Aging: Link with oxidative stress

Prepared For Prepared By

A. F. M. Towheedur Rahman Md Naimur Rahman(142 046)

Lecturer Towfiqur rahman (142 046)
North South University K.M.Naimul Islam (142 1389 046)
Ahasan Habib Opu (142 0879 046)
Md.Babor Khan (142 1623 046)
Shafiqul Islam (142 0426 046)
Course: Basic pathology and toxicology
Section: 04
Date: 08.11.2017
*Aging is an extremely complex and
multifactorial process that proceeds to
the gradual deterioration in functions.
It usually manifest after maturity and
leads to disability and death.
*If scientists would discover a drug for
healing all major chronic degenerative
diseases, the average lifetime would
be increased for just 12 years. People
would still die from complications
connected with the aging process
 Free-radical theory of aging
The Free Radical Theory of Aging proposed in the 1950s by Denham
Harman , postulates that oxygen free radicals formed endogenously
from normal metabolic processes play a role in the aging process
because of an increase in oxidative damage to macromolecules. The
Free Radical Theory of Aging has sense been modified to the
Oxidative Stress Theory of Aging because oxygen species such as
peroxides and aldehydes, which are not technically free radicals,
also play a role in oxidative damage to cells. The imbalance between
prooxidants and antioxidants leads to an accumulation of oxidative
damage in a variety of macromolecules with age resulting in a
progressive loss in functional cellular processes, leading to the aging
phenotype
 Free-radical theory of aging
*The theory proposes that aging is actually caused by the toxicity of
ROS through a vicious cycle in which ROS damage to the
constituents of mitochondria leads to the generation of more ROS

*Aging is also associated with an increase in the levels of oxidatively

damaged proteins, lipids and DNA .

* Aging in mammals is universal, degenerative, and appears

unavoidable even in very sheltered environments.
 A free radicals molecules is an oxygen
containing molecule that has one or
more unpaired electrons making it highly
reactive with other molecule. Not all
reactive oxygen species are harmful to
the body some of them are useful in
killing invading pathogens or microbes.
However free radicals can chemically
interact with cell components such as
DNA protein of lipid and steal their
electrons in order to become stabilized.
Free radicals can damage the
mitochondrial inner membrane,
creating a positive feedback-loop
for increased free-radical creation.
Induction of ROS generates
mtDNA mutations, in turn leading
to a defective respiratory chain.
Defective respiratory chain
generates even more ROS and
Figure: Oxidative stress from endogenous or exogenous
generates a vicious cycle. The sources can trigger the chain reaction, which leads to
accelerated aging process of cells and organisms.
result is even more damage.
*The formation of free radicals or oxidants is a
well-established physiological event in
aerobic cells, which convene enzymic and
nonenzymic resources, known as antioxidant
defenses,to remove these oxidizing species.
*An imbalance between oxidants(ROS) and
antioxidants known as oxidative stress, and
the consequent damage to cell molecules
constitutes the basic tenet of several
pathophysiological states, such as
neurodegeneration, cancer, mutagenesis,
cardiovascular diseases, and aging.
 Types of Free Radicals
*Reactive Oxygen Species (ROS) –

*Reactive Nitrogen Species (RNS) - NO.

*Reactive Metabolites or Intermediates

- metabolic activation of drugs, toxins, pollutants, cigarette
smokes, etc.
Chemically reactive molecules
containing oxygen, highly
reactive
Under normal conditions, ROS
are natural byproducts.
It also can be generated by
exogenous sources.
Major sources of ROS:
mitochondria, peroxisome,
plasma membrane/cytoplasm.
 How are ROS Formed?
Primary source is our body during energy production

Environmental contaminants

Ionizing and ultraviolet radiation

Prolonged low blood flow states (atherosclerosis, heart attacks and

stroke)

Diet (fatty and processed foods)

Low levels of antioxidants

 Antioxidant
* An antioxidant is a molecule capable
of inhibiting the oxidation of other
molecules.

*Oxidation reactions can form free

radicals and these start chain
reactions that damage cells .
Antioxidants terminate these chain
reactions by removing free radical
intermediates and inhibit other
oxidation reactions.

*The lichens have played an important

role as a source for new antioxidant
agents.
 Causes of decreased antioxidant defense

 reduced activity of endogenous

antioxidative enzymes
 reduced biokinetics of antioxidant
metabolism
 reduced intake of antioxidants
 reduced bioabsorption of antioxidants
 others
 ENDOGENOUS SOURCE

*Body's normal use of oxygen such as respiration and

*some cell mediated immune functions
*Immune cell activation
*Inflammation
*Mental stress etc.

EXOGENOUS SOURCE

*Environmental pollutants
*Cigarette smoke
*Radiations etc.
 Oxidative stress is caused mainly by

•mutation or reduced activity of enzymes (catalase, SOD, glutathione peroxidase)

• decreased intake of exogenous antioxidants from food

• increased metal ion intake (e.g., Fe, Cu, Cr)

• easiliy peroxidized amino acids (e.g., lysine)

• increased triplet oxigen (3O2) concentration

• increased physical activity of an untrained individual

• ROS from ionizing radiation, air pollution, smoking

• chronic inflammation
oxidative damage of ROS
 HOW DO CELLS PROTECT THEMSELVES
AGAINST OXIDANTS?
The cell convenes specific enzymic defenses against oxygen radical attack, which
can be considered preventive antioxidants. On the other hand, there exist small antioxidant
molecules, which can react with a variety of free radicals and that may be considered as
chain-breaking antioxidants.

Specific enzymic defenses or preventive antioxidants

Mammalian cells contain specific enzymes, which remove either
superoxide anion or hydrogen peroxide, the two required precursors of
hydroxyl radical (HO.).
 Removal of Superoxide Anion: Superoxide Dismutases
Superoxide anion radical is formed by different nonenzymic and enzymic reactions
within the cell. Superoxide dismutases (abbreviated SOD) catalyze the rapid dismutation
of superoxide radical to hydrogen peroxide and oxygen. The rate of this reaction is
10,000-fold higher than that of the spontaneous dismutation

 O2.– + O2.– + 2H+ H2O2 + O2 spontaneous, nonezymic dismutation

 O2.– + O2.– + 2H+ H2O2 + O2 enzymic dismutation

Removal of Hydrogen Peroxide: Catalase and Glutathione Peroxidases

Catalase: This enzyme is located in the peroxisomes and catalyses the following reaction:
H2O2 + H2O2 → 2H2O + O2
* Glutathione Peroxidase: The enzyme occurs in cytosol and the mitochondrial
matrix and it requires glutathione, a tripeptide present in high concentrations in most
mammalian cells. During this reaction hydrogen peroxide (H2O2) is reduced to
water and glutathione (GSH) is oxidized to glutathione disulfide (GSSG).
* H2O2 + 2GSH → H2O + GSSG
catalase

O2 O2.– H2 O2 HO. H2O

glutathione peroxidase
superoxide dismutase

2 GSH
GSSG
Conclusion
Increasing evidence suggests that the generation of these
oxygen free radicals plays an important role in the
pathophysiology of at least three disease states: ischemia
reperfusion injury, phagocyte-dependent inflammatory
damage and neurodegenerative disorders as well as aging.
 References

• Principles of Pharmacolgy, 2nd edition –H L Sharma, K K Sharma

• Reactive Oxygen Species in Biological Systems-An Interdisciplinary

Approach (Gilbert,2002).

• Free-Radical-Induced DNA Damage and Its Repair - A Chemical Perspective

(Springer, 2006)

• Harpers Biochemistry 26th ed

• Lehninger's Principles of Biochemistry 4th Edition - D L Nelson, Cox

Lehninger - W H Freeman 2004