Oxidative stress in brain aging: Implications for therapeutics of neurodegenerative diseases

doi:10.1016/S0197-4580(02)00019-2

Neurobiology of Aging

Volume 23, Issue 5, September–October 2002, Pages 795-807

https://doi.org/10.1016/S0197-4580(02)00019-2 Get rights and content

Abstract

Age has a powerful effect on enhanced susceptibility to neurodegenerative diseases, including susceptibility to stroke and cognitive impairment (CI) even in optimally healthy individuals. We critically evaluated the notion that oxidative stress increases in aging brain. Rigorous studies show logarithmic age-dependent increases in oxidized proteins and oxidized DNA lesions. Decreased activity of antioxidant protective enzymes does not account for the observed increases. The reactivity of the lipid oxidation product 4-hydroxy-2-nonenal (HNE) with key mitochondria enzymes may be important in the age-dependent loss in energy generation and enhanced susceptibility of neurons to apoptosis. Age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) show significant promise. Vitamin E supplementation did not show major beneficial effect on cognitive functions. Major clinical trials for Alzheimer’s disease (AD) involving cycloxygenase-II (COX II) inhibitors and amyloid-beta vaccination have been discontinued. Novel therapeutics based on blocking neuron damaging neuroinflammatory processes show great promise for abating dementia progression although they have yet to make it to clinical practice.

Introduction

Brain aging has become an area of intense research and a subject of much speculation fueled largely from the widely recognized fact that age is the biggest risk factor in most neurodegenerative diseases. It is widely held that oxidative stress increases in brain during aging. In this report we present a fresh examination of this concept based upon a selective and careful review of the recent literature. This review has primarily focused on the most rigorous data obtained from human studies. Trends from these studies have then been compared, in some cases, with some of the best experimental animal studies to help evaluate the general validity of the observations. We have especially focused on those reports where rigorous techniques and protocols have examined parameters useful in evaluating if the basic science supports the concept that oxidative stress increases with brain age.

In conducting a fresh examination of this field, we have kept foremost in mind these basic questions: (a) does oxidative stress (and oxidative damage) increase as brain aging occurs; (b) what parameters can be used to unambiguously answer the questions posed; (c) what are the underlying processes involved causing the oxidative stress changes observed with age; and (d) are there approaches and/or therapeutic possibilities that may act fundamentally to alter and/or inhibit the age-mediated changes in oxidative stress that influence the development of neurodegenerative diseases? This review provides a critical perspective on these questions.

Section snippets

Basic concepts of oxidative stress in brain

We and others have previously reviewed the field of oxidative stress in brain [23], [24], [25]. Our original overall rationale to examine oxidative stress in aging brain focused on the following premise: (a) brain has a high content of easily peroxidizable unsaturated fatty acids (especially high in 20:4 and 22:6 fatty acids); (b) brain requires very high amounts of oxygen per unit weight (about 20% of the total amount used in humans); (c) brain has a high content of both Fe and ascorbate

Importance of age in neurodegenerative diseases

Two recent studies provide some of the best data illustrating very clearly the importance of age on the incidence of stroke [112] and on cognitive impairment (CI) as well as development of Alzheimer’s disease (AD) [79]. Fig. 2 presents a summary of the stroke data and clearly shows the effect of age on the incidence of stroke in men and women. Earlier we showed that increasing age was extremely important on the severity of outcome of experimental stroke in gerbils [28] and until now a careful

Does microvascular changes occur in aging brain?

In the case of the significant increase of stroke with age, it is reasonable to expect that age-dependent changes in the brain vasculature may be one primary factor. Brain microvasculature represents a very large surface area, i.e., we have estimated 400 ft.² for a human brain based on neuronanatomical estimates of the total length of the microvasculature from which the surface area was calculated. Microvasculature alteration with age and its contribution to neurodegenerative diseases is most

Does oxidized protein increase in aging brain?

Accumulation of oxidized proteins in many tissues is widely considered a hallmark of aging [105]. There is a paucity of careful studies of oxidized protein in brain. Nevertheless, most of the studies done in this area conclude that the amount of oxidized protein does increase with age. Perhaps the best study conducted thus far in humans was done by Smith et al. [103]. In this study, the amount of protein oxidation was measured by a general 2,4-dinitrophenylhydrazine assay of protein carbonyl

Do lipid peroxidation products increase in aging brain?

Peroxidation of biological lipids yields a large number of compounds. The most widely studied and apparently the most important from a biomedical perspective are the active aldehydes and the isoprostanes. Non-enzymatic peroxidation of arachidonic acid causes the formation of specific peroxidation products referred to as F₂-isoprostanes [94]. Measurement of the level of these compounds has recently become considered one of the best methods to index in vivo oxidative damage to lipids. In the

Does oxidative damage to DNA increase in brain aging?

In general, oxidative damage to DNA occurs at all times leading to many oxidation-damaged bases and strand breaks. Utilizing mass spectroscopy and other analytical methods, about 100 different oxidative damaged bases have been found. Many repair enzyme systems have evolved to remove and replace the damaged nucleosides and repair the broken strands. One of the most widely studied base lesions is 8-OHdG. This oxidized base is mutagenic and at least three different proteins are involved in its

Do neuroinflammatory processes occur in aging brain?

The hallmark of inflammatory processes, in general, is enhanced production of ROS. Therefore, it is rationale to associate enhanced oxidative stress with neuroinflammatory processes. The association of enhanced ROS with neuroinflammatory processes has been reviewed recently [16]. Numerous reports have emphasized a clear association of enhanced neuroinflammatory processes with neurodegenerative diseases [22], [52], [85], [120], [121]. The question remains, however, does normal aging brain have

Novel therapeutics for neurodegenerative diseases

Basic research into the mechanistic basis of oxidative stress in aging brain has provided many new leads and approaches for the possible treatment of neurodegenerative diseases. This is a very intensely studied area and the subject area is much too large except for only briefly summarizing it here. Probably the two major categories of therapeutic approaches that have arisen directly from the subject areas we have discussed include Vitamin E supplementation and anti-neuroinflammatory drugs. Two

Acknowledgements

This research was made possible by monies from the Merrick Chair for Aging Research and in part by the National Institutes of Health (NS35747, PO1-AG05119 and 5P50-AG05144), the Oklahoma Center for the Advancement of Science and Technology (OCAST H67-097), and the Abercrombie Foundation.

References (121)

S Agarwal et al.
Aging and proteolysis of oxidized proteins
Arch. Biochem. Biophys.
(1994)
M.V Aksenova et al.
Protein oxidation and enzyme activity decline in old Brown–Norway rats are reduced by dietary restriction
Mech. Ageing Dev.
(1998)
F Bosch-Morell et al.
4-Hydroxynonenal inhibits glutathione peroxidase: protection by glutathione
Free Radic. Biol. Med.
(1999)
S Boschi-Muller et al.
A sulfenic acid enzyme intermediate is involved in the catalytic mechanism of peptide methionine sulfoxide reductase from Escherichia coli
J. Biol. Chem.
(2000)
U Cakatay et al.
Relation of oxidative protein damage and nitrotyrosine levels in the aging rat brain
Exp. Gerontol.
(2001)
W Cao et al.
Oxygen free radical involvement in ischemia and reperfusion injury to brain
Neurosci. Lett.
(1988)
R.A Cherny et al.
Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice
Neuron
(2001)
K.J.A Davies
Degradation of oxidized proteins by the 20S proteasome
Biochimie
(2001)
S.M.K Davies et al.
Measurements of protein carbonyls, ortho- and meta-tyrosine and oxidative phosphorylation complex activity in mitochondria from young and old rats
Free Radic. Biol. Med.
(2001)
M.-A Dorheim et al.
Nitric oxide synthase activity is elevated in brain microvessels in Alzheimer’s disease
Biochem. Biophys. Res. Commun.
(1994)

A Dubey et al.

Effect of spin-trapping compound N-tert-butyl-α-phenylnitrone on protein oxidation and life span

Arch. Biochem. Biophys.

(1995)

P Eikelenboom et al.

The role of complement and activated microglia in the pathogenesis of Alzheimer’s disease

Neurobiol. Aging

(1996)

H Esterbauer et al.

Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes

Free Radic. Biol. Med.

(1991)

E Farkas et al.

Cerebral microvascular pathology in aging and Alzheimer’s disease

Prog. Neurobiol.

(2001)

C.E Finch et al.

Evolutionary perspectives on amyloid and inflammatory features of Alzheimer’s disease

Neurobiol. Aging

(1996)

R.A Floyd et al.

Age influence on oxidative events during brain ischemia/reperfusion

Arch. Gerontol. Geriatr.

(1991)

R.A Floyd et al.

Conditions influencing yield and analysis of 8-hydroxy-2′-deoxyguanosine in oxidatively damaged DNA

Anal. Biochem.

(1990)

R.A Floyd et al.

Oxidative biochemical markers clues to understanding aging in long-lived species

Exp. Gerontol.

(2001)

R.A Floyd et al.

Hydroxyl free radical mediated formation of 8-hydroxyguanine in isolated DNA

Arch. Biochem. Biophys.

(1988)

R.A Floyd

Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development

Free Radic. Biol. Med.

(1999)

A Giovanni et al.

Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F-DP, in β-amyloid-induced neuronal death

J. Biol. Chem.

(1999)

P Grammas et al.

Anoxia/reoxygenation induces hydroxyl free radical formation in brain microvessels

Free Radic. Biol. Med.

(1993)

M Grundman

Vitamin E and Alzheimer’s disease: the basis for additional clinical trials

Am. J. Clin. Nutr.

(2000)

M Guichardant et al.

Covalent modifications of aminophospholipids by 4-hydroxynonenal

Free Radic. Biol. Med.

(1998)

H.J Helbock et al.

8-Hydroxydeoxyguanosine and 8-hydroxyguanine as biomarkers of oxidative DNA damage

Methods Enzymol.

(1999)

K Hensley et al.

CP1-1189 inhibits interleukin 1β-induced p38-mitogen-activated protein kinase phosphorylation: an explanation for its neuroprotective properties?

Neurosci. Lett.

(2000)

Y Kato et al.

Immunohistochemical detection of dityrosine in lipofuscin pigments in the aged human brain

FEBS Lett.

(1998)

J.N Keller et al.

Decreased levels of proteasome activity and proteasome expression in aging spinal cord

Neuroscience

(2000)

Y Kotake et al.

Inhibition of NF-κB, iNOS mRNA, COX II mRNA, and COX catalytic activity by phenyl-N-tert-butylnitrone (PBN)

Biochim. Biophys. Acta

(1998)

Y Kotake et al.

Phenyl N-tert-butylnitrone provides protection from endotoxin shock through amplified production of the anti-inflammatory cytokine interleukin-10

Arch. Biochem. Biophys.

(1999)

B.S Kristal et al.

4-Hydroxyhexenal is a potent inducer of the mitochondrial permeability transition

J. Biol. Chem.

(1996)

C Leeuwenburgh et al.

Caloric restriction attenuates dityrosine cross-linking of cardiac and skeletal muscle proteins in aging mice

Arch. Biochem. Biophys.

(1997)

R.L Levine et al.

Methionine residues may protect proteins from critical oxidative damage

Mech. Ageing Dev.

(1999)

W.R Markesbery

Oxidative stress hypothesis in Alzheimer’s disease

Free Radic. Biol. Med.

(1997)

W.R Markesbery et al.

4-Hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease

Neurobiol. Aging

(1998)

M.P Mattson et al.

Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms

Mech. Ageing Dev.

(2001)

T.J Montine et al.

Increased cerebral cortical lipid peroxidation and abnormal phospholipids in aged homozygous apoE-deficient C57BL/6J mice

Exp. Neurol.

(1999)

D Nakae et al.

Improved genomic/nuclear DNA extraction for 8-hydroxydeoxyguanosine analysis of small amounts of rat liver tissue

Cancer Lett.

(1995)

D Nakae et al.

Age and organ dependent spontaneous generation of nuclear 8-hydroxydeoxyguanosine in male Fischer 344 rats

Lab. Invest.

(2000)

M.K O’Banion et al.

Inflammatory mechanisms and anti-inflammatory therapy in Alzheimer’s disease

Neurobiol. Aging

(1996)

G.M Pasinetti

Cycloxygenase and Alzheimer’s disease: implications for preventive initiatives to slow the progression of clinical dementia

Arch. Gerontol. Geriatr.

(2001)

S Pizzimenti et al.

Inhibition of D1, D2, and a cyclin expression in HL-60 cells by the lipid peroxidation product 4-hydroxynonenal

Free Radic. Biol. Med.

(1999)

E.E Reich et al.

Brain regional quantification of F-ring and D/E-ring isoprostanes and neuroprostanes in Alzheimer’s disease

Am. J. Pathol.

(2001)

L.J Roberts et al.

Measurement of F₂-isoprostanes as an index of oxidative stress in vivo

Free Radic. Biol. Med.

(2000)

L.J Roberts et al.

Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid

J. Biol. Chem.

(1998)

I Rozovsky et al.

Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation

Neurobiol. Aging

(1998)

H Sang et al.

Expression of cytokines and activation of transcription factors in lipopolysaccharide-administered rats and their inhibition by phenyl N-tert-butylnitrone (PBN)

Arch. Biochem. Biophys.

(1999)

J.J Chen et al.

Detoxification of reactive aldehydes in mitochondria: effects of age and dietary restriction

Aging

(1996)

A Copani et al.

Mitotic signaling by β-amyloid causes neuronal death

FASEB J.

(1999)

A Del Corso et al.

Site-specific inactivation of aldose reductase by 4-hydroxynonenal

Arch. Biochem. Biophys.

(1998)

Cited by (717)

Nanozyme enabled protective therapy for neurological diseases
2024, Nano Today
Nanozymes are nanomaterials that mimic enzymatic activities found in natural human biological processes. Nanozymes can perform reactive oxidative species (ROS) scavenging activities of catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD), thereby relieving oxidative stress, which is a common pathophysiological factor for multiple neurological disorders. Current nanozyme developments have led to increasing applications of these unique molecules in novel treatments for neurological disorders. In this review article, we provide a comprehensive review of the mechanisms and structures of current nanozymes that are used in neurological disorders, focusing primarily on the oxidative stress-mediating mechanisms. We then discuss the roles of oxidative stress in various neurological diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, epilepsy, traumatic brain injury (TBI), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and summarize current nanozyme therapeutics developed to treat these diseases, both through mechanisms that counter oxidative stress as well as through synergistic mechanisms that couple targeting oxidative stress with pathological protein clearance and neuroinflammation reduction.
Effects of Red ginseng on neuroinflammation in neurodegenerative diseases
2024, Journal of Ginseng Research
Red ginseng (RG) is widely used as a herbal medicine. As the human lifespan has increased, numerous diseases have developed, and RG has also been used to treat various diseases. Neurodegenerative diseases are major problems that modern people face through their lives. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are featured by progressive nerve system damage. Recently, neuroinflammation has emerged as a degenerative factor and is an immune response in which cytokines with nerve cells that constitute the nervous system. RG, a natural herbal medicine with fewer side effects than chemically synthesized drugs, is currently in the spotlight. Therefore, we reviewed studies reporting the roles of RG in treating neuroinflammation and neurodegenerative diseases and found that RG might help alleviate neurodegenerative diseases by regulating neuroinflammation.
The intrinsic apoptotic pathway lies upstream of reactive species production in cortical neurons and age-related oxidative stress in the brain
2023, Molecular and Cellular Neuroscience
A BAX- and mitochondria-dependent production of reactive oxygen species (ROS) and reactive species (reactive nitrogen species, RNS) lying downstream of these ROS occurs in apoptotic and nonapoptotic mouse sympathetic neurons and cerebellar granule cells in cell culture. These ROS have been shown to lie downstream of caspase 3 in mouse sympathetic neurons. Here we show that BAX is necessary for similar ROS production in apoptotic and nonapoptotic mouse cortical neurons in cell culture and that it also positively regulates oxidative stress in the brains of mice of different ages. Brains from mice with genetically reduced levels of mitochondrial superoxide dismutase 2 (SOD2) exhibited elevated levels of DNA strand breaks consistent with oxidative damage. Lipid peroxides were also elevated at some ages in comparison to the brains of wild type animals. BAX deletion in these mice reduced both brain DNA strand breaks and lipid peroxide levels to well below those of wild type animals. Deletion of caspase 3 greatly reduced age-augmented levels of brain oxidative stress markers including lipid peroxides, oxidized DNA, and nitrosylated proteins. These findings indicate that BAX contributes to ROS production in mouse cortical neurons, to oxidative stress their brains, and that this effect is likely mediated via caspase 3 activity.
Antioxidative effect of Aloe vera against malathion induced neurotoxic response in Wistar rats
2023, Arabian Journal of Chemistry
Insight about the impact of malathion on human physiology is still a challenge in environmental health. The present work was focused on the neurotoxic effects of malathion followed by impact of Aloe vera, if any, which is not known. The malathion has significantly altered the levels of the body weight, brain weight and relative weight of the brain. The significant levels of alteration were also observed in the levels of antioxidant potential and oxidative stress biomarkers such as NO, PCO, MDA, GSH, SOD, CAT, GST, and GPx antioxidants. The increased levels of SOD, CAT, GPx and decreased levels of GST were observed in the malathion treated experimental rats. In addition of these, the contents of inflammatory markers such as IL-6, COX-2, TNF-α, and NF-κB were also found to be altered significantly. A significant alteration was also recorded in the activity of AChE. The histological examination of liver tissue sections revealed the severe injury to the central vein and hepatic cords due to malathion toxicity. However, the pre-administration of A. vera markedly ameliorated the neurotoxic effect of malathion. These results suggested that the metabolites present in A. vera may be utilized as a potential and sustainable supplement in the proper management of pesticide induced neurotoxicity in association with the relevant therapeutics.
Oxytocin as neuro-hormone and neuro-regulator exert neuroprotective properties: A mechanistic graphical review
2023, Neuropeptides
Neurodegeneration is progressive cell loss in specific neuronal populations, often resulting in clinical consequences with significant medical, societal, and economic implications. Because of its antioxidant, anti-inflammatory, and anti-apoptotic properties, oxytocin has been proposed as a potential neuroprotective and neurobehavioral therapeutic agent, including modulating mood disturbances and cognitive enchantment.
Literature searches were conducted using the following databases Web of Science, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, and Cochrane from January 2000 to February 2023 for articles dealing with oxytocin neuroprotective properties in preventing or treating neurodegenerative disorders and diseases with a focus on oxidative stress, inflammation, and apoptosis/cell death.
The neuroprotective effects of oxytocin appears to be mediated by its anti-inflammatory properties, inhibition of neuro inflammation, activation of several antioxidant enzymes, inhibition of oxidative stress and free radical formation, activation of free radical scavengers, prevent of mitochondrial dysfunction, and inhibition of apoptosis.
Oxytocin acts as a neuroprotective agent by preventing neuro-apoptosis, neuro-inflammation, and neuronal oxidative stress, and by restoring mitochondrial function.
Characterization and anti-aging effects of polysaccharide from Gomphus clavatus Gray
2023, International Journal of Biological Macromolecules
In this study, a highly branched polysaccharide (GPF, 112.0 kDa) was isolated and purified from Gomphus clavatus Gray fruiting bodies. GPF was primarily composed of mannose, galactose, arabinose, xylose, and glucose at a molar ratio of 3.2:1.9:1.6:1.2:1.0. GPF was a highly branched heteropolysaccharide composed of 13 glucosidic bonds, with a degree of branching (DB) of 48.85 %. GPF exhibited anti-aging activity in vivo, significantly increased antioxidant enzymes activities (SOD, CAT and GSH-Px), improved total antioxidant capability (T-AOC) and decreased MDA level in the serum and brain of d-Gal induced aging mice. Behavioral experiments showed that GPF effectively improved learning and memory deficits in d-Gal induced aging mice. Mechanistic studies indicated that GPF could activate AMPK by increasing AMPK phosphorylation and upregulating SIRT1 and PGC-1α expression. These findings suggest that GPF has significant potential as a natural candidate to slow down aging and prevent aging-related diseases.

View all citing articles on Scopus

View full text

Oxidative stress in brain aging: Implications for therapeutics of neurodegenerative diseases

Abstract

Introduction

Section snippets

Basic concepts of oxidative stress in brain

Importance of age in neurodegenerative diseases

Does microvascular changes occur in aging brain?

Does oxidized protein increase in aging brain?

Do lipid peroxidation products increase in aging brain?

Does oxidative damage to DNA increase in brain aging?

Do neuroinflammatory processes occur in aging brain?

Novel therapeutics for neurodegenerative diseases

Acknowledgements

Arch. Biochem. Biophys.

Mech. Ageing Dev.

Free Radic. Biol. Med.

J. Biol. Chem.

Exp. Gerontol.

Neurosci. Lett.

Neuron

Biochimie

Free Radic. Biol. Med.

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Neurobiol. Aging

Free Radic. Biol. Med.

Prog. Neurobiol.

Neurobiol. Aging

Arch. Gerontol. Geriatr.

Anal. Biochem.

Exp. Gerontol.

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

J. Biol. Chem.

Free Radic. Biol. Med.

Am. J. Clin. Nutr.

Free Radic. Biol. Med.

Methods Enzymol.

Neurosci. Lett.

FEBS Lett.

Neuroscience

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

J. Biol. Chem.

Arch. Biochem. Biophys.

Mech. Ageing Dev.

Free Radic. Biol. Med.

Neurobiol. Aging

Mech. Ageing Dev.

Exp. Neurol.

Cancer Lett.

Lab. Invest.

Neurobiol. Aging

Arch. Gerontol. Geriatr.

Free Radic. Biol. Med.

Am. J. Pathol.

Free Radic. Biol. Med.

J. Biol. Chem.

Neurobiol. Aging

Arch. Biochem. Biophys.

Detoxification of reactive aldehydes in mitochondria: effects of age and dietary restriction

Aging

Mitotic signaling by β-amyloid causes neuronal death

FASEB J.

Site-specific inactivation of aldose reductase by 4-hydroxynonenal

Arch. Biochem. Biophys.