Genetics

Oxidative Stress, Clinical Evidences in Aging and Age Related Diseases

Written by seerat baig

Aging is a condition that involves changes at all biological levels like cellular, tissue and organ levels which may results in faulty functioning, development of disease, and eventually death. For quite some time now Scientists are discussing more about the relationship of aging and oxidizing agents.

According to medvedev, more than 300 theories about aging exist. Which are based on two factors:

(1) Intrinsic factors which involve the study of genomic effects and genetic process.

(2) Extrinsic factors which involves the relation of external environmental factors on living beings.

Historically, they are divided into two categories.

(1) Stochastic theories: somatic mutation and DNA repair protein modification.

(2) developmental-genetic theories: recognizes the aging process to be part of the genetically programmed and controlled scale of development and maturation.

No theory has been generally accepted. Then the hypothesis of Free Radicals on the theory of aging was after modified in 1972 and gave the fresh version is the oxidative stress theory. The OS hypothesis of aging postulates that” the damage at macromolecular level and then its accumulation is due to the redox imbalance. Means the net difference between the amount of ROS generation and counter-acting anti-oxidative forces.

Oxidative stress to macromolecules:

The oxidative damage to the variety of molecules like lipids, proteins and DNA occur ranging from invertebrates to human level. General observation shows due to increase in ROS production and a decline in DNA repair capacity with age cause DNA damage with age. ROS mediated damage to proteins is particularly important in aging, because the increase of oxidized proteins in a relation to reduced proteolysis, elimination or both. The oxidative damage to macromolecule varies greatly among different tissues, species. On the other hand oxidative damage to the key genes plus proteins may results in effectiveness of cell functioning

Protein oxidation

Proteins are the major component of biological system and play the key role in variety of cellular functions. Almost all amino acid in proteins would-be the main target for oxidation by ROS.

  • Methionine will oxidize to methionine sulfoxide.
  • Cysteine will oxidize to variety of product e.g. disulfides S-nitrosylation products, sulfinic acid, and sulfonic acid.
  • Phenylalanine will oxidize to hydroxyl derivatives.

Many of the oxidative modifications of proteins or amino acids are irreversible and to repair the protein we rely on protein turnover

Oxidative stress and aging:

Mitochondria is the major source of reactive oxygen species in cell and play important role in cellular ageing .It was hypothesize long time ago that their dysfunction could be responsible for ageing, due to accumulation of oxidative damage by lowering mitochondrial membrane potential, mitochondrial DNA damage, and increased superoxide production. Mitochondrial DNA is major targeting site of free radical attack as the existence of oxidative damage to mtDNA is more than those of nuclear DNA. This includes single and double strand breaks, deletions, base changes, oxidative damage and even chromosomal aberrations

P53 act as anti-oxidatative stress:

P53 play key roles for the protection of cellular damage to oxidative stress. At low levels of oxidative stress, p53 act as antioxidant. A significant amount of p53 target the gene like glutathione peroxides (GPX), Sestrin, and aldehyde dehydrogenase (ALDH), involved in reducing oxidative stresses.p53 reduces the intracellular level of ROS by regulating cellular metabolism via slow glycolysis and promote the production of NADPH to decrease ROS levels. In response to high levels of oxidative stress, P53 exhibit pro-oxidative activities by genes such as PIG3 and proline oxidase.

Role of mitochondria in oxidative stress:

As we know the mitochondria is the major organelle in cell whose primary function depends upon environment of cell and on the endothelial cell. It regulates the oxidants for cell signaling, while within a cardiac myocyte it may cause generation of ATP or combination of functions like ATP and oxidant generation. Mitochondria for the maintenance of metabolic homeostasis can also play critical roles in the initiation and promotion of cancer.NAD (P) H oxidase is a major source of oxidative stress in the vasculature and Damage to mitochondrial electron transport chain can cause the neurodegenerative diseases.

Cure:

It has been reported that the oral administration of GSH protects against the age-associated decline in immune responsiveness.more over administration of some sulphur containing antioxidants fight and protect against the age associated GSH depletion. Mitochondrial aging is prevented by antioxidants because it prevent the impairment in physiological performance and motor co-ordination that occur upon aging

Conclusions:

The finding that accumulation of molecular damages cause the aging effect remain in doubt that really the damage is the reason of aging like increased morbidity and mortality rate. Taking into account that causes of aging are complex and complicated and the recognition of molecular and cellular concert involved are crucial. However a strong possibility is previously suggested that the wasting process related to aging and diseases, at some point, may not be irreversible in principle.

Reference:

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  3. Comfort, A., The biology of senescence, 3rd edition New York: Elsevier; 1979.
  4. Strehler, B. L. A critique of theories of biological aging. In: Dietz, A. A., ed. Aging–Its chemistry. Washington, DC. Am. Assoc. Clinical Chem.; 1980:25-45.
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  1. Harman D. Ageing: a theory based on free radical and radiation chemistry. J Gerontol (1956) 11:298–300.

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seerat baig