A way to build Europe"). IRB Lleida ...

Maximum longevity (ML) varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of ML could to converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study is a comparative approach using heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot and mass spectrometry, respectively. Our results demonstrate 1) the existence of differences species-specific in gene expression and protein content of mTORC1; 2) that the achievement of a longevity phenotype requires decreased and inhibited mTORC1; 3) decreased content of mTORC1 activators in long-lived animals, and 4) independence of phylogeny relationships on these changes. Altogether, our findings support mTORC1 down-regulation to achieve a longevous phenotype. ; This work was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (grant number PI14/00328), the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250) to R.P. This study has been co-financed by FEDER funds from the European Union ("A way to build Europe").

Metformin is one of the treatments used for pcoS pathology decreasing body weight, plasma androgen, FSH and glucose levels. Unfortunately, there is little known about metformin's effects on lipid metabolism, a crucial process in pcoS pathology. We have employed a lipidomic approach to explore alterations in the plasma lipid profile of patients with PCOS following metformin treatment. The aim is to offer new insights about the effect of metformin in PCOS patients. Plasma samples were obtained from 27 subjects prior to and following 12 weeks of metformin treatment. A detailed biochemical characterization and lipidomic profile was performed. Metformin reduces BMI, HOMA-IR, fSH and androstenedione and increases DHeA-S but no changes were found in glucose levels after treatment. Multivariate statistics revealed a specific lipidomic signature due to the effect of 12 weeks of metformin treatment in pcoS patients. this signature includes changes in sphingolipid metabolism suggesting a crosstalk between these lipid species and the androgenic metabolism and a decrease in oxidized lipids reinforcing that metformin treatment improves oxidative stress status. our study confirms the specific effect of metformin in lipid metabolism on women with PCOS after 12 weeks of treatment. ; We thank Maria Rosa Gomez and David Argiles for technical support. This research was funded by grants from Carlos III Health Institute (ISCIII) (PI16/1083, PI16/0301) to V.M.V and M.R, respectively and CIBERehd (CB06/04/0071)−initiatives of the ISCIII to M.R and V.M.V, the European Regional Development Fund (ERDF "A way to build Europe"). Unrestricted grant from Menarini S.A to M.R. V.M.V. and M.R. are recipients of contracts from the Ministry of Health of the Valencian Regional Government and Carlos III Health Institute (CES10/030 and CP10/0360, respectively). R. P. is recipient of contracts from the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (grant number PI14/00328); Spanish Ministry of Science, Innovation and Universities (grant number RTI2018-099200-B-I00), and the Generalitat of Catalonia, Department of Health (grant number SLT002/16/00250) and Department of Business and Knowledge (grant number 2017SGR696). This study has been co-financed by FEDER funds from the European Union ('A way to build Europe'). I.P. received a predoctoral fellowship from the Lleida University. S.R-LL. is recipient of a Juan de la Cierva contract from Spanish Ministry of Economy and Competitiveness (FJCI-2015-25040). C.B. is recipient of a Sara Borrell contract from Institute of Health Carlos III (CD14/00043). M.J is a Serra Húnter Fellow.

Purpose: In this work, a non-targeted approach was used to unravel changes in the plasma lipidome of PCOS patients. The aim is to offer new insights in PCOS patients strictly selected in order to avoid confounding factors such as dyslipemia, obesity, altered glucose/insulin metabolism, cardiovascular disease, or cancer. Results: Multivariate statistics revealed a specific lipidomic signature for PCOS patients without associated pathologies. This signature implies changes, mainly by down-regulation, in glycerolipid, glycerophospholipid and sphingolipid metabolism suggesting an altered biosynthetic pathway of glycerophospholipids and cell signaling as second messengers in women with PCOS. Conclusions: Our study confirms that a lipidomic approach discriminates a specific phenotype from PCOS women without associated pathologies from healthy controls. Methods: In a cross-sectional pilot study, data were obtained from 34 subjects, allocated to one of two groups: a) lean, healthy controls (n = 20), b) PCOS patients (n = 14) with diagnosis based on hyperandrogenaemia, oligo-anovulation and abnormal ovaries with small follicular cysts. A detailed biochemical characterization was made and lipidomic profiling was performed via an untargeted approach using LC-ESI-QTOF MS/MS. ; We acknowledge funding from the Fund for Health Research (FIS) and co-funding from the European Regional Development Fund of the European Union (FEDER, 'Una manera de hacer Europa'): PI15/1424, PI16/1083, PI16/0301 and UGP15-193 by FISABIO, to A.H.M, M.R. and V.M.V, respectively. This research was also in part funded by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (FIS grants PI14/00328), and the Autonomous Government of Catalonia (2017SGR and SLT002/16/00250) to R.P. This study was co-financed by FEDER funds from the European Union ('Una manera de hacer Europa').

The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3b. We find that GSK-3b inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models (Abcd1 and Abcd1 /Abcd2 / mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross-talk governing energetic and redox homeostasis in XALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK- 3b/NRF2 axis. ; This study was supported by grants from the Spanish Institute for Health Carlos III and "Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa" [PFIS FI12/00457] to P.R-R., [FIS PI14/ 01115, FIS PI17/00134] to M.P.O., [FIS PI13/00584, FIS PI14/00328] to R.P., [FIS PI11/01043, FIS PI14/00410, FIS PI17/00916] to A.P., [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/00857] to S.F.; the European Commission [FP7-241622] to A.P., the European Leukodystrophy Association [ELA2012-033C1] to A.P; the Autonomous Government of Catalonia [SGR 2017SGR696] to R.P. and [SGR 2014SGR1430; 2017SGR1206] to A.P.; and the Centre for Biomedical Research on Rare Diseases (CIBERER) to N.L. and M.R. Locomotor experiments were performed by the SEFALer unit F5 (CIBERER) led by A.P.

The membrane fatty acid unsaturation hypothesis of aging and longevity is experimentally tested for the first time in mammals. Lifelong treatment of mice with the b1-blocker atenolol increased the amount of the extracellular-signal-regulated kinase signaling protein and successfully decreased one of the two traits appropriately correlating with animal longevity, the membrane fatty acid unsaturation degree of cardiac and skeletal muscle mitochondria, changing their lipid profile toward that present in much more longer-lived mammals. This was mainly due to decreases in 22:6n-3 and increases in 18:1n-9 fatty acids. The atenolol treatment also lowered visceral adiposity (by 24%), decreased mitochondrial protein oxidative, glycoxidative, and lipoxidative damage in both organs, and lowered oxidative damage in heart mitochondrial DNA. Atenolol also improved various immune (chemotaxis and natural killer activities) and behavioral functions (equilibrium, motor coordination, and muscular vigor). It also totally or partially prevented the aging-related detrimental changes observed in mitochondrial membrane unsaturation, protein oxidative modifications, and immune and behavioral functions, without changing longevity. The controls reached 3.93 years of age, a substantially higher maximum longevity than the best previously described for this strain (3.0 years). Side effects of the drug could have masked a likely lowering of the endogenous aging rate induced by the decrease in membrane fatty acid unsaturation. Weconclude that it is atenolol that failed to increase longevity, and likely not the decrease in membrane unsaturation induced by the drug. ; This investigation was supported by I + D grants from the Spanish Ministry of Science and Innovation (BFU2011-23888 to G.Barja); UCMGroups of Research (910379ENEROINN), BFU2011-30336, and RETICEF (RD 12/0043/0018) from ISCIII-FEDER of the European Union to M. De la Fuente; Spanish Ministry of Health (PI11/01532) to M.Portero Otin; and Spanish Ministry of Science and Innovation ...

Aging is a multifactorial process which affects all animals. Aging as a result of damage accumulation is the most accepted explanation but the proximal causes remain to be elucidated. There is also evidence indicating that aging has an important genetic component. Animal species age at different rates and specific signaling pathways, such as insulin/insulin-like growth factor, can regulate life span of individuals within a species by reprogramming cells in response to environmental changes. Here, we use an unbiased approach to identify novel factors that regulate life span in Drosophila melanogaster. We compare the transcriptome and metabolome of two wild-type strains used widely in aging research: short-lived Dahomey and long-lived Oregon R flies. We found that Dahomey flies carry several traits associated with short-lived individuals and species such as increased lipoxidative stress, decreased mitochondrial gene expression, and increased Target of Rapamycin signaling. Dahomey flies also have upregulated octopamine signaling known to stimulate foraging behavior. Accordingly, we present evidence that increased foraging behavior, under laboratory conditions where nutrients are in excess increases damage generation and accelerates aging. In summary, we have identified several new pathways, which influence longevity highlighting the contribution and importance of the genetic component of aging. ; This work was supported by the European Research Council (260632 - ComplexI&Aging to A.S.); the Academy of Finland (252048 to A.S); the Biotechnology and Biological Sciences Research Council ( BB/M023311/1 to A.S.); the Centre for International Mobility (CIMO) (TM-12- 8391 and TM-13-8919 to N.G.); the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI14/00328 to R.P. and PI17/01286 to P.N.); the Autonomous Government of Catalonia (2017SGR696 and SLT002/16/00250 to R.P.); the Ministry of Education and Science of Ukraine (grant number 0117U006426 to O.L.); FEDER funds from the European Union ("A way to build Europe" to R.P.); and the Doctoral Programme in Medicine and Life Sciences of University of Tampere (to T.R). R.S is a Sir Henry Wellcome Postdoctoral Fellow funded by Wellcome (204715/Z/16/Z)

Oxidative stress has been implicated in diabetes long-term complications. In this paper, we summarize the growing evidence suggesting that hyperglycemia-induced overproduction of superoxide by mitochondrial electron transport chain triggers a maladaptive response by affecting severalmetabolic and signaling pathways involved in the pathophysiology of cellular dysfunction and diabetic complications. In particular, it is our goal to describe physiological mechanisms underlying the mitochondrial free radical production and regulation to explain the oxidative stress derived from a high intracellular glucose concentration and the resulting maladaptive response that leads to a cellular dysfunction and pathological state. Finally, we outline potential therapies for diabetes focused to the prevention of mitochondrial oxidative damage. ; Investigations of the authors of this paper have been supported by Grants ref. BFI2003-01287, BFU2006-14495/BFI and BFU2009-11879/BFI; Reticef RD06/0013/0012, and 2005SGR00101, and 2009SGR735 from the Ministry of Science and Innovation, Ministry of Health, and the Autonomous Government of Catalonia, respectively.

Sirtuin 2 (SIRT2) is a member of a family of NAD+-dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice. In addition, these Sirt2−/− mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT2 in orchestrating its metabolic regulation. This underscores the value of SIRT2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis. ; This study was supported by grants from the Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa' [FIS PI11/01043, FIS PI14/00410], the Autonomous Government of Catalonia [SGR 2014SGR1430] to A.P., The Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa' [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/ 00857] to S.F. and the Center for Biomedical Research on Rare Diseases (CIBERER) to M.R., and the Spanish Institute for Health Carlos III and FEDER funds from European Union ('A way to build Europe') [FIS grants PI14/01115, PI13/00584, and PI14/00328], Foundation La Marató de TV3 [345/C/2014], and the Autonomous Government of Catalonia [2014SGR168] to M.J., M.P.O., and R.P. The studies conducted at the Chromatin Biology Laboratory were supported by the Spanish Ministry of Economy and Competitiveness-MINECO [SAF2011-25860, SAF2014-55964R] to A.V.

Mitochondria have been increasingly recognized as a central regulatory nexus for multiple metabolic pathways, in addition to ATP production via oxidative phosphorylation (OXPHOS). Here we show that inducing mitochondrial DNA (mtDNA) stress in Drosophila using a mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results in unexpected metabolic reprogramming in adult flies, distinct from effects on OXPHOS. Carbohydrate utilization was repressed, with catabolism shifted towards lipid oxidation, accompanied by elevated serine synthesis. Cleavage and translocation, the two modes of mtEcoBI action, repressed carbohydrate rmetabolism via two different mechanisms. DNA cleavage activity induced a type II diabetes-like phenotype involving deactivation of Akt kinase and inhibition of pyruvate dehydrogenase, whilst translocation decreased post-translational protein acetylation by cytonuclear depletion of acetyl-CoA (AcCoA). The associated decrease in the concentrations of ketogenic amino acids also produced downstream effects on physiology and behavior, attributable to decreased neurotransmitter levels. We thus provide evidence for novel signaling pathways connecting mtDNA to metabolism, distinct from its role in supporting OXPHOS. ; This work was supported by following grants: Academy of Finland postdoctoral grant nr. 132997 and exploratory research grant nr. PUT573 from Estonian Research Council to Priit Jõers; Academy Professorship (255365) and Centre of Excellence grants (272376 and 307431) by Academy of Finland to Howard T Jacobs; Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00), the Generalitat of Catalonia, Agency for Management of University and Research Grants (2017SGR696) and Department of Health (SLT002/16/00250), and by FEDER funds from European Union ("A way to build Europe") to Reinald Pamplona; Vilho Rossin Fund (Finnish Cultural Foundation) grant to Ana Andjelković; Estonian Research Council grant nr. PUT1223 and Latvian Council of Science grant nr. lzp-2018/1-0393 to Indrikis Krams, IUT36-2 to Tatjana Krama; and AFM grant nr. 17424 to Eric Dufour. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Human brain aging is the physiological process which underlies as cause of cognitive decline in the elderly and the main risk factor for neurodegenerative diseases such as Alzheimer's disease. Human neurons are functional throughout a healthy adult lifespan, yet the mechanisms that maintain function and protect against neurodegenerative processes during aging are unknown. Here we show that protein oxidative and glycoxidative damage significantly increases during human brain aging, with a breakpoint at 60 years old. This trajectory is coincident with a decrease in the content of the mitochondrial respiratory chain complex I–IV. We suggest that the deterioration in oxidative stress homeostasis during aging induces an adaptive response of stress resistance mechanisms based on the sustained expression of REST, and increased or decreased expression of Akt and mTOR, respectively, over the adult lifespan in order to preserve cell neural survival and function. ; R.C. received predoctoral fellowships from the Autonomous Government of Catalonia. We thank T. Yohannan for editorial help. Research reported in this publication was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (FIS Grants PI14/00757 and PI14/00328), and the Autonomous Government of Catalonia (2014SGR69 and 2014SGR168) to I.F. and R.P. This study was co-financed by FEDER funds from the European Union ('a way to build Europe').

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260. ; This study was funded by grants from the Spanish Ministry of Health, Social Services and Equality (EC10-137), the Spanish Institute Health Carlos III (ICI14/0076) (co-funded by European Regional Development Fund, a way to build Europe), the Hesperia Foundation, the European Commission (Leukotreat FP7-241622), and the Autonomous Government of Catalonia (2014SGR1430; 2017SGR1206) to Aurora Pujol. Montserrat Ruiz was funded by the Center for Biomedical Research on Rare Diseases, an initiative of the Institute of Health Carlos III. Stéphane Fourcade was funded by Miguel Servet Program (CPII16/00016) (co-funded by European Social Fund, investing in your future). Alba Naudí, Manuel Portero-Otín, and Reinald Pamplona have received funding support from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI).