Oxidative Damage and Senescence

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Keith
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Oxidative Damage and Senescence

Postby Keith » Fri Jun 08, 2007 3:12 am UTC

Does oxidative damage contribute to cellular senescence, i.e. does the damage inhibit the diploidy cells from dividing? I am doing a project on oxidative stress and aging and I can't seem to figure out if the aging is caused by damage that causes cellular senescence or if it is the damage that is the aging.

Please help. Thanks in advance.
Sapere Aude.

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Gwydion
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Postby Gwydion » Sat Jun 09, 2007 1:26 am UTC

I think the short answer is yes, but the long answer might take a while.

Oxidative stresses on a cell lead to a number of effects, but the most relevant to your project is probably DNA damage. Damaged DNA can be repaired, but this is dependent on the extent of the damage and the cell-cycle state of the cell in question. A number of molecules, most notably p53, are responsible for "double-checking" that the DNA isn't irreparably damaged. If it is, cyclin-dependent interactions lead to the cell basically eating itself. p53 is also responsible for preventing the progress of the cell cycle if there is any significant damage, so that hopefully the cell can repair any mistakes before mitosis. This, of course, is why p53 mutations have been implicated in a majority of human cancers. The interactions between cyclins, cyclin-dependent-kinases, and damaged DNA is at the center of apoptosis signalling, the process by which damged, aged, or otherwise defective cells commit pre-programmed seppuku of sorts.

As cells age, their ability to handle increased oxidant stresses decreases. Red blood cells may be among the best examples here, as over time their ability to regenerate reducing equivalents declines. Eventually, the oxidation causes changes in the RBC membrane which are sensed by cells in the spleen and which lead to the cells' destruction. (Be aware that since RBCs are anucleate, the discussion of p53 and apoptosis doesn't apply to them.)

It isn't clear to me whether the physical age of the cells is the most important factor, but I don't believe this to be the case. In patients with certain genetic differences (sickle-cell, G6PD deficiency, etc), the average lifespan of RBCs is shorter than in normal patients. Oxidant stress is the major cause of the changes in this cell which lead to their early demise. In other cell types, "aging" in the global sense may be more closely related to telomere loss at the ends of chromosomes, but this is the type of aging we associate with the elderly, and doesn't appear to be what you're asking about.

I think, then, the sequence you're looking for is:
Oxidative damage --> "Aging" of cells --> Apoptosis

This is a hot area of research, so my opinion may not necessarily reflect the most recent popular theories, but it does reflect my training in college and med school. Hope it helps.

Keith
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Joined: Wed May 30, 2007 2:53 am UTC
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Postby Keith » Sat Jun 09, 2007 3:20 am UTC

okay

/me uses your response as my entire essay.

Just kidding of course but thanks a ton, it really helps.

And oh yea, if you guys have any good sources where I could do more research, feel free to share. I'm looking for some good journal articles from pubmed or something like that. That is what my teacher really wants to see.
Sapere Aude.


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