The predominant ageing mechanism of post-mitotic cells (i.e. neurons, myoblasts and osteocytes) is often thought to be due to the accumulation of damage to DNA, protein and lipids caused by reactive oxygen species (ROS). Since these cells do not divide in tissues and can potentially persist for a lifetime, they are more likely to accumulate damage which may subsequently result in an age-related phenotype. Also, since mitotic cells are mostly found in a non-dividing state in vivo known as quiescence, with very little cell turnover, they could also in some regard be treated similar to post-mitotic cells.
ROS are thought to cause accumulative damage to DNA, protein and lipids, but how and if such damage results in an ageing phenotype still remains unclear. Damage from ROS is thought to be imposed on tissues as we age due to three possible factors:
1) An increase in ROS production.
2) A decrease in antioxidant defences.
3) A failure to repair oxidative damage.
Increase in ROS
Increases in ROS production is thought to be the result of mitochondrial dysfunction which leads to an increase in electrons leaking out of the respiratory chain within the mitochondria as we age (Wei et al, 2001). This increase in ROS is thought to increase damage to genomic DNA, mitochondrial DNA, proteins and lipids. Despite this theory, there appears to be little evidence to suggest that the levels of oxidative stress increases with age. One study however investigated age-induced ROS generation in healthy subjects ranging in age from 20-80 years quantifying ROS production using a chemiluminescence assay (Chaves et al, 2002). Results demonstrated a significant increase of ROS production from 40 years of age suggesting ROS does increase with age. However, little is known about the source of ROS. As mentioned, respiratory chain dysfunction leading to electron leakage is one suggestion.
With this in mind, a mutator mouse was created to investigate whether the mutations which were introduced in the mitochondrial resulted in mutant mitochondrial proteins that are defective in coupling of oxygen metabolism with ATP causing increased ROS production (Trifunovic et al, 2004, Trifunovic et al, 2005). Results indicated that despite the presence of severe respiratory chain dysfunction, the amount of ROS produced in these mice was normal, no increased sensitivity to oxidative stress-induced cell death was observed and no difference in oxidative damage to protein was seen. This data thus suggests that if ROS does increase with age, it may not be due to respiratory chain dysfunction.
An alternative source of ROS may come from age-dependent up-regulation of the inflammatory response. Inflammation has been implicated in many age-related diseases such as rheumatoid arthritis, osteoarthritis and cardiovascular disease (Licastro et al, 2005). The presence of inflammation is associated with increased ROS production, promoting the destruction of normal tissue (Winrow et al, 1993). This production of ROS during an inflammatory response may also initiate and/or amplify inflammation via the up-regulation of several genes involved in the pro-inflammatory response (Conner and Grisham, 1996). In some instances however, inflammation associated with ageing may result from direct damage from ROS (Chung et al, 2001). It is therefore difficult to determine to determine what come first, the inflammation leading ROS production or ROS production leading to damage leading to an inflammatory response and further ROS production.
One source of inflammation, as discussed later, may come from the presence of senescent cells within tissues which adopt a proinflammatory phenotype. It is hypothesised that the accumulation of senescent cells within tissues contributes to ageing (Hayflick, 1965). As the number of senescent cells increases, so does the intensity of the inflammatory response. In part, this proinflammatory phenotype is thought to damage tissues by the production of ROS.
Another alternative for increase in ROS with age may be due to a reduction in antioxidant defences and/or a decrease in the failure to repair oxidative damage.