Effects of aging and methionine restriction on rat kidney metabolome

Methionine restriction (MetR) in animal models extends maximum longevity and seems to promote renoprotection by attenuating kidney injury. MetR has also been proven to affect several metabolic pathways including lipid metabolism. However, there is a lack of studies about the effect of MetR at old age on the kidney metabolome. In view of this, a mass spectrometry-based high-throughput metabolomic and lipidomic profiling was undertaken of renal cortex samples of three groups of male rats—An 8-month-old Adult group, a 26-month-old Aged group, and a MetR group that also comprised of 26-month-old rats but were subjected to an 80% MetR diet for 7 weeks. Additionally, markers of mitochondrial stress and protein oxidative damage were analyzed by mass spectrometry. Our results showed minor changes during aging in the renal cortex metabolome, with less than 59 differential metabolites between the Adult and Aged groups, which represents about 4% of changes in the kidney metabolome. Among the compounds identified are glycerolipids and lipid species derived from arachidonic acid metabolism. MetR at old age preferentially induces lipid changes affecting glycerophospholipids, docosanoids, and eicosanoids. No significant differences were observed between the experimental groups in the markers of mitochondrial stress and tissue protein damage. More than rejuvenation, MetR seems to induce a metabolic reprogrammingWe acknowledge funding from 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”). I.P. was supported by a University of Lleida Predoctoral Fellowship. R.C. and N.M.M. were supported by a Generalitat of Catalonia Predoctoral Fellowship. M.J. is a Serra Húnter Fellow

Membrane lipid unsaturation as physiological adaptation to animal longevity

The appearance of oxygen in the terrestrial atmosphere represented an important selective pressure for ancestral living organisms and contributed toward setting up the pace of evolutionary changes in structural and functional systems. The evolution of using oxygen for efficient energy production served as a driving force for the evolution of complex organisms. The redox reactions associated with its use were, however, responsible for the production of reactive species (derived from oxygen and lipids) with damaging effects due to oxidative chemical modifications of essential cellular components. Consequently, aerobic life required the emergence and selection of antioxidant defense systems. As a result, a high diversity in molecular and structural antioxidant defenses evolved. In the following paragraphs, we analyze the adaptation of biological membranes as a dynamic structural defense against reactive species evolved by animals. In particular, our goal is to describe the physiological mechanisms underlying the structural adaptation of cellular membranes to oxidative stress and to explain the meaning of this adaptive mechanism, and to review the state of the art about the link between membrane composition and longevity of animal species.Investigations of the author of this review have been supported in part by I+D grants from the Spanish Ministry of Science and Innovation (BFU2011-23888), and BSCH-UCM (2009-2010) to Gustavo Barja; and grants from the Spanish Ministry of Education and Science (BFU2009-11879/BFI), the Spanish Ministry of Economy and Competitiveness-Institute of Health Carlos III (PI13/00584) and the Generalitat of Catalunya (2009SGR735) to Reinald Pamplona

Regulation of membrane unsaturation as antioxidant adaptive mechanism in long-lived animal species

Oxidative stress resulting from biomolecular oxidative damage due to the imbalance between reactive species production and antioxidant response has become an universal constraint of life-history evolution in animals and a modulator of phenotypic development and trade-offs. Redox balance is an important selective pressure faced by most organisms, and a myriad of mechanisms have evolved to regulate and adjust this balance. This diversity of mechanisms means that organisms have a great deal of flexibility in how they deal with reactive species challenges across time, conditions, and tissue types, as well as that different organisms may evolve different strategies for dealing with similar challenges. In the following paragraphs, we review the adaption of biological membranes as structural antioxidant defense against reactive species evolved by animals. In particular, it is our goal to describe the physiological mechanisms underlying the structural adaption of cellular membranes to oxidative stress, to explain the meaning of this adaptive mechanism, and to review the state of the art about the link between membrane composition and longevity of animal species.Investigations of the author of this review have been supported in part by I + D grants from the Spanish Ministry of Science and Innovation (BFU2008-00335/ BFI and BFU2011-23888), and BSCH-UCM (2009-2010) to G.B; and grants from the Spanish Ministry of Education and Science (BFU2009-11879/BFI), the Spanish Ministry of Health (RD06/0013/0012), and the Generalitat of Catalunya (2009SGR735) to R.P

Non-enzymatic modification of aminophospholipids by carbonyl-amine reactions

Non-enzymatic modification of aminophospholipids by lipid peroxidation-derived aldehydes and reducing sugars through carbonyl-amine reactions are thought to contribute to the age-related deterioration of cellular membranes and to the pathogenesis of diabetic complications. Much evidence demonstrates the modification of aminophospholipids by glycation, glycoxidation and lipoxidation reactions. Therefore, a number of early and advanced Maillard reaction-lipid products have been detected and quantified in different biological membranes. These modifications may be accumulated during aging and diabetes, introducing changes in cell membrane physico-chemical and biological properties

The advanced lipoxidation end-product malondialdehyde-lysine in aging and longevity

The nonenzymatic adduction of malondialdehyde (MDA) to the protein amino groups leads to the formation of malondialdehyde-lysine (MDALys). The degree of unsaturation of biological membranes and the intracellular oxidative conditions are the main factors that modulate MDALys formation. The low concentration of this modification in the different cellular components, found in a wide diversity of tissues and animal species, is indicative of the presence of a complex network of cellular protection mechanisms that avoid its cytotoxic effects. In this review, we will focus on the chemistry of this lipoxidation-derived protein modification, the specificity of MDALys formation in proteins, the methodology used for its detection and quantification, the MDA-lipoxidized proteome, the metabolism of MDA-modified proteins, and the detrimental effects of this protein modification. We also propose that MDALys is an indicator of the rate of aging based on findings which demonstrate that (i) MDALys accumulates in tissues with age, (ii) the lower the concentration of MDALys the greater the longevity of the animal species, and (iii) its concentration is attenuated by anti-aging nutritional and pharmacological interventionsResearch by the authors was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (FIS grants PI13/00584 and PI14/00328), the Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00), and the Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696), and Department of Health (SLT002/16/00250) to RP. 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

Target of rapamycin activation predicts lifespan in fruit flies

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)

Nonalcoholic Fatty Liver Disease and the Gut-Liver Axis: Exploring an Undernutrition Perspective

Nonalcoholic fatty liver disease (NAFLD) is a chronic con dition affecting one quarter of the global population. Although primarily linked to obesity and metabolic syn drome, undernutrition and the altered (dysbiotic) gut microbiome influence NAFLD progression. Both undernu trition and NAFLD prevalence are predicted to considerably increase, but how the undernourished gut microbiome contributes to hepatic pathophysiology remains far less studied. Here, we present undernutrition conditions with fatty liver features, including kwashiorkor and micro nutrient deficiency. We then review the gut microbiota-liver axis, highlighting key pathways linked to NAFLD progres sion within both overnutrition and undernutrition. To conclude, we identify challenges and collaborative possi bilities of emerging multiomic research addressing the pa thology and treatment of undernourished NAFLD.Authors from the Finlay lab are grateful for funding through a Foundation Grant from the Canadian Institutes of Health Research. The Ayala Lab has received financial support from Spanish Ministries and the Generalitat of Catalonia

The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer's Disease Pathology

Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer’s disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress conditions that favor increased mitochondrial molecular damage with early bioenergetic involvement. This alteration of energy metabolism is the starting point for subsequent changes in a multitude of cell mechanisms, leading to neuronal dysfunction and, ultimately, cell death. These events are induced by changes that come with age, creating the substrate for the alteration of several neuronal pathways that will evolve toward neurodegeneration and, consequently, the development of AD pathology. In this context, the present review will focus on description of the biological mechanisms that confer vulnerability specifically to neurons of the entorhinal cortex, the changes induced by the aging process in this brain region, and the alterations at the mitochondrial level as the earliest mechanism for the development of AD pathology. Current findings allow us to propose the existence of an altered allostatic mechanism at the entorhinal cortex whose core is made up of mitochondrial oxidative stress, lipid metabolism, and energy production, and which, in a positive loop, evolves to neurodegeneration, laying the basis for the onset and progression of AD pathology.Research by the authors was supported by the Institute of Health Carlos III (FIS grantsPI14/00757, PI14/00328, PI20/0155), the Spanish Ministry of Science, Innovation, and Universities(Ministerio de Ciencia, Innovación y Universidades, grant RTI2018-099200-B-I00), and the Generalitatof Catalonia: Agency for Management of University and Research Grants (2017SGR696) to M.P-O.,I.F., and R.P. This study was co-financed by FEDER funds from the European Union (‘A way tobuild Europe’)

Succination of protein thiols in human brain aging

Human brain evolution toward complexity has been achieved with increasing energy supply as the main adaptation in brain metabolism. Energy metabolism, like other biochemical reactions in aerobic cells, is under enzymatic control and strictly regulated. Nevertheless, physiologically uncontrolled and deleterious reactions take place. It has been proposed that these reactions constitute the basic molecular mechanisms that underlie the maintenance or loss-of-function of neurons and, by extension, cerebral functions during brain aging. In this review article, we focus attention on the role of the nonenzymatic and irreversible adduction of fumarate to the protein thiols, which leads to the formation of S-(2-succino)cysteine (2SC; protein succination) in the human brain. In particular, we first offer a brief approach to the succination reaction, features related to the specificity of protein succination, methods for their detection and quantification, the bases for considering 2SC as a biomarker of mitochondrial stress, the succinated proteome, the cross-regional differences in 2SC content, and changes during brain aging, as well as the potential regulatory significance of fumarate and 2SC. We propose that 2SC defines cross-regional differences of metabolic mitochondrial stress in the human brain and that mitochondrial stress is sustained throughout the healthy adult lifespan in order to preserve neuronal function and survival.Research by the authors was supported by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (FIS grants PI13/00584 and PI14/00328), the Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, 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 RP. 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. IP was supported by a University of Lleida Predoctoral Fellowship. RC and NM-M were supported by a Generalitat of Catalonia Predoctoral Fellowship. MJ is a “Serra Húnter” Fellow

Lipidomics Reveals a Tissue-Specific Fingerprint

In biological systems lipids generate membranes and have a key role in cell signaling and energy storage. Therefore, there is a wide diversity of molecular lipid expressed at the compositional level in cell membranes and organelles, as well as in tissues, whose lipid distribution remains unclear. Here, we report a mass spectrometry study of lipid abundance across 7 rat tissues, detecting and quantifying 652 lipid molecular species from the glycerolipid, glycerophospholipid, fatty acyl, sphingolipid, sterol lipid and prenol lipid categories. Our results demonstrate that every tissue analyzed presents a specific lipid distribution and concentration. Thus, glycerophospholipids are the most abundant tissue lipid, they share a similar tissue distribution but differ in particular lipid species between tissues. Sphingolipids are more concentrated in the renal cortex and sterol lipids can be found mainly in both liver and kidney. Both types of white adipose tissue, visceral and subcutaneous, are rich in glycerolipids but differing the amount. Acylcarnitines are mainly in the skeletal muscle, gluteus and soleus, while heart presents higher levels of ubiquinone than other tissues. The present study demonstrates the existence of a rat tissue-specific fingerprint.We acknowledge funding from the Spanish Ministry of Economy and Competitiveness (ref. PI1400328), and the Autonomous Government of Catalonia (ref. 2017SGR696) to RP. This study has been co-financed by FEDER funds from the European Union (Una manera de hacer Europa). IP was supported by a University of Lleida Predoctoral Fellowship. RC was supported by a Generalitat of Catalonia Predoctoral Fellowship