Free-radical theory of aging
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The free radical theory of aging states that organisms
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]
In some model organisms, such as
Background
The free radical theory of aging was conceived by
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.
Since Harman first proposed the free radical theory of aging, there have been continual modifications and extensions to his original theory.[16]
Processes
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]
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
The mitochondrial theory of aging was first proposed in 1978,
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
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
- Life extension
- List of life extension-related topics
- Senescence
- Mitochondrial theory of ageing
References
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