Dosage produces poison. This adage applies not only to hazardous chemicals but also to life-sustaining substances like water and oxygen. For example, the foul-smelling hydrogen sulfide (H2Too much S) gas can be fatal if someone inhales it in a sewer or swamp, but human cells produce it in small amounts as a key signaling molecule.
Recently published in Proceedings of the National Academy of Sciencesa team of researchers evaluated the effects of mitochondria-targeted H2Effects of S Treatment on Health and Longevity Caenorhabditis elegans elegans (1). The researchers hope their work will lead to better strategies for using the gas to improve human health, particularly by slowing the progression of muscle and nerve decline and other diseases that often affect older adults. They don’t necessarily expect to find the elixir of life. “It’s just about slowing down aging and staying healthy for as long as possible,” said Matt Whiteman, a pharmacologist at the University of Exeter and one of the leaders of the project.
Most diseases are associated with mitochondrial dysfunction.if you can fix it [it]you have a good chance of at least slowing the progression of the disease or hopefully reversing some of it.
-Matt Whiteman, University of Exeter
Whiteman has been exploring the health benefits of treating animals with small amounts of externally generated H.2S for many years.He is particularly interested in understanding the effects of H2S is present on mitochondria because there is evidence that H2S has multiple biological functions that support mitochondrial health, such as promoting mitochondrial DNA repair and providing antioxidant protection (2).Aging bodies tend to lose mitochondria, but treating these organelles with H2S can prevent this loss and mitigate associated health consequences (3).
Whiteman previously helped develop a molecule called GYY4137 that dissolves in water and releases H2Over time, sulfur species are gradually introduced into cells in an untargeted manner (4). He later described a compound called AP39, which consisted of one set of atoms that helped locate mitochondria within the cell and another set of atoms that slowly produced H2Once the compound is in place (5). In both cases, the goal is to avoid flooding the cells with large amounts of H2.2It was done in one go.
Current research shows that because AP39 specifically targets mitochondria, it can produce health benefits in lower amounts than GYY4137.Whiteman and his team found that both treatments extended lifespan Nematodes larvae, but they had to treat the animals with 1,000 times more GYY4137 to achieve the same effect. Physiologist Chris Hine of Cleveland Clinic’s Lerner Institute, who was not involved in the study, was pleased to see the AP39 results. “That might help you avoid potential toxicity once you potentially use it in humans, where not all cell types are equally resistant to hydrogen sulfide,” he said. “It’s best to use the lowest effective dose.”
Matt Whiteman studies the effects of hydrogen sulfide on the health and lifespan of model organisms, such as animals Nematodes nematodes.
Image source: istock.com/HeitiPaves
AP39 not only extends the life Nematodes worms, but it also keeps them healthy later in life. Worms treated during the larval stage remained more active throughout their life cycles and showed higher strength than untreated worms. Similar health benefits were seen even in worms that received AP39 as adults, although the compound did not extend the lifespan of these worms. Mitochondria in untreated nematode cells rapidly disintegrated as adults, whereas mitochondria in worms treated with AP39 remained healthy longer at any life stage.
Whiteman sees huge potential in the results. “Most diseases are associated with mitochondrial dysfunction,” he said. “If you can solve [it], you have a good chance of at least slowing the progression of the disease, or hopefully reversing some of it. ”
Whiteman’s team also found that the knockout allowed cells to Nematodes Worms generate their own H2S prevents animals from recognizing any health benefits of AP39. Researchers speculate that H2In addition to direct effects of H, S-generating mechanisms play a larger role in cellular health2S on mitochondria, and eliminating this mechanism can have deleterious consequences.
Hein found the idea intriguing. “You would think, ‘Well, if you take away endogenous production and supplement it with exogenous production, you should be fine.’ That’s not the case. In this case, the results are surprising,” he said . “This opens new doors for the investigation.”
Currently, the team is exploring the effects of additional mitochondria-targeted H2S-delivery compounds. Since discovering AP39 in 2014, Whiteman has developed new and improved (proprietary) molecules at his company, MitoRx Therapeutics. “If we put the latest stuff into the same model, they would behave the same way, but better,” he said. The company’s scientists are also working to identify disease-specific applications for its products.
“Aging is difficult to treat with drugs. It’s very complex,” Whiteman said. “Choosing the right disease indication will be key.”
- Ventila, A. et al.. Mitochondrial sulfide extends lifespan and healthspan through different mechanisms in developing C. elegans versus adult treated C. elegans. Proceedings of the National Academy of Sciences 120e2216141120 (2023).
- Szabo, C. and Papapetropoulos, A. International Union of Basic and Clinical Pharmacology. CII: Pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. pharmacology revised edition 69497-564 (2017).
- López-Otín, C. et al.. Characteristics of aging. cell 1531194-1217 (2013).
- Lee, L. et al.. Characterization of a novel water-soluble hydrogen sulfide releasing molecule (GYY4137). cycle 1172351-2360 (2008).
- Szczesny, B. et al.. AP39 is a novel mitochondria-targeted hydrogen sulfide donor that stimulates cellular bioenergetics, exerts cytoprotective effects, and prevents loss of mitochondrial DNA integrity in endothelial cells under oxidative stress in vitro. Nitric oxide 41120-130 (2014).