The dose makes the poison. That adage is just as true of hazardous chemicals as it is of life-sustaining substances like water and oxygen. For instance, foul-smelling hydrogen sulfide (H2S) gas can be lethal if someone inhales too much in a sewer or a swamp, and yet, human cells produce it in small quantities as a critical signaling molecule.
In a recent study published in the Proceedings of the National Academy of Sciences, a team of researchers evaluated the effects of a mitochondria-targeted H2S treatment on the health and longevity of Caenorhabditis elegans nematodes (1). The researchers hope that their work will inform better strategies for using the gas to improve health in humans, particularly by slowing the progression of muscular and neurological decline as well as other diseases that typically affect the elderly. They’re not necessarily expecting to find the elixir of life. “It’s just delaying the onset of age and maintaining health for as long as possible,” said Matt Whiteman, one of the leaders of the project and a pharmacologist at the University of Exeter.
Most diseases will have a mitochondrial dysfunction component to them. If you can fix [it], you’ve got a high chance of at least delaying the disease progression or hopefully reversing some of it.
- Matt Whiteman, University of Exeter
Whiteman has been exploring the health benefits of treating animals with low quantities of externally produced H2S for years. He became particularly interested in understanding the effects of H2S on mitochondria because evidence suggests that H2S performs a number of biological functions that support mitochondrial health, such as facilitating mitochondrial DNA repair and providing antioxidant protection (2). Aging bodies tend to lose their mitochondria, but treating these organelles with H2S could prevent that loss and alleviate associated health consequences (3).
Whiteman previously helped develop a molecule called GYY4137 that dissolves in water and releases H2S gradually over time, introducing the sulfurous substance to the cell in an untargeted manner (4). He later described a compound called AP39, which consists of one group of atoms that helps locate mitochondria within cells and another that slowly generates H2S once the compound is in place (5). In both cases, the goal was to avoid flooding cells with large amounts of H2S all at once.
The current study revealed that because AP39 specifically targets the mitochondria, it can produce health benefits at even lower quantities than GYY4137. Whiteman and his team found that both treatments extended the lifespan of C. elegans larvae, but that they had to treat the animals with 1,000 times more GYY4137 to achieve the same effect. Chris Hine, a physiologist at the Cleveland Clinic Lerner Research Institute who was not involved in the study, was excited to see this result for AP39. “That might help you avoid potential toxicities once you potentially use this in humans because in humans, not all cell types have the same resistance to hydrogen sulfide,” he said. “It’s always best to have a lowest effective dose.”
Not only did AP39 increase the longevity of the C. elegans worms, but it also kept them healthier later in life. Worms that received the treatment as larvae stayed more active and displayed higher strength across their lifespan than untreated worms. Similar health benefits occurred even for worms that received AP39 as adults, although the compound did not extend the lifespans of those worms. While the mitochondria in the untreated worms’ cells broke down rapidly once they reached adulthood, the mitochondria in the worms treated with AP39 at either life stage remained healthy for longer.
Whiteman sees a world of potential in that result. “Most diseases will have a mitochondrial dysfunction component to them,” he said. “If you can fix [it], you’ve got a high chance of at least delaying the disease progression or hopefully reversing some of it.”
Whiteman’s team also found that knocking down the genes that enable cells in the C. elegans worms to produce their own H2S prevented the animals from realizing any health benefits from AP39. The researchers speculate that the H2S-producing machinery plays a larger role in cellular health beyond the direct effects of H2S on mitochondria, and that eliminating that machinery had deleterious consequences.
Hine found this idea intriguing. “You think, ‘Well, if you take away the endogenous production and you supplement it with exogenous, you should be okay.’ It wasn’t. The results are surprising in that context,” he said. “It opens up new doors for investigation.”
For now, the team is exploring the effects of additional mitochondria-targeting H2S-delivering compounds. Since the discovery of AP39 in 2014, Whiteman has developed new and improved (and propriety) molecules at his company MitoRx Therapeutics. “If we put the newest stuff in the same models, they behave the same way but better,” he said. Scientists at the company are also working to identify specific disease applications for their products.
“Aging is difficult to drug. There’s so much complexity with it,” Whiteman said. “Picking the right disease indications is going to be key.”
- Vintila, A. et al. Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans. PNAS 120, e2216141120 (2023).
- Szabo, C. & Papapetropoulos, A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors. Pharmocol Rev 69, 497-564 (2017).
- López-Otín, C. et al. The hallmarks of aging. Cell 153, 1194-1217 (2013).
- Li, L. et al. Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137). Circulation 117, 2351-2360 (2008).
- Szczesny, B. et al. AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro. Nitric Oxide 41, 120-130 (2014).