One key source of aging — oxidative damage — comes form the very air that we breathe. Mitochondrial oxidative phosphorylation is essential for cellular ATP production, but inevitably results in the formation of reactive oxygen species (ROS), which in turn oxidize macromolecules including DNA.
We recently learned that mitochondrial uncouplers — compounds that cause proton leakage across the mitochondrial membrane and thereby separate oxidative phosphorylation from the electron transport chain — can reduce the production of ROS. Indeed, treatment with uncouplers reproduces many of the other hallmarks of calorie restriction (CR), including decreased steady-state oxidative damage to DNA and protein, lower blood sugar and triglycerides, and — crucially — extended lifespan.
Chemicals aren’t the only way to uncouple ox/phos from electron transport. Mammalian genomes encode uncoupling proteins (UCP), generally expressed in tissues involved in thermogenesis, such as the mitochondria-rich “brown fat” that maintains body temperature during rodent hibernation and proteins the brainstem of human infants. (When electron transport is uncoupled from the proton gradient, the lost energy is dissipated as heat.)
A new study has shown that expression of one specific UCP is associated with enhanced longevity and decreased oxidative stress in the mouse. From Andrews & Horvath:
Uncoupling Protein 2 regulates lifespan in mice
The long-term effects of uncoupled mitochondrial respiration by uncoupling protein 2 (UCP2) in mammalian physiology remains controversial. Here we show that increased mitochondrial uncoupling activity of different tissues predicts longer lifespan of rats compared to mice. UCP2 reduces reactive oxygen species (ROS) production and oxidative stress throughout the aging process in different tissues in mice. The absence of UCP2 shortens life span in wild type mice, and, the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals. Thus, UCP2 has a beneficial influence on cell and tissue function leading to increased lifespan.
The most surprising result is that UCP2 mutants have shorter lives, implying that mitochondrial uncoupling is a key mechanism for controlling oxidative stress throughout the lifespan.
The results from the genetic cross with the Sod2 mutant is consistent with what we already know about mitochondrial uncoupling: Without Sod2 (encoding mitochondrial superoxide dismutase), ROS production and oxidative damage increase, causing premature aging). Higher levels of UCP2 (resulting from overexpression) would cause uncoupling, which decreases the production of ROS, and in turn presumably decreases the oxidative load on the Sod2 mutant.