Trends Neurosci Effective caloric intake 10 — CAS Aginh Google Scholar Barreiro Cellukar, Coronell C, Lavina Snd, Ramirez-Sarmiento A, Lice treatment products M, Gea Dellular Aging, celular differences, and oxidative stress in human respiratory znd limb muscles. Overexpression of heme oxygenase in ane Free radicals and cellular aging, the possible interaction with tau. In- Radicais Fre e a resposta celular ao estresse oxidativo ed. Sex and age alter plasma membranes of cultured fibroblasts. Due to the possible relation among dietary restriction, oxidative stress and cardiovascular disorders, the study of the effects of the caloric restriction on lipid rich diets is very important, since this kind of diet has many effects on heart tissue, as long as the type of fatty acid present on the diet is related to the composition of phospholipids on myocardium cell membranes Diniz et al. Antioxidants are substances found in plants that soak up free radicals like sponges and are believed to minimize free radical damage If your body has plenty of antioxidants available, it can minimize the damage caused by free radicals.

Free radicals and cellular aging -

He assumed that the conflicting experiments—which had been done by other scientists—simply had not been controlled very well. Perhaps the animals could not absorb the antioxidants that they had been fed, and thus the overall level of free radicals in their blood had not changed.

By the s, however, genetic advances allowed scientists to test the effects of antioxidants in a more precise way—by directly manipulating genomes to change the amount of antioxidant enzymes animals were capable of producing.

Time and again, Richardson's experiments with genetically modified mice showed that the levels of free radical molecules circulating in the animals' bodies—and subsequently the amount of oxidative damage they endured—had no bearing on how long they lived.

More recently, Siegfried Hekimi, a biologist at McGill University, has bred roundworms that overproduce a specific free radical known as superoxide. Instead he reported in a paper in PLOS Biology that the engineered worms did not develop high levels of oxidative damage and that they lived, on average, 32 percent longer than normal worms.

Indeed, treating these genetically modified worms with the antioxidant vitamin C prevented this increase in life span. Hekimi speculates that superoxide acts not as a destructive molecule but as a protective signal in the worms' bodies, turning up the expression of genes that help to repair cellular damage.

In a follow-up experiment, Hekimi exposed normal worms, from birth, to low levels of a common weed-controlling herbicide that initiates free radical production in animals as well as plants. In the same paper he reported the counterintuitive result: the toxin-bathed worms lived 58 percent longer than untreated worms.

Again, feeding the worms antioxidants quenched the toxin's beneficial effects. Finally, in April , he and his colleagues showed that knocking out, or deactivating, all five of the genes that code for superoxide dismutase enzymes in worms has virtually no effect on worm life span.

Do these discoveries mean that the free radical theory is flat-out wrong? Simon Melov, a biochemist at the Buck Institute for Research on Aging in Novato, Calif. Large amounts of oxidative damage have indisputably been shown to cause cancer and organ damage, and plenty of evidence indicates that oxidative damage plays a role in the development of some chronic conditions, such as heart disease.

In addition, researchers at the University of Washington have demonstrated that mice live longer when they are genetically engineered to produce high levels of an antioxidant known as catalase.

Aging probably is not a monolithic entity with a single cause and a single cure, he argues, and it was wishful thinking to ever suppose it was one.

Assuming free radicals accumulate during aging but do not necessarily cause it, what effects do they have? So far that question has led to more speculation than definitive data. Free radicals might, in some cases, be produced in response to cellular damage—as a way to signal the body's own repair mechanisms, for example.

In this scenario, free radicals are a consequence of age-related damage, not a cause of it. In large amounts, however, Hekimi says, free radicals may create damage as well. The general idea that minor insults might help the body withstand bigger ones is not new.

Indeed, that is how muscles grow stronger in response to a steady increase in the amount of strain that is placed on them. Many occasional athletes, on the other hand, have learned from painful firsthand experience that an abrupt increase in the physical demands they place on their body after a long week of sitting at an office desk is instead almost guaranteed to lead to pulled calves and hamstrings, among other significant injuries.

In researchers at the University of Colorado at Boulder briefly exposed worms to heat or to chemicals that induced the production of free radicals, showing that the environmental stressors each boosted the worms' ability to survive larger insults later.

The interventions also increased the worms' life expectancy by 20 percent. It is unclear how these interventions affected overall levels of oxidative damage, however, because the investigators did not assess these changes.

In researchers at the University of California, San Francisco, and Pohang University of Science and Technology in South Korea reported in Current Biology that some free radicals turn on a gene called HIF-1 that is itself responsible for activating a number of genes involved in cellular repair, including one that helps to repair mutated DNA.

Free radicals may also explain in part why exercise is beneficial. For years researchers assumed that exercise was good in spite of the fact that it produces free radicals, not because of it.

Yet in a study published in the Proceedings of the National Academy of Sciences USA , Michael Ristow, a nutrition professor at the Friedrich Schiller University of Jena in Germany, and his colleagues compared the physiological profiles of exercisers who took antioxidants with exercisers who did not.

Cell Calcium — PubMed Central PubMed Google Scholar. Harman D Ageing: a theory based on free radical and radiation chemistry. J Gerontol — Harman D The biological clock: the mitochondria? J Am Geriatr Soc — Hidalgo C, Sánchez G, Barrientos G, Aracena-Parks P A transverse tubule NADPH oxidase activity stimulates calcium release from isolated triads via ryanodine receptor type 1 S-glutathionylation.

J Biol Chem 36 — Irrcher I, Ljubicic V, Hood D Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. Am J Physiol Cell Physiol C—C Ishii N Role of oxidative stress from mitochondria on aging and cancer.

Cornea S3—S9. Jackson MJ, McArdle A Age-related changes in skeletal muscle reactive oxygen species generation and adaptive responses to reactive oxygen species.

J Physiol Pt 9 — Ji LL, Dillon D, Wu E Alteration of antioxidant enzymes with aging in rat skeletal muscle and liver. Am J Physiol 4 Pt 2 :R—R Ji LL, Gomez-Cabrera MC, Vina J Exercise and hormesis: activation of cellular antioxidant signaling pathway.

Ann NY Acad Sci — Joseph AM, Adhihetty PJ, Buford TW, Wohlgemuth SE, Lees HA, Nguyen LM, Aranda JM, Sandesara BD, Pahor M, Manini TM, Marzetti E, Leeuwenburgh C The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals.

Aging Cell 11 5 — Kadi F, Charifi N, Denis C, Lexell J Satellite cells and myonuclei in young and elderly women and men. Muscle Nerve — Klitgaard H, Zhou M, Schiaffino S, Betto R, Salviati G, Saltin B Ageing alters the myosin heavy chain composition of single fibres from human skeletal muscle.

Acta Physiol Scand — Lammi-Keefe CJ, Swan PB, Hegarty PV Copper-zinc and manganese superoxide dismutase activities in cardiac and skeletal muscles during aging in male rats. Gerontology 30 3 — Lang T, Streeper T, Cawthon P, Baldwin K, Taaffe DR, Harris TB Sarcopenia: etiology, clinical consequences, intervention, and assessment.

Osteoporos Int — Lauretani F, Semba RD, Bandinelli S, Dayhoff-Brannigan M, Lauretani F, Corsi AM, Guralnik JM, Ferrucci L Carotenoids as protection against disability in older persons. Rejuvenation Res 11 3 — Leeuwenburgh C, Fiebig R, Chandwaney R, Ji LL Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems.

Am J Physiol 2 Pt 2 :R—R Leeuwenburgh C, Hollander J, Leichtweis S, Griffiths M, Gore M, Ji LL Adaptations of glutathione antioxidant system to endurance training are tissue and muscle fiber specific. Am J Physiol 1 Pt 2 :R—R Lenk K, Schuler G, Adams V Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training.

J Cachex Sarcopenia Muscle — Levine RL Carbonyl modified proteins in cellular regulation, aging, and disease. Li YP, Chen Y, Li AS, Reid MB Hydrogen peroxide stimulates ubiquitin-conjugating activity and expression of genes for specific E2 and E3 proteins in skeletal muscle myotubes. Human Mol Genet — CAS Google Scholar.

Liu CJ, Latham NK Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev 3:CD Ljubicic V, Hood DA Kinase-specific responsiveness to incremental contractile activity in skeletal muscle with low and high mitochondrial content.

Basic Appl Myol — Marzani B, Felzani G, Bellomo RG, Vecchiet J, Marzatico F Human muscle aging: ROS-mediated alterations in rectus abdominis and vastus lateralis muscles.

Exp Gerontol — Marzani B, Balage M, Venien A, Astruc T, Papet I, Dardevet D, Mosoni L Antioxidant supplementation restores defective leucine stimulation of protein synthesis in skeletal muscle from old rats.

J Nutr — Matsuo M In: Yu BP ed Free radical in aging. CRC Press, Boca Raton, pp — Mayer F, Scharhag-Rosenberger F, Carlsohn A, Cassel M, Müller S, Scharhag J The intensity and effects of strength training in the elderly.

Dtsch Arztebl Int 21 — McArdle A, Pattwell D, Vasilaki A, Griffiths RD, Jackson MJ Contractile activity-induced oxidative stress: cellular origin and adaptive responses. Mecocci P, Fanò G, Fulle S, MacGarvey U, Shinobu L, Polidori MC, Cherubini A, Vecchiet J, Senin U, Beal MF Age dependent increase in oxidative damage to DNA, lipids, and protein in human skeletal muscle.

Meissner C, Bruse P, Oehmichen M Tissue-specific deletion patterns of the mitochondrial genome with advancing age. Moylan JS, Reid MB Oxidative stress, chronic disease, and muscle wasting.

Murdock DG, Christacos NC, Wallace DC The age-related accumulation of a mitochondrial DNA control region mutation in muscle, but not brain, detected by a sensitive PNA-directed PCR clamping based method. Nucleic Acid Res — Nagasawa T, Hatayama T, Watanabe Y, Tanaka M, Niisato Y, Kitts Y Free radical-mediated effects on skeletal muscle protein in rats treated with Fe-nitrilotriacetate.

Neels JG, Olefsky JM Inflamed fat: what starts the fire? J Clin Invest — Nicotera P, Orrenius S Molecular mechanism of toxic cell death: an overview. Methods Toxicol 1B Niki E, Noguchi N, Tsuchihashi H, Gotoh N Interaction among vitamin C, vitamin E, and beta-carotene.

Am J Clin Nutr 62 6 S—S. Okayasu T, Curtis MT, Farber JL Structural alterations of the inner mitochondrial membrane in ischemic liver cell injury.

Arch Biochem Biophys — Pansarasa O, Castagna L, Colombi B, Vecchiet J, Felzani G, Marzatico F Age and sex differences in human skeletal muscle: role of reactive oxygen species. Free Radic Res — Pansarasa O, Felzani G, Vecchiet J, Marzatico F Antioxidant pathways in human aged skeletal muscle: relationship with the distribution of type II fibers.

Paradies G, Petrosillo G, Ruggiero FM Cardiolipin-dependent decrease of cytochrome c oxidase activity in heart mitochondria from hypothyroid rats.

Biochim Biophys Acta —8. Parise G, Kaczor JJ, Douglas MJ, Stuart PM, Tarnopolsky MA Oxidative stress and the mitochondrial theory of aging in human skeletal muscle. Pellegrino MA, Desaphy JF, Brocca L, Pierno S, Conte Camerino D, Bottinelli R Redox homeostasis, oxidative stress and disuse muscle atrophy.

J Physiol 9 — Powers SK, Jackson MJ Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production.

Physiol Rev 88 4 — Powers SK, Quindry JC, Kavazis AN Exercise-induced cardioprotection against myocardial ischemia-reperfusion injury. Free Radic Biol Med 44 2 — Powers SK, Duarte J, Kavazis AN, Talbert EE Reactive oxygen species are signalling molecules for skeletal muscle adaptation.

Exp Physiol —9. Preedy VR, Adachi J, Ueno Y, Ahmed S, Mantle D, Mullatti N, Rajendram R, Peters TJ Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosis.

Eur J Neurol — Rebrin I, Zicker S, Wedekind KJ, Paetau-Robinson I, Packer L, Sohal RS Effect of antioxidant-enriched diets on glutathione redox status in tissue homogenates and mitochondria of the senescence-accelerated mouse.

Renault V, Thornell LE, Butler-Browne G, Mouly V Human skeletal muscle satellite cells: aging, oxidative stress and the mitotic clock. Richter C Biophysical consequences of lipid peroxidation in membranes. Chem Phys Lipids 44 24 — Rolland Y, Czerwinski S, Abellan Van Kan G, Morley JE, Cesari M, Onder G, Woo J, Baumgartner R, Pillard F, Boirie Y, Chumlea WM, Vellas B Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives.

J Nutr Health Aging — Rosenberg I Summary comments: epidemiological and methodological problems in determining nutritional status of older persons.

Rossi P, Marzani B, Giardina S, Negro M, Marzatico F Human skeletal muscle aging and the oxidative system: cellular events. Curr Aging Sci — Roubenoff R Sarcopenia and its implications for the elderly. Eur J Clin Nutr 54 3 :S40—S Ryan MJ, Dudash HJ, Docherty M, Geronilla KB, Baker BA, Haff GG, Cutlip RG, Alway SE Vitamin E and C supplementation reduces oxidative stress, improves antioxidant enzymes and positive muscle work in chronically loaded muscles of aged rats.

Exp Gerontol 45 11 — Sanz A, Pamplona R, Barja G Is the mitochondrial free radical theory of aging intact? Antioxid Redox Signal — Semba RD, Blaum C, Guralnik JM, Totin D, Ricks MO, Fried LP Low carotenoid and vitamin E status are associated with indicators of sarcopenia among older women living in the community.

Aging Clin Exp Res — Free Radic Biol Med 10 3—4 — Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 15 — Taaffe DR, Duret C, Wheeler S, Marcus R Once-weekly resistance exercise improves muscle strength and neuromuscular performance in older adults.

J Am Geriatr Soc 47 10 — Taaffe DR, Henwood TR, Nalls MA, Walker DG, Lang TF, Harris TB Alterations in muscle attenuation following detraining and retraining in resistance-trained older adults.

Gerontology — Turrens JF Mitochondrial formation of reactive oxygen species. J Physiol Pt 2 — Van Raamsdonk JM, Hekimi S Superoxide dismutase is dispensable for normal animal lifespan. Iron is reduced to its ferrous state through the action of NADPH cytochrome c P reductase. Carbon monoxide is released by elimination of the α-methylene bridge of the porphyrin ring.

Further degradation of biliverdin to bilirubin occurs through the action of a cytosolic enzyme, biliverdin reductase.

Biliverdin complexes with iron until its final release. HO is present in various tissues with the highest activity in the brain, liver, spleen, and testes. There are 3 isoforms of heme oxygenase: HO-1 or inducible isoform , HO-2 or constitutive isoform , and HO-3, cloned only in rats to date They are all products of different genes and, unlike HO-3, which is a poor heme catalyst, both HO-1 and HO-2 catalyze the same reaction i.

These isoforms have different localization, similar substrate, and cofactor requirements, while presenting a different molecular weight. They also display different antigenicity, electrophoretic mobility, and inducibility as well as susceptibility to degradation.

The proteins for HO-1 and HO-2 are immunologically distinct and, in humans, the two genes are located on different chromosomes, i.

Various tissues have different amounts of HO-1 and HO The brain and testes have a predominance of HO-2, whereas HO-1 predominates in the spleen. This also occurs in brain tissue, where HO isoforms appear to be distributed in a cell-specific manner and HO-1 distribution is widely apparent after heat shock or oxidative stress.

Although previous reports from our group and other groups have not found detectable levels of HO-1 protein in the normal brain , , we have recently demonstrated that HO-1 mRNA expression is physiologically detectable in the brain and shows a characteristic regional distribution, with a high level of expression in the hippocampus and the cerebellum , This evidence may suggest the possible existence of a cellular reserve of HO-1 transcript quickly available for protein synthesis and a posttranscriptional regulation of its expression.

HO isoenzymes are also seen to colocalize with different enzymes depending on the cell type. In the kidney, HO-1 colocalizes with erythropoietin, whereas in smooth muscle cells, HO-1 colocalizes with nitric oxide synthase.

In neurons, HO-2 colocalizes with NOS, whereas the endothelium exhibits the same isoform to colocalize with NOS III. The cellular specificity of this pattern of colocalization lends further support to the concept that CO may serve a function similar to that of NO. Furthermore, the brain expression pattern shown by HO-2 protein and HO-1 mRNA overlaps with distribution of guanylate cyclase , the main CO functional target.

Both HO-2 and HO-3, but not HO-1, are endowed with 2 Cys-Pro residues considered the core of the heme-responsive motif HRM , a domain critical for heme binding but not for its catalysis , Although the biological properties of this isoenzyme still remain to be elucidated, the presence of 2 HRM motifs in its amino acidic sequence might suggest a role in cellular heme regulation Studying the HO-3 mRNA sequence GenBank accession n.

Based on the close similarity to a paralogous gene HO-2 and the preliminary data from our group demonstrating no introns in the HO-3 gene , it is possible that HO-3 could have originated from the retrotransposition of the HO-2 gene. In addition, this genetic mutation in the rat may represent a specie -specific event since no other sequence in the public databases matches the rat HO The HO-2 gene consists of 5 exons and 4 introns.

It is generally considered a constitutive isoenzyme, however, in situ hybridization studies have shown increases in HO-2 mRNA synthesis associated with increased HO-2 protein and enzyme activity in neonatal rat brain after treatment with corticosterone The organization of the HO-2 gene needs to be fully elucidated, although a consensus sequence of the glucocorticoid response element GRE has been demonstrated in the promoter region of the HO-2 gene In addition, endothelial cells treated with the NOS inhibitor L-NAME and HO inhibitor zinc mesophorphyrin exhibited a significant up-regulation of HO-2 mRNA.

The regulation of the HO-1 gene as well as its promoter has received more elucidation that constitutive HO The HO-1 gene is induced by a variety of factors, including metallophorphyrins and hemin, as well as ultraviolet A UVA irradiation, hydrogen peroxide, prooxidant states, or inflammation , This characteristic inducibility of the HO-1 gene strictly relies on its configuration: the 6.

A promoter sequence is located approximately 28 base pairs upstream from the transcriptional site of initiation. Also, inducer-responsive sequences have been identified in the proximal enhancer located upstream from the promoter and, more distally, in 2 enhancers located 4 kb and 10 kb upstream from the initiation site The transcriptional activation of HO-1 in response to hyperoxia requires the cooperation between the promoter and an enhancer element located 4 kb upstream from the transcription site This response is also mediated by increased binding activity of AP The HO-1 promoter contains an antioxidant responsive element with a consensus sequence GCnnnGTA similar to that of other antioxidant enzymes , Heme treatment results in increased binding activity of NFkB and AP-2 transcription factors at the proximal part of the promoter, but also of AP The promoter region also contains 2 metal-responsive elements, similar to those found in the metallothionein-1 gene, which respond to heavy metals cadmium and zinc only after recruitment of another fragment located upstream, between —3.

In addition, a bp fragment containing 2 binding sites for HSF-1, which mediates the HO-1 transcription, are located 9. The distal enhancer regions are important in regulating HO-1 in inflammation, since it has been demonstrated that these enhancer regions are responsive to endotoxin.

In the promoter region also resides a 56 bp fragment that responds to the STAT-3 acute-phase response factor involved in the down-regulation of the HO-1 gene induced by 1 glucocorticoid In the brain, the HO system has been reported to be very active and its modulation seems to play a crucial role in the pathogenesis of neurodegenerative disorders.

The heme oxygenase pathway, in fact, has been shown to act as a fundamental defensive mechanism for neurons exposed to an oxidant challenge — Induction of HO occurs together with the induction of other HSPs in the brain during various experimental conditions including ischemia Injection of blood or hemoglobin results in increased expression of the gene encoding HO-1, which has been shown to occur mainly in microglia throughout the brain This suggests that microglia take up extracellular heme protein following cell lysis or hemorrhage.

Once in the microglia, heme induces the transcription of HO Since the expression of HSPs is closely related to that of the amyloid precursor protein APP , HSPs have been studied in the brain of patients with AD.

Significant increases in the levels of HO-1 have been observed in AD brains in association with neurofibrillary tangles , , and also HO-1 mRNA was found to be increased in AD neocortex and cerebral vessels An HO-1 increase was not only in association with neurofibrillary tangles, but also colocalized with senile plaques and glial fibrillary acidic protein-positive astrocytes in AD brains It is conceivable that the dramatic increase in HO-1 in AD may be a direct response to increased free heme associated with neurodegeneration and an attempt to convert the highly damaging heme into the antioxidants biliverdin and bilirubin Up-regulation of HO-1 in the substantia nigra of Parkinson's disease patients has been demonstrated.

In these patients, nigral neurons containing cytoplasmic Lewy bodies exhibited in their proximity maximum HO-1 immunoreactivity New evidences showed a specific up-regulation of HO-1 in the nigral dopaminergic neurons by oxidative stress , It has been recently demonstrated that hemin, an inducer of HO-1, inhibited effectively experimental autoimmune encephalomyelitis EAE , an animal model of the human disease multiple sclerosis MS In contrast, tin mesoporphyrin, an inhibitor of HO-1, markedly exacerbated EAE.

These results suggest that endogenous HO-1 plays an important protective role in EAE and MS. All of these findings have opened up new perspectives in medicine and pharmacology, as molecules activating this defense mechanism appear to be possible candidates for novel therapeutic neuroprotective strategies see below.

Increasing evidence implicates CO as an emerging chemical messenger molecule that can influence physiological and pathological processes in both the central and peripheral nervous systems. This gaseous molecule is now considered a putative neurotransmitter, owing to its capability to diffuse freely from one cell to another, thereby influencing intracellular signal transduction mechanisms.

However, unlike a conventional neurotransmitter, carbon monoxide is not stored in synaptic vesicles and is not released by membrane depolarization and exocitosis. It seems likely that CO is involved in the mechanism of cell injury , This is evidenced by the fact that CO binds to the heme moiety in guanylate cyclase to activate cGMP , It has been found that CO is responsible for maintaining endogenous levels of cGMP.

This effect is blocked by potent HO inhibitors but not by NO inhibitors , Based on the endogenous distribution of HO in the CNS, it has been suggested that CO can influence neurotransmission like NO CO appears to be involved as a retrograde messenger in LTP and also is involved in mediating glutamate action at metabotropic receptors This is evident from the observation that metabotropic receptor activation in the brain regulates the conductance of specific ion channels via a cGMP-dependent mechanism that is blocked by HO inhibitors Experimental evidence suggests that CO plays a similar role as NO in the signal transduction mechanism for the regulation of cell function and cell-to-cell communication CO, like NO, binds to iron in the heme moiety of guanylate cyclase.

However there are some differences in function between CO and NO. Thus, NO mainly mediates glutamate effects at NMDA receptors, while CO is primarily responsible for glutamate action at metabotropic receptors.

Taken together, it appears that CO and NO play an important role in the regulation of CNS function; thus, impairment of CO and NO metabolism results in abnormal brain function , A number of reports suggest a possible role of CO in regulating the transmission of nitrogen compounds.

Endogenous CO has been suggested to control constitutive NOS activity. Moreover, CO may interfere with NO binding to guanylate cyclase.

This is in addition to the important role of HO in regulating NO generation, owing to its function in the control of heme intracellular levels, as part of normal protein turnover This hypothesis is sustained by recent findings showing that HO inhibition increases NO production in mouse macrophages exposed to endotoxin CO may also act as a signaling effector molecule by interacting with targets different from guanylate cyclase.

Notably, it has been recently demonstrated that K Ca channels are activated by CO in a GMPc-independent manner , and also that CO-induced vascular relaxation results from the inhibition of the synthesis of the vasoconstrictor endothelin-1 However, little is known about how CO is sensed on a biological ground.

Interestingly, the photosynthetic bacterium Rhodospirillum rubrum has the ability to respond to CO through the heme protein CooA, which, upon exposure to CO, acquires DNA-binding transcriptional activity for the CO dehydrogenase gene. This property hereby encodes for CO dehydrogenase, which is the key enzyme involved in the oxidative conversion of CO to CO 2.

Remarkably, heart cytochrome c oxidase possesses CO oxygenase activity, thus metabolizing CO to CO 2 Whether this occurs also in brain mitochondria remains to be elucidated. This is a plausible reason whereby bilirubin has generally been recognized as a cytotoxic waste product.

However, only in recent years, its emerging role as a powerful antioxidant has received wide interest. The specific role of endogenously derived bilirubin as a potent antioxidant has been demonstrated in hippocampal and cortical neurons, in which accumulation of this metabolite protected against H 2 O 2 -induced cytotoxicity , Moreover, nanomolar concentrations of bilirubin resulted in a significant protection against hydrogen peroxide-induced toxicity in cultured neurons as well as in glial cells following experimental subarachnoid hemorrhage.

In addition, neuronal damage following middle cerebral artery occlusion was substantially worsened in HO-2 knock-out mice Bilirubin can become particularly important as a cytoprotective agent for tissues with relatively weak endogenous antioxidant defences, such as the central nervous system and the myocardium.

Interestingly, increased levels of bilirubin have been found in the CSF of AD patients, which may reflect the increase of degraded bilirubin metabolites in the AD brain derived from the scavenging reaction against chronic oxidative stress Similarly, a decreased risk for coronary artery disease is associated with mildly elevated serum bilirubin, with a protective effect comparable to that of high-density lipoprotein cholesterol The most likely explanation for the potent neuroprotective effect of bilirubin is that a redox cycle exists between bilirubin and biliverdin, the major oxidation product of bilirubin.

In mediating the antioxidant actions, bilirubin would be transformed in biliverdin, then rapidly converted back to bilirubin by biliverdine reductase, which in the brain is present in large functional excess.

Remarkably, the rapid activation of HO-2 by protein kinase C PKC phosphorylation parallels the disposition of nNOS. Both are constitutive enzymes localized to neurons, and nNOS is activated by calcium entry into cells binding to calmodulin on nNOS.

Similarly, PKC phosphorylation of HO-2 and the transient increase in intracellular bilirubin would provide a way for a rapid response to calcium entry, a major activator of PKC. Whether the antioxidant bilirubin possess antinitrosative properties still remains an open question, although this possibility could partially account for the effect of NO and peroxynitrite in up-regulating HO-1 expression Recent literature provide increasing evidence of accumulation of the oxidatively modified proteins, DNAs, and lipids in the aged brain.

Numerous marker compounds of lipid peroxidation were detected, such as MDA, HNE, and acrolein. These products react with DNA and proteins to produce further damage in aged brains 20 , It was reported that 10, oxidative interactions occur between DNA and endogenously generated free radicals per human cell per day Additionally, at least 1 of every 3 proteins in the cells of older animals is dysfunctional as enzyme or structural protein due to oxidative modification Although much evidence shows the important role of free radicals in brain aging, some argue otherwise.

Some contend that damage produced by endogenously generated oxygen free radicals by mitochondria resulting in distinctive biochemical profiles only occurs under exceptional conditions Others claim that elongated life span from caloric restriction is not accredited to reducing free radical production, but by metabolic-shift activation of the SIR2 protein, which slices chromatin by deacetylating the histones in targeted regions of the genome, including the rDNA It was also reported that inactive SIR2 mutants shorten the life span while over-expression of SIR2 extends it However, these experiments did not eliminate the likely involvement of free radicals during the aging process.

As matter of fact, many studies showed a connection between other theories of aging and free radicals. However, this toxin accumulation, such as UV and estrogens, could affect ROS production and indicate the involvement of free radicals in aging Also, the programmed death theory stated that the unique genetic code and genetic inheritance within DNA decide the longevity of the individual.

DNA can be compared to a biological clock set to go off at a particular time Telomeres are the tails of DNA that shorten every time cells divide. Once the telomeres become too short, cell division slows and finally ceases, causing the cell to die It was reported that the telomere repairing enzyme telomerase is activated by free iron, and iron is responsible for the production of O 2 · by Fenton reaction and activating xanthine oxidase This suggests that the loss of telomerase activity is possibly due to insufficient free iron in cells caused by free radicals.

HO provides free iron as well as CO and the antioxidant bilirubin via biliverdin. The HSP response to oxidative stress in aging and age-related neurodegenerative diseases is primal, powerful, and pervasive Therapeutic strategies aimed at inducing HO-1 may be a promising approach to the oxidative stress characteristic of brain aging and age-related neurodegenerative disorders , , , , All of the studies described do not imply that free radicals are the only direct cause of brain aging.

However, while other factors may be involved in the cascade of damaging effects in the brain, the significant key role of free radicals in this process cannot be underestimated. Therefore, this review supports the proposition that free radicals are, indeed, the key to brain aging.

The carbonyl group was introduced to protein lysine P-Lys , histidine P-His , or cysteine P-Cys residues by Michael addition This work was supported in part by grants from the National Institutes of Health to D.

Butterfield AG, AG and by a Wellcome Trust Grant to V. Ashok BT, Ali R. The aging paradox: free radical theory of aging. Exp Gerontol. Harman D. The aging process: major risk factor for disease and death. Proc Natl Acad Sci U S A.

Sohal RS, Mockett RJ, Orr WC. Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med. Gilgun-Sherki Y, Melamed E, Offen D. Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier.

Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med. Halliwell B, Gutteridge JM.

Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett. Frankel EN. Chemistry of free radical and singlet oxidation of lipids.

Prog Lipid Res. Spiteller G. Peroxidation of linoleic acid and its relation to aging and age dependent diseases. Mech Ageing Dev. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.

Delsal JL. Nouveau procede d'extraction des lipids du serum per le methylal. Applications aux, icrodpsages du chlesterol total, des phosphoaminolipides et des proteines.

Bull Soc Chim Biol. Vitiello F, Zanetta JP. Thin-layer chromatography of phospholipids. J Chromatogr. Hedegaard E, Jensen B. Nano-scale densitometric quantitation of phospholipids.

Lanza E, Zyren J, Slover HT. Fatty acid analysis on short glass capillary columns. J Agric Food Chem. Murphy EJ, Stephens R, Jurkowitz-Alexander M, Horrocks LA. Acidic hydrolysis of plasmalogens followed by high-performance liquid chromatography.

Schroeder F, Goetz I, Roberts E. Sex and age alter plasma membranes of cultured fibroblasts. Eur J Biochem. Lopez GH. Ilincheta de Boschero MG, Castagnet PI, Giusto NM. Age-associated changes in the content and fatty acid composition of brain glycerophospholipids.

Comp Biochem Physiol B Biochem Mol Biol. Giusto NM, Salvador GA, Castagnet PI, Pasquare SJ. Ilincheta de Boschero MG. Age-associated changes in central nervous system glycerolipid composition and metabolism. Neurochem Res. Ulmann L, Mimouni V, Roux S, Porsolt R, Poisson JP. Brain and hippocampus fatty acid composition in phospholipid classes of aged-relative cognitive deficit rats.

Prostagl Leukot Essent Fatty Acids. Lynch MA. Analysis of the mechanisms underlying the age-related impairment in long-term potentiation in the rat. Rev Neurosci.

Butterfield DA, Stadtman ER. Protein oxidation processes in aging brain. Adv Cell Aging Gerontol. Pizzimenti S, Barrera G, Dianzani MU, Brusselbach S.

Inhibition of D1, D2, and A-cyclin expression in HL cells by the lipid peroxydation product 4-hydroxynonenal. Uchida K, Stadtman ER. Modification of histidine residues in proteins by reaction with 4-hydroxynonenal.

Guichardant M, Taibi-Tronche P, Fay LB, Lagarde M. Covalent modifications of aminophospholipids by 4-hydroxynonenal. Del Corso A, Dal Monte M, Vilardo PG, et al. Site-specific inactivation of aldose reductase by 4-hydroxynonenal.

Arch Biochem Biophys. Boschi-Muller S, Azza S, Sanglier-Cianferani S, Talfournier F, Van Dorsselear A, Branlant G. A sulfenic acid enzyme intermediate is involved in the catalytic mechanism of peptide methionine sulfoxide reductase from Escherichia coli.

J Biol Chem. Siems WG, Hapner SJ, van Kuijk FJ. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress.

Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide.

J Neurochem. Uchida K, Kanematsu M, Sakai K, et al. Protein-bound acrolein: potential markers for oxidative stress. Lovell MA, Xie C, Markesbery WR. Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures.

Neurobiol Aging. Pocernich CB, Cardin AL, Racine CL, Lauderback CM, Butterfield DA. Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative disease.

Neurochem Int. Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y.

Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Papaioannou N, Tooten PC, van Ederen AM, et al. Immunohistochemical investigation of the brain of aged dogs.

Detection of neurofibrillary tangles and of 4-hydroxynonenal protein, an oxidative damage product, in senile plaques. Markesbery WR, Lovell MA. Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease. Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA.

Michiels C, Remacle J. Cytotoxicity of linoleic acid peroxide, malondialdehyde and 4-hydroxynonenal towards human fibroblasts. Esterbauer H. Cytotoxicity and genotoxicity of lipid-oxidation products. Am J Clin Nutr. Basu AK, Marnett LJ. Unequivocal demonstration that malondialdehyde is a mutagen.

Nair V, Offerman RJ, Turner GA, Pryor AN. Fluorescent 1,4-dihydropyridines—the malondialdehyde connection. Nair V, Vietti DE, Cooper CS. Degenerative chemistry of malondialdehyde. Structure, stereochemistry, and kinetics of formation of enaminals from reaction with amino acids. J Am Chem Soc. Slatter DA, Murray M, Bailey AJ.

Formation of a dihydropyridine derivative as a potential cross-link derived from malondialdehyde in physiological systems.

King TP. Selective chemical modification of arginyl residues. Slatter DA, Paul RG, Murray M, Bailey AJ. Reactions of lipid-derived malondialdehyde with collagen. Xu D, Thiele GM, Beckenhauer JL, Klassen LW, Sorrell MF, Tuma DJ.

Detection of circulating antibodies to malondialdehyde-acetaldehyde adducts in ethanol-fed rats. Slatter DA, Bolton CH, Bailey AJ. The importance of lipid-derived malondialdehyde in diabetes mellitus. Agarwal S, Draper HH. Isolation of a malondialdehyde-deoxyguanosine adduct from rat liver DNA.

Ji C, Rouzer CA, Marnett LJ, Pietenpol JA. Induction of cell cycle arrest by the endogenous product of lipid peroxidation, malondialdehyde. Yagi K. Lipid peroxides and related radicals in clinical medicine. Adv Exp Med Biol. Assay for serum lipid peroxide level and its clinical significance.

In: K Yagi, ed. Lipid Peroxides in Biology and Medicine. New York: Academic; — Fukunaga K, Yoshida M, Nakazono N. A simple, rapid, highly sensitive and reproducible quantification method for plasma malondialdehyde by high-performance liquid chromatography.

Biomed Chromatogr. Wong SH, Knight JA, Hopfer SM, Zaharia O, Leach CN, Jr, Sunderman FW, Jr. Lipoperoxides in plasma as measured by liquid-chromatographic separation of malondialdehyde-thiobarbituric acid adduct.

Clin Chem. Young IS, Trimble ER. Measurement of malondialdehyde in plasma by high performance liquid chromatography with fluorimetric detection. Ann Clin Biochem. Palinski W, Yla-Herttuala S, Rosenfeld ME, et al. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein.

Dei R, Takeda A, Niwa H, et al. Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease. Acta Neuropathol Berl. Head E, Liu J, Hagen TM, et al.

Oxidative damage increases with age in a canine model of human brain aging. Mooradian AD, Lung CC, Shah G, Mahmoud S, Pinnas JL. Age-related changes in tissue content of malondialdehyde-modified proteins.

Life Sci. Cini M, Moretti A. Studies on lipid peroxidation and protein oxidation in the aging brain. Cai Q, Tian L, Wei H. Age-dependent increase of indigenous DNA adducts in rat brain is associated with a lipid peroxidation product.

Randerath K, Li D, Moorthy B, Randerath E. I-compounds—endogenous DNA markers of nutritional status, ageing, tumour promotion and carcinogenesis. IARC Sci Publ. Randerath K, Li DH, Randerath E. Age-related DNA modifications I-compounds : modulation by physiological and pathological processes.

Mutat Res. Randerath K, Liehr JG, Gladek A, Randerath E. Age-dependent covalent DNA alterations I-compounds in rodent tissues: species, tissue and sex specificities. Gupta KP, van Golen KL, Randerath E, Randerath K.

Age-dependent covalent DNA alterations I-compounds in rat liver mitochondrial DNA. Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ, II. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism.

Chen Y, Morrow JD, Roberts LJ, II. Formation of reactive cyclopentenone compounds in vivo as products of the isoprostane pathway. Morrow JD, Minton TA, Mukundan CR, et al. Free radical-induced generation of isoprostanes in vivo. Evidence for the formation of D-ring and E-ring isoprostanes.

Morrow JD, Awad JA, Wu A, Zackert WE, Daniel VC, Roberts LJ, II. Nonenzymatic free radical-catalyzed generation of thromboxane-like compounds isothromboxanes in vivo. Taber DF, Herr RJ, Gleave DM. J Org Chem. Morrow JD, Roberts LJ. The isoprostanes: unique bioactive products of lipid peroxidation.

Brame CJ, Salomon RG, Morrow JD, Roberts LJ, II. Identification of extremely reactive gamma-ketoaldehydes isolevuglandins as products of the isoprostane pathway and characterization of their lysyl protein adducts.

Roberts LJ, II, Morrow JD. The generation and actions of isoprostanes. Biochim Biophys Acta. Roberts LJ, II, Reckelhoff JF. Measurement of F 2 -isoprostanes unveils profound oxidative stress in aged rats. Biochem Biophys Res Commun.

Roberts LJ, Morrow JD. Measurement of F 2 -isoprostanes as an index of oxidative stress in vivo. Morrow JD, Awad JA, Kato T, et al. Formation of novel non-cyclooxygenase-derived prostanoids F2-isoprostanes in carbon tetrachloride hepatotoxicity.

An animal model of lipid peroxidation. J Clin Invest. Granstrom E, Kindahl H. Radioimmunoassay of prostaglandins and thromboxanes. Adv Prostaglandin Thromboxane Res. Proudfoot J, Barden A, Mori TA, Burke V, Croft KD, Beilin LJ, Puddey IB.

Anal Biochem. Morrow JD, Roberts LJ, II. Mass spectrometric quantification of F2-isoprostanes in biological fluids and tissues as measure of oxidant stress. Methods Enzymol.

Aging is an inevitable xnd process, characterized by Digestive health and stress general decline in physiological dadicals biochemical functions of major Effective caloric intake systems. In the case Effective caloric intake the neuromuscular system, reductions in strength and mobility cause a deterioration raicals motor radicalls, impaired rdicals, and disability. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in accumulation of reactive oxygen species ROS. As the level of oxidative stress in skeletal muscle increases with age, advancing age is characterized by an imbalance between an increase in ROS production in the organism and antioxidant cellulzr as a whole. Finally, we analyze data, present in literature, regarding the beneficial effects of nutrition and physical activity in preventing oxidative damage associated with sarcopenia.