This area of scientific investigation is less well known to both the lay and professional reader, but it has profound practical importance. It concerns how our bodies handle oxygen in health and disease and adapt to low oxygen states. One issue of the Journal of Molecular Medicine is entirely devoted to hypoxia (low oxygen) and human disease. It contains papers encompassing a range of conditions including cardiovascular, gastrointestinal, kidney and lung diseases, cancer and more. The focus here is on one paper that extensively reviews the regulation of oxygen in immunity and the response to infection. This is particularly important because there seem to be many clinicians who assume that increasing oxygen saturation in the locale of an infection helps to get rid of it (through oxidative damage to the pathogen and healthier surrounding tissues). Due to the research over the past several years on the powerful and important role of hypoxia inducible factor (HIF) we can understand that this is incorrect. “The hypoxia-inducible transcription factor (HIF-1α) is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress.” It exerts powerful control over the white blood cells that respond to infection: “HIF-1α has been discovered to function as a global regulator of macrophage and neutrophil inflammatory and innate immune functions.” They refer to HIF-1α as “a master regulator of innate immunity.” This is a fascinating review with references to many other studies if you care to read it, but the main point I want to bring to your attention is this: “A paradoxical result of these findings is that, due to HIF-1α activation, macrophages actually phagocytose and kill bacteria better under hypoxic conditions than they do under normoxic conditions.” This means white blood cells kill bacteria more effectively in a low oxygen environment than they do when oxygen in that location is normal. They go on to explain its role in viral and parasitic infections and the progression of viral infections to cancer. They go on to conclude: “The proof-of-principle experiments described suggest further exploration of HIF-1α augmentation to boost innate defense function. This may be of interest as a therapeutic strategy in infectious disease conditions complicated by antibiotic resistance or compromised host immunity.” Certainly this is a complex system and much more could be said, but the practical message is this: think each case through very carefully before advising or receiving oxidative therapies for infection.

A new study in mice finds that a protein that plays a role in responding to certain kinds of stress may help regulate a metabolic pathway important for controlling blood sugar, burning fat and even making tumors grow. The study shows that the protein, known to play a role in aging, is part of a protein family that has its finger on the pulse of both major pathways cells use to make energy.

The study indicates that the protein, known as sirtuin 6, or SIRT6, is what's known as a master regulator, in this case helping cells switch between oxidative metabolism, the major form of energy production in cells; and anaerobic glycolysis, a less efficient way of making energy and can be tapped when oxygen or nutrients are in short supply. The anaerobic form of glycolysis needs more glucose to generate the same amount of energy as oxidative processes. The study could lead the way to new therapies for diabetes and obesity.

Sirtuins are a family of proteins found in many organisms from yeast to humans. The most famous of the seven sirtuin proteins in humans, SIRT1, has been studied as a possible antiaging compound. That protein also helps regulate oxidative metabolism. Until recently, not much was known about the roles of other sirtuins.

Mice that lack SIRT6 seem normal at birth but die a few weeks later of hypoglycemia, or low blood sugar. No one knew how absence of the sirtuin protein could affect blood sugar levels so dramatically, says Raul Mostoslavsky, a molecular biologist at Massachusetts General Hospital Cancer Center and Harvard Medical School, both in Boston. In the new study, Mostoslavsky and his colleagues show that SIRT6 works with a stress-response protein known as Hif1alpha to control when and whether cells switch to anaerobic glycolysis.

Hif1alpha was already known to go to work when oxygen or glucose levels drop. Under such stress, the protein turns on genes involved in glycolysis and inhibits oxidative metabolism. During the stress of heavy exercise, for example, this switch occurs in muscles and leads to the buildup of lactate, which is responsible for feeling the burn after a workout. The new work demonstrates that SIRT6 acts as a safeguard mechanism to prevent Hif1alpha from becoming active when it is not supposed to.

When SIRT6 is missing or not working correctly, Hif1alpha inappropriately turns on anaerobic glycolysis and, the researchers found, turns off mitochondria, the cellular power plants where oxidative metabolism takes place. That explains why mice missing SIRT6 become hypoglycemic. The animals burn all of their glucose trying to make enough energy to stay alive. For the first 10 to 12 days of life, these mice manage, but eventually the animals burn through all of their reserves, including fat stores, and die.

"Since the mice are using glucose for glycolysis, they are burning fat like crazy," Mostoslavsky says.

Mostoslavsky suggests that drugs could be designed to turn down SIRT6 activity slightly. Targeting the protein might help diabetics lower blood sugar by burning that extra sugar for energy. And obese people might be able to lose weight by turning excess fat into energy the way SIRT6 mutant mice do.

Cell, Jan. 22, 2010