Free Radicals and Mammalian Aging

Sanz, Alberto; Barja, Gustavo; Pamplona, Reinald; Leeuwenburgh, Christiaan

doi:10.1002/9783527627585.ch19

Cited by 6 publications

(8 citation statements)

References 272 publications

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“…In agreement with their low rates of mtROS production, most long-lived animal species studied have lower steady-state levels of 8-oxodG (a biomarker of DNA oxidation) in their mtDNA (Barja and Herrero 2000;Sanz et al 2009) and lower rates of urinary excretion of 8-oxo-7,8-dihydroguanine (Foksinski et al 2004) than short-lived ones. Long-lived birds also usually show lower oxidative damage to mtDNA in their tissues than short-lived rodents of similar body size .…”

Section: Mtdna Oxidation and Animal Longevitymentioning

confidence: 62%

“…Thus, long-lived animal species, including vertebrates and invertebrates, constitutively have lower (instead of higher) tissue levels of antioxidant enzymes and low molecular weight endogenous antioxidants (Perez-Campo et al 1998;Sanz et al 2010a, b), as well as repair systems (Salway et al 2010), than short-lived ones (reviewed in Pamplona and Barja 2007;Sanz et al 2009). That characteristic can thus explain why endogenous tissue antioxidants correlate negatively with longevity across species: long-lived animals have constitutively low levels of antioxidants because they produce ROS at a low rate.…”

Section: Mitochondrial Ros Production and Animal Longevitymentioning

confidence: 98%

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An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms

Pamplona

Barja

2011

Biogerontology

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Key mechanisms relating oxidative stress to longevity from an interespecies comparative approach are reviewed. Long-lived animal species show low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. Comparative physiology also shows that the specific compositional pattern of tissue macromolecules (proteins, lipids and nucleic acids) in long-lived animal species gives them an intrinsically high resistance to modification that likely contributes to their superior longevity. This is obtained in the case of lipids by decreasing the degree of fatty acid unsaturation, and in the case of proteins by lowering their methionine content. These findings are also substantiated from a phylogenomic approach. Nutritional or/and pharmacological interventions focused to modify some of these molecular traits were translated with modifications in animal longevity. It is proposed that natural selection tends to decrease the mitochondrial ROS generation and to increase the molecular resistance to the oxidative damage in long-lived species.

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Section: Mtdna Oxidation and Animal Longevitymentioning

confidence: 62%

Section: Mitochondrial Ros Production and Animal Longevitymentioning

confidence: 98%

An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms

Pamplona

Barja

2011

Biogerontology

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“…The mild uncoupling caused by proton transport lowers ⌬p and slightly stimulates electron transport, causing the complexes to become more oxidized and lowering the local concentration of oxygen; both of these effects decrease superoxide production. Thus, the induction of proton leak by hydroxynonenal limits mitochondrial ROS production as a feedback response to overproduction of superoxide by the respiratory chain (21,68,186). So, a possible antioxidant physiological function for UCPs has been proposed (68).…”

Section: Antioxidant Defense Mechanisms As Evolutionary Adaptations Tmentioning

confidence: 99%

“…With reference to mitochondrial free radical generation and maximum life span, all the published investigations about this subject have found that the rate of mitochondrial RS production is lower in the tissues of long-lived than in those of short-lived animal species independently of their mass-adjusted rates of O 2 consumption (12,117,154,156,185,186). In accordance with this low mitochondrial free radical production of long-lived species, there is an adaptive response concerning endogenous cellular antioxidant systems (154 -155).…”

Section: R855mentioning

confidence: 99%

Molecular and structural antioxidant defenses against oxidative stress in animals

Pamplona

Costantini

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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275

199

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In this review, it is our aim 1) to describe the high diversity in molecular and structural antioxidant defenses against oxidative stress in animals, 2) to extend the traditional concept of antioxidant to other structural and functional factors affecting the "whole" organism, 3) to incorporate, when supportable by evidence, mechanisms into models of life-history trade-offs and maternal/epigenetic inheritance, 4) to highlight the importance of studying the biochemical integration of redox systems, and 5) to discuss the link between maximum life span and antioxidant defenses. The traditional concept of antioxidant defenses emphasizes the importance of the chemical nature of molecules with antioxidant properties. Research in the past 20 years shows that animals have also evolved a high diversity in structural defenses that should be incorporated in research on antioxidant responses to reactive species. Although there is a high diversity in antioxidant defenses, many of them are evolutionary conserved across animal taxa. In particular, enzymatic defenses and heat shock response mediated by proteins show a low degree of variation. Importantly, activation of an antioxidant response may be also energetically and nutrient demanding. So knowledge of antioxidant mechanisms could allow us to identify and to quantify any underlying costs, which can help explain life-history trade-offs. Moreover, the study of inheritance mechanisms of antioxidant mechanisms has clear potential to evaluate the contribution of epigenetic mechanisms to stress response phenotype variation.

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“…Long-lived animals do not only produce fewer mtROS but their biological molecules are also more resistant to oxidative stress. The importance of such changes in longevity has been reviewed elsewhere [56]. The existence of such correlations indicates a strong evolutionary pressure to reduce oxidative damage in long-lived animals, but it does not prove that mitochondrial free radical production is the main driving force behind the aging process.…”

Section: Comparative Biology: Mitochondrial Free Radical Production mentioning

confidence: 99%

The Mitochondrial Free Radical Theory of Aging: A Critical View

Sanz¹,

Stefanatos²

2008

CAS

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156

109

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The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA. At its most orthodox MFRTA proposes that these free radicals damage mitochondrial DNA (mtDNA) and in turn provoke mutations that alter mitochondrial function (e.g. ATP production). According to this, oxidative damage to mtDNA negatively correlates with maximum life span in mammals. However, in contrast to MFRTA predictions, high levels of oxidative damage in mtDNA do not decrease longevity in mice. Moreover, mice with alterations in polymerase gamma (the mitochondrial DNA polymerase) accumulate 500 times higher levels of point mutations in mtDNA without suffering from accelerated aging. Dietary restriction (DR) is the only non-genetic treatment that clearly increases mean and maximum life span. According to MFRTA caloric restricted animals produce fewer mitochondrial reactive oxygen species (mtROS). However, DR alters more than free radical production (e.g. it decreases insulin signalling) and therefore the increase in longevity cannot be exclusively attributed to a decrease in mtROS generation. Thus, moderate exercise produces similar changes in free radical production and oxidative damage without increasing maximum life span. In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.

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Free Radicals and Mammalian Aging

Cited by 6 publications

References 272 publications

An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms

An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms

Molecular and structural antioxidant defenses against oxidative stress in animals

The Mitochondrial Free Radical Theory of Aging: A Critical View

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