Structural Biochemistry/Cell Aging

Definition
The decrease in the cell's ability to proliferate with the passing of time. Each cell is programmed for a certain number of cell divisions and at the end of that time proliferation halts. The cell enters a quiescent state after which it experiences cell death via the process of apoptosis.

Overview
Aging is inevitable as it is an accumulation of damage over time that eventually affects the function and survival of organisms. It is evident that this occurs because the accumulation of damages is contributed by the inability of the biological systems to maintain and protect the somatic tissues over a long duration of time. There are approaches that contribute to aging. One approach is outlined by the degradation of physiological systems output which directly leads to functional decline. Functional decline changes in cell number which affects metabolic record of the cell. This simple pathway serves as a framework for analyzing methods involved in aging. Physiological and Metabolic Processes All organisms’ functions are described as a set of physiological systems that interact with each other and the environment. Their system only communicates with other systems through “inputs” and “outputs”. The diagram on the left shows the network of the physiological system that gives a overview of organism’s function. System aging happens over time when output becomes inappropriate and impairs organisms’ function. The progressive dysfunction with aging of an organism is due to the decline influenced by some other outside forces. Physiological Decline From an evolutionary perspective, natural selection will try to maximize reproductive success in tissues in order to slow down mortality. Inversely, many physiological systems within an organism will wear out at similar rates. Similar rates of functional decline could occur because the output of the dysfunctioning system maybe directly be connected to other systems. Another possible explanation for analogous rates would be the existence of an aging process common to different physiological systems. For example, mutations in a single gene ameliorate many forms of aging-related damages. Furthermore, the evolutionary effects on aging raises the probably of similar aging process in different organisms. Cell Number Cell number change is directly correlated to aging. Change in the outputs of a system is influenced by alterations in their constituent cells. Even changes outside the extracellular matrix of exoskeleton can be ascribed to changes in cell function. Accumulation of extracellular debris such as fatty plaques can cause dysfunction of macrophages. Even age related modification such as glycation-mediated loss of elasticity of blood vessel wall or damage to lens protein may contribute to the effectiveness of cell function. Since modifications occur at same hierarchical level as cell changes, they inherently affect system function in much the same way as cell function. Therefore, the decline in physiological systems during aging is caused by changes in cell count and/or changes in noncellular component of the system. Metabolic Control Analysis (MCA) and Aging MCA has been used to describe the control and regulation of metabolic pathways and networks. Activity of each enzymatic step is varies very slightly and the effect of the overall flux is determined. Simple definition of the control is where the greater the change in flux, the greater the control of that enzyme over the flux. Thus, the control lover flux is a property of pathway that can share control and distribution of control as metabolic conditions are altered. Further research is still required in this field of study but scientists have built a concrete foundation in which they can experimentally build upon.

Major Forms of Cell Death
There are three main forms of death that are widely recognized: Apoptotic death, Autophagic death, and Necrotic death. Apoptotic death is also known as the programmed cell death. It occurs when cells are no longer needed and they “commit suicide by activating a intracellular death program”. [4] Autophagic death is also another type of cell death, commonly known as autophagic Programmed Cell Death (PCD). [5] This type of death occurs by the delivery of autophagic vesicles into lysosomes [2]. Necrosis death is a more abrupt form of death that cells undergo. Necrosis is when the plasma membrane of a cell brakes. It is important to take into account that these types of deaths could not be exactly the cause of cell death but could happen before, or after.

Premature Cell Death by Phagoptosis
Phagocytosis is important because it is a major homeostatic mechanism in multicellular organisms. For example, it defends against pathogens by removing defective cells. However, excessive or lack of cell death is harmful and can lead to pathology. Recent discoveries have shown that cells that are still considered viable can be marked for phagocytosis prematurely in a process known as phagoptosis. Prior to this discovery, phagocytosis was believed to only eat dead cell or cells that are close to death. However, recent studies show that healthy cells can be marked for phagocytosis if they possess a signal marking it for phagocytosis or lack a signal to prevent it from being eaten by phagocytosis. The phagoptosis of neurons is particularly concerning due to the limited capacity of the brain to replace these neurons. By the same logic, prevention of phagoptosis of cancer cells are also of concern.

Phagocytosis ( process of cell devouring) is started by the release of signals (‘ find me’ signals) which attracts macrophages that are close by to the cell. When the macrophage is close enough to the cell it recognizes signals of ‘eat me’ and ‘don’t eat me’ from its surface. The most common “eat-me” signal is generated when cell surface is exposed to phospholipid PS. PS exposure occurs when aminophospholipid translocase (enzyme that assists proteins to move across a membrane) is inhibited or phospholipid scramblase is stimulated or both. Healthy cells usually have aminophospholipid translocase that uses ATP to keep phospholipid PS in the inner plasma membrane. When this translocase is inhibited, PS flows out to the outer membrane and is exposed to cell surface, thereby creating “eat-me” signals. Moreover, any condition that activates phospholipid scramblase, which changes phospholipid distribution on the plasma membrane, can cause PS exposure. Conditions such calcium elevation, ATP depletion, oxidative stress can stimulate scramblase and inhibit the translocase. However, exposure of PS is not the sole indicator on whether or not a cell is marked by a phagocyte and additional environmental conditions must also be met. In addition of having an "eat-me" signal of exposed PS, the cell can also posses a "don't-eat me" signal which can be expressed by the protein CD47. Cells can expose this CD47 "do-not-eat" region causing the binding of certain residues to the protein, resulting in the phagocyte being unable to bind to the protein. Moreover, not all cells that are PS-exposed are sufficient to start phagocytosis. Some cells have strong “don’t eat me” signal or require other more potent signals to induce phagocytosis. Therefore, phagocytosis depends on the net exposure of both types of signals and the amount of PS or CD47 expressed determines if phagocytosis occurs. PS exposure can be reversible if and only if the induced eat me signal on the cell surface is quickly removed before macrophage finds the cell. [2]

The most applicable connection is to current cancer research. Unsurprisingly, cancer cells possess an overwhelming amount of "don't-eat me" or CD47 signals. It was recently shown that high levels of CD47 have a strong correlation to the capability of producing tumors in both mice and humans. Antibodies that identify CD47 have shown to induce phagocytosis of these cancer cells and show promise in future cancer treatment.[2]

Phagoptosis of Neurons
Destruction of neurons can be a serious potential health risk if the natural process goes amiss. The cells responsible for the phagocytosis of living neurons are microglia, which are brain cell macrophages. Microglia cells become activated by lipopolysaccharide (LPS) to consume and destroy inflamed neurons via phagocytosis. This activation of the microglia cells, in essence, makes them hunt for inflamed neurons by discharging MFG-E8, a binding protein. When living neurons become inflamed, they bare the phospholipid phosphatidylserine (PS) on the exterior surface of the cell. Once the PS is out in the open, MFG-E8 binds to PS marking it for the microglia to come engulf and destroy the neuron.[3]

Scientists have been looking for a way to inhibit or block this targeting and destruction of healthy neurons. In one experiment they use mice that have been genetically altered to deactivate a specific gene that is used to make MFG-E8 binding proteins. Their results showed that the mice without the MFG-E8 binding protein did not have phagoptosis of regular inflamed neurons. However, by adding pure MFG-E8 binding proteins back into those mice, phagoptosis of the inflamed neurons resumed as usual. They also found that if LPS is inserted in close proximity to the neurons of a mouse that inflammation would occur and microglia targeted the neurons. Additionally to support their findings, when LPS was inserted into the MFG-E8 deficient mice neuron destruction was much less than it was in the normal mice. [3]

In conclusion, inflammation activates microglia cells to destroy healthy neurons but this can be averted by inhibiting the marking of neurons for destruction. This is not to say that microglia are troublesome, they actually help clean up dead and dying neurons to keep inflammation down. In turn, inflammation would make the microglia go on the hunt for living neurons as well as neurons that need to be disposed of. [3]

Cancer
It has been found that cancers usually expose a great quantity of “don’t eat me” signals in order to not undergo cell death, this being the reason why cancer is so difficult to fight. The “don’t eat me” signal majorly exposed by cancers is the CD47 which has been found to have a correlation with tumourigenicity and its exposure amount. [2] The “don’t eat me” signal is usually neautralized by our bodies by the CRT(Cell Surface Calreticulin) “ eat me” signal, which is greatly exposed in the human body.

Programmed Necrotic Cell Injury
Necrotic cell death has been revealed to be more coordinated than random as was previously understood. Known as ‘programmed’ necrotic cell injury, this form of cell death is regulated by TNF receptors which are involved in apoptosis as well. Necrotic cell injury differs from apoptosis in that it is characterized by extensive swelling, plasma membrane rupture, and distinct biochemical components involved in the pathway-specifically RIP serine/threonine protein kinases. Apoptosis and programmed necrosis are therefore induced in response to similar cellular conditions with minor disparities in the degree of cell damage as cells communicate and coordinate the proper course of action through molecular cross talk involving structural modification at the cell membrane and signalling between cells. [6]

Reference
[1]Toward a Control Theory Analysis of AgingAnnual Review of BiochemistryVol. 77: 777-798 (Volume publication date July 2008) First published online as a Review in Advance on March 4, 2008DOI: 10.1146/annurev.biochem.77.070606.101605Murphy, Michael. Partridge, Linda.

[2]Eaten alive! Cell death by primary phagocytosis: 'phagoptosis'. Brown GC, Neher JJ. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.

[3]Brown, Guy C. and Neher, Jonas J..”Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’.” Trends in Biochemical Sciences 37.8 (2012): 325-332. Print.

[4]Alberts, Bruce. "Apoptosis Is Mediated by an Intracellular Proteolytic Cascade." Programmed Cell Death (Apoptosis). U.S. National Library of Medicine, 18 Feb. 0000. Web. 29 Oct. 2012. .

[5]Nature.com. Nature Publishing Group, n.d. Web. 29 Oct. 2012. .

[6]Moquin D, Chan FK. "The molecular regulation of programmed necrotic cell injury." Trends Biochem Sci. 2010 Aug;35(8):434-41. Epub 2010 Mar 26. Review.