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Journal ArticleDOI

Updating the Free Radical Theory of Aging.

TL;DR: The observation of oxidative damage in the form of 7,8-dihydro-8-oxo-deoxyguanosine (8-OxodG) DNA oxidative lesions accumulating with age has been a cornerstone of the free radical theory of aging.
Abstract: The free radical theory of aging, one of the nine suggested hallmarks of aging (López-Otín et al., 2016), implicates the gradual accumulation of oxidative cellular damage as a fundamental driver of cellular aging (Harman, 1956; Miquel et al., 1980). This theory has evolved over time to emphasize the role of free radical induced mitochondrial DNA (mtDNA) mutations and the accumulation of mtDNA deletions (Miquel et al., 1980; Cortopassi et al., 1992; Michikawa et al., 1999). Given the proximity of mtDNA to the electron transport chain, a primary producer of free radicals, it postulates that the mutations would promote mitochondrial dysfunction and concomitantly increase free radical production in a positive feedback loop. The observation of oxidative damage in the form of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) DNA oxidative lesions accumulating with age has been a cornerstone of the free radical theory of aging (Fraga et al., 1990).

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Citations
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Journal ArticleDOI
TL;DR: In this paper , a review highlights various miniaturized surface engineered biosensors for the detection of reactive oxygen species (ROS) and highlights the developed sensors for detection through the help of various illustrative schemes.

5 citations

Journal ArticleDOI
TL;DR: In this paper , the authors investigated the anti-aging properties of Rhododendron nivale Hook (RNEA) and found that it possesses antiaging properties and the interaction of gut microbiota with RNEA is responsible for its antiaging effects.

5 citations

Posted ContentDOI
19 Feb 2022-bioRxiv
TL;DR: The results suggest that under normal in vivo conditions methionine oxidation is a biologically regulated process rather than a result of stochastic chemical damage.
Abstract: The oxidation of methionine side chains has emerged as an important posttranslational modification of proteins. A diverse array of low-throughput and targeted studies have suggested that the oxidation of methionine residues in select proteins can have diverse impacts on cell physiology, ranging from detrimental effects on protein structure and stability to functional roles in cell signaling. Despite its importance, the large-scale investigation of methionine oxidation in a complex matrix, such as the cellular proteome, has been historically hampered by technical limitations. Herein we report a methodology, Methionine Oxidation by Blocking (MobB), that allows for accurate and precise quantification of low levels of methionine oxidation typically observed in vivo. To demonstrate the utility of this methodology, we applied MobB to the brain tissues of young (6 m.o.) and old (20 m.o.) mice and identified over 280 novel sites for in vivo methionine oxidation. We further demonstrated that oxidation stoichiometries for specific methionine residues are highly consistent between individual animals and methionine sulfoxides are enriched in clusters of functionally related gene products including membrane and extracellular proteins. However, we did not detect significant changes in methionine oxidation in brains of old mice. Our results suggest that under normal in vivo conditions methionine oxidation is a biologically regulated process rather than a result of stochastic chemical damage.

4 citations

Journal ArticleDOI
TL;DR: In this article , a methodology called methionine oxidation by blocking (MobB) was proposed for quantifying low levels of methionines typically observed in vivo, which can have diverse impacts on cell physiology, ranging from detrimental effects on protein stability to functional roles in cell signaling.
Abstract: The oxidation of methionine has emerged as an important post-translational modification of proteins. A number of studies have suggested that the oxidation of methionines in select proteins can have diverse impacts on cell physiology, ranging from detrimental effects on protein stability to functional roles in cell signaling. Despite its importance, the large-scale investigation of methionine oxidation in a complex matrix, such as the cellular proteome, has been hampered by technical limitations. We report a methodology, methionine oxidation by blocking (MobB), that allows for accurate and precise quantification of low levels of methionine oxidation typically observed in vivo. To demonstrate the utility of this methodology, we analyzed the brain tissues of young (6 m.o.) and old (20 m.o.) mice and identified over 280 novel sites for in vivo methionine oxidation. We further demonstrated that oxidation stoichiometries for specific methionine residues are highly consistent between individual animals and methionine sulfoxides are enriched in clusters of functionally related gene products including membrane and extracellular proteins. However, we did not detect significant changes in methionine oxidation in brains of old mice. Our results suggest that under normal conditions, methionine oxidation may be a biologically regulated process rather than a result of stochastic chemical damage.

4 citations

Journal ArticleDOI
TL;DR: In this article , the authors examined the physiological function of the renin-angiotensin (RAS) and reactive oxygen species (ROS) sources in detail, highlighting how Ang II amplifies or drives mitochondrial dysfunction and telomere attrition underlying each hallmark of aging and contributes to the development of age-linked diseases.
Abstract: Aging is an inevitable progressive decline in physiological organ function that increases the chance of disease and death. The renin–angiotensin system (RAS) is involved in the regulation of vasoconstriction, fluid homeostasis, cell growth, fibrosis, inflammation, and oxidative stress. In recent years, unprecedented advancement has been made in the RAS study, particularly with the observation that angiotensin II (Ang II), the central product of the RAS, plays a significant role in aging and chronic disease burden with aging. Binding to its receptors (Ang II type 1 receptor – AT1R in particular), Ang II acts as a mediator in the aging process by increasing free radical production and, consequently, mitochondrial dysfunction and telomere attrition. In this review, we examine the physiological function of the RAS and reactive oxygen species (ROS) sources in detail, highlighting how Ang II amplifies or drives mitochondrial dysfunction and telomere attrition underlying each hallmark of aging and contributes to the development of aging and age-linked diseases. Accordingly, the Ang II/AT1R pathway opens a new preventive and therapeutic direction for delaying aging and reducing the incidence of age-related diseases in the future.

4 citations

References
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Journal ArticleDOI
TL;DR: It seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.
Abstract: The phenomenon of growth, decline and death—aging—has been the source of considerable speculation (1, 8, 10). This cycle seems to be a more or less direct function of the metabolic rate and this in turn depends on the species (animal or plant) on which are superimposed the factors of heredity and the effects of the stresses and strains of life—which alter the metabolic activity. The universality of this phenomenon suggests that the reactions which cause it are basically the same in all living things. Viewing this process in the light of present day free radical and radiation chemistry and of radiobiology, it seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.* Irradiation of living things induces mutation, cancer, and aging (9). Inasmuch as these also arise spontaneously in nature, it is natural to inquire if the processes might not be similar. It is believed that one mechanism of irradiation effect is through liberation of OH and HO 2 radicals (12). There is evidence, although indirect, that these two highly active free radicals are produced normally in living systems. In the first place, free radicals are present in living cells; this was recently demonstrated in vivo by a paramagnetic resonance absorption method (3). Further, it was shown that the concentration of free radicals increased with increasing metabolic activity in conformity with the postulates set forth some years ago that free radicals were involved in biologic oxidation-reduction reactions (11, 13). Are some of these free radicals OH and/or HO2, or radicals of a similar high order of reactivity, and where might they arise in the cell? The most likely source of OH and HO2 radicals, at least in the animal cell, would be the interaction of the respiratory enzymes involved

7,917 citations


"Updating the Free Radical Theory of..." refers background in this paper

  • ...The free radical theory of aging, one of the nine suggested hallmarks of aging (López-Otín et al., 2016), implicates the gradual accumulation of oxidative cellular damage as a fundamental driver of cellular aging (Harman, 1956; Miquel et al., 1980)....

    [...]

  • ...A major assumption of the free radical theory of aging is that random de novo or somatic mtDNA mutations gradually accumulate over time, eventually reaching pathological levels (Harman, 1956, 1972)....

    [...]

  • ..., 2016), implicates the gradual accumulation of oxidative cellular damage as a fundamental driver of cellular aging (Harman, 1956; Miquel et al., 1980)....

    [...]

Journal ArticleDOI
27 May 2004-Nature
TL;DR: The results provide a causative link between mtDNA mutations and ageing phenotypes in mammals by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase.
Abstract: Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.

2,429 citations


"Updating the Free Radical Theory of..." refers background in this paper

  • ...These mice not only showed an increase in mtDNA mutation burden, the vast majority of which were transition mutations, they also displayed a reduced lifespan and the premature onset of agingrelated phenotype with no evidence of increased oxidative stress (Trifunovic et al., 2004)....

    [...]

  • ...This paper provided a causative link between the buildup of polymerase induced mtDNA mutations and aging, forming the foundation for a new polymerase γ focused theory of mitochondrial aging (Trifunovic et al., 2004; Matkarimov and Saparbaev, 2020)....

    [...]

  • ...However, recent studies showing the accumulation of mtDNA mutations with aging did not observe increases in mtDNA transversion mutations, but rather increases in mtDNA transition mutations (A↔ G, C↔ T) (Trifunovic et al., 2004; Kennedy et al., 2013), believed to be the hallmark of mitochondrial polymerase γ errors rather than oxidative damage (Spelbrink et al....

    [...]

Journal ArticleDOI
TL;DR: The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization, the rate increasing with the rates of oxygen consumption, which ultimately causes death.
Abstract: : The author suggests that the maximal life span of a given mammalian species is largely an expression of genetic control over the rate of oxygen utilization. The latter determines the rate of accumulation of mitochondrial damage produced by free radical reactions, the rate increasing with the rate of oxygen consumption, which ultimately causes death.

1,858 citations

Journal ArticleDOI
TL;DR: Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients.

1,362 citations


"Updating the Free Radical Theory of..." refers background in this paper

  • ...HIV-positive individuals experience a reported decrease in lifespan of up to 10 years (Lohse et al., 2007; Antiretroviral Therapy Cohort Collaboration, 2008), as well as earlier onset and higher prevalence of agerelated comorbidities (Guaraldi et al., 2011)....

    [...]

Journal ArticleDOI
TL;DR: The weight of evidence strongly suggests a link between such damage and the pathogenesis of disease, and the role of 8-OH-dG in disease, although exact roles remain to be elucidated.
Abstract: The generation of reactive oxygen species may be both beneficial to cells, performing a function in inter- and intracellular signalling, and detrimental, modifying cellular biomolecules, accumulation of which has been associated with numerous diseases. Of the molecules subject to oxidative modification, DNA has received the greatest attention, with biomarkers of exposure and effect closest to validation. Despite nearly a quarter of a century of study, and a large number of base- and sugar-derived DNA lesions having been identified, the majority of studies have focussed upon the guanine modification, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-OH-dG). For the most part, the biological significance of other lesions has not, as yet, been investigated. In contrast, the description and characterisation of enzyme systems responsible for repairing oxidative DNA base damage is growing rapidly, being the subject of intense study. However, there remain notable gaps in our knowledge of which repair proteins remove which lesions, plus, as more lesions identified, new processes/substrates need to be determined. There are many reports describing elevated levels of oxidatively modified DNA lesions, in various biological matrices, in a plethora of diseases; however, for the majority of these the association could merely be coincidental, and more detailed studies are required. Nevertheless, even based simply upon reports of studies investigating the potential role of 8-OH-dG in disease, the weight of evidence strongly suggests a link between such damage and the pathogenesis of disease. However, exact roles remain to be elucidated.

1,268 citations


"Updating the Free Radical Theory of..." refers background in this paper

  • ..., 2014), is one of the 37major oxidative lesions, and is known to induce transversion mutations (A↔ C, A ↔ T, C ↔ G, G ↔ T) (Evans et al., 2004)....

    [...]

  • ..., 1989; Kreutzer and Essigmann, 1998), one or more of the other 37 products of oxidative damage (Evans et al., 2004), some of which induce transition mutations, may contribute to the somatic mtDNA transition mutation burden observed with older age (Kennedy et al....

    [...]

Trending Questions (1)
How does the free radical ageing theory explain the ageing process?

The free radical theory of aging suggests that the gradual accumulation of oxidative cellular damage, caused by free radicals, is a fundamental driver of cellular aging. This theory emphasizes the role of mitochondrial DNA mutations and the accumulation of mtDNA deletions in promoting mitochondrial dysfunction and increasing free radical production.