The
free-radical theory of aging (FRTA) states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as
melaninMelanin is a class of compounds found in plants, animals, and protists, where it serves predominantly as a pigment. The class of pigments are derivatives of the amino acid tyrosine. Many melanins are insoluble salts and show affinity to water...
are not chemically reactive, most biologically-relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with
oxidativeOxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. All forms of life maintain a reducing environment within their cells...
damage.
AntioxidantAn antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells...
s are
reducing agentA reducing agent is the element or compound in a redox reaction that reduces another species. In doing so, it becomes oxidized, and is therefore the electron donor in the redox...
s, and limit oxidative damage to biological structures by
passivatingPassivation is the process of making a material "passive" in relation to another material prior to using the materials together. For example, prior to storing hydrogen peroxide in an aluminium container, the container can be passivated by rinsing it with a dilute solution of nitric acid and...
free radicals.
Strictly speaking, the free radical theory is only concerned with free radicals, but it has since been expanded to encompass oxidative damage from
reactive oxygen speciesReactive oxygen species are free radicals that contain the oxygen atom. They are very small molecules that include oxygen ions and peroxides and can be either inorganic or organic. They are highly reactive due to the presence of unpaired valence shell electrons.ROS form as a natural byproduct of...
such as O
2-,
H2O2Hydrogen peroxide is a very pale blue liquid, slightly more viscous than water, that appears colorless in dilute solution. It is a weak acid, has strong oxidizing properties, and is a powerful bleaching agent. It is used as a disinfectant, antiseptic, oxidizer, and in rocketry as a propellant...
, or
OH-In chemistry, hydroxide is the name for the diatomic anion OH−, consisting of oxygen and hydrogen atoms, usually derived from the dissociation of a base. It is one of the simplest diatomic ions known....
.
Denham HarmanDenham Harman , MD, PhD, FACP, FAAA biogerontologist is Professor emeritus at the University of Nebraska Medical Center. Harman is widely known as the "father of the free radical theory of aging".-Background:...
first proposed the free radical theory of aging in the 1950s, and in the 1970s extended the idea to implicate mitochondrial production of reactive oxygen species.
In some model organisms, such as
yeastYeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with about 1,500 species currently described; they dominate fungal diversity in the oceans. Most reproduce asexually by budding, although a few do so by binary fission...
and
DrosophilaDrosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
, there is evidence that reducing oxidative damage does, as the theory would predict, extend lifespan. In mice, interventions that enhance oxidative damage generally shorten lifespan. However, in roundworms (
Caenorhabditis elegansCaenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
), blocking the production of the naturally occurring antioxidant
superoxide dismutaseSuperoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
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
Denham HarmanDenham Harman , MD, PhD, FACP, FAAA biogerontologist is Professor emeritus at the University of Nebraska Medical Center. Harman is widely known as the "father of the free radical theory of aging".-Background:...
in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems, and before anybody had invoked free radicals as a cause of degenerative diseases. Harman drew inspiration from two sources: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate, which is proportional to oxygen consumption; and 2) Rebbeca Gershman'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
cancerCancer is a class of diseases in which a group of cells display uncontrolled growth , invasion , and sometimes metastasis...
,
arthritisArthritis is a group of conditions involving damage to the joints of the body....
,
atherosclerosisAtherosclerosis is the condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol...
,
Alzheimer's diseaseAlzheimer's disease , also called Alzheimer disease, Senile Dementia of the Alzheimer Type or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was...
, and diabetes. Free radical chemistry is an important aspect of
phagocytosisPhagocytosis is the cellular process of phagocytes and protists of engulfing solid particles by the cell membrane to form an internal phagosome...
,
inflammationInflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...
, and
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
. Cell suicide, or apoptosis, is the body's way of controlling cell death and involves free radicals and redox signalling. Redox factors play an even greater part in other forms of cell death such as
necrosisNecrosis is the premature death of cells and living tissue. Necrosis is caused by external factors, such as infection, toxins , or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
or autoschizis.
More recently, the relationship between disease and free radicals has led to the formulation of a greater generalization about the relationship between aging and free radicals. In its "strong" form, the hypothesis states that aging
per se is a free radical process. The "weak" hypothesis holds that the degenerative diseases associated with aging generally involve free radical processes and that, cumulatively, these make you age. The latter is generally accepted, but the "strong" hypothesis is presently controversial pending further investigation. Both models trace back to Harman's work.
Evidence
- A large body of comparative biochemical evidence suggests that longer lived species exhibit decreased levels of oxidative damage, decreased susceptibility to oxidative stress, and decreased generation of reactive oxygen species.
- Results have demonstrated that the overexpression of catalase
Catalase is a common enzyme found in nearly all living organisms which are exposed to oxygen, where it functions to catalyze the decomposition of hydrogen peroxide to water and oxygen...
, an enzyme involved in the decomposition of hydrogen peroxideHydrogen peroxide is a very pale blue liquid, slightly more viscous than water, that appears colorless in dilute solution. It is a weak acid, has strong oxidizing properties, and is a powerful bleaching agent. It is used as a disinfectant, antiseptic, oxidizer, and in rocketry as a propellant...
, increased both the average lifespan and maximum lifespan of mice by 20%. The authors of that paper also indicated that the lifespan extension effect had apparently lessened in new generations of these mice. However, other authors have been unable to repeat these observations, with a 2009 paper reporting that overexpression of both catalase and superoxide dismutase had no effect on lifespan in mice.
- Mutant strains of the roundworm Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
that are more susceptible to free radicals have shortened lifespans, and vice versa. However, increasing atmospheric oxygen tension above the normal 21% O2, does not meaningfully decrease lifespan of C. elegans.
- Drosophila that have mutations in enzymes relating to reactive oxygen species metabolism have also been shown to have dramatically reduced life-spans, increased susceptibility to oxidative stress and ionizing radiation, partial female and complete male sterility, and a general "enfeebled" phenotype characterized by deformed wings and abdomen.
- While genetic manipulations that increase the levels of oxidative damage generally do shorten lifespan in mice, there is at present very limited evidence that decreasing free radicals below their normal levels actually extends average or maximum lifespan.
- Consumption of high levels of antioxidants, which should increase lifespan under the theory, may extend average but not maximum lifespan in mice. The effect, if present, is weak and only inconsistently observed.
- Phenybutylnitrone (PBN) was shown to produce about a 10% extension of maximum lifespan in experimental animals in one laboratory, however, this finding has not been reproduced
Reproducibility is one of the main principles of the scientific method, and refers to the ability of a test or experiment to be accurately reproduced, or replicated, by someone else working independently....
by other laboratories.
- Antioxidant supplementation has not been conclusively shown to produce an extension of lifespan in a mammal.
Mitohormesis
Oxidative stress may promote life expectancy of
Caenorhabditis elegansCaenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
by inducing a secondary response to initially increased levels of reactive oxygen species. This observation was initially named mitohormesis, or mitochondrial
hormesisHormesis is the term for generally-favorable biological responses to low exposures to toxins and other stressors...
on a purely hypothetical basis.. In mammals, the question of the net effect of reactive oxygen species on aging is even less clear. Recent epidemiological findings support the process of mitohormesis in humans, and even suggest that the intake of exogenous antioxidants may increase disease
prevalenceIn epidemiology, the prevalence of a disease in a statistical population is defined as the total number of cases of the disease in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population. It is used as an estimate of how...
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).
Calorie restriction
Severe caloric restriction has been found to reduce reactive oxidative species and to increase the life-span of rodents, possibly by promoting mitohormesis. Studies have shown that both calorie restriction and reduced meal frequency or
intermittent fastingIntermittent fasting is a pattern of eating that alternates between periods of fasting and non-fasting. A specific form of IF is alternate day fasting , which is a 48-hour routine typically composed of a 24-hour fast followed by a 24-hour non-fasting period...
can suppress the development of various diseases and can increase life span in rodents by 30-40% by mechanisms involving stress resistance and reduced oxidative damage. Extreme calorie restriction, over 50%, resulted in increased mortality.
One of the most prominent proponents of calorie restriction as a way to longer life was the late Dr.
Roy WalfordRoy Lee Walford, M. D. was a pioneer in the field of life extension. He died at age 79 of respiratory failure as a complication of amyotrophic lateral sclerosis...
(
1924-2004), formerly Professor of Pathology at the
University of California, Los AngelesThe University of California, Los Angeles is a research university located in the Westwood neighborhood of Los Angeles, California, in the United States. It was founded in 1919 and is the second-oldest general-purpose campus in the University of California system...
School of Medicine. Dr. Walford died of
Amyotrophic Lateral SclerosisAmyotrophic lateral sclerosis is a form of motor neuron disease. ALS, sometimes called Maladie de Charcot, is a progressive, fatal, neurodegenerative disease caused by the degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary muscle movement...
(ALS).
Antioxidant therapy
The free radical theory of aging implies that
antioxidantAn antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells...
s such as
Vitamin AVitamin A is linked to a family of similarly shaped molecules, the retinoids, which complete the remainder of the vitamin sequence. Its important part is the retinyl group, which can be found in several forms. In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl...
,
vitamin CVitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate is required for a range of essential metabolic reactions in all animals and plants...
,
vitamin EVitamin E is a generic term for tocopherols and tocotrienols. Vitamin E is a family of α-, β-, γ-, and δ-tocopherols and corresponding four tocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive oxygen species formed when fat undergoes oxidation...
, and
Superoxide dismutaseSuperoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
will slow the process of aging by preventing free radicals from
oxidizingOxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. All forms of life maintain a reducing environment within their cells...
sensitive biological molecules or reducing the formation of free radicals. The antioxidant chemicals found in many foods are frequently cited as the basis of claims for the benefits of a high intake of
vegetableA vegetable is an edible plant or part of a plant. However, the word is not scientific, and its meaning is largely based on culinary and cultural tradition. Therefore the application of the word is somewhat arbitrary and subjective. For example, some people consider mushrooms to be vegetables,...
s and
fruitThe term fruit has different meanings dependent on context, and the term is not synonymous in food preparation and biology. Fruits are the means by which flowering plants disseminate seeds, and the presence of seeds indicates that a structure is most likely a fruit, though not all seeds come from...
s in the diet.
Nonetheless, some recent studies tend to show that antioxidant therapy have no effect and can even increase mortality . Proponents of the theory claim that this phenomenon can be explained by
hormesisHormesis is the term for generally-favorable biological responses to low exposures to toxins and other stressors...
: The addition of antioxidants can lead to a decrease of normal biological response to free radicals and lead to a more sensitive environment to oxidation.
See also
- American Aging Association
The American Aging Association is a non-profit, tax-exempt biogerontology organization of scientists and laypeople dedicated to biomedical aging studies intended to slow the aging process...
- Life extension
Life extension, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, refers to attempts to slow down or reverse the processes of aging to extend both the maximum and average lifespan...
- List of life extension-related topics
- Senescence
Senescence refers to the biological changes which take place in organisms as they age. It encompasses all of the biological processes of a living organism's approaching an advanced age...
- Calorie restriction
Calorie restriction, or caloric restriction , is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects. CR when not associated with malnutrition, improves age related health and slows the...
Biology of Aging