Free-radical theory of aging

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The free radical theory of aging 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]

Contents

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 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-oxygen.jpg
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]

Oxidative free radicals, such as the hydroxyl radical and the superoxide radical, can cause DNA damages, and such damages have been proposed to play a key role in the aging of crucial tissues. [20] DNA damage can result in reduced gene expression, cell death and ultimately tissue dysfunction. [20]

DNA cross-linking can in turn lead to various effects of aging, especially cancer. [21] Other cross-linking can occur between fat and protein molecules, which leads to wrinkles. [22] Free radicals can oxidize LDL, and this is a key event in the formation of plaque in arteries, leading to heart disease and stroke. [23] These are examples of how the free-radical theory of aging has been used to neatly "explain" the origin of many chronic diseases. [24]

Free radicals that are thought to be involved in the process of aging include superoxide and nitric oxide. [25] Specifically, an increase in superoxide affects aging whereas a decrease in nitric oxide formation, or its bioavailability, does the same. [25]

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

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. [26] :81 Several modifications have been proposed to integrate current research into the overall theory.

Mitochondria

Major sources of reactive oxygen species in living systems Major cellular sources of Reactive Oxygen Species in living cells.jpg
Major sources of reactive oxygen species in living systems

The mitochondrial theory of aging was first proposed in 1978, [27] [28] and two years later, the mitochondrial free-radical theory of aging was introduced. [29] 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. [30] 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. [26]

This theory has been widely debated [31] and it is still unclear how ROS induced mtDNA mutations develop. [26] 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. [32]

Afanas'ev suggests the superoxide dismutation activity of CuZnSOD demonstrates an important link between life span and free radicals. [33] 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. [34]

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. [35]

Epigenetic oxidative redox shift

Brewer proposed a theory which integrates the free radical theory of aging with the insulin signalling effects in aging. [36] Brewer's theory suggests "sedentary behaviour associated with age triggers an oxidized redox shift and impaired mitochondrial function". [36] This mitochondrial impairment leads to more sedentary behaviour and accelerated aging. [36]

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. [37] This theory criticizes the free radical theory because it ignores that ROS are specific signalling molecules which are necessary for maintaining normal cell functions. [37]

Mitohormesis

Oxidative stress may promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of ROS. [38] In mammals, the question of the net effect of reactive oxygen species on aging is even less clear. [39] [40] [41] 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). [42]

Challenges

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. [43] These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging. [43]

See also

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Mitochondrion</span> Organelle in eukaryotic cells responsible for respiration

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 used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.

<span class="mw-page-title-main">Superoxide dismutase</span> Class of enzymes

Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O
2
) radical into ordinary molecular oxygen (O2) and hydrogen peroxide (H
2
O
2
). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is Lactobacillus plantarum and related lactobacilli, which use a different mechanism to prevent damage from reactive O
2
.

<span class="mw-page-title-main">Mitochondrial DNA</span> DNA located in mitochondria

Mitochondrial DNA 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 is only a small portion of the DNA in a eukaryotic cell; most of the DNA can be found in the cell nucleus and, in plants and algae, also in plastids such as chloroplasts.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">Biogerontology</span> Sub-field of gerontology

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick has said that the natural average lifespan for a human is around 92 years and, if humans do not invent new approaches to treat aging, they will be stuck with this lifespan. James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000. Many surveyed biogerontologists have predicted life expectancies of more than three centuries for people born after the year 2100. Other scientists, more controversially, suggest the possibility of unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age". The idea of this approach is to use presently available technology to extend lifespans of currently living humans long enough for future technological progress to resolve any remaining aging-related issues. This concept has been referred to as longevity escape velocity.

Lipid peroxidation is the conversion of lipids to peroxide and hydroperoxide derivatives. These derivatives, known as lipid peroxides or lipid oxidation products (LOPs), are susceptible to further reactions that are relevant to "DNA and protein modification, radiation damage, aging..." Lipid peroxidation mainly applies to unsaturated fats, especially polyunsaturated fats such as those derived from linoleic acid.

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2 (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

<span class="mw-page-title-main">Myricetin</span> Chemical compound

Myricetin is a member of the flavonoid class of polyphenolic compounds, with antioxidant properties. Common dietary sources include vegetables, fruits, nuts, berries, tea, and red wine.

<span class="mw-page-title-main">Michael Ristow</span> German medical researcher (born 1967)

Michael Ristow is a German medical researcher who has published influential articles on biochemical aspects of mitochondrial metabolism and particularly the possibly health-promoting role of reactive oxygen species in diseases like type 2 diabetes, obesity and cancer, as well as general aging due to a process called mitohormesis.

<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">SOD2</span> Enzyme

Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the SOD2 gene on chromosome 6. A related pseudogene has been identified on chromosome 1. Alternative splicing of this gene results in multiple transcript variants. This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer.

SkQ is a class of mitochondria-targeted antioxidants, developed by Professor Vladimir Skulachev and his team. In a broad sense, SkQ is a lipophilic cation, linked via saturated hydrocarbon chain to an antioxidant. Due to its lipophilic properties, SkQ can effectively penetrate through various cell membranes. The positive charge provides directed transport of the whole molecule including antioxidant moiety into the negatively charged mitochondrial matrix. Substances of this type, various drugs that are based on them, as well as methods of their use are patented in Russia and other countries such as United States, China, Japan, and in Europe. Sometimes the term SkQ is used in a narrow sense for the denomination of a cationic derivative of the plant antioxidant plastoquinone.

All living cells produce reactive oxygen species (ROS) as a byproduct of metabolism. ROS are reduced oxygen intermediates that include the superoxide radical (O2) and the hydroxyl radical (OH•), as well as the non-radical species hydrogen peroxide (H2O2). These ROS are important in the normal functioning of cells, playing a role in signal transduction and the expression of transcription factors. However, when present in excess, ROS can cause damage to proteins, lipids and DNA by reacting with these biomolecules to modify or destroy their intended function. As an example, the occurrence of ROS have been linked to the aging process in humans, as well as several other diseases including Alzheimer's, rheumatoid arthritis, Parkinson's, and some cancers. Their potential for damage also makes reactive oxygen species useful in direct protection from invading pathogens, as a defense response to physical injury, and as a mechanism for stopping the spread of bacteria and viruses by inducing programmed cell death.

<span class="mw-page-title-main">Mitochondrial ROS</span> Reactive oxygen species produced by mitochondria

Mitochondrial ROS are reactive oxygen species (ROS) that are produced by mitochondria. Generation of mitochondrial ROS mainly takes place at the electron transport chain located on the inner mitochondrial membrane during the process of oxidative phosphorylation. Leakage of electrons at complex I and complex III from electron transport chains leads to partial reduction of oxygen to form superoxide. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by two dismutases including superoxide dismutase 2 (SOD2) in mitochondrial matrix and superoxide dismutase 1 (SOD1) in mitochondrial intermembrane space. Collectively, both superoxide and hydrogen peroxide generated in this process are considered as mitochondrial ROS.

<span class="mw-page-title-main">Superoxide dismutase mimetics</span> Synthetic compounds

Superoxide dismutase (SOD) mimetics are synthetic compounds that mimic the native superoxide dismutase enzyme. SOD mimetics effectively convert the superoxide anion, a reactive oxygen species, into hydrogen peroxide, which is further converted into water by catalase. Reactive oxygen species are natural byproducts of cellular respiration and cause oxidative stress and cell damage, which has been linked to causing cancers, neurodegeneration, age-related declines in health, and inflammatory diseases. SOD mimetics are a prime interest in therapeutic treatment of oxidative stress because of their smaller size, longer half-life, and similarity in function to the native enzyme.

Reductive stress (RS) is defined as an abnormal accumulation of reducing equivalents despite being in the presence of intact oxidation and reduction systems. A redox reaction involves the transfer of electrons from reducing agents (reductants) to oxidizing agents (oxidants) and redox couples are accountable for the majority of the cellular electron flow. RS is a state where there are more reducing equivalents compared to reductive oxygen species (ROS) in the form of known biological redox couples such as GSH/GSSG, NADP+/NADPH, and NAD+/NADH. Reductive stress is the counterpart to oxidative stress, where electron acceptors are expected to be mostly reduced. Reductive stress is likely derived from intrinsic signals that allow for the cellular defense against pro-oxidative conditions. There is a feedback regulation balance between reductive and oxidative stress where chronic RS induce oxidative species (OS), resulting in an increase in production of RS, again.

<span class="mw-page-title-main">Mitochondrial theory of ageing</span> Theory of ageing

The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978.

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