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| Animal model (specie) and tissue | Sample and age | Results related to oxidative stress or ROS influence on aging | Main proteins altered in aging* | References |
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Invertebrate Caenorhabditis elegans (worm) | In vitro knocked down by RNAi | Ten iRNA tested caused substantial reduction in adult lifespan. When these genes are disturbed defensive mechanisms against oxidative stress become altered. | UBH-1, UBH-3, PRDX2, PRDX3, AMPK-β1, AMPK-β2, LBP-4, LBP-6, LBP-9, RHI-1 | [80] |
| In vitro knocked down by RNAi for K10C2.4 | K10C2.4 RNAi activates oxidative stress and endoplasmic reticulum stress response in the worm intestine by accumulation of tyrosine metabolites. | Enzymes in the tyrosine degradation pathway | [81] |
| Long-lived daf-2(e1370) strain | Components of the enhanced longevity system identified in daf-2 deficient mutant include the alpha-crystallin family of small heat shock proteins, anti-ROS defense systems, and cellular phase II detoxification. GSTP were significantly URg, which detoxify and/or bind short-chain aldehydic natural toxic products of lipid peroxidation and long-chained fatty-acids at physiologically relevant concentrations, indicating a role in longevity. | GPX, SOD1, NME, RPS12, STK, LBP-6, HSP-12.6, HSP-12.3 | [82] |
| Exposure of prdx-2 defective worms under H2O2-induced OS | Identified oxidation-sensitive cysteins in 40 different proteins involved in mobility (muscle contraction), feeding, protein translation, homeostasis, and ATP regeneration. | MYO-2, LET-75, EFT-1, HSP1, NME | [83] |
| xpa-1 mutant UV-sensitive with shortened lifespan | Proteome changes in xpa-1 mutants correspond to transcriptome modulation by suffering oxidative stress and inducing antioxidative defenses. Polyubiquinated proteins accumulate, cyclopurine levels are reduced, and lesion-detection enzymes play active roles to generate a genomic stress signal. | NTH-1, XPC-1, DDB-1 | [84] |
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Rodents
Mus musculus (mice) | KO mice for 5 adenylyl cyclase (AC5) | AC5 KO mice are protected from aging-induced cardiomyopathy and their fibroblasts exhibited ERK-dependent resistance to oxidative stress. AC5 KO leads to upregulation of the Raf/MEK/ERK signaling pathway, which in turn mediates upregulation of SOD, an important mechanism mediating lifespan extension and stress resistance. | Increased: RSK, p-Bad, Bcl-xl, XIAP, HSP70, p-ERK, p-Raf-1 | [46] |
| SAMP8 | Brain and liver from SAMP8 | Progressive accumulation of oxidative damage to Cu, Zn-SOD may cause a dysfunction of defense systems against oxidative stress in SAMP8, with a higher oxidative stress and leading to the acceleration of aging. | SOD1, HCNP-pp | [85] |
| Hippocampus and cortex from 5 to 15 month old SAMP8 | 7 protein are related to age rather than strain and might be associated with brain aging process. One protein might be specifically associated with pathologically accelerated aging in SAMP8 mice; HEBP1. | NDRG2, enolase 2, SOD1, myosin, two unnamed protein (gi∣74214304; gi∣74178239), HEBP1 | [86] |
| Brain | Brain tissue from 3 weeks to 18 months old C57B mice | Carbonylated proteins increased with aging are involved in cytoskeletal organization, mitochondrial energy metabolism, redox regulation (oxidative damage), and signal transduction. | Approximately 100 carbonylated proteins | [87] |
| Brain tissue from 3-, 6-, 12- to 15-month-old male Kunming mice | 60 proteins vary their expression on aging; 27 of them decrease, may be responsible for brain aging. Related with decline of protein quality control, shortage of energy and reducing agent, increase of DNA damage and transcription detuning, and disturbance of synaptic transport and ion signals. 6 proteins increase, may be involved in antiaging processes. | PSMA6, PSMA3, CALR, UCHL3, VCP, GLUD1, IDH1, UQCRC2, UBE2N, CALB1, HNRPA2/B1, AMPH, TKT, CKMT1, MRPL37, TPI1 | [49] |
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Brain | Adult NPCs from brain of C57BL/6 mice from 3, 15–18 months of age | Aging is correlated with a loss of mitochondria and oxidative metabolism in NPCs. A coordinated shift in protein expression, subcellular structure, and metabolic physiology in aging NPCs, allowing resistance to hypoxia and mitochondrial inhibition. 124 proteins result as age-related. | Increased: PGK1, SEPT9. Decreased: ATP5 α and β | [88] |
| Liver | Livers from male C57BL6/J mice of 10-week-old and 18-month-old. Peroxisome enriched fraction | Most of the proteins identified are related to ROS production/breakdown; however, high biological variability between individuals is even more pronounced than changes induced by aging. | EPHX2, Acaa1, Pipox, Amy2a, Decr2, Phb2, COX6c, UQCRC2 | [89] |
| Kidney | Male and female mice CD1-Swiss outbred strain of 28, 52, 76-week-old | Differential protein expression of 8 aging related proteins (both genders). Increase in oxidative and proteolytic proteins and decrease in glycolytic proteins, and antioxidant enzymes with aging. | ATP syntase, Transferrin, HSP9A, Hibadh, IDH1 | [90] |
| Cardiac muscle | Hearts from male CB6F1 mice from 3, 15 to 23 months old | Detected age-related alterations in the levels of 73 proteins. Mithocondrial metabolism is affected and a net loss in antioxidants occurs with aging. | Mortalin, PRDX3, EPHX, SOD1, SOD2 | [70] |
| Adipose tissue | Male mutant mice deficient in Zmpste24 metalloproteinase | Zmpste24 deficiency causes premature aging. It enhanced lipolysis, fatty acid biogenesis, and β-oxidation as well as decreased fatty acid reesterification. Also URg protein networks related to tricarboxylic acid cycle and oxidative phosphorylation and increased mitochondrial response to oxidative stress and cytoskeleton. 37 proteins URg and 9 DRg. | Increased: ME1, PRDX3, HMGB1, CPT1, UCP1; Decreased: PCK1, vimentin isoforms | [91] |
| Macrophages | Peritoneal macrophages from male Balb/c mice (3-4 and 14-15 months) | An age-dependent increase in the extent of recruitment of macrophages into the peritoneum, as well as ex vivo functional changes involving enhanced nitric oxide production under resting conditions. Identified age-dependent increases in levels of proteins linked to immune cell pathways under basal conditions and following LPS activation. Immune pathways URg in macrophages isolated from aged mice include proteins critical to the formation of the immunoproteasome. | Hundreds of proteins | [92] |
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| Rattus novergicus (rat) | Male Wistar rats weighing 80–90 g, 6 and 24 months old | A beneficial role for virgin olive oil in modulating inflammation, homeostasis, oxidative stress, and cardiovascular risk during aging. Diet diminishes in general the changes that occurred with age. | Decreased: HPX, HP, AHSG, PRDX2, FGg, T-KNG, APO H, APO E, APO A-IV Increased: APO A-1 | [93] |
| Serum from young and old Fischer 344 rats | 16 of the modified proteins by peroxynitrite and 4-hydroxy-2-nonenal are involved in blood coagulation, lipid transport, blood pressure regulation, and protease inhibition. | 16 modified proteins | [94] |
| Brain | Hippocampus from 8 to 27-month-old Wistar rats, and also treated with the anti-Parkinson drug; rasagiline or the anti-Alzheimer’s disease drug; ladostigil | Significant molecular changes related to neurodegeneration were identified in aged rat hippocampus. Both drugs reversed the effect of aging on the expression of various mitochondrial and key regulator genes involved in neurodegeneration, cell survival, synaptogenesis, oxidation, and metabolism. Changes in proteins related to the iron-mediated oxidative stress pathway, including reduction in antioxidant enzymes. Oxidative stress and mitochondrial dysfunction may play a pivotal role in aging and age-associated neurodegenerative diseases. | Aprox. 200 proteins showed differential expression. NEFL, FTH1, TUFM, PEA15, PEBP, PFN1, CCT2, IDH3A, COX5A, COX5B, PRDX2 | [58] |
| cerebellum from Fisher 344/Brown Norway rats from 5-, 22- and 34-month-old rats | Genes encoding proteins of stress response and inflammatory processes show a significantly higher age dependent upregulation in the cerebellum suggesting higher levels of oxidative stress. Identification of nitrated proteins. | Ryr3, Lrp2, Nrap, Cnp | [95] |
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Brain | Brain from male Wistar rats from 12 to 28 months old (hippocampus, cortex, striatum, and cerebellum) | Senescent animals showed significantly higher levels of oxidation. 11 proteins carbonylated in hippocampus, 15 in cortex, 10 in striatum, 11 in cerebellum, associated with significant changes in both cytosolic and mitochondrial redox status in all brain regions analyzed. | Decreased: PK, ATP5a1, ALDOC, CKB, a-enolase. Activity of PK and GAPDH diminished | [48] |
| Hypotalamus and hypophysis from male Wistar rats from 3, 12 to 24 months old treated with an antioxidant | Alterations of eEF-2 levels, secondary to lipid peroxidation and adduct formation with aldehydes could contribute to the suboptimal hormone production from these tissues during aging | eEF-2, ALDOA, GSTA, CKB, PPIA, PK, GADPH, INA, CFL1 | [96] |
| MSC cultures from the tibial and femoral BM of 83-week- and 12-month-old Sprague-Dawley rats | Number of MSCs is reduced in aged animals. Aged MSCs are more susceptible toward senescence and display a lower migratory capacity. Aging affects MSCs antioxidant defense and cytoskeleton turnover. | Several proteins as members of the actin-binding protein family of calponins, galectin-3 | [97] |
| Retina | Fisher 344/Brown Norway F1 rats from 3-4 to 24-25 months old | Decrease of antioxidant enzymes was detected in the old F344BN retina sections and increased presence of ROS and oxidative stress. | Increased: CD46, GABA2, DJ-1, EBP50, Ezrin, Cathepsin D. Decreased: NG, DDAH1, DPPX | [98] |
| Primary cell cultures from retinas of newborn (PD 1 or 2) Sprague-Dawley rats under H2O2-induced OS | Retinal pigmentary epithelium (RPE) and retina have higher O2 tension and ROS concentration with aging; this environment may contribute to the pathogenesis and progression of eye diseases. Decreased prohibitin in H2O2 treated RPE cells may indicate an antioxidative role. | Prohibitin | [99] |
| Adipose tissue | White adipose tissue from male Wistar rats from 6 and 24-month-old under caloric restriction (CR) | Caloric restriction (CR) improves oxidative stress and prevents age-associated changes in several antioxidant enzymes. Metabolic enzymes involved in energy metabolism and transduction (glucose and lipid), oxidative stress response, cytoskeleton, and iron homeostasis were also modulated by age and/or CR. Several enzymes involved in cell protection against oxidative stress are increased by CR, whereas these protein levels decrease or do not change with age. | 133 differentially expressed spots, 57 of which were identified | [100] |
| Skeletal muscle | Skeletal muscles from Fisher 344/Brown Norway F1 rats, 34 months old | 11 nitrated proteins were identified as age-related. | CKM, TPM1, GAPDH, MYL2, ALDOA, PKM, PYGM, NOTCH1, ACTN1, ACTC1, RYR3 | [74] |
| Gastrocnemius muscle from Lou/c/jall male rats from 7, 18, to 30 months old | Aging is associated with differential expression of myofibrillar regulatory proteins, up-regulation of cytoskeletal proteins, perturbations in the energy metabolism, and detoxification of cytotoxic products. | 40 proteins differentially expressed | [101] |
| Gastrocnemius muscle of 26-month-old Wistar rats | Mitochondria-enriched fraction revealed an age-related change in 39 protein species. An age-related increase in mitochondrial enzyme activity belonging to the inner membrane system, matrix, outer membrane, and intermembrane space, increasing aerobic-oxidative metabolism, involved in oxidative phosphorylation, ATP formation, and fatty acid oxidation. | Increased: NADH-DH, Immt mitofilin, PRDX3, F1-ATPase, SDH, Fis1, SUCLA2, ACAD, porin VDAC2, UQCRC1, prohibitin | [102] |
| Cardiac muscle | Left ventricle from Fisher 344 rats from 4 to 24-month-old | 117 proteins differentially expressed: 23 signalling proteins, 25 metabolic proteins, 7 fatty acid metabolism, 19 energy metabolism, 13 oxidative stress related (antioxidant proteins and chaperones). First network describing proteins affecting cellular organization and morphology is presented. | α β-Crystallin, GST π isoform, GST μ type, GST Ω1, C1qbp, HSP90b1, GPX1, DJ-1, SOD2, PRDX5, PRDX3, HSP8 | [69] |
| Heart from Fisher 344/Brown Norway F1 rats, 5 and 26 months old | 48 differentially nitrated proteins were identified that undergo an age-dependent protein tyrosine nitration. | α-Enolase, Aldolase, Desmin, ACO1, Aldh6a1, Acaa1a, GAPDH, MDH1, CKM, ETF, SOD2, F1-ATPase, VDAC | [103] |
| Heart from Fisher 344/Brown Norway F1 rats, 5 and 34 months old | Abundance of 10 nitrated proteins identified in cardiac tissue increase with age. | N-RAP, neurofibromin, tropomyosin, MYO-HC | [73] |
| Heterocephalus glaber (Naked mole-rat) | Liver, heart, and kidney tissues from naked mole-rats (NMRs; 2 years) and wild-type C57BL/6 mice (0.3 year) | Global protein carbonylation in citosolic fraction was elevated in all three tissues. NMRs have a protective cellular environment which restores enzyme function and prevents formation of oligomers during oxidative stress, modulating structure and function of structural proteins and enzymes. Activation of NRF2 pathway, which increases the transcription of antioxidant response elements, proteasome, antioxidants, and autophagy, could be a potential mechanism for these processes. | TPI, PRDX1 | [104] |
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| Porcine (Sus scrofa) | Porcine oocyte and effect of caffeine | 38 proteins were identified, 23 URg and 3 DRg by aging. Involved in metabolism, stress response, ROS, and cell cycle regulation. | CDK5, PCNA, AHCY, SLC25A6 | [105] |
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| Canine (Canis domesticus) | Brain from beagle dogs from 8.05 to 12.35 years old. Feeded with antioxidant-fortified food and growth in an enriched environment | Combined treatment (food and environment) significantly decreases protein cabonylation, nitrosylation, and lipid peroxidation, reducing the levels of oxidative damage and improving the antioxidant reserve systems in the brain. Propose a diagram of a functional interacteome of all parietal cortex proteins identified to be significantly less oxidatively modified following the combined treatment. | Decreased: GLUD1, GAPDH, a-Enolase, GST, FSCN1, NF-L. Increased: SOD1, ALDOC, CKB, GLUD1 (P), GAPDH (P) | [106] |
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| Primate (Homo sapiens) | Human female of 20–39, 100, and 106–109 years old | Results suggest that systemic redox regulation is important for the longevity of supercentenarians in humans. | Decreased: PON1, APO E. Increased: Hp-b, AMBP, CLU | [36] |
| Brain | Inferior parietal lobule tissue samples from AD patients autopsy | Protein modification by ROS occurs to a greater extent in AD suggesting a possible role for oxidation-related decrease in protein function in the process of neurodegeneration. Oxidative damage to proteins, assessed by measuring the protein carbonyl content, is involved in several events such as loss in specific protein function, abnormal protein clearance, depletion of the cellular redox-balance and interference with the cell cycle, and, ultimately, neuronal death. | Increased in AD: DRP-2, α-Enolase, HSC-71 | [54, 55] |
| CSF | Lumbar CSF samples from probable AD patients | Decreased concentrations of proteins in CSF may also be a secondary event to increased oxidative stress, since excessive carbonylation leads to an enhanced aggregation of proteins. Extent of protein carbonylation can vary between men and women, emphasizing the importance of sex-matched patients when studying carbonylation. | Decreased in AD: PTGDS, IgL, TTR. Increased carbonylation in AD: IgL and one unidentified protein | [57] |
| Blood | Whole blood from healthy volunteer donors. Stored for various periods | A progressive linkage of typical cytosolic proteins to the membrane was detected, including both antioxidant and metabolic enzymes. This phenomenon was unequivocally related to oxidative stress, since storage under anaerobic conditions suppresses it. | Prx2 | [79] |
| Skin | Fresh punch biopsies from the forearm of 21–30 and 75–92 years old donors | 22 proteins were consistently deregulated. Support that aging is linked with increased oxidative stress that could lead to apoptosis in vivo. | Mx-A, SOD1, WARS, PIK3r2, proteasomal PA28-α and SSP 0107 | [107] |
| Fibroblast | WI-38 human embryonic fibroblasts. Two stages PD < 25 and PD > 42 | Oxidized proteins accumulate with aging in vivo and during replicative senescence in vitro. 37 proteins were modified related to protein quality control, energy metabolism, and cytoskeleton. Impairment of glyoxal- and aldehyde-detoxification mitochondrial systems. | Decrease activity of proteasomal CT-L, PGPH and detoxification GLO1 | [39] |
| HCA3 human dermal fibroblasts under H2O2-induced OS | H2O2-induced senescent like human diploid fibroblasts increase the production of IGFBP-6 protein. | Increased: Collagen 1(VI), collagen 2(I), fibronectin, lumican, MMP-2, IGFBP-6 | [108] |
| HCA3 human dermal fibroblasts under H2O2-induced OS | H2O2 treatment caused elevated levels of TXNRD1. Differences between mRNA versus proteins that vary under oxidative stress may be related to the regulatory mechanism of protein translation under oxidative stress. | Increased: TXNRD1, MMP-3, AURKA Decreased: Akap12, MDH1 | [109] |
| Colon epithelial | Human normal colonic epithelial tissue from 25–30 to 60–65 years old | 35 differentially expressed proteins, 16 URg and 19 DRg. Involved in metabolism, energy generation, chaperone, antioxidation, signal transduction, protein folding, and apoptosis. | Increased: ATPB, ETFA, catalase, GPX1, annexin A2, HSP7C; decreased: FUBP1, NDK B, ERp6C, VDAC-2 | [110] |
| MSCs | Human BM-derived MSCs | Differentially expressed proteins under the low glucose condition may provide further information on the aging and differentiation of stem cells. | Increased: ALDH, neuropolypeptide h3, P4HA; Decreased: laminin-BP, actin, Sec 13, RPS12, PSMA1, SOD1, SNAP | [111] |
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