In recent decades, we have made enormous progress toward understanding the cellular basis of aging, and our current knowledge suggests that the very thing that allows cells to survive is also inherently linked to their degeneration. The oxidative stress theory proposes that mitochondria produce, as a natural by-product of respiration, harmful reactive oxygen species (ROS) that accumulate, damaging molecules (proteins, lipids and nucleic acids) and deleteriously affecting cell function over time. Thus, over the years researchers have manipulated the diets or the genetics of animals to alter their susceptibility to oxidative damage, with the aim of extending their longevity. However, nature has provided us with a striking example of differential longevity in the pigeon and the rat; pigeons can live up to 7 times longer than rats. This comparison has baffled researchers for decades as pigeons have a higher metabolic rate and a higher body temperature (both of which promote a higher rate of ROS production and shorten life expectancy), yet they outlive their furry cousins by three decades! Previous comparisons between the capacity of rats and pigeons to detoxify ROS or prevent oxidative damage to biomolecules generated contradictory results. Magdalene Montgomery, Anthony Hulbert and William Buttemer decided to try to reconcile these apparent contradictions and attempt to identify factors that may be responsible for that difference in longevity between rats and pigeons.
The team initially looked at in vitro mitochondrial production of ROS in liver, skeletal muscle and heart. Their findings suggest that rats do not consistently produce more ROS in these tissues when compared with pigeons. However, when they compared ROS production with mitochondrial oxygen consumption, only rat cardiac muscles ‘leaked’ relatively more free radicals than pigeons. Next, the team evaluated the differences in antioxidant defences in the plasma, liver, heart and muscle of the two animals. Overall, the different indicators (enzymatic and non-enzymatic antioxidants) were not consistently higher in one animal or the other across tissues. Montgomery and colleagues then looked at the phospholipid composition of tissues and mitochondria from rats and pigeons to calculate a peroxidation index, a measure of membrane susceptibility to oxidative damage, as some fatty acids are more prone to peroxidation. In most tissues examined, the team found that rat cellular and mitochondrial membranes were more susceptible to peroxidation than the corresponding membranes in pigeon. Finally, the authors looked at oxidative damage at the DNA, protein and lipid level and found that rats had a higher level of mitochondrial DNA damage in the heart and higher protein damage in plasma, while pigeons had higher lipid damage in the liver.
In this comprehensive study, Montgomery and colleagues shed light on some inconsistencies previously reported in the comparison of oxidative stress markers between the long-lived pigeon and relatively short-lived rat. Overall, this work suggests that of all the components of the oxidative stress axis, the membrane peroxidation index is the most consistent with the oxidative stress theory of aging in these animals. More importantly, the variability of the other factors examined certainly warrants comprehensive examination of the different components of the oxidative stress axis in future investigations.