The free radical theory of aging states that organisms

age Age or AGE may refer to: Time and its effects * Age, the amount of time someone has been alive or something 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 Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabolic disorders Metabolism ...

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 (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...

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 or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

damage.

Antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

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 common reducing agents include hydrogen, carbon ...

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 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 t ...

( O₂⁻ ), but it has since been expanded to encompass oxidative damage from other

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(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 viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

(H₂O₂), or peroxynitrite (OONO⁻). Denham Harman 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 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 us ...

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

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

and ''

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

'', 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 ; ; ), roundworms or eelworms constitute the phylum Nematoda. Species in the phylum inhabit a broad range of environments. Most species are free-living, feeding on microorganisms, but many are parasitic. Parasitic worms (hel ...

(''

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 Hybrid word, blend of the Greek ''caeno-'' (recent), ''r ...

''), 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 () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...

has 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 Denham Harman 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, 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. 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 Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, and

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

. 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 ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

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. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

. 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 "molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass." Polymers are physi ...

including

lipids Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...

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, re ...

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 in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

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 sys ...

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. Oxidative free radicals, such as the

hydroxyl radical The hydroxyl radical, •HO, is the neutral form of the hydroxide ion (HO–). Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are pr ...

and the

radical, can cause DNA damages, and such damages have been proposed to play a key role in the aging of crucial tissues.Gensler, H.L., Hall, J.J., and Bernstein, H. (1987). The DNA damage hypothesis of aging: Importance of oxidative damage. In "Review of Biological Research in Aging." Vol. 3 (M. Rothstein, ed.), pp. 451–465. Alan R. Liss, New York DNA damage can result in reduced

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

, cell death and ultimately tissue dysfunction. 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 specif ...

and

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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 any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...

and

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

. 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 (also known as chronic disease or chronic illness) 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 ...

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

and

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, 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 den ...

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

s 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.

Vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...

, for example, can lose an electron to a free radical and remain stable itself by passing its unstable electron around the antioxidant molecule.

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 loosely defined as a molecule produced by a living organism and essential to one or more typically biological processes. Biomolecules include large macromolecules such as proteins, carbohydrates, lipids ...

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 appro ...

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

Mitochondria

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 and mDNA) is the DNA located in the mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the DNA contained in ...

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 ''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 cellular processes; the ...

processes in the mitochondria like the

Electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which 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

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 th ...

, or via an indirect route 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 where the outcome of a process reinforces the inciting process to build momentum. As such, these forces can exacerbate the effects ...

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

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 insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

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

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

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

Metabolic stability

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 Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...

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)..

Challenges

Birds

Among birds,

parrot Parrots (Psittaciformes), also known as psittacines (), are birds with a strong curved beak, upright stance, and clawed feet. They are classified in four families that contain roughly 410 species in 101 genus (biology), genera, found mostly in ...

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 ...

. 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

{{DEFAULTSORT:Free-Radical Theory Senescence * Theories of ageing Theories of biological ageing Proximate theories of biological ageing