HIF-1 and AMPK in Regulation of Mitochondrial Generation of Reactive Oxygen Species
Many of the varied genes and proteins that can be manipulated to extend longevity in lower animals are associated with mitochondrial function, and specifically the pace at which mitochondria generate reactive oxygen species (ROS) in the course of performing the task of generating adenosine_triphosphate, a chemical energy store used to power cellular processes. Cells react to the levels of ROS produced by their mitochondria, such as by dialing up their housekeeping and repair efforts when ROS output increases during exercise. More extended periods of increased cellular housekeeping lead to extended longevity for all the obvious reasons, as damaged molecular machinery and metabolic wastes are given less time to cause further damage.
Thus it isn't too surprising given current knowledge to find links between genes and proteins involved in cellular housekeeping and the behavior of mitochondria, and further between those involved in nutrient sensing and immune system regulation. Researchers interested in the intersection of metabolism and aging are exploring a network of interacting machines and feedback loops, in which every change causes reactions and adaptations elsewhere in the grand collection of machinery we call a cell:
Reactive oxygen species (ROS) have long been thought to cause aging and considered to be toxic byproducts generated during mitochondrial respiration. Surprisingly, recent studies show that modestly increased ROS levels lengthen lifespan, at least in the roundworm Caenorhabditis elegans. It was unclear how the levels of potentially toxic ROS are regulated and how ROS promote longevity. Here we demonstrate that ROS activate two proteins, AMP-activated kinase (AMPK) and hypoxia-inducible factor 1 (HIF-1), to promote longevity by increasing immunity.Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMPK. We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, balancing ROS at optimal levels appears to be crucial for organismal health and longevity. AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.