Unraveling the Potential of Hydrogen Sulfide for Healthspan Extension in Aging Adults

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Medical advances have significantly increased human life expectancy, leading to longer lifespans for individuals worldwide. However, this achievement has brought about a new challenge: an extended period of frailty and poor health in the later years of life.

The burden on healthcare systems and reduced quality of life for elderly individuals have become prominent issues. As a result, there is an urgent need to explore interventions that not only increase lifespan but also enhance healthspan, the period of life spent in good health and without significant impairment.

Studies conducted on lower organisms have identified therapeutics that extend lifespan, but the relationship between increased lifespan and healthspan remains uncertain. For instance, long-lived mutants in Caenorhabditis elegans, a model organism for aging research, spend more time in a frail state, a phenomenon also observed in long-living humans.

Hydrogen sulfide (H2S) is a colorless gas with a strong odor of rotten eggs. It is a naturally occurring molecule that is produced by the body and by some bacteria. H2S has a number of important physiological functions, including regulating blood pressure, inflammation, and oxidative stress. In recent years, there has been increasing interest in the potential of H2S as a therapeutic molecule for a variety of diseases.

Some of the potential therapeutic applications of H2S include:

  • Cardiovascular disease: H2S has been shown to improve blood flow and reduce inflammation, which could make it a potential treatment for heart disease, stroke, and other cardiovascular conditions.
  • Neurological disorders: H2S has neuroprotective effects, which means that it can protect neurons from damage. This has led to interest in H2S as a potential treatment for Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders.
  • Cancer: H2S has been shown to inhibit the growth of cancer cells and induce apoptosis, or programmed cell death. This has led to interest in H2S as a potential treatment for cancer.
  • Inflammatory diseases: H2S has anti-inflammatory effects, which could make it a potential treatment for conditions such as rheumatoid arthritis, asthma, and inflammatory bowel disease.

There are still many challenges that need to be overcome before H2S can be used as a safe and effective therapeutic molecule. However, the potential benefits of H2S are significant, and research in this area is ongoing.

Here are some of the challenges that need to be overcome before H2S can be used as a therapeutic molecule:

  • Delivery: H2S is a gas, so it is difficult to deliver it to the target tissues in the body.
  • Safety: H2S is toxic at high levels, so it is important to develop safe and effective delivery methods.
  • Efficacy: More research is needed to confirm the efficacy of H2S in treating various diseases.

Despite these challenges, the potential benefits of H2S are significant, and research in this area is ongoing. If H2S can be safely and effectively delivered to the target tissues in the body, it could have a major impact on the treatment of a variety of diseases.

Hydrogen Sulfide (H2S) as a Therapeutic Molecule

Hydrogen sulfide is an ancient and essential molecule that played a crucial role in the emergence of life on Earth. In recent years, it has gained recognition as a physiologically relevant signaling molecule with promising therapeutic properties.

Studies have shown that exogenous H2S treatments, often in the form of crude impure sulfide salts at supraphysiological concentrations, have cytoprotective effects across various disease states, including age-related conditions. In particular, H2S has been associated with both lifespan extension and healthspan extension in C. elegans when administered from birth.

However, the developmental stages during which H2S is administered might influence the observed effects. Thus, the efficacy of H2S treatments during “normal” aging needs further investigation to determine the potential of adult H2S-based therapies.

Understanding the Mechanisms of H2S-Mediated Healthspan Extension

The mechanisms underlying the healthspan extension mediated by H2S are not yet fully understood. However, a growing body of evidence suggests that H2S primarily exerts its effects through mitochondria, the energy-generating powerhouses of cells. Several processes responsive to H2S have been implicated in regulating its effects on longevity.

One prevailing theory suggests that H2S donates electrons to the mitochondrial electron transport chain, influences mitochondrial cAMP phosphodiesterases, repairs mitochondrial DNA, enhances antioxidant protection, and promotes mitochondrial respiration and ATP production.

As mitochondrial loss is considered one of the hallmarks of aging, therapies that leverage H2S’s positive effects on mitochondria present a promising anti-aging strategy. In particular, the mitochondrial sulfide delivery molecule AP39, which targets H2S to mitochondria, shows potential for effective healthspan extension at much lower concentrations compared to other untargeted H2S donors.

Investigating the Efficacy of mtH2S for Healthspan Promotion

To better understand the efficacy of AP39 (mtH2S) for promoting healthspan via mitochondrion-mediated effects compared to untargeted H2S donors, researchers used C. elegans as a model organism for aging. The study also examined the healthspan effects of adult-onset H2S treatments to determine the therapeutic potential of H2S in aging adults.

The findings suggest that mtH2S is a requirement for and site of action of H2S-mediated healthspan promotion. Moreover, mtH2S was found to increase healthspan when administered to young and middle-aged adults, and this effect was reflected at the transcriptomic level, influenced by GATA family transcription factors.

These results indicate that mitochondrial sulfide augmentation may serve as a druggable target and a promising therapeutic approach to maintain health in aging individuals, particularly at a stage when the negative effects of aging have already manifested.

Conclusion

In this groundbreaking study, the researchers have made significant progress in understanding the role of hydrogen sulfide (H2S) as a diatomic signaling molecule that promotes healthy aging in the nematode worm, Caenorhabditis elegans.

Previous research had demonstrated that H2S could enhance the lifespan and health span of these worms, but the underlying mechanisms and therapeutic potential across the entire lifespan were not fully understood.

The researchers in this study utilized a mitochondrion-targeted H2S donor at extremely low doses (1 to 10 nM), which was 1000-fold lower than the amounts used in previous studies. Remarkably, they found that these minute doses of H2S were sufficient to extend the health span of C. elegans, resulting in improved mitochondrial integrity from young adulthood through old age.

The findings also revealed that several elements of the H2S metabolic pathways and FoxO transcription factors play crucial roles in governing both lifespan and health span. However, the Nrf2 antioxidant system, which had been previously associated with H2S-based longevity, was found to be dispensable for the health span extension induced by mitochondrial H2S.

Furthermore, the researchers explored the therapeutic potential of adult-onset H2S treatments. They discovered that initiating the treatment during young adulthood, in the presence of existing aging tissue pathologies, could extend the health span alone. This suggests that mitochondria are the primary target site for H2S action in mitigating aging-related changes.

The transcriptomic analysis of adult-onset H2S treatments revealed that the gene expression patterns differed from those seen with developmental treatments. Adult-onset H2S administration led to a rejuvenation of the aging transcriptome, demonstrating its ability to reverse aging-related gene expression changes towards a more youthful profile.

Interestingly, the researchers identified the GATA transcription factor circuit, elt-6/elt-3, as a key regulator of the health span benefits of adult-onset H2S treatments. This circuit, which plays a role in aging adaptation, may promote longevity but may come at the expense of health span.

The researchers demonstrated that H2S treatment could reverse the aging signaling axis controlled by this GATA transcription factor circuit, thus improving health span.

The study provides compelling evidence that mitochondria are central to the beneficial effects of H2S on aging health. By targeting mitochondria, H2S can delay the age-related decline in mitochondrial integrity, peroxisomal metabolism, and cytoskeletal function, thereby enhancing health span.

Overall, the findings have significant implications for the development of anti-aging therapies. The use of mitochondrion-targeted H2S at extremely low doses appears to be a promising approach, and its efficacy in adult animals suggests its potential translational relevance.

By shedding light on the distinct molecular mechanisms governing lifespan and health span extension, this study paves the way for further research to explore the therapeutic viability of H2S-based interventions in promoting healthy aging.

Understanding the complex interplay between mitochondrial function, transcription factors, and various metabolic pathways is crucial for developing effective strategies to address the growing societal burden of life span-health span dissociation. The knowledge gained from this study not only deepens our understanding of aging but also opens up new avenues for research aimed at improving human health and longevity.


reference link : https://www.pnas.org/doi/10.1073/pnas.2216141120

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