In energy metabolism, there are two means of ATP production: glycolysis and oxidative phosphorylation in mitochondria. The fact that mitochondria produce roughly 15 times more ATP per mole of glucose than glycolysis usually makes them the ideal choice for ATP production. However, relying on mitochondrial metabolism has its costs; mitochondria are the main source of reactive oxygen species (ROS), molecules that can attack DNA, lipids and proteins in cells. It is thought that the accumulation of oxidative damage over time is responsible for aging; this has been called the free radical theory of aging. One implicit assumption of this theory is that reducing ROS levels in cells should extend lifespan.
This is exactly what Samuel Schriner and collaborators tested. They studied the effect of overexpressing catalase, an ROS- removing enzyme, on lifespan in mice. Catalase is normally found in peroxisomes, organelles that contain oxidative enzymes, where it converts the ROS hydrogen peroxide(H2O2) to water. The scientific team generated three groups of mice, either overexpressing catalase in peroxisomes (PCAT), the nucleus (NCAT) or the mitochondria (MCAT). They found that the PCAT and NCAT groups showed a slight increase in median lifespan but found no increase in maximum lifespan compared with wild-type (WT) mice. On the other hand, the MCAT mice lived 20% longer than the WT cohort of mice. It seems that removing ROS from mitochondria can extend a mouse's lifespan.
The team decided to take a closer look at the MCAT mice; they compared the physiological state of various organs during aging between WT and MCAT mice by carrying out a histopathology analysis. They noticed pronounced differences in histopathology between WT and MCAT old mice, notably in the heart. Indeed,many indicators of cardiac pathology were elevated in WT mice compared with MCAT animals, indicating that overexpression of catalase in heart mitochondria affords protection against age-related heart problems. To directly assess whether the healthier hearts of MCAT mice were due to increased protection from ROS, the authors measured the activity of the mitochondrial enzyme aconitase, which is rapidly inactivated in the presence of ROS. When the team added a pulse of H2O2 to the mitochondria, they saw that aconitase activity decreased significantly in mitochondria from WT mice,whereas the drop was drastically smaller in mitochondria from MCAT mice. The team concluded that heart mitochondria from MCAT mice are more resistant to oxidative stress than those from WT mice.
Finally, to show conclusively that ROS levels are lower in cells and mitochondria of MCAT mice, the team measured the level of a marker of oxidative damage to DNA called 8-hydroxydeoxyguanosine (8-OHdG) in muscle and heart. They saw that 8-OHdG increased with age in skeletal muscle of control animals but did not increase in the MCAT group, indicating that MCAT mice indeed experience less oxidative damage, in their muscles at least. However,none of the mice hearts showed an age-related change in 8-OHdG levels. The team also noted a trend with age towards a smaller accumulation of mitochondrial DNA deletions, which are associated with oxidative damage, in skeletal muscle and heart of MCAT mice compared with WT animals.
This study demonstrates that mitochondria are at the heart of the aging process and that limiting ROS production by mitochondria can extend lifespan. Given the negative correlation between standard metabolic rate and aging, this study will probably stimulate comparative physiologists to identify key intrinsic differences in mitochondrial ROS metabolism among species.
