Post-mitotic tissue

Damage to proteins

Damage from ROS is also thought to have an age-related impact on proteins. Such damage is thought to result in amino acid modifications, fragmentation of peptide chains, altered electrical charge and protein aggregation (Davies, 1987). Since the structure of proteins is pivotal for performing its functions then any structural changes would therefore result in an impairment of function. As discussed previously, the turn-over rate of proteins is an important factor in determining whether any protein damage is going to have a significant affect. Since the majority of intra-cellular proteins have high turn-over rates, damage proteins are not going to persist long enough to cause any problems. Therefore, long-lived proteins which may be affected by AGE formation may also be affected by oxidative damage. Examination of extracellular tissues in the lens, skin collagen and articular cartilage (low turnover proteins) of humans ranging in age from infancy to 80 years showed an increase in oxidative markers with age (Linton et al, 2001). The same study also looked at intracellular proteins with high turnover rates and found no evidence to suggest that intracellular proteins accumulate oxidative damage with age.

Damage to Lipids

Lipids which make up the membranes of cells are also potential targets for ROS which may consequently result in biologically significant alterations to membrane proteins. ROS are thought to attack membrane phospholipids and act on unsaturated fatty acids to produce lipid peroxidation. The consequent of this may be alterations in membrane fluidity, increased permeability and loss of membrane integrity. Experimental evidence suggests that altered membrane fluidity might affect permeability, transport systems, receptor functions or enzyme activities (Stark, 2005). The functionality of proteins in the membrane is critically dependant on membrane fluidity, especially when proteins have to collide with other molecules to exert their effects (such as G-proteins). This is seen in many receptor mediated pathways. For example, cardiac membranes from rats with cirrhotic cardiomyopathy are rigid and associated with diminished cAMP production. When the fluidity of these membranes are restored to control values cAMP production was significantly increased (Ma et al, 1997).

Biological impact of ROS

The above discussion on ageing of post-mitotic cells reviews the mechanisms thought to result in an overall increase in cellular damage by ROS, but little evidence is provided for the age-related biological consequence of such damage. If accumulative damage from ROS is an ageing mechanism of post-mitotic tissue, then such damage may result in three possible outcomes:

1) Post-mitotic cells become damaged and are subsequently removed. Post-mitotic-cells cannot be replaced, thereby resulting in a decrease in overall cell number and a decrease in tissue function.

2) Damage to post-mitotic cells results in an impairment of cellular function but such damage is not extensive enough for the removal of cells and so they persist.

3) Cells are removed due to damage and are subsequently replaced (i.e. by mitotic cells). However, the ageing mechanism in this case may therefore be a decline in the capacity to replace cells due to an ageing mechanism specific for mitotic tissues which will be discussed later. This may result in an observation similar to point 1).

The literature was reviewed to identify whether these three possible outcomes are present in ageing of post-mitotic tissues. One study observed a substantial increase in the amount of DNA single strand breaks in hippocampal pyramidal and granule cells as well as cerebellar granule cells but not in cerebellar Purkinje cells in the brain of ageing rats (Rutten et al, 2007). However, a reverse pattern was found for age-related reductions in total numbers of neurons. Cerebellar Purkinje cells were found to be significantly reduced during ageing (point 1 above) whereas the total number of hippocampal pyramidal and granule cells as well as cerebellar granule cells were not (points 2 or 3 above). This may seem as a confusing result since those cells which have undergone the most DNA damage may be expected to decline in numbers. This result may be explained if there are processes in place that replace damaged pyramidal and granule cells but do not, or cannot, replace damaged Purkinje cells. Cells that may be more prone to damage may have a higher potential capacity to be replaced than cells that are less prone to damage. It is also possible that the damage inflicted on hippocampal pyramidal and granule cells is not severe enough to warrant their removal. These findings suggest that if ROS does cause detrimental damage leading to an ageing phenotype, such damage is not tissue specific damage, but rather, cell type specific. All post-mitotic cells cannot therefore be treated equally.

A decline in cell numbers may not be related to damage from ROS but instead due to the loss or dysfunction of mitotic cells such as glial cells and astrocytes which are known to provide support and protection for neurons. Discussed later in more detail in ageing of mitotic tissue, mitotic cells can undergo an irreversible cell cycle growth-arrest known as replicative senescence. Senescent cells display a radically altered phenotype with potentially detrimental consequences on other cells if they accumulate in tissue. For example, a recent study has demonstrated that alterations in astrocyte function with ageing may not only affect its neuroprotective capacity, but may also contribute to neuronal injury in age-related neurodegenerative processes (Pertusa et al, 2007). Also, microglial, cells involved in immunological surveillance and neuroprotection have been shown to be subject to replicative senescence and it has been suggested that the dysfunction of these cells may contribute to the development of neurodegenerative disease by diminishing glial neuroprotection (Streit, 2006).

Myocytes, also known as muscle fibres are post-mitotic cells found in skeletal, smooth and cardiac muscle. Studies have shown that ageing muscle results in a decline in myocyte numbers, signs of atrophy and increased susceptibility to contraction-induced injury (Alnaqeeb and Goldspink 1986, Musaro and Rosenthal, 1999, McArdle et al 2002,). When myocytes become damaged and need to be repaired, mitotic satellite cells are able to differentiate and fuse to augment existing muscle fibres and to form new fibres. Decline in myocyte numbers and increases in damage with age may therefore, at least in part, be due to a reduction in number or the impairment of satellite cells (point 3). Such a reduction in satellite cell numbers would result in a decrease in cellular maintenance and an increase in cellular damage, possibly leading to the removal of the cll altogether. One study has found that the abundance of satellite cells does appear to decline with age, however, the myogenic potential of these cells does not diminish with age (Shefer et al, 2006).