The Exacerbation of Aging and Oxidative Stress in the Epididymis of Sod1 Null Mice

There is growing evidence that the quality of spermatozoa decreases with age and that children of older fathers have a higher incidence of birth defects and genetic mutations. The free radical theory of aging proposes that changes with aging are due to the accumulation of damage induced by exposure to excess reactive oxygen species. We showed previously that absence of the superoxide dismutase 1 (Sod1) antioxidant gene results in impaired mechanisms of repairing DNA damage in the testis in young Sod1−/− mice. In this study, we examined the effects of aging and the Sod−/− mutation on mice epididymal histology and the expression of markers of oxidative damage. We found that both oxidative nucleic acid damage (via 8-hydroxyguanosine) and lipid peroxidation (via 4-hydroxynonenal) increased with age and in Sod1−/− mice. These findings indicate that lack of SOD1 results in an exacerbation of the oxidative damage accumulation-related aging phenotype.

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Mitochondria, oxidative stress and aging

Orvosi Hetilap ◽

10.1556/oh.2014.29852 ◽

2014 ◽

Vol 155 (12) ◽

pp. 447-452

Author(s):

András Szarka ◽

Gábor Bánhegyi ◽

Balázs Sümegi

Keyword(s):

Reactive Oxygen Species ◽

Mitochondrial Dna ◽

Mitochondrial Respiration ◽

Accelerated Aging ◽

Reactive Oxygen ◽

Oxygen Species ◽

Vicious Cycle ◽

Free Radical Theory ◽

Radical Theory ◽

Theory Of Aging

The free radical theory of aging was defined in the 1950s. On the base of this theory, the reactive oxygen species formed in the metabolic pathways can play pivotal role in ageing. The theory was modified by defining the mitochondrial respiration as the major cellular source of reactive oxygen species and got the new name mitochondrial theory of aging. Later on the existence of a “vicious cycle” was proposed, in which the reactive oxygen species formed in the mitochondrial respiration impair the mitochondrial DNA and its functions. The formation of reactive oxygen species are elevated due to mitochondrial dysfunction. The formation of mitochondrial DNA mutations can be accelerated by this “vicious cycle”, which can lead to accelerated aging. The exonuclease activity of DNA polymerase γ, the polymerase responsible for the replication of mitochondrial DNA was impaired in mtDNA mutator mouse recently. The rate of somatic mutations in mitochondrial DNA was elevated and an aging phenotype could have been observed in these mice. Surprisingly, no oxidative impairment neither elevated reactive oxygen species formation could have been observed in the mtDNA mutator mice, which may question the existence of the “vicious cycle”. Orv. Hetil., 2014, 155(12), 447–452.

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Mitophagy in Hypertension-Associated Premature Vascular Aging

American Journal of Hypertension ◽

10.1093/ajh/hpaa058 ◽

2020 ◽

Vol 33 (9) ◽

pp. 804-812

Author(s):

Zachary J Schreckenberger ◽

Camilla F Wenceslau ◽

Bina Joe ◽

Cameron G McCarthy

Keyword(s):

Vascular Function ◽

Oxygen Species ◽

Vascular Aging ◽

Free Radical Theory ◽

Radical Theory ◽

Cellular Debris ◽

Vascular Physiology ◽

Theory Of Aging ◽

Vascular Age

Abstract Hypertension has been described as a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated and exacerbated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype of arteries from hypertensive patients and animals remain elusive. Classically, the aged phenotype is the buildup of cellular debris and dysfunctional organelles. One means by which this can occur is insufficient degradation and cellular recycling. Mitophagy is the selective catabolism of damaged mitochondria. Mitochondria are organelles that contribute importantly to the determination of cellular age via their production of reactive oxygen species (ROS; Harman’s free radical theory of aging). Therefore, the accumulation of dysfunctional and ROS-producing mitochondria could contribute to the acceleration of vascular age in hypertension. This review will address and critically evaluate the current literature on mitophagy in vascular physiology and hypertension.

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Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.628157 ◽

2021 ◽

Vol 9 ◽

Author(s):

Hazel J. Shields ◽

Annika Traa ◽

Jeremy M. Van Raamsdonk

Keyword(s):

Reactive Oxygen Species ◽

Oxidative Damage ◽

Comparative Studies ◽

Experimental Studies ◽

Reactive Oxygen ◽

Model Organisms ◽

Oxygen Species ◽

Free Radical Theory ◽

Radical Theory ◽

The Relationship

Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.

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LFMD: detecting low-frequency mutations in high-depth genome sequencing data without molecular tags

10.1101/617381 ◽

2019 ◽

Author(s):

Rui Ye ◽

Xuehan Zhuang ◽

Jie Ruan ◽

Yanwei Qi ◽

Yitai An ◽

...

Keyword(s):

Oxidative Damage ◽

Low Frequency ◽

Sequencing Data ◽

Free Radical Theory ◽

Radical Theory ◽

Drug Resistance Prediction ◽

Theory Of Aging ◽

Mitochondrial Heterogeneity ◽

Duplex Sequencing ◽

Next Generation Sequencing Ngs

AbstractAs next-generation sequencing (NGS) and liquid biopsy become more prevalent in research and in the clinic, there is an increasing need for better methods to reduce cost and improve sensitivity and specificity of low-frequency mutation detection (where the Alternative Allele Frequency, or AAF, is less than 1%). Here we propose a likelihood-based approach, called Low-Frequency Mutation Detector (LFMD), which combines the advantages of duplex sequencing (DS) and the bottleneck sequencing system (BotSeqS) to maximize the utilization of duplicate reads. Compared with the existing state-of-the-art methods, DS, Du Novo, UMI-tools, and Unified Consensus Maker, our method achieves higher sensitivity, higher specificity (< 4 × 10−10 errors per base sequenced) and lower cost (reduced by ~70% at best) without involving additional experimental steps, customized adapters or molecular tags. LFMD is useful in areas where high precision is required, such as drug resistance prediction and cancer screening. As an example of LFMD’s applications, mitochondrial heterogeneity analysis of 28 human brain samples across different stages of Alzheimer’s Disease (AD) showed that the canonical oxidative damage related mutations, C:G>A:T, are significantly increased in the mid-stage group. This is consistent with the Mitochondrial Free Radical Theory of Aging, suggesting that AD may be linked to the aging of brain cells induced by oxidative damage.

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Deleterious consequences of antioxidant supplementation on lifespan in a wild-derived mammal

Biology Letters ◽

10.1098/rsbl.2013.0432 ◽

2013 ◽

Vol 9 (4) ◽

pp. 20130432 ◽

Cited By ~ 34

Author(s):

Colin Selman ◽

Jane S. McLaren ◽

Andrew R. Collins ◽

Garry G. Duthie ◽

John R. Speakman

Keyword(s):

Oxidative Damage ◽

Dietary Supplementation ◽

Causative Role ◽

Oxygen Species ◽

Antioxidant Supplementation ◽

Free Radical Theory ◽

Radical Theory ◽

Dna Oxidative Damage ◽

Age Related ◽

Hepatic Lipid Peroxidation

While oxidative damage owing to reactive oxygen species (ROS) often increases with advancing age and is associated with many age-related diseases, its causative role in ageing is controversial. In particular, studies that have attempted to modulate ROS-induced damage, either upwards or downwards, using antioxidant or genetic approaches, generally do not show a predictable effect on lifespan. Here, we investigated whether dietary supplementation with either vitamin E (α-tocopherol) or vitamin C (ascorbic acid) affected oxidative damage and lifespan in short-tailed field voles, Microtus agrestis . We predicted that antioxidant supplementation would reduce ROS-induced oxidative damage and increase lifespan relative to unsupplemented controls. Antioxidant supplementation for nine months reduced hepatic lipid peroxidation, but DNA oxidative damage to hepatocytes and lymphocytes was unaffected. Surprisingly, antioxidant supplementation significantly shortened lifespan in voles maintained under both cold (7 ± 2°C) and warm (22 ± 2°C) conditions. These data further question the predictions of free-radical theory of ageing and critically, given our previous research in mice, indicate that similar levels of antioxidants can induce widely different interspecific effects on lifespan.

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Reactive oxygen species and the free radical theory of aging

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2013.02.011 ◽

2013 ◽

Vol 60 ◽

pp. 1-4 ◽

Cited By ~ 333

Author(s):

Stefan I. Liochev

Keyword(s):

Reactive Oxygen Species ◽

Free Radical ◽

Reactive Oxygen ◽

Oxygen Species ◽

Free Radical Theory ◽

Radical Theory ◽

Theory Of Aging

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Effects of Caloric Restriction on Cardiac Oxidative Stress and Mitochondrial Bioenergetics: Potential Role of Cardiac Sirtuins

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/528935 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 29

Author(s):

Ken Shinmura

Keyword(s):

Oxidative Stress ◽

Free Radical ◽

Oxidative Damage ◽

Caloric Restriction ◽

Functional Decline ◽

Cellular Damage ◽

Free Radical Theory ◽

Radical Theory ◽

Stress Theory

The biology of aging has not been fully clarified, but the free radical theory of aging is one of the strongest aging theories proposed to date. The free radical theory has been expanded to the oxidative stress theory, in which mitochondria play a central role in the development of the aging process because of their critical roles in bioenergetics, oxidant production, and regulation of cell death. A decline in cardiac mitochondrial function associated with the accumulation of oxidative damage might be responsible, at least in part, for the decline in cardiac performance with age. In contrast, lifelong caloric restriction can attenuate functional decline with age, delay the onset of morbidity, and extend lifespan in various species. The effect of caloric restriction appears to be related to a reduction in cellular damage induced by reactive oxygen species. There is increasing evidence that sirtuins play an essential role in the reduction of mitochondrial oxidative stress during caloric restriction. We speculate that cardiac sirtuins attenuate the accumulation of oxidative damage associated with age by modifying specific mitochondrial proteins posttranscriptionally. Therefore, the distinct role of each sirtuin in the heart subjected to caloric restriction should be clarified to translate sirtuin biology into clinical practice.

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