Free-radical theory
Encyclopedia
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 melanin
are not chemically reactive, most biologically-relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative
damage. Antioxidant
s are reducing agent
s, and limit oxidative damage to biological structures by passivating
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 reactive oxygen species
such as H2O2
, or OH-
.
Denham Harman
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 yeast
and Drosophila
, there is evidence that reducing oxidative damage can extend lifespan. In mice, interventions that enhance oxidative damage generally shorten lifespan. However, in roundworms (Caenorhabditis elegans
), blocking the production of the naturally occurring antioxidant superoxide dismutase
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.
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. Two sources inspired Harman: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate. In turn, this 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 cancer
, arthritis
, atherosclerosis
, Alzheimer's disease
, and diabetes. Free radical chemistry is an important aspect of phagocytosis, inflammation
, and apoptosis
. Cell suicide, or apoptosis, is the body's way of controlling cell death and involves free radicals and redox signaling
. Redox factors play an even greater part in other forms of cell death such as necrosis
or autoschizis
.
More recently, the relationship between disease and free radicals has led to the formulation of a more generalized theory 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.
by inducing a secondary response to initially increased levels of reactive oxygen species. This observation was initially named mitohormesis, or mitochondrial hormesis
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 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).
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 Walford
(1924-2004), formerly Professor of Pathology at the University of California, Los Angeles
School of Medicine. Dr. Walford died of Amyotrophic Lateral Sclerosis
(ALS).
s such as Vitamin A
, vitamin C
, vitamin E
, and Superoxide dismutase
will slow the process of aging by preventing free radicals from oxidizing
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 vegetable
s and fruit
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 hormesis
: 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. Furthermore, a recent study tracking the eating habits of 478,000 Europeans suggests that consuming lots of fruits and vegetables has little if any effect on preventing cancer.. More recently, it has been suggested http://stroke.ahajournals.org/content/39/8/e126.fullhttp://stroke.ahajournals.org/content/39/5/e88.full.pdf+html that in humans extraordinarily-high levels of endogenous antioxidants such as uric acid
do not leave a lot of "therapeutic room" for ectopic antioxidants to work.
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
are not chemically reactive, most biologically-relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
damage. Antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
s are reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...
s, and limit oxidative damage to biological structures by passivating
Passivation
Passivation is the process of making a material "passive", and thus less reactive with surrounding air, water, or other gases or liquids. The goal is to inhibit corrosion, whether for structural or cosmetic reasons. Passivation of metals is usually achieved by the deposition of a layer of oxide...
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 reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
such as H2O2
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
, or OH-
Hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and a hydrogen atom held together by a covalent bond, and carrying a negative electric charge. It is an important but usually minor constituent of water. It functions as a base, as a ligand, a nucleophile, and a...
.
Denham Harman
Denham Harman
Denham 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 yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
and Drosophila
Drosophila
Drosophila 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 can extend lifespan. In mice, interventions that enhance oxidative damage generally shorten lifespan. However, in roundworms (Caenorhabditis elegans
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...
), blocking the production of the naturally occurring antioxidant superoxide dismutase
Superoxide dismutase
Superoxide 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
Denham 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. Two sources inspired Harman: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate. In turn, this 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 cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, and diabetes. Free radical chemistry is an important aspect of phagocytosis, inflammation
Inflammation
Inflammation is part of 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 and to initiate the healing process...
, and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Cell suicide, or apoptosis, is the body's way of controlling cell death and involves free radicals and redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
. Redox factors play an even greater part in other forms of cell death such as necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
or autoschizis
Autoschizis
Autoschizis is a term derived from the Greek roots "auto" meaning self, and "skhizein" to split. It used to describe a novel form of cancer cell death characterized by a reduction in cell size that occurs due to the loss of cytoplasm through self-excision without the loss of cell organelles,...
.
More recently, the relationship between disease and free radicals has led to the formulation of a more generalized theory 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
- Mutant strains of the roundworm Caenorhabditis elegansCaenorhabditis 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...
that are more susceptible to free radicals have shortened lifespans, and those with less susceptibility have longer lifespans. - 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 reproducedReproducibilityReproducibility is the ability of an experiment or study 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
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...
by inducing a secondary response to initially increased levels of reactive oxygen species. This observation was initially named mitohormesis, or mitochondrial hormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
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 prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor 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...
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
Intermittent 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 Walford
Roy Walford
Roy Lee Walford, M. D. was a pioneer in the field of caloric restriction. 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 Angeles
University of California, Los Angeles
The University of California, Los Angeles is a public research university located in the Westwood neighborhood of Los Angeles, California, USA. It was founded in 1919 as the "Southern Branch" of the University of California and is the second oldest of the ten campuses...
School of Medicine. Dr. Walford died of Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
(ALS).
Antioxidant therapy
The free radical theory of aging implies that antioxidantAntioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
s such as Vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
, vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
, vitamin E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
, and Superoxide dismutase
Superoxide dismutase
Superoxide 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 oxidizing
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
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 vegetable
Vegetable
The noun vegetable usually means an edible plant or part of a plant other than a sweet fruit or seed. This typically means the leaf, stem, or root of a plant....
s and fruit
Fruit
In broad terms, a fruit is a structure of a plant that contains its seeds.The term has different meanings dependent on context. In non-technical usage, such as food preparation, fruit normally means the fleshy seed-associated structures of certain plants that are sweet and edible in the raw state,...
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 hormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
: 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. Furthermore, a recent study tracking the eating habits of 478,000 Europeans suggests that consuming lots of fruits and vegetables has little if any effect on preventing cancer.. More recently, it has been suggested http://stroke.ahajournals.org/content/39/8/e126.fullhttp://stroke.ahajournals.org/content/39/5/e88.full.pdf+html that in humans extraordinarily-high levels of endogenous antioxidants such as uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
do not leave a lot of "therapeutic room" for ectopic antioxidants to work.
See also
- American Aging AssociationAmerican Aging AssociationThe 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. The abbreviation AGE is intended to be representative of the organization, even though it is not an acronym...
- Life extensionLife extensionLife extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
- List of life extension-related topics
- SenescenceSenescenceSenescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
- Calorie restrictionCalorie restrictionCaloric restriction , or calorie 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...
Biology of Aging
- Damage-Based Theories of Aging Includes a discussion of the free radical theory of aging.
- The Free Radical Theory of Aging
- Free Radicals and Human Disease--a Review