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The Free Radicals Theory And Oxidative Stress On Aging

 

Approaching The Free Radicals Theory And Oxidative Stress On Aging

Scientific work property of Resurgen®.

Date: 18/08/12

Dra. Ela M. Céspedes Miranda. Biomedical Research Centre. Top Institute of Basic and Preclinical Sciences “Victoria de Girón” . La Habana City, Cuba.

 

Decline in infants birth and death rates, improvement in health care, infectotransmissible diseases control and increase in life expectancy have originated population aging. According with United Nations calculations in 1950 there were about 200.000.000 people about 60 years old that increased up to 350.000.000 in 1975. Demographic projections shows by year 2000 the number will be increased up to 590.000.000 and by 2025 the number might become up to 1.100.000.000 what means and increase equivalent to 224% regarding year 1975. (1)

 

No question about the morphological, biochemical, physiological and psychological modifications that occur as a consequence of time action upon living beings. According with scientist Bernard Sthreler (1) aging is a “biological, universal, endogenous, intrinsic., deleterious, progressive and irreversible process characterized by a deterioration of the organism capabilities to accommodate both with its internal environment as with the external one, the detention of our auto regulating systems leading inevitably to death”.

 

Theory of free radicals and oxidative stress on aging

Along year 1956 Harman proposed the free radicals theory on aging suggesting that free radicals produced during aerobic respiration cause oxidative damage which accumulates and results in a gradual loss of homeostatic mechanisms, Interference of gene expressions patterns and loss of functional cell capacity, leading to aging and death. At that time relatively little was known regarding cells sites for free radicals generation and subsequent molecular reactions. Taking into account advances achieved in this field, original hypothesis for free radicals action on aging has been modified as an answer to that advancement.


According with that theory exists inter relationship in between oxidants generation, anti oxidant protection and the repair of oxidative damage (the two last ones can be induced as an answer to the damage). Life expectancy might be increased by reducing the degree of oxidant phenomena. All of this could be achieved by the improvement of hygienic-dietetic habits and the increase of anti oxidant defences.

 

It is believed that mitochondria is the most important reactive oxygen species generating source (ERO) (4) Enlargement in the formation of 02 and H202 is explained by the found fact that while aging become modified electrons flow conditions in their transport chain (5) . Researches postulate those generated ERO might damage mitochondrial internal membrane as well as electrons transport chain components or to mitochondrial AND, increasing in turn ERO production and consequently more mitochondrial damage and increase oxidative stress while enlarging oxidants production.

 

Mitochondrial genome is most susceptible to free radicals attack produced in the mitochondria itself. Time coming along all this produces changes exposes ATP formation and proteins synthesis. During the last years studies keep working on the damage produced in the mitochondria by free radicals as soon as the functioning of the processes taking place in this organelle. There are multiple evidences corroborating how important mitochondrial dysfunction becomes in cell destruction pathogenesis causing oldness, and oxidative stress is the most important inductor for those alterations. (5)

 

Numerous studies were made to determine if anti oxidant defences decline with age. (5,6) Among those, analysis of main components of: Activity or expression of enzymes superoxide dismutase, catalase, glutathione, Peroxidasa, glutathione reductase, glutathione-S-transferasa and Concentration of low molecular weight compounds with antioxidant properties. Sohal and others over expressed superoxide dismutase and catalase in Drosophila melanogaster increasing life expectancy 30% lessening proteins oxidative damage. (7)

 

The cell tends to generate oxidants and anti oxidants independently shaped. While oxidants stimulate anti oxidants endogenous production, administering anti oxidants suppresses several endogenous defences components. Those findings suggest cell oxidative state is maintained by feedback mechanisms.

 

Sohal found there is relationship in between maximum life potential and the levels of anti oxidant defences in 6 different mammals species and in insects (7,8) Stress oxidative hypothesis in aging reconciles and conceptualizes existing information regarding this item and attempts to answer questions generated from free radicals theory.

 

Stress oxidative hypothesis in aging refers the completion of genetic programme governing the sequence and duration of several ontogenetic phases is linked to defined energy amount expenditure. Oxidative stress level depends on the oxidants generation speed and on the antioxidants defence levels, which are genetically controlled but as well under epigenetic factors influence. Oxidative stress exerts regulatory influence on genetic expression and becomes different on the different development stages.

 

Studies shows although maximum living time could be changed varying metabolic rate, total energy expenditure along life time (metabolic potential) remains constant and it is species characteristic . A mechanism whereby metabolic index influences the development and aging could be through modulations on the oxidative stress level (9). These study results shows oxidants generation, antioxidant defence levels and metabolic index are interactive.

 

Aging is associated with alterations on oxidative stress level and genetic expression changes

Aging is characterized by disturbances indicative of gradual genome wear such as cells receptors decreased number, abnormal proteins appearance, the oncogenes derepression, decreased transcription, ARN translating and processing.

 

Although oxidative stress level is under the influence of genetic mechanisms, increases in the ERO formation is an epigenetic phenomenon. During development oxidative stress level changes, genetically programmed, induce new proteins expression or suppression of certain genes making it possible in the adult phase of life oxidative stress modifications by epigenetic factors also delete certain gens expression. From these observations Sohal and Allen (9) postulated aging is not governed by a genetic programme per se, but it happens under the influence of oxidative stress on the genetic programme.

 

It has been suggested oxidative stress effect on genetic expression might be through two different mechanisms:

- Direct effect on AND production and processing

- Changes on cell ionic distribution.

 

Level effects of transcriptional control

One protein known as OxyR, in E.Coli, Salmonella and Typhimorium when oxidized by H2O2 acts as transcriptional activator inducing catalase expression superoxide dismutase , glutathione reductase , alkilhydro- peroxide reductase, among some others. (10)

 

In eukaryotic cells still is unclear how is controlled expression of encoding genes for su-peroxide-dismutase, two different mechanisms are proposed:

- Through transcriptional factor AP-1 which in its component c-fos has a critical.
cysteine residue most sensitive to oxidation

- Through oxidation of nuclear kB transcription factor inhibitory subunit.

 

SOD-Mn is specifically induced by tumoral necrosis factor (TNFα) about which there are evidences that is induced by ERO which in turn activates NF-kB (11) what suggests there is relationship in between oxidative activation of NF-kB and SOD-Mn induction.

 

Level effects of post transcriptional modifications

Recently has been observed ARN processing is altered by cell exposure to oxygen radicals generator systems. In developing organisms, in senescent individuals tissues and O2 bombarded tissues, has been found immature ARN at the cytoplasm suggesting that changes so far associated with aging and development may be mediated by ERO generation and elimination. (9)

 

There are abundant evidences sustaining aging theories, although most of them are not mutually excluding; moreover all or some of them may act simultaneously. The prevailing view among gerontologists is that aging is a multi causal phenomenon. This does not exclude the existence of “a root cause” having a pleiotropic expression that is, producing numerous secondary and tertiary changes.

 

Summary

The increase of life expectancy has caused an aging of the population and consequently a relative rise of the diseases associated with it. During the last years more studies have been conducted on this topic and numerous hypotheses have been made. In this paper some theories on aging are presented, among them, those ones programmed from the genetic point of view that state that aging occur in a predetermined way, and the theories on non-genetically programmed aging, in particular, the theory of free radicals and oxidative stress, whose central dogma is based on how during the aerobial metabolism radical species derived from oxygen are produced incidentally and in an uncontrollable way, the molecules are irreversibly damaged, damage that is accumulated in the course of time, and this results in a gradual lost of the homeostatic mechanisms, interference of the patterns of genic expression and lost of the functional capacity of the cell.

Subject headiongs: Life Expectancy, Demographic Aging, Aging/Genetics, Free Radicals, Oxidative Stress.

 

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