How Oxidative Stress Is Implicated In Ageing: Part 2
When lipids are oxidised by Reactive oxygen species, the resultant products can have a variety of affects on an organism. For example, Malonaldehyde (a lipid oxidation product) is capable of reacting with various molecules (proteins, nucleic acids) and can alter their structural confirmation. This alteration then leads to the immobilization of immune function. Furthermore researchers have found that many sufferers of age related diseases such as liver disease, diabetes and atherosclerosis, have high levels of lipid oxidation products present in cells (Lee, 2004). Frei (1995) also noted that the oxidation of LDLs can lead to the development of cardiovascular disease.
When reactive oxygen species interact with protein molecules, they lead to the oxidation of amino acid side chains as well as other alterations to the protein molecules. The resultant oxidation products are modified amino acid molecules and carbonyls (Lee, 2004). Protein oxidation of important protein molecules such as transporters and enzymes can cause significant disruption to various signalling pathways and important biochemical pathways (Berlett et al, 1997). Changes in the functionality of enzymes, is seen in ageing (Berlett et al, 1997). One way in which DNA can be damaged is by a hydroxyl species which can cause guanosine to be oxidised to 8-hydroxy-2-deoxyguanosine. This product does not stop DNA synthesis from occurring and can pair with either a cytosine or adenosine base (Nicole, 2007). This leads to the formation of mutagenic DNA which has mis-paired bases, and can consequently advance on to more devastating effects such as the initiation of carcinogenesis (Ames 1993). Kasai (1997) noted that the levels of 8-hydroxy-2-deoxyguanosine within cells could be used as an indicator of oxidative stress.
Post replication mismatch repair is one example of a DNA repair pathway. The pathway involves two main enzymes: DNA polymerase and Nuclease. DNA polymerase initially detects the miss-paired nucleotide and then nuclease is involved in its removal. This mis-paired nucleotide is then replaced with the correct nucleotide (Royle, 2007). Another mechanism known as base excision repair uses the enzyme glycosylase, but in patients with high levels of oxidative stress this mechanism cannot operate properly and may fail to function. If this scenario occurs mutagenic DNA could be produced (Lee, 2004)
Damage to DNA caused by reactive oxygen species can lead to drastic changes within an organism. Mitochondria have their own DNA (mtDNA) separate from nuclear DNA. Because mtDNA is not associated with any histones (protective proteins), it is very susceptible to damage from reactive oxygen species (Nicole, 2007). The fact that it is the site of the electron transport chain and that it is in very close proximity to the main sites of ROS production lead to this susceptibility (Lee, 2004). Mitochondria have their own DNA polymerase called DNA polymerase gamma (POLG). This is involved in replication proofreading and DNA repair in mitochondria (Nicole, 2007). Mutation in the proof reading component of gamma DNA polymerase results in decreased longevity. Furthermore mice heterozygous for the polymerase gene have many mutations in the DNA but they do not have altered longevity, which suggests that mutations in mtDNA do not have a role in ageing, but the true relationship is still not known (Trifunovic et al, 2004) (Nicole, 2007).
Enzymes such as catalase, glutathione peroxidase and superoxide dimutase (SOD) all act as defensive mechanisms to remove excess ROS. All of these antioxidant enzymes operate by converting ROS into non reactive oxygen species (Lee, 2004). Research conducted by Duthie et al (1996) showed that consumption of vitamin A and E can increase life expectancy in mammals. This is due to their ability to act as scavengers and “mop up” excess free radicals.
