Cited by 757Mitochondrial Function and PathologyGenetics, Aging, and Longevity in Model OrganismsDNA Repair Mechanisms

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Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain

Mecocci, Patrizia, MacGarvey, Usha, Kaufman, Allan E., Koontz, Deborah, Shoffner, John M., Wallace, Douglas C., Beal, M. Flint·1993·Annals of Neurology

DOI 10.1002/ana.410340416

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Abstract

A major theory of aging is that oxidative damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age-related accumulation of oxidative damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/micrograms of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10-fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15-fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age-related accumulation in oxidative damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such damage may contribute to age-dependent increases in incidence of neurodegenerative diseases.

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Method
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Age-associated change in mitochondrial DNA damage
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Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression
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“Oxidative Stress and Brain Aging A landmark study comparing the levels of oxidized nucleoside 8-hydroxy-2′-deoxyguanosine (OH8dG) in nuclear and mitochondrial DNA isolated from various regions of the cerebral cortex and cerebellum of humans aged 42 to 97 years found a progressive increase of OH8dG with age, although t…”
Background
Alzheimer's disease β‐secretase BACE1 is not a neuron‐specific enzyme
Roßner, S., Lange‐Dohna, C., Zeitschel, U., & Perez-Polo, J. R. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02857.x · Cited by 174
“…2003) and proinflammatory cytokines, such as IL-1b or TGF-b, which are expressed by b-amyloid plaque associated microglial cells in brain of both AD patients (Kalaria 1999; Benveniste et al. 2001) and APP transgenic mice (see e.g. Benzing et al. 1999; Mehlhorn et al. 2000; Apelt and Schliebs 2001).”
Background
DNA adducts and chronic degenerative disease. Pathogenetic relevance and implications in preventive medicine.
Flora, S. D., Izzotti, A., Randerath, K., Randerath, E., Bartsch, H., Nair, J., Balansky, R. M., van Schooten, F., Degan, P., Fronza, G., et al. (1996) · PubMed · Cited by 162
Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration
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Mitochondrial respiratory chain activity in the human brain as a function of age
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Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system.
Wei, Y., Lu, C. Y., Wei, C. Y., Ma, Y. S., & Lee, H. (2001) · PubMed · Cited by 158
Thrombin-Induced Oxidative Stress Contributes to the Death of Hippocampal NeuronsIn Vivo: Role of Microglial NADPH Oxidase
Choi, S., Lee, D. Y., Kim, S. U., & Jin, B. K. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4306-04.2005 · Cited by 155
Oxidative damage and age-related functional declines
Martin, I., & Grotewiel, M. S. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.01.008 · Cited by 152
DNA Oxidation in Alzheimer's Disease
Markesbery, W. R., & Lovell, M. A. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.2039 · Cited by 151
Oxidative Stress, Mitochondrial Dysfunction, and Epilepsy
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Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer’s amyloid β-peptide 1–42
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“[54] Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, et al.”
Mitochondrial Disorders: Clinical and Genetic Features
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Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging
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The Eye, Oxidative Damage and Polyunsaturated Fatty Acids
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“Moreover, high levels of 8-OHdG have been found in nuclear DNA (nDNA) and in mtDNA in post mortem brains of elderly subjects [42], and in trabecular mtDNA this damage has been seen to be greater in glaucoma patients than in healthy subjects.”
Background
Ratio of 8-Hydroxyguanine in Intact DNA to Free 8-Hydroxyguanine Is Increased in Alzheimer Disease Ventricular Cerebrospinal Fluid
Lovell, M. A., & Markesbery, W. R. (2001) · Archives of Neurology · doi:10.1001/archneur.58.3.392 · Cited by 150
“Intact DNA was isolated from ventricular CSF using a modified procedure of Mecocci et al.(7) The CSF was mixed with a 1:10 volume of 1mol/L disodium EDTA, 5% sodium dodecyl sulfate, and 50-mmol/L Tris-hydrochloride (pH 8.”
MethodInfluential
Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson?s disease and related neurodegenerative disorders
Fukae, J., Takanashi, M., Kubo, S.-I., Nishioka, K., Nakabeppu, Y., Mori, H., Mizuno, Y., & Hattori, N. (2004) · Acta Neuropathologica · doi:10.1007/s00401-004-0937-9 · Cited by 148
“mtDNA is more vulnerable to oxidative stress than nuclear DNA [18, 26], because mtDNA is located in the inner mitochondria membrane in which electron transport chain generates ROS.”
Direct Detection of 8-Oxodeoxyguanosine and 8-Oxoguanine by Avidin and Its Analogues
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Repair of DNA damage in mitochondria
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DNA adducts and chronic degenerative diseases. Pathogenetic relevance and implications in preventive medicine
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Redox Mechanisms in Neurodegeneration: From Disease Outcomes to Therapeutic Opportunities
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“Age-dependent increase in oxidative damage to mtDNA has been reported, which can lead to impaired mitochondrial energetics and elevated oxidative stress (344).”
Background
Age‐dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria
Chen, D., Cao, G., Hastings, T. G., Feng, Y., Pei, W., O'Horo, C., & Chen, J. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00916.x · Cited by 139
“…than that of the liver (Ames et al. 1993; Nagayama et al. 2000; de Souza-Pinto et al. 2001; Hamilton et al. 2001a), and why there is an increased accumulation of oxidative lesions in the aged brain compared with the young adult brain (Mecocci et al. 1993; Hudson et al. 1998; Hamilton et al. 2001b).”
BackgroundInfluential
Oxidative damage to DNA in plaques of MS brains
Vladimirova, O. V., O'Connor, J. J., Cahill, A., Alder, H., Butunoi, C., & Kálmán, B. (1998) · Multiple Sclerosis Journal · doi:10.1177/135245859800400503 · Cited by 138
E-4-hydroxy-2-nonenal is cytotoxic and cross-links cytoskeletal proteins in P19 neuroglial cultures.
Montine, T. J., Amarnath, K., Martin, M. E., Strittmatter, W. J., & Graham, D. G. (1996) · Europe PMC (PubMed Central) · Cited by 136
Oxidative Damage and Cognitive Dysfunction: Antioxidant Treatments to Promote Healthy Brain Aging
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“Studies of human autopsy tissue show higher levels of oxidative damage to DNA/RNA [23–25], proteins [24, 26–29], lipids [25, 29, 30] in aged as compared to young human brain.”
Background
Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease
Aliev, G., Smith, M. A., Obrenovich, M. E., de la Torre, J. C., & Perry, G. L. (2003) · Neurotoxicity Research · doi:10.1007/bf03033159 · Cited by 134
“Moreover, it has been reported that mitochondrial DNA isolated from the brains of AD patients shows oxidative modifications containing 8-hydroxy2'-deoxyguanosine (8OHdG) (Mecocci et al., 1993; 1994; 1997).”
Resistance, vulnerability and resilience: A review of the cognitive cerebellum in aging and neurodegenerative diseases
Liang, K. J., & Carlson, E. S. (2019) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2019.01.004 · Cited by 131
“Corral-Debrinski M, et al., Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age.”
BackgroundInfluential
Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey
Duce, J. A., Podvin, S., Hollander, W., Kipling, D., Rosene, D. L., & Abraham, C. R. (2007) · Glia · doi:10.1002/glia.20593 · Cited by 134
“Peroxynitrite, iron as well as reactive oxygen and nitrogen species are all highly expressed in aging white matter and have been demonstrated to impair mitochondrial respiration (Lu et al., 2004; Mecocci et al., 1993; Vatassery, 2004).”
Background
DNA damage, repair, and antioxidant systems in brain regions: a correlative study
Cardozo‐Pelaez, F., Brooks, P. J., Stedeford, T. J., Song, S., & Sanchez‐Ramos, J. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00172-6 · Cited by 131
Sex-dependent differences in aged rat brain mitochondrial function and oxidative stress
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Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
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“Increased oxidative DNA damage is observed in brain tissue from aged individuals (Mecocci et al , 1993) and patients with AD (Nuno-mura et al , 2001; Lovell & Markesbery, 2007; Weissman et al , 2007), Parkinson’s disease (PD) (Alam et al , 1997), Huntington’s disease (HD) (Browne et al , 1997), and…”
Brain Metabolic Alterations in Alzheimer’s Disease
Ardanaz, C. G., Ramírez, M. J., & Solas, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073785 · Cited by 135
“The presence of damaged mitochondria is a common feature in aging that correlates with the accumulation of damaged and dysfunctional organelles [85,120].”
Background
Oxidative stress in Parkinson’s disease
Nikam, S., Nikam, P., Ahaley, S. K., & Sontakke, A. V. (2009) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-009-0017-y · Cited by 126
Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells
Zhou, D., Borsa, M., & Simon, A. K. (2021) · Aging Cell · doi:10.1111/acel.13316 · Cited by 138
“As mitochondrial DNA is more vulnerable to oxidative stress due to its structure and location, it displays increased 8-oxoG both in vivo and in vitro (Barreau et al., 1996; Mecocci et al., 1993).”
Background

Authors: Mecocci, P., MacGarvey, U., Kaufman, A. E., Koontz, D., Shoffner, J. M., Wallace, D. C., & Beal, M. F.
Affiliations: Harvard University (US)
Emory University (US)
Corresponding author: Beal, M. Flint
ORCID: Mecocci, Patrizia
Shoffner, John M.
Wallace, Douglas C.
Beal, M. Flint
Venue: Annals of Neurology
Publisher: Wiley
Published: 1993-10
Volume: 34
Issue: 4
Pages: 609-616
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.410340416
OpenAlex: W2130753450
Cited by: 757
References: 50
Citations by year: 2026: 5 · 2025: 7 · 2024: 12 · 2023: 12 · 2022: 15 · 2021: 18 · 2020: 19 · 2019: 22 · 2018: 17 · 2017: 16 · 2016: 19 · 2015: 18 · 2014: 24 · 2013: 29 · 2012: 22
FWCI: 7.34
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 4025 d)
Locations: Annals of Neurology (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Public Health Service (16367)
National Institute on Aging (IP50 AG05134)
National Institute of Neurological Disorders and Stroke (NS-21328, R01NS021328)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords: oxidative DNA damage, mitochondrial DNA, 8-hydroxy-2'-deoxyguanosine, brain aging, cerebral cortex, cerebellum, nuclear DNA, age-related accumulation, neurodegenerative diseases
MeSH terms: 8-Hydroxy-2'-Deoxyguanosine, Adult, Aged, Aged, 80 and over, Aging, Brain, Cell Nucleus, Deoxyguanosine, DNA, DNA, Mitochondrial, Female, Humans, Male, Middle Aged, Oxidation-Reduction

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Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain

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