The free radical theory of aging (FRTA) states that organisms

age Age or AGE may refer to: Time and its effects * Age, the amount of time someone or something has been alive or has existed ** East Asian age reckoning, an Asian system of marking age starting at 1 * Ageing or aging, the process of becoming older ...

because cells accumulate

free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...

damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell.Erbas M, Sekerci H. "Importance of Free Radicals and Occurring During Food Processing". Serbest Radïkallerïn Onemï Ve Gida Ïsleme Sirasinda Olusumu. 2011: 36(6) 349–56. While a few free radicals such as

melanin Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...

are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with

oxidative Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

damage.

Antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...

s are

reducing agent In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ). Examples of substances that are commonly reducing agents include the Earth meta ...

s, and limit oxidative damage to biological structures by passivating them from free radicals. 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 In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

(ROS) such as

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%� ...

(H₂O₂), or

peroxynitrite Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate, Preparation Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide: : It is prepared by the react ...

(OONO⁻).

Denham Harman Denham Harman (February 14, 1916 – November 25, 2014) was an American medical academic who latterly served as professor emeritus at the University of Nebraska Medical Center. Harman is known as the "father of the free radical theory of aging". ...

first proposed the free radical theory of aging in the 1950s, and in the 1970s extended the idea to implicate

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

l production of ROS. In some model organisms, such as

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...

and ''

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...

'', there is evidence that reducing oxidative damage can extend lifespan. However, in mice, only 1 of the 18 genetic alterations (SOD-1 deletion) that block antioxidant defences, shortened lifespan. Similarly, in

roundworms The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...

(''

Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...

''), blocking the production of the naturally occurring antioxidant

superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxygen me ...

has recently been shown to ''increase'' lifespan. 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

in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems. This was also before anyone invoked free radicals as a cause of degenerative diseases. Two sources inspired Harman: 1) the

rate of living theory The rate of living theory postulates that the faster an organism’s metabolism, the shorter its lifespan. The theory was originally created by Max Rubner in 1908 after his observation that larger animals outlived smaller ones, and that the large ...

, which holds that lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption, and 2)

Rebeca Gerschman Rebeca Gerschman (June 19, 1903 – April 4, 1986) was an Argentinian biologist and physiologist who received a Ph.D. in Biochemistry and Pharmacy from the University of Buenos Aires. Known for her advances in the field of biochemistry, she was th ...

's observation that hyperbaric oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon: oxygen free radicals. 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. In later years, the free radical theory was expanded to include not only aging ''per se'', but also age-related diseases. Free radical damage within cells has been linked to a range of disorders including

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, and

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

. 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

and in extreme cases

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

. In 1972, Harman modified his original theory. In its current form, this theory proposes that

(ROS) that are produced in the

, causes damage to certain

macromolecules A macromolecule is a very large molecule important to biophysical processes, such as a protein or nucleic acid. It is composed of thousands of covalently bonded atoms. Many macromolecules are polymers of smaller molecules called monomers. The ...

including

lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

and most importantly mitochondrial DNA. This damage then causes mutations which lead to an increase of ROS production and greatly enhance the accumulation of free radicals within cells. This mitochondrial theory has been more widely accepted that it could play a major role in contributing to the aging process. Since Harman first proposed the free radical theory of aging, there have been continual modifications and extensions to his original theory.

Processes

Free radicals are atoms or molecules containing unpaired electrons.

Electron The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no kn ...

s normally exist in pairs in specific orbitals in atoms or molecules.Orchin M, Macomber RS, Pinhas A, Wilson RM, editors. The Vocabulary and Concepts of Organic Chemistry. 2 ed: John Wiley & Sons; 2005. 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. 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 A chain reaction is a sequence of reactions where a reactive product or by-product causes additional reactions to take place. In a chain reaction, positive feedback leads to a self-amplifying chain of events. Chain reactions are one way that syst ...

of radical production occurs. 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 A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

molecules in a strand of DNA, the DNA can become cross-linked. DNA cross-linking can in turn lead to various effects of aging, especially

. Other cross-linking can occur between

fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers spec ...

and

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

molecules, which leads to wrinkles. Free radicals can oxidize

LDL Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

, and this is a key event in the formation of plaque in arteries, leading to

heart disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...

and

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

. These are examples of how the free-radical theory of aging has been used to neatly "explain" the origin of many

chronic disease A chronic condition is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term ''chronic'' is often applied when the course of the disease lasts for more than three mo ...

s. Free radicals that are thought to be involved in the process of aging include

superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...

and

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

. Specifically, an increase in superoxide affects aging whereas a decrease in nitric oxide formation, or its bioavailability, does the same.

Antioxidants Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...

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 Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...

, for example, can lose an electron to a free radical and remain stable itself by passing its unstable electron around the antioxidant molecule. This has led to the hypothesis that large amounts of antioxidants, 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

s in the aging process and thus tentatively support the free radical theory of aging. Studies have shown a significant increase in

superoxide radical In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...

(SOR) formation and

lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which radical (chemistry), free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by ...

in aging rats. Chung et al. suggest ROS production increases with age and indicated the conversion of XDH to XOD may be an important contributing factor. This was supported by a study that showed superoxide production by

xanthine oxidase Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthin ...

and NO synthase in

mesenteric arteries The mesenteric arteries take blood from the aorta and distribute it to a large portion of the gastrointestinal tract. Both the superior and inferior mesenteric arteries arise from the abdominal aorta. Each of these arteries travel through the m ...

was higher in older rats than young ones. Hamilton et al. examined the similarities in impaired

endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

function in

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

and aging in humans and found a significant overproduction of superoxide in both. This finding is supported by a 2007 study which found that endothelial

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

develops with aging in healthy men and is related to reductions in endothelium-dependent dilation. Furthermore, a study using cultured smooth muscle cells displayed increased ROS in cells derived from older mice. These findings were supported by a second study using

Leydig cells Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...

isolated from the testes of young and old rats. 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. Lener et al. suggest

Nox4 NADPH oxidase 4 is an enzyme that in humans is encoded by the ''NOX4'' gene, and is a member of the NOX family of NADPH oxidases. Function Oxygen sensing is essential for homeostasis in all aerobic organisms. A phagocyte-type oxidase, similar t ...

activity increases oxidative damage in human umbilical vein endothelial cells via superoxide overproduction. Furthermore, Rodriguez-Manas et al. found endothelial dysfunction in human vessels is due to the collective effect of vascular inflammation and oxidative stress. Sasaki et al. reported superoxide-dependent

chemiluminescence Chemiluminescence (also chemoluminescence) is the emission of light (luminescence) as the result of a chemical reaction. There may also be limited emission of heat. Given reactants A and B, with an excited intermediate ◊, : + -> lozenge -> ...

was inversely proportionate to maximum lifespan in mice, Wistar rats, and pigeons. They suggest ROS signalling may be a determinant in the aging process. In humans, Mendoza-Nunez et al. propose an age of 60 years or older may be linked with increased oxidative stress. Miyazawa found

mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

superoxide anion production can lead to organ

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

and dysfunction via mitochondrial- mediated

. In addition, they suggest mitochondrial superoxide anion plays an essential part in aging. Lund et al. demonstrated the role of

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

extracellular

in protecting against endothelial dysfunction during the aging process using mice.

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

biomolecule A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or development. Biomolecules include large ...

s, thus being a major reason for

cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approxi ...

and organismal aging. Several modifications have been proposed to integrate current research into the overall theory.

Mitochondrial theory of aging

Major cellular sources of Reactive Oxygen Species in living cells

The mitochondrial theory of aging was first proposed in 1978, and two years later, the mitochondrial free-radical theory of aging was introduced. 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 Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DNA ...

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. Electrons may escape from

metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

processes in the mitochondria like the

Electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

, and these electrons may in turn react with water to form ROS such as the

, or via an indirect route the

hydroxyl radical The hydroxyl radical is the diatomic molecule . The hydroxyl radical is very stable as a dilute gas, but it decays very rapidly in the condensed phase. It is pervasive in some situations. Most notably the hydroxyl radicals are produced from the ...

. 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 Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...

of oxidative stress is established that, over time, can lead to the deterioration of cells and later organs and the entire body. This theory has been widely debated and it is still unclear how ROS induced mtDNA mutations develop. 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. Afanas'ev suggests the superoxide dismutation activity of CuZnSOD demonstrates an important link between life span and free radicals.Afanas'ev I. Signaling and Damaging Functions of Free Radicals in Aging-Free Radical Theory, Hormesis, and TOR. Aging And Disease. 2010;1(2) 75-88. 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. 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.

Epigenetic oxidative redox shift (EORS) theory of aging

Brewer proposed a theory which integrates the free radical theory of aging with the

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

signalling effects in aging. Brewer's theory suggests "sedentary behaviour associated with age triggers an oxidized

redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...

shift and impaired mitochondrial function". This mitochondrial impairment leads to more sedentary behaviour and accelerated aging.

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. This theory criticizes the free radical theory because it ignores that ROS are specific signalling molecules which are necessary for maintaining normal cell functions.

Mitohormesis

Oxidative stress may promote life expectancy of ''

'' by inducing a secondary response to initially increased levels of ROS. In mammals, the question of the net effect of reactive oxygen species on aging is even less clear. Recent

epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evidenc ...

findings support the process of mitohormesis in humans, and even suggest that the intake of exogenous antioxidants may increase disease

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

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).

Effects of 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. Many studies suggest this may be due to anti-oxidative action, oxidative stress suppression, or oxidative stress resistanceUngvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R. Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging" ''Circulation Research'' 2008;102(5) 519-28. which occurs in calorie restriction. Fontana et al. suggest calorie restriction influenced numerous signal pathways through the reduction of

insulin-like growth factor I Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans is ...

(IGF-1).Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science (New York, NY). 2010;328(5976) 321-6. Additionally they suggest antioxidant SOD and catalase are involved in the inhibition of this nutrient signalling pathway. 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.Barja G. Mitochondrial oxygen consumption and reactive oxygen species production are independently modulated: implications for aging studies. Rejuvenation Research. 2007;10(2) 215-24. 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 Aerobic exercise (also known as endurance activities, cardio or cardio-respiratory exercise) is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, inv ...

, chronic exercise, and

hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism ...

. Additionally, mitochondrial oxygen radical generation is lower in long-lived birds than in short-lived mammals of comparable body size and

metabolic rate Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

. Thus, mitochondrial ROS production must be regulated independently of O₂ consumption in a variety of species, tissues and physiologic states.

Challenges to the theory

Naked mole-rat

The naked mole-rat is a long-lived (32 years)

rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...

. As reviewed by Lewis et al., (2013), levels of ROS production in the naked mole rat are similar to that of another rodent, the relatively short-lived

mouse A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

(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. In the naked mole-rat, a likely important cytoprotective mechanism that could provide longevity assurance is elevated expression of

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

genes involved in several key DNA repair pathways. (See

DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear ...

.) 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 DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, r ...

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...

and

base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...

Birds

Among birds,

parrot Parrots, also known as psittacines (), are birds of the roughly 398 species in 92 genera comprising the order Psittaciformes (), found mostly in tropical and subtropical regions. The order is subdivided into three superfamilies: the Psittacoid ...

s live about five times longer than

quail Quail is a collective name for several genera of mid-sized birds generally placed in the order Galliformes. The collective noun for a group of quail is a flock, covey, or bevy. Old World quail are placed in the family Phasianidae, and New Wor ...

. 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. These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging.

References

External links

Calorie restriction

Calorie Restriction Society

Biology of Aging

Includes a discussion of the free radical theory of aging. {{DEFAULTSORT:Free-Radical Theory Senescence * Theories of ageing Theories of biological ageing Proximate theories of biological ageing