cellular aging and death

CELLULAR AGING AND DEATH: 

CELLULAR AGING AND DEATH BY MOHD. SHARIQ ANSARI DEPARTMENT OF PHARMACOLOGY H.S.K. COLLEGE OF PHARMACY BAGALKOT KARNATAKA SEMINAR ON

General terms: 

General terms HYPERPLASIA is increase in the no. of cell or tissues. Hyperplasia takes place if the cellular population is capable of synthesizing DNA, thus permitting mitotic division. e.g. removal of liver part. Hyperplasia is generally caused by increased local production of growth factors or activation of particular intracellular signaling pathways and net resultant is cellular proliferation. Stem cell also contributes to increase in tissue mass.

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HYPERTROPHY refers to an increase in the size of the cells, resulting in increase in the size of the organs. Stated another way, in pure hypertrophy there are no new cells, just bigger cells, enlarged by an increased amount of structural proteins and organelles. Hypertrophy occurs when cells are incapable of dividing. e.g. The striated muscle cells in both the skeletal muscle and the heart can undergo hypertrophy in response to increased demand because in the adult they have limited capacity to divide

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ATROPHY shrinkage in the size of the cell by loss of cell substance is known as atrophy. e.g. The uterus decreases in size shortly after parturition. Causes are Decreased workload. Diminished blood suply Inadequate nutrition. Aging. Etc.

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METAPLASIA is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another cell type. e.g. in habitual cigarette smoker, normal ciliated columnar epithelial cells of the trachea and bronchi are often replaced by focally or widely by stratified squamous epithelial cells.

INJURY: 

INJURY Cells are constantly exposed to a variety of stresses, when severe causes injury. Injury alters the normal steady state of the cell. If the injury is ACUTE, then It can either survive in a damaged state and adapt to the reversible injury or it can die irreversible injury or cell death. If the nature of injury is CHRONIC then the cell may be able to adapt to it, resulting in a variety of cellular changes known as adaptations ( by hyperplasia, hypertrophy, atrophy, intracellular accumulations, metaplasia and dysplasia ) The Point of No Return.

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REVERSIBLE CELL INJURY Injury is manifested as functional and morphologic changes that are reversible if the damaging stimulus is removed. irreversible CELL INJURY with the continuing damage, injury becomes irreversible, at which time the cell cannot be recover i.e. point of no return. Irreversible injured cells invariably undergo morphologic changes that are recognized as cell death. Two types of cell death i.e. necrosis and apoptosis which differ in their morphology, mechanism and roles in disease and physiology.

CAUSES OF CELL INJURY: 

CAUSES OF CELL INJURY Oxygen deprivation hypoxia (causes cell injury by reducing oxidative respiration), and ischemia (reduction of oxygen through blood supply and also metabolic substrate, including glucose). Physical agents mechanical trauma, extreme temperature, sudden change in atmospheric pressure etc. Chemical agents and drugs glucose and salt hypertonic solution, arsenic, cyanide, mercuric salt, CO, etc. INFECTIOUS AGENT bacteria, viruses, fungi etc. Genetic derangements sickle cell anemia. Nutritional imbalances PEM, obesity, atherosclerosis etc.

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Cellular & biochemical sites of damage in cell injury

Mechanism of cellular injury: 

Mechanism of cellular injury DEPLETION OF ATP

Mitochondrial damage: 

Mitochondrial damage

Influx of intracellular ca2+ & loss of calcium homeostasis: 

Influx of intracellular ca 2+ & loss of calcium homeostasis

ACCUMULATION OF ROS: 

ACCUMULATION OF ROS

Defects in membrane permeability: 

Defects in membrane permeability

REVERSIBLE & irreversible CELL INJURY: 

REVERSIBLE & irreversible CELL INJURY The earliest changes associated with various forms of cell injury are decreased generation of ATP, loss of cell membrane integrity, defects in protein synthesis and DNA damage. Within limits, the cell can compensate for these derangements, and if injurious stimulus abates, will return to normalcy. Persistent or excessive injury causes cells to pass threshold into irreversible injury, associated with extensive damage to all cellular membrane, swelling of lysosomes, vacuolization of mitochondria with reduced capacity to generate ATP.

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Extracellular calcium enters the cell and intracellular calcium are released, resulting in the activation of enzymes that can catabolize membranes, protein, ATP, and nucleic acids, results in continued loss of proteins, essential coenzymes, and ribonucleic acids from hyper permeable plasma membrane, with cells leaking metabolites vital for reconstitution of ATP and further depleting intracellular high-energy phosphates.

NECROSIS: 

NECROSIS Spectrum of morphological changes that follow cell death in living tissue largely resulting from degradative action of enzymes on lethally injured cell. Causes are irreversible injury Hypoxic and ischemic injury, free radical injury, chemical injury.

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Hypoxic and ischemic injury

Chemical injury: 

Chemical injury

APOPTOSIS: 

APOPTOSIS Human possess 10 14 cells, consisting of more than 200 differentiated types. Starting from only single cell, all the diverse cell type of body are produced and organized into tissues and organs. This process involves cell proliferation and death. A balance is maintained between two to maintain constant number, by a mechanism called programmed cell death. e.g. About 5 X 10 11 blood cell are eliminated daily in our body. Provide defence mechanism by which damaged &

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potentially danger cells can be eliminated. EVENTS - It usually proceeds by a distinct series of cellular changes known as apoptosis. During apoptosis chromosomal DNA is usually fragmented as a result of cleavage b/w nucleosomes. Chromatin condenses and nucleus breaks into small pieces. The cell shrink and breaks up into membrane enclosed fragment called apoptotic bodies, recognized by macrophages and neighboring cells and removed from body.

Gene for regulating apoptosis: 

Gene for regulating apoptosis In 1986 Robert Horvitz identified two genes that were required for developmental cell death, these are ced-3 & ced-4 and a third gene ced-9 function as a negative regulator of apoptosis. If ced-3 & ced-4 was inactivated by mutation then no normal programmed cell death. If ced-9 is mutated then cell that would normally survive failed to do so. Genes related to ced-3, ced-4 & ced-9 have also identified in mammals.

The executioner of apoptosis: 

The executioner of apoptosis Caspases The ced-3 gene encoded a protease, providing first insight into molecular mechanism of apoptosis. Ced-3 is the prototype of a family of dozen protease, known as Caspases. It affect the programmed cell death by inhibit DNase, which when activated is responsible for fragmentation of DNA. Caspases cleave nuclear lamin fragmentation of nucleus, cytoskeletal protein disruption.

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Mammalian contain family of atleast 7 caspases, classified as either initiator or effector. Subsequent studies shows that Apaf-1 which is mammalian homology of ced-4 binds to ced-9 and promote their activation in a multicellular complex called Apoptosome.

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Caspase activation The mammalian initiator caspase-9 is activated as a complex with Apaf-1 and cytochrome c in the apoptosome. Caspase-9 then cleaves and activates effector caspases, such as caspase-3. The effector caspases cleave a variety of cell proteins, including nuclear lamins, cytoskeletal proteins, and an inhibitor of DNase, leading to death of the cell.

Central regulation of apoptosis: 

Central regulation of apoptosis The third gene identified as a key regulator is C. elegans ced-9 was found to be closely related to mammalian gene called Bcl-2 The inhibitory role of Bcl-2 first focus attention on the important of cell survival in cancer development. Mammals encode a family of approximately 20 proteins related to Bcl-2, which are divided into three functional groups

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The Bcl-2 family The Bcl-2 family of proteins is divided into three functional groups. Antiapoptotic proteins (e.g., Bcl-2 and Bcl-xL ) have four Bcl-2 homology domains (BH1-BH4). The multidomain proapoptotic proteins (e.g., Bax and Bak ) have three homology domains (BH1-BH3), whereas the BH3-only proapoptotic proteins (e.g., Bid, Bad, Noxa , Puma, and Bim ) have only one homology domain (BH3).

Alternative pathway that regulates apoptosis: 

Alternative pathway that regulates apoptosis Alternative pathway of programmed cell death Although apoptosis is the most common form of regulated cell death, recent research has shown that cell death can also occur by alterative non-apoptotic mechanism. One of these alternative pathway of regulated cell death is Autophagy Autophagy provides a mechanics for the gradual turnover of the cell’s component by the uptake of protein or organelles into vesicle that fuse with lysosomes.

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Autophagic cell death does not require caspases and the dying cells are characterized by an accumulation of lysosomes. IMPORTANT provide alternative pathway when apoptosis is blocked. The important of both autophagy and necrosis as alternatives to apoptosis remain to be fully explored, not only in normal cells but also in disease such as cancer, heart, neurodegeneration which involve abnormalities of cell survival.

Extrinsic pathway of apoptosis: 

Extrinsic pathway of apoptosis Also called as Death Receptor-Initiated pathway. Initiated by cell surface death receptor. Death receptor are member of TNF family that contain a cytoplasmic domain involved in protein protein interaction, called death domain (delivers death signals). Best known death receptors are type 1 receptor (TNFR1) and related protein called Fas (CD95). This pathway can be inhibited by protein called FLIP, which binds to pro-caspases 8.

intrinsic pathway of apoptosis: 

intrinsic pathway of apoptosis Also called as Mitochondrial pathway. This pathway is the results of increased mitochondrial permeability & release of pro apoptotic molecules into the cytoplasm. Growth factors and other survival signals stimulate the production of Bcl-2 family of protein. Two main anti-apoptotic protein are Bcl-2 and Bcl -x, which resides in mitochondrial membranes and cytoplasm. When cells are deprived of survival signals or subjected to stress, Bcl-2 and/or Bcl -x are lost, and replaced by pro-apoptotic members of family, such as

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as Bax , Bak and Bim . When Bcl-2 and/or Bcl -x level decreases, mitochondrial permeability increases and release several protein that can activates caspases. Activation of caspases. Executioner caspases. Removal of dead cells.

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Autophagy Lysosomes contain various digestive enzymes, including proteases. Lysosomes take up cellular proteins by fusion with autophagosomes, which are formed by the enclosure of areas of cytoplasm or organelles (e.g., a mitochondrion) in fragments of the endoplasmic reticulum. This fusion yields a phagolysosome, which digests the contents of the autophagosome.

Features of Necrosis & Apoptosis: 

Features of Necrosis & Apoptosis

reference: 

reference Pathologic Basis Of Disease by Kumar, Abbas , and Fausto , 7 th edition, ELSEVIER Publications. THE CELL, A Molecular Approach, by Cooper and Hausmen , 5 th Edition.

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QUESTIONS

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