Hydrogen sulfide does not induce hypometabolism in sheep

In a widely publicized series of experiments by Blackstone et al., hydrogen sulfide (H2S) was found to induce hypometabolism in mice. These experiments raised interest in whether such “suspended animation” could be achieved in humans. If administration of H2S would be able to reduce metabolic rate in humans to the same extent as observed in mice, the practical applications could range from management of trauma victims to space travel.

Recent work by Haouzi et al. is not encouraging. The researchers were able to induce hypometabolism in mice but did not find any change in metabolic rate in sedated sheep after exposing them to 60 ppm H2S. What the investigators did report, and which was left implicit in previous experiments with mice, is that H2S-induced hypometabolism preceded hypothermia. H2S-induced hypometabolism in mice is not just the result of hypothermia, so the inability of H2S to produce hypometabolism in sheep cannot be attributed to thermal inertia of large animals.

How can H2S induce hypometabolism in mice? The authors state that “the present results have little to offer on the pathways that are responsible for H2S-induced decrease of metabolism.” They raise the point that in small animals such as mice a large portion of metabolism is devoted to heat production instead of ATP production. In contrast, small reductions in oxygen utilization in humans, as produced by H2S exposure, will affect ATP generation. Or as Ikaria‘s Csaba Szabo speculates in “Hydrogen sulphide and its therapeutic potential”, “the window of opportunity to compromise oxidative phosphorylation in a human, therefore, must be smaller than in the mouse.

The authors do not expect that higher dosages of H2S will produce hypometabolism in large mammals because the 60 ppm that was administered to sheep already exceeds what is known to be toxic in humans.

The search for molecules that induce hypometabolism, let alone hibernation-on-demand, in humans remains elusive. So far most research in this area involves attempts to activate conserved metabolic pathways of hibernating animals in non-hibernating animals instead of direct pharmacological inhibition of high energy consuming physiological activities.

Energy metabolism and sepsis

In this recent paper the authors argue that “multi-organ failure secondary to sepsis may actually represent an adaptive hypometabolic response to preserve ATP homeostasis in the face of a prolonged inflammatory insult.” Unlike organ specific diseases, mitochondrial dysfunction in multiple organ failure may be potentially reversible by careful timing of proper treatment. The authors warn against conventional attempts to jumpstart these “hibernating” organs back to life.

A similar situation may exist during stabilization of some cryonics patients. Instead of delivering oxygen to dysfunctional mitochondria that will only leak from the respiratory chain to generate harmful oxygen and nitrogen species, stabilization technologies may benefit from research into novel strategies to reduce metabolic demand by inhibition of non-essential functional processes in the brain. Systematic study of the biochemistry of hypometabolism in hibernating and estivating animals may provide important clues for such a research agenda.