The accumulation of damage on many proteins is most likely to have little or no effect on tissues if the proteins are constantly being turned-over. Damaged proteins would be removed and replaced, eliminating any detrimental affect such damage may have caused if it persisted. However, a number of studies have focused on proteasome damage as an ageing mechanism (Friguet, 2002, Farout and Friguet, 2006). The proteasome is the main proteolytic system responsible for protein degradation and is itself a protein. Therefore, accumulating damage to the proteasome may result in the non-removal and accumulation of damaged proteins which may subsequently have a detrimental impact on tissues. However, if the proteasome itself has a high turnover rate, then protein damage should have little if no affect overall. Data for proteasome turnover rates is lacking but one study found that many components which make up the proteasome display high turnover rates (Hayter et al, 2005). Since there is little evidence to suggest accumulated protein damage in these proteins has any impact on age-related tissue dysfunction, more focus will be given to proteins with low rates of turnover.
Long-lived proteins are commonly extracellular and normally involved as structural components of tissues, and these includes collagen, the most abundant protein in the body found in skin, bones, tendons and teeth. Crystallin is also a long-lived protein found in the lens of the eye. Since these proteins have a very low turnover rate they are more likely to accumulate, as yet, irreversible damage and thus impair tissue function. One study investigated turnover rates of collagen and calculated the half-life of cartilage collagen to be over 100 years and that of skin to be 15 years (Verijl et al, 2000).
Damage may result in chemical modifications resulting in structural changes to the proteins and consequently altering its interactions with other proteins. One of these chemical modifications which have been researched extensively in regard to ageing and disease are the formation of advanced glycation end-products (AGEs). AGEs are formed when reducing sugars such as glucose or fructose react spontaneously with lysine or arginine residues in proteins (Wautier and Schmidt, 2004). The formation of AGEs can result in the cross-linking of proteins such as collagen and lens crystalline. Since these proteins are functionally different, the biological impact of protein cross-linking is going to be different. Cross-linking of collagen may result in arterial and joint stiffening whereas the formation of cataracts may be observed in lens crystalline.
The accumulation of AGEs in cartilage affects not only biochemical but also biomechanical and cellular properties of the tissue (Verzijl et al, 2003). At the biomechanical level, the accumulation of AGEs results in increased stiffness of the tissue and increased brittleness of the cartilage collagen network, increasing the risk of mechanical damage. Changes at the cellular level in response to AGE accumulation include decreases in proteoglycan and collagen synthesis by chondrocytes and decreased susceptibility of the cartilage matrix components towards proteinase-mediated degradation. Both these cellular alterations suggest that chondrocytes in a glycated environment have a reduced capacity to remodel their matrix and as a result reduce the capacity of chondrocytes to repair damage.
Since glucose is needed for the production of AGEs, their accumulation and consequently increasing stiffness is most likely to be proportional to blood glucose levels and the length of time these persist. Therefore, metabolic disorders such as diabetes mellitus in which blood glucose are often high would be affected more severely by AGEs compared with normal ageing. Arterial stiffness has been shown to be greatly accelerated in patients suffering from type 1 and type 2 diabetes (Schram et al, 2002, 2003). The exact mechanisms resulting in arterial stiffness are currently unknown. However, AGE formation leading to cross-linking of collagen and elastin and subsequent loss of elasticity is thought to be a key contributor. With this in mind, one study used ALT-711, a breaker of AGE crosslinks and determined whether arterial compliance was improved (Kass et al, 2001). Results showed that subjects treated with ALT-711 displayed an improvement in arterial compliance in aged humans with vascular stiffening. Arterial compliance rose 15% in ALT-711 treated subjects compared with no change with placebo. Similar experiments on aged dogs found that after 1 month of treatment with ALT-711, a significant reduction (~40%) in ventricular stiffness was observed and accompanied by improvement in cardiac function (Asif et al, 2000). These results suggest that AGEs are at least partly a contributor to arterial stiffness.
Another secondary effect of diabetes, which is possibly due to AGE formation is that seen with the development of cataracts (Ulrich and Cerami, 2001). Human lens crystallins are important long-lived proteins involved in retaining optical clarity required for normal vision. It is possible that glucose and other substances modify lens crystallins, causing conformational changes which subsequently result in the scattering of light and producing a cataract. One study investigated the occurrence of AGEs in human lenses and found a strong relationship between lens AGE content and the state of the cataract (Franke et al 2003). Another study compared AGEs in human diabetic and non-diabetic cataractous lenses and also found an overall increase of AGEs in diabetic lenses compared with non-diabetic lens samples (Pokupec, et al, 2003). Both these studies provide correlative support for the notion that AGEs play a causal role in cataracts.
In any biological system the structure-function relationship is essential for normal activity. These two examples demonstrate how a change in structure can have a detrimental impact on normal biological function. It also demonstrates how one ageing mechanism can have multiple consequences depending on the tissue in question.
More recently, findings have suggested that AGE formation may not only affect the structure-function of long-lived proteins but may also have an impact on cellular activities. This idea comes from studies that have demonstrated the interaction of AGEs with specific cell surface receptors, of which the best characterised receptor is RAGE (receptor for AGE). RAGE is a cell surface receptor present on different cell types including endothelial cells, smooth muscle cells, lymphocytes and macrophages (Wautier and Guillausseau, 1998). The binding of AGEs to specific receptors is thought to lead to cellular activation, increased expression of extracellular matrix proteins and the release of pro-inflammatory cytokines and growth factors (Simm et al, 2004). Therefore, the interaction of accumulating AGEs with receptors may cause undesirable changes in cell function, which may in turn affect the functioning abilities of tissues.
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