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Free-radical theory of aging

February 27, 2023

The free radical theory of aging (FRTA) states that organisms age because cells accumulate free radical damage over time.[1] A free radical is any atom or molecule that has a single unpaired electron in an outer shell.[2] While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive.[3] For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.[4]

Strictly speaking, the free radical theory is only concerned with free radicals such as superoxide ( O2− ), but it has since been expanded to encompass oxidative damage from other reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), or peroxynitrite (OONO−).[4]

Denham Harman first proposed the free radical theory of aging in the 1950s,[5] and in the 1970s extended the idea to implicate mitochondrial production of ROS.[6]

In some model organisms, such as yeast and Drosophila, there is evidence that reducing oxidative damage can extend lifespan.[7] However, in mice, only 1 of the 18 genetic alterations (SOD-1 deletion) that block antioxidant defences, shortened lifespan.[8] Similarly, in roundworms (Caenorhabditis elegans), blocking the production of the naturally occurring antioxidant superoxide dismutase has recently been shown to increase lifespan.[9] Whether reducing oxidative damage below normal levels is sufficient to extend lifespan remains an open and controversial question.

Background

The free radical theory of aging was conceived by Denham Harman in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems.[10] This was also before anyone invoked free radicals as a cause of degenerative diseases.[11] Two sources inspired Harman: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption, and 2) Rebeca Gerschman's observation that hyperbaric oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon: oxygen free radicals.[10][12] Noting that radiation causes "mutation, cancer and aging", Harman argued that oxygen free radicals produced during normal respiration would cause cumulative damage which would eventually lead to organismal loss of functionality, and ultimately death.[10][12]

In later years, the free radical theory was expanded to include not only aging per se, but also age-related diseases.[11] Free radical damage within cells has been linked to a range of disorders including cancer, arthritis, atherosclerosis, Alzheimer's disease, and diabetes.[13] There has been some evidence to suggest that free radicals and some reactive nitrogen species trigger and increase cell death mechanisms within the body such as apoptosis and in extreme cases necrosis.[14]

In 1972, Harman modified his original theory.[11] In its current form, this theory proposes that reactive oxygen species (ROS) that are produced in the mitochondria, causes damage to certain macromolecules including lipids, proteins and most importantly mitochondrial DNA.[15] This damage then causes mutations which lead to an increase of ROS production and greatly enhance the accumulation of free radicals within cells.[15] This mitochondrial theory has been more widely accepted that it could play a major role in contributing to the aging process.[16]

Since Harman first proposed the free radical theory of aging, there have been continual modifications and extensions to his original theory.[16]

Processes

 
In chemistry, a free radical is any atom, molecule or ion with an unpaired valence electron.

Free radicals are atoms or molecules containing unpaired electrons.[2] Electrons normally exist in pairs in specific orbitals in atoms or molecules.[17] Free radicals, which contain only a single electron in any orbital, are usually unstable toward losing or picking up an extra electron, so that all electrons in the atom or molecule will be paired.[17]

The unpaired electron does not imply charge; free radicals can be positively charged, negatively charged, or neutral.

Damage occurs when the free radical encounters another molecule and seeks to find another electron to pair its unpaired electron. The free radical often pulls an electron off a neighboring molecule, causing the affected molecule to become a free radical itself. The new free radical can then pull an electron off the next molecule, and a chemical chain reaction of radical production occurs.[18] The free radicals produced in such reactions often terminate by removing an electron from a molecule which becomes changed or cannot function without it, especially in biology. Such an event causes damage to the molecule, and thus to the cell that contains it (since the molecule often becomes dysfunctional).

The chain reaction caused by free radicals can lead to cross-linking of atomic structures. In cases where the free radical-induced chain reaction involves base pair molecules in a strand of DNA, the DNA can become cross-linked.[19]

DNA cross-linking can in turn lead to various effects of aging, especially cancer.[20] Other cross-linking can occur between fat and protein molecules, which leads to wrinkles.[21] Free radicals can oxidize LDL, and this is a key event in the formation of plaque in arteries, leading to heart disease and stroke.[22] These are examples of how the free-radical theory of aging has been used to neatly "explain" the origin of many chronic diseases.[23]

Free radicals that are thought to be involved in the process of aging include superoxide and nitric oxide.[24] Specifically, an increase in superoxide affects aging whereas a decrease in nitric oxide formation, or its bioavailability, does the same.[24]

Antioxidants are helpful in reducing and preventing damage from free radical reactions because of their ability to donate electrons which neutralize the radical without forming another. Ascorbic acid, for example, can lose an electron to a free radical and remain stable itself by passing its unstable electron around the antioxidant molecule.[25]

This has led to the hypothesis that large amounts of antioxidants,[26] with their ability to decrease the numbers of free radicals, might lessen the radical damage causing chronic diseases, and even radical damage responsible for aging.

Evidence

Numerous studies have demonstrated a role for free radicals in the aging process and thus tentatively support the free radical theory of aging. Studies have shown a significant increase in superoxide radical (SOR) formation and lipid peroxidation in aging rats.[27] Chung et al. suggest ROS production increases with age and indicated the conversion of XDH to XOD may be an important contributing factor.[28] This was supported by a study that showed superoxide production by xanthine oxidase and NO synthase in mesenteric arteries was higher in older rats than young ones.[29]

Hamilton et al. examined the similarities in impaired endothelial function in hypertension and aging in humans and found a significant overproduction of superoxide in both.[30] This finding is supported by a 2007 study which found that endothelial oxidative stress develops with aging in healthy men and is related to reductions in endothelium-dependent dilation.[31] Furthermore, a study using cultured smooth muscle cells displayed increased ROS in cells derived from older mice.[32] These findings were supported by a second study using Leydig cells isolated from the testes of young and old rats.[33]

The Choksi et al. experiment with Ames dwarf (DW) mice suggests the lower levels of endogenous ROS production in DW mice may be a factor in their resistance to oxidative stress and long life.[34] Lener et al. suggest Nox4 activity increases oxidative damage in human umbilical vein endothelial cells via superoxide overproduction.[35] Furthermore, Rodriguez-Manas et al. found endothelial dysfunction in human vessels is due to the collective effect of vascular inflammation and oxidative stress.[36]

Sasaki et al. reported superoxide-dependent chemiluminescence was inversely proportionate to maximum lifespan in mice, Wistar rats, and pigeons.[37] They suggest ROS signalling may be a determinant in the aging process.[37] In humans, Mendoza-Nunez et al. propose an age of 60 years or older may be linked with increased oxidative stress.[38] Miyazawa found mitochondrial superoxide anion production can lead to organ atrophy and dysfunction via mitochondrial- mediated apoptosis.[39] In addition, they suggest mitochondrial superoxide anion plays an essential part in aging.[40] Lund et al. demonstrated the role of endogenous extracellular superoxide dismutase in protecting against endothelial dysfunction during the aging process using mice.[41]

Modifications of the theory

One of the main criticisms of the free radical theory of aging is directed at the suggestion that free radicals are responsible for the damage of biomolecules, thus being a major reason for cellular senescence and organismal aging.[42]: 81  Several modifications have been proposed to integrate current research into the overall theory.

Mitochondrial theory of aging

Main article: Mitochondrial theory of ageing
 
Major sources of reactive oxygen species in living systems

The mitochondrial theory of aging was first proposed in 1978,[43][44] and two years later, the mitochondrial free-radical theory of aging was introduced.[45] The theory implicates the mitochondria as the chief target of radical damage, since there is a known chemical mechanism by which mitochondria can produce ROS, mitochondrial components such as mtDNA are not as well protected as nuclear DNA, and by studies comparing damage to nuclear and mtDNA that demonstrate higher levels of radical damage on the mitochondrial molecules.[46] Electrons may escape from metabolic processes in the mitochondria like the Electron transport chain, and these electrons may in turn react with water to form ROS such as the superoxide radical, or via an indirect route the hydroxyl radical. These radicals then damage the mitochondria's DNA and proteins, and these damage components in turn are more liable to produce ROS byproducts. Thus a positive feedback loop of oxidative stress is established that, over time, can lead to the deterioration of cells and later organs and the entire body.[42]

This theory has been widely debated[47] and it is still unclear how ROS induced mtDNA mutations develop.[42] Conte et al. suggest iron-substituted zinc fingers may generate free radicals due to the zinc finger proximity to DNA and thus lead to DNA damage.[48]

Afanas'ev suggests the superoxide dismutation activity of CuZnSOD demonstrates an important link between life span and free radicals.[49] The link between CuZnSOD and life span was demonstrated by Perez et al. who indicated mice life span was affected by the deletion of the Sod1 gene which encodes CuZnSOD.[50]

Contrary to the usually observed association between mitochondrial ROS (mtROS) and a decline in longevity, Yee et al. recently observed increased longevity mediated by mtROS signaling in an apoptosis pathway. This serves to support the possibility that observed correlations between ROS damage and aging are not necessarily indicative of the causal involvement of ROS in the aging process but are more likely due to their modulating signal transduction pathways that are part of cellular responses to the aging process.[51]

Epigenetic oxidative redox shift (EORS) theory of aging

Brewer proposed a theory which integrates the free radical theory of aging with the insulin signalling effects in aging.[52] Brewer's theory suggests "sedentary behaviour associated with age triggers an oxidized redox shift and impaired mitochondrial function".[52] This mitochondrial impairment leads to more sedentary behaviour and accelerated aging.[52]

Metabolic stability theory of aging

The metabolic stability theory of aging suggests it is the cells ability to maintain stable concentration of ROS which is the primary determinant of lifespan.[53] This theory criticizes the free radical theory because it ignores that ROS are specific signalling molecules which are necessary for maintaining normal cell functions.[53]

Mitohormesis

Oxidative stress may promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of ROS.[54] In mammals, the question of the net effect of reactive oxygen species on aging is even less clear.[55][56][57] Recent epidemiological findings support the process of mitohormesis in humans, and even suggest that the intake of exogenous antioxidants may increase disease prevalence in humans (according to the theory, because they prevent the stimulation of the organism's natural response to the oxidant compounds which not only neutralizes them but provides other benefits as well).[58]

Effects of calorie restriction

Main article: Calorie restriction

Studies have demonstrated that calorie restriction displays positive effects on the lifespan of organisms even though it is accompanied by increases in oxidative stress.[49] Many studies suggest this may be due to anti-oxidative action,[49] oxidative stress suppression,[59] or oxidative stress resistance[60] which occurs in calorie restriction. Fontana et al. suggest calorie restriction influenced numerous signal pathways through the reduction of insulin-like growth factor I (IGF-1).[61] Additionally they suggest antioxidant SOD and catalase are involved in the inhibition of this nutrient signalling pathway.[61]

The increase in life expectancy observed during some calorie restriction studies which can occur with lack of decreases or even increases in O2 consumption is often inferred as opposing the mitochondrial free radical theory of aging.[49][62] According to a study by G. Barja, significant decreases in mitochondrial oxygen radical production (per unit of O2 consumed) occur during dietary restriction, aerobic exercise, chronic exercise, and hyperthyroidism.[62] Additionally, mitochondrial oxygen radical generation is lower in long-lived birds than in short-lived mammals of comparable body size and metabolic rate. Thus, mitochondrial ROS production must be regulated independently of O2 consumption in a variety of species, tissues and physiologic states.[62]

Challenges to the theory

Naked mole-rat

The naked mole-rat is a long-lived (32 years) rodent. As reviewed by Lewis et al.,[63] (2013), levels of ROS production in the naked mole rat are similar to that of another rodent, the relatively short-lived mouse (4 years). They concluded that it is not oxidative stress that modulates health-span and longevity in these rodents, but rather other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress.[63] In the naked mole-rat, a likely important cytoprotective mechanism that could provide longevity assurance is elevated expression of DNA repair genes involved in several key DNA repair pathways.[64] (See DNA damage theory of aging.) Compared with the mouse, the naked mole rat had significantly higher expression levels of genes essential for the DNA repair pathways of DNA mismatch repair, non-homologous end joining and base excision repair.[64]

Birds

Among birds, parrots live about five times longer than quail. ROS production in heart, skeletal muscle, liver and intact erythrocytes was found to be similar in parrots and quail and showed no correspondence with longevity difference.[65] These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging.[65]

See also

References

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  64. ^ a b MacRae SL, Croken MM, Calder RB, Aliper A, Milholland B, White RR, Zhavoronkov A, Gladyshev VN, Seluanov A, Gorbunova V, Zhang ZD, Vijg J (2015). "DNA repair in species with extreme lifespan differences". Aging. 7 (12): 1171–84. doi:10.18632/aging.100866. PMC 4712340. PMID 26729707.
  65. ^ a b Montgomery MK, Hulbert AJ, Buttemer WA (2012). "Does the oxidative stress theory of aging explain longevity differences in birds? I. Mitochondrial ROS production". Exp. Gerontol. 47 (3): 203–10. doi:10.1016/j.exger.2011.11.006. PMID 22123429. S2CID 984298.

External links

Calorie restriction

  • Calorie Restriction Society.

Biology of Aging

  • Damage-Based Theories of Aging Includes a discussion of the free radical theory of aging.

February 27, 2023
free, radical, theory, aging, this, article, needs, more, medical, references, verification, relies, heavily, primary, sources, please, review, contents, article, appropriate, references, unsourced, poorly, sourced, material, challenged, removed, find, sources. This article needs more medical references for verification or relies too heavily on primary sources Please review the contents of the article and add the appropriate references if you can Unsourced or poorly sourced material may be challenged and removed Find sources Free radical theory of aging news newspapers books scholar JSTOR May 2015 The free radical theory of aging FRTA states that organisms age because cells accumulate free radical damage over time 1 A free radical is any atom or molecule that has a single unpaired electron in an outer shell 2 While a few free radicals such as melanin are not chemically reactive most biologically relevant free radicals are highly reactive 3 For most biological structures free radical damage is closely associated with oxidative damage Antioxidants are reducing agents and limit oxidative damage to biological structures by passivating them from free radicals 4 Strictly speaking the free radical theory is only concerned with free radicals such as superoxide O2 but it has since been expanded to encompass oxidative damage from other reactive oxygen species ROS such as hydrogen peroxide H2O2 or peroxynitrite OONO 4 Denham Harman first proposed the free radical theory of aging in the 1950s 5 and in the 1970s extended the idea to implicate mitochondrial production of ROS 6 In some model organisms such as yeast and Drosophila there is evidence that reducing oxidative damage can extend lifespan 7 However in mice only 1 of the 18 genetic alterations SOD 1 deletion that block antioxidant defences shortened lifespan 8 Similarly in roundworms Caenorhabditis elegans blocking the production of the naturally occurring antioxidant superoxide dismutase has recently been shown to increase lifespan 9 Whether reducing oxidative damage below normal levels is sufficient to extend lifespan remains an open and controversial question Contents 1 Background 2 Processes 3 Evidence 4 Modifications of the theory 4 1 Mitochondrial theory of aging 4 2 Epigenetic oxidative redox shift EORS theory of aging 4 3 Metabolic stability theory of aging 4 4 Mitohormesis 4 5 Effects of calorie restriction 5 Challenges to the theory 5 1 Naked mole rat 5 2 Birds 6 See also 7 References 8 External links 8 1 Calorie restriction 8 2 Biology of AgingBackground EditThe free radical theory of aging was conceived by Denham Harman in the 1950s when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems 10 This was also before anyone invoked free radicals as a cause of degenerative diseases 11 Two sources inspired Harman 1 the rate of living theory which holds that lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption and 2 Rebeca Gerschman s observation that hyperbaric oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon oxygen free radicals 10 12 Noting that radiation causes mutation cancer and aging Harman argued that oxygen free radicals produced during normal respiration would cause cumulative damage which would eventually lead to organismal loss of functionality and ultimately death 10 12 In later years the free radical theory was expanded to include not only aging per se but also age related diseases 11 Free radical damage within cells has been linked to a range of disorders including cancer arthritis atherosclerosis Alzheimer s disease and diabetes 13 There has been some evidence to suggest that free radicals and some reactive nitrogen species trigger and increase cell death mechanisms within the body such as apoptosis and in extreme cases necrosis 14 In 1972 Harman modified his original theory 11 In its current form this theory proposes that reactive oxygen species ROS that are produced in the mitochondria causes damage to certain macromolecules including lipids proteins and most importantly mitochondrial DNA 15 This damage then causes mutations which lead to an increase of ROS production and greatly enhance the accumulation of free radicals within cells 15 This mitochondrial theory has been more widely accepted that it could play a major role in contributing to the aging process 16 Since Harman first proposed the free radical theory of aging there have been continual modifications and extensions to his original theory 16 Processes Edit In chemistry a free radical is any atom molecule or ion with an unpaired valence electron Free radicals are atoms or molecules containing unpaired electrons 2 Electrons normally exist in pairs in specific orbitals in atoms or molecules 17 Free radicals which contain only a single electron in any orbital are usually unstable toward losing or picking up an extra electron so that all electrons in the atom or molecule will be paired 17 The unpaired electron does not imply charge free radicals can be positively charged negatively charged or neutral Damage occurs when the free radical encounters another molecule and seeks to find another electron to pair its unpaired electron The free radical often pulls an electron off a neighboring molecule causing the affected molecule to become a free radical itself The new free radical can then pull an electron off the next molecule and a chemical chain reaction of radical production occurs 18 The free radicals produced in such reactions often terminate by removing an electron from a molecule which becomes changed or cannot function without it especially in biology Such an event causes damage to the molecule and thus to the cell that contains it since the molecule often becomes dysfunctional The chain reaction caused by free radicals can lead to cross linking of atomic structures In cases where the free radical induced chain reaction involves base pair molecules in a strand of DNA the DNA can become cross linked 19 DNA cross linking can in turn lead to various effects of aging especially cancer 20 Other cross linking can occur between fat and protein molecules which leads to wrinkles 21 Free radicals can oxidize LDL and this is a key event in the formation of plaque in arteries leading to heart disease and stroke 22 These are examples of how the free radical theory of aging has been used to neatly explain the origin of many chronic diseases 23 Free radicals that are thought to be involved in the process of aging include superoxide and nitric oxide 24 Specifically an increase in superoxide affects aging whereas a decrease in nitric oxide formation or its bioavailability does the same 24 Antioxidants are helpful in reducing and preventing damage from free radical reactions because of their ability to donate electrons which neutralize the radical without forming another Ascorbic acid for example can lose an electron to a free radical and remain stable itself by passing its unstable electron around the antioxidant molecule 25 This has led to the hypothesis that large amounts of antioxidants 26 with their ability to decrease the numbers of free radicals might lessen the radical damage causing chronic diseases and even radical damage responsible for aging Evidence EditNumerous studies have demonstrated a role for free radicals in the aging process and thus tentatively support the free radical theory of aging Studies have shown a significant increase in superoxide radical SOR formation and lipid peroxidation in aging rats 27 Chung et al suggest ROS production increases with age and indicated the conversion of XDH to XOD may be an important contributing factor 28 This was supported by a study that showed superoxide production by xanthine oxidase and NO synthase in mesenteric arteries was higher in older rats than young ones 29 Hamilton et al examined the similarities in impaired endothelial function in hypertension and aging in humans and found a significant overproduction of superoxide in both 30 This finding is supported by a 2007 study which found that endothelial oxidative stress develops with aging in healthy men and is related to reductions in endothelium dependent dilation 31 Furthermore a study using cultured smooth muscle cells displayed increased ROS in cells derived from older mice 32 These findings were supported by a second study using Leydig cells isolated from the testes of young and old rats 33 The Choksi et al experiment with Ames dwarf DW mice suggests the lower levels of endogenous ROS production in DW mice may be a factor in their resistance to oxidative stress and long life 34 Lener et al suggest Nox4 activity increases oxidative damage in human umbilical vein endothelial cells via superoxide overproduction 35 Furthermore Rodriguez Manas et al found endothelial dysfunction in human vessels is due to the collective effect of vascular inflammation and oxidative stress 36 Sasaki et al reported superoxide dependent chemiluminescence was inversely proportionate to maximum lifespan in mice Wistar rats and pigeons 37 They suggest ROS signalling may be a determinant in the aging process 37 In humans Mendoza Nunez et al propose an age of 60 years or older may be linked with increased oxidative stress 38 Miyazawa found mitochondrial superoxide anion production can lead to organ atrophy and dysfunction via mitochondrial mediated apoptosis 39 In addition they suggest mitochondrial superoxide anion plays an essential part in aging 40 Lund et al demonstrated the role of endogenous extracellular superoxide dismutase in protecting against endothelial dysfunction during the aging process using mice 41 Modifications of the theory EditOne of the main criticisms of the free radical theory of aging is directed at the suggestion that free radicals are responsible for the damage of biomolecules thus being a major reason for cellular senescence and organismal aging 42 81 Several modifications have been proposed to integrate current research into the overall theory Mitochondrial theory of aging Edit Main article Mitochondrial theory of ageing Major sources of reactive oxygen species in living systems The mitochondrial theory of aging was first proposed in 1978 43 44 and two years later the mitochondrial free radical theory of aging was introduced 45 The theory implicates the mitochondria as the chief target of radical damage since there is a known chemical mechanism by which mitochondria can produce ROS mitochondrial components such as mtDNA are not as well protected as nuclear DNA and by studies comparing damage to nuclear and mtDNA that demonstrate higher levels of radical damage on the mitochondrial molecules 46 Electrons may escape from metabolic processes in the mitochondria like the Electron transport chain and these electrons may in turn react with water to form ROS such as the superoxide radical or via an indirect route the hydroxyl radical These radicals then damage the mitochondria s DNA and proteins and these damage components in turn are more liable to produce ROS byproducts Thus a positive feedback loop of oxidative stress is established that over time can lead to the deterioration of cells and later organs and the entire body 42 This theory has been widely debated 47 and it is still unclear how ROS induced mtDNA mutations develop 42 Conte et al suggest iron substituted zinc fingers may generate free radicals due to the zinc finger proximity to DNA and thus lead to DNA damage 48 Afanas ev suggests the superoxide dismutation activity of CuZnSOD demonstrates an important link between life span and free radicals 49 The link between CuZnSOD and life span was demonstrated by Perez et al who indicated mice life span was affected by the deletion of the Sod1 gene which encodes CuZnSOD 50 Contrary to the usually observed association between mitochondrial ROS mtROS and a decline in longevity Yee et al recently observed increased longevity mediated by mtROS signaling in an apoptosis pathway This serves to support the possibility that observed correlations between ROS damage and aging are not necessarily indicative of the causal involvement of ROS in the aging process but are more likely due to their modulating signal transduction pathways that are part of cellular responses to the aging process 51 Epigenetic oxidative redox shift EORS theory of aging Edit Brewer proposed a theory which integrates the free radical theory of aging with the insulin signalling effects in aging 52 Brewer s theory suggests sedentary behaviour associated with age triggers an oxidized redox shift and impaired mitochondrial function 52 This mitochondrial impairment leads to more sedentary behaviour and accelerated aging 52 Metabolic stability theory of aging Edit The metabolic stability theory of aging suggests it is the cells ability to maintain stable concentration of ROS which is the primary determinant of lifespan 53 This theory criticizes the free radical theory because it ignores that ROS are specific signalling molecules which are necessary for maintaining normal cell functions 53 Mitohormesis Edit Oxidative stress may promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of ROS 54 In mammals the question of the net effect of reactive oxygen species on aging is even less clear 55 56 57 Recent epidemiological findings support the process of mitohormesis in humans and even suggest that the intake of exogenous antioxidants may increase disease prevalence in humans according to the theory because they prevent the stimulation of the organism s natural response to the oxidant compounds which not only neutralizes them but provides other benefits as well 58 Effects of calorie restriction Edit Main article Calorie restriction Studies have demonstrated that calorie restriction displays positive effects on the lifespan of organisms even though it is accompanied by increases in oxidative stress 49 Many studies suggest this may be due to anti oxidative action 49 oxidative stress suppression 59 or oxidative stress resistance 60 which occurs in calorie restriction Fontana et al suggest calorie restriction influenced numerous signal pathways through the reduction of insulin like growth factor I IGF 1 61 Additionally they suggest antioxidant SOD and catalase are involved in the inhibition of this nutrient signalling pathway 61 The increase in life expectancy observed during some calorie restriction studies which can occur with lack of decreases or even increases in O2 consumption is often inferred as opposing the mitochondrial free radical theory of aging 49 62 According to a study by G Barja significant decreases in mitochondrial oxygen radical production per unit of O2 consumed occur during dietary restriction aerobic exercise chronic exercise and hyperthyroidism 62 Additionally mitochondrial oxygen radical generation is lower in long lived birds than in short lived mammals of comparable body size and metabolic rate Thus mitochondrial ROS production must be regulated independently of O2 consumption in a variety of species tissues and physiologic states 62 Challenges to the theory EditNaked mole rat Edit The naked mole rat is a long lived 32 years rodent As reviewed by Lewis et al 63 2013 levels of ROS production in the naked mole rat are similar to that of another rodent the relatively short lived mouse 4 years They concluded that it is not oxidative stress that modulates health span and longevity in these rodents but rather other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress 63 In the naked mole rat a likely important cytoprotective mechanism that could provide longevity assurance is elevated expression of DNA repair genes involved in several key DNA repair pathways 64 See DNA damage theory of aging Compared with the mouse the naked mole rat had significantly higher expression levels of genes essential for the DNA repair pathways of DNA mismatch repair non homologous end joining and base excision repair 64 Birds Edit Among birds parrots live about five times longer than quail ROS production in heart skeletal muscle liver and intact erythrocytes was found to be similar in parrots and quail and showed no correspondence with longevity difference 65 These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging 65 See also EditAmerican Aging Association Life extension List of life extension related topics Senescence Calorie restriction Denham Harman Mitochondrial theory of ageingReferences Edit Hekimi S Lapointe J Wen Y Taking a good look at free radicals in the aging process Trends In Cell Biology 2011 21 10 569 76 a b Erbas M Sekerci H Importance of Free Radicals and Occurring During Food Processing Serbest Radikallerin Onemi Ve Gida Isleme Sirasinda Olusumu 2011 36 6 349 56 Herrling T Jung K Fuchs J 2008 The role of melanin as protector against free radicals in skin and its role as free radical indicator in hair Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy 69 5 1429 35 Bibcode 2008AcSpA 69 1429H doi 10 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Partridge L Longo VD Extending healthy life span from yeast to humans Science New York NY 2010 328 5976 321 6 a b c Barja G Mitochondrial oxygen consumption and reactive oxygen species production are independently modulated implications for aging studies Rejuvenation Research 2007 10 2 215 24 a b Lewis KN Andziak B Yang T Buffenstein R 2013 The naked mole rat response to oxidative stress just deal with it Antioxid Redox Signal 19 12 1388 99 doi 10 1089 ars 2012 4911 PMC 3791056 PMID 23025341 a b MacRae SL Croken MM Calder RB Aliper A Milholland B White RR Zhavoronkov A Gladyshev VN Seluanov A Gorbunova V Zhang ZD Vijg J 2015 DNA repair in species with extreme lifespan differences Aging 7 12 1171 84 doi 10 18632 aging 100866 PMC 4712340 PMID 26729707 a b Montgomery MK Hulbert AJ Buttemer WA 2012 Does the oxidative stress theory of aging explain longevity differences in birds I Mitochondrial ROS production Exp Gerontol 47 3 203 10 doi 10 1016 j exger 2011 11 006 PMID 22123429 S2CID 984298 External links EditCalorie restriction Edit Calorie Restriction Society Biology of Aging Edit Damage Based Theories of Aging Includes a discussion of the free radical theory of aging Retrieved from https en wikipedia org w index php title Free radical theory of aging amp oldid 1140011965, wikipedia, wiki, book, books, library,

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