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Journal ArticleDOI

The Free Radical Theory of Aging Is Dead. Long Live the Damage Theory

21 Jan 2014-Antioxidants & Redox Signaling (Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA)-Vol. 20, Iss: 4, pp 727-731
TL;DR: It is discussed that infidelity, heterogeneity, and imperfectness of each and every biological process may be responsible for the inevitable accumulation of by-products and other damage forms and biological imperfectness may help define the true root of aging.
Abstract: The free radical theory of aging posits that aging is caused by accumulation of damage inflicted by reactive oxygen species (ROS). Although this concept has been very useful in defining the contribution of oxidative damage to the aging process, an increasing number of studies contradict it. The idea that oxidative damage represents only one of many causes of aging also has limitations, as it does not explain causal relationships and inevitability of damage accumulation. Here, it is discussed that infidelity, heterogeneity, and imperfectness of each and every biological process may be responsible for the inevitable accumulation of by-products and other damage forms. Although ROS are prototypical by-products, their contribution to aging is governed by the metabolic organization of the cell, its protective systems, and genotype. These factors are controlled by natural selection and, like dietary and genetic interventions that extend lifespan, change the composition of cumulative damage and the rates...

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Citations
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Journal ArticleDOI
TL;DR: Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age- related diseases and promoting a healthy life span.
Abstract: Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.

239 citations

Journal ArticleDOI
TL;DR: In-depth knowledge of the molecular mechanisms of ROS actuation and their influence under steady-state and stressful conditions will pave the way for the development of novel therapeutic interventions to mitigate the harmful outcomes of ROS in the onset and progression of a variety of chronic inflammatory and age-related diseases.
Abstract: Since the Great Oxidation Event, about 2.4 billion years ago, the Earth is immersed in an oxidizing atmosphere. Thus, it has been proposed that excess oxygen, originally a waste product of photosynthetic cyanobacteria, induced oxidative stress and the production of reactive oxygen species (ROS), which have since acted as fundamental drivers of biologic evolution and eukaryogenesis. Indeed, throughout an organism's lifespan, ROS affect directly (as mutagens) or indirectly (as messengers and regulators) all structural and functional components of cells, and many aspects of cell biology. Whether left unchecked by protective antioxidant systems, excess ROS not only cause genomic mutations but also induce irreversible oxidative modification of proteins (protein oxidation and peroxidation), lipids and glycans (advanced lipoxidation and glycation end products), impairing their function and promoting disease or cell death. Conversely, low-level local ROS play an important role both as redox-signaling molecules in a wide spectrum of pathways involved in the maintenance of cellular homeostasis (MAPK/ERK, PTK/PTP, PI3K-AKT-mTOR), and regulating key transcription factors (NFκB/IκB, Nrf2/KEAP1, AP-1, p53, HIF-1). Consequently, ROS can shape a variety of cellular functions, including proliferation, differentiation, migration and apoptosis. In this review, we will give a brief overview of the relevance of ROS in both physiological and pathological processes, particularly inflammation and aging. In-depth knowledge of the molecular mechanisms of ROS actuation and their influence under steady-state and stressful conditions will pave the way for the development of novel therapeutic interventions. This will mitigate the harmful outcomes of ROS in the onset and progression of a variety of chronic inflammatory and age-related diseases.

225 citations


Cites background from "The Free Radical Theory of Aging Is..."

  • ...biological imperfectness drives the aging process, and 3) cumulative damage defines lifespan.(143,144) Accordingly,...

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Journal ArticleDOI
TL;DR: Recent developments in the understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases are discussed, with particular focus on the neurovascular component of these conditions.
Abstract: For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91phox and was considered to be a peculiarity of professional phagocytic cells. Over the last decade, several more homologs have been identified and based on current research, the NOX family consists of NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2 enzymes. NOXs are electron transporting membrane proteins that are responsible for reactive oxygen species (ROS) generation—primarily superoxide anion (O2●−), although hydrogen peroxide (H2O2) can also be generated. Elevated ROS leads to oxidative stress (OS), which has been associated with a myriad of inflammatory and degenerative pathologies. Interestingly, OS is also the commonality in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NOX enzymes are expressed in neurons, glial cells and cerebrovascular endothelial cells. NOX-mediated OS is identified as one of the main causes of cerebrovascular damage in neurodegenerative diseases. In this review, we will discuss recent developments in our understanding of the mechanisms linking NOX activity, OS and neurodegenerative diseases, with particular focus on the neurovascular component of these conditions. We conclude highlighting current challenges and future opportunities to combat age-related neurodegenerative disorders by targeting NOXs.

225 citations

Journal ArticleDOI
TL;DR: This paper reviews data on model organisms concerning the effects of exogenous antioxidants on the lifespan of model organisms and the legitimacy of antioxidant supplementation in human is considered.
Abstract: If aging is due to or contributed by free radical reactions, as postulated by the free radical theory of aging, lifespan of organisms should be extended by administration of exogenous antioxidants. This paper reviews data on model organisms concerning the effects of exogenous antioxidants (antioxidant vitamins, lipoic acid, coenzyme Q, melatonin, resveratrol, curcumin, other polyphenols, and synthetic antioxidants including antioxidant nanoparticles) on the lifespan of model organisms. Mechanisms of effects of antioxidants, often due to indirect antioxidant action or to action not related to the antioxidant properties of the compounds administered, are discussed. The legitimacy of antioxidant supplementation in human is considered.

219 citations


Cites background from "The Free Radical Theory of Aging Is..."

  • ...Ascorbic acid partially rescued the lifespan of superoxide dismutase (SOD)-deficient yeast Saccharomyces cerevisiae which was considerably reduced as a result of lack of this vital antioxidant enzyme [12]....

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  • ...Seen from that perspective, the “Free Radical Theory of Aging” (FRTA) [10], now more commonly termed the oxidative damage theory of ageing, seems to address a key facet of intrinsic biological instability of living systems [11, 12]....

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Journal ArticleDOI
TL;DR: The effect of ROS on osteoclasts differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases are examined.
Abstract: Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O2−) and hydrogen peroxide (H2O2), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.

204 citations


Cites background from "The Free Radical Theory of Aging Is..."

  • ...Rather, O2− interacts with NO to form peroxynitrite (ONOO●−), a strong oxidant capable of inducing DNA damage, disruption of the mitochondrial architecture, and irreversible protein modification [30]....

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  • ...Rather, O2− interacts with NO to form peroxynitrite (ONOO•−), a strong oxidant capable of inducing DNA damage, disruption of the mitochondrial architecture, and irreversible protein modification [30]....

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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


"The Free Radical Theory of Aging Is..." refers background in this paper

  • ...The free radical theory of aging [26] was originally described by Denham Harman in the 1950s [11]....

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Journal ArticleDOI
05 Jul 1996-Science
TL;DR: Support for this hypothesis includes the following observations: (i) Overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster and (ii) Variations in longevity among different species inversely correlate with the rates of mitochondrial generation of the superoxide anion radical and hydrogen peroxide.
Abstract: Under normal physiological conditions, the use of oxygen by cells of aerobic organisms generates potentially deleterious reactive oxygen metabolites. A chronic state of oxidative stress exists in cells because of an imbalance between prooxidants and antioxidants. The amount of oxidative damage increases as an organism ages and is postulated to be a major causal factor of senescence. Support for this hypothesis includes the following observations: (i) Overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster. (ii) Variations in longevity among different species inversely correlate with the rates of mitochondrial generation of the superoxide anion radical (O2) and hydrogen peroxide. (iii) Restriction of caloric intake lowers steady-state levels of oxidative stress and damage, retards age-associated changes, and extends the maximum life-span in mammals.

3,103 citations


"The Free Radical Theory of Aging Is..." refers background in this paper

  • ...The free radical theory of aging [26] was originally described by Denham Harman in the 1950s [11]....

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Journal ArticleDOI
28 Aug 1992-Science
TL;DR: The importance of protein oxidation in aging is supported by the observation that levels of oxidized proteins increase with animal age and may reflect age-related increases in rates of ROS generation, decreases in antioxidant activities, or losses in the capacity to degrade oxidized protein.
Abstract: A number of systems that generate oxygen free radicals catalyze the oxidative modification of proteins. Such modifications mark enzymes for degradation by cytosolic neutral alkaline proteases. Protein oxidation contributes to the pool of damaged enzymes, which increases in size during aging and in various pathological states. The age-related increase in amounts of oxidized protein may reflect the age-dependent accumulation of unrepaired DNA damage that, in a random manner, affects the concentrations or activities of numerous factors that govern the rates of protein oxidation and the degradation of oxidized protein.

2,498 citations


"The Free Radical Theory of Aging Is..." refers background in this paper

  • ...Oxidative damage received much attention in the field of aging because it could be monitored by using established analytical techniques [28] and be regulated by designated enzyme systems (superoxide dismutase, catalase, peroxiredoxin, glutathione peroxidase, methionine sulfoxide reductase, etc....

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  • ...Nevertheless, there is abundant literature on damage accumulation during aging that considers processes beyond oxidative damage [28]....

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  • ...There are numerous studies that demonstrate that ROS and oxidative damage increase with age [28], that reducing oxidative damage extends lifespan of various model organisms (yeast, nematodes, fruit flies, mice, etc....

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Journal ArticleDOI
24 Mar 2010-Nature
TL;DR: The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more, which means that over evolutionary time mutations have increased lifespan more than 2,000-fold.
Abstract: The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.

2,466 citations

Journal ArticleDOI
TL;DR: This review attempts to present the still-incomplete understanding of how reactive oxygen species are formed inside cells and the mechanisms by which they damage specific target molecules.
Abstract: The phenomenon of oxygen toxicity is universal, but only recently have we begun to understand its basis in molecular terms. Redox enzymes are notoriously nonspecific, transferring electrons to any good acceptor with which they make electronic contact. This poses a problem for aerobic organisms, since molecular oxygen is small enough to penetrate all but the most shielded active sites of redox enzymes. Adventitious electron transfers to oxygen create superoxide and hydrogen peroxide, which are partially reduced species that can oxidize biomolecules with which oxygen itself reacts poorly. This review attempts to present our still-incomplete understanding of how reactive oxygen species are formed inside cells and the mechanisms by which they damage specific target molecules. The vulnerability of cells to oxidation lies at the root of obligate anaerobiosis, spontaneous mutagenesis, and the use of oxidative stress as a biological weapon.

2,023 citations


"The Free Radical Theory of Aging Is..." refers background in this paper

  • ...Molecular oxygen is a prototypical reactive compound, which adventitiously reacts with the active sites of various enzymes, resulting in partially reduced oxygen species, the ROS, which damage cellular biomolecules [12]....

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

The paper discusses that the free radical theory of aging proposes that aging is caused by the accumulation of damage inflicted by reactive oxygen species (ROS). However, the paper also mentions that this theory has limitations and does not fully explain the aging process.