Introduction
Aging is a complex process that affects various aspects of our health, making us more susceptible to certain diseases and conditions. Researchers have been studying the role of antioxidants and other compounds in combating the negative effects of aging. One such compound, ergothioneine (ERG), has recently gained attention for its potential benefits in age-related diseases, such as frailty and dementia. In this article, we will discuss the role of ERG in aging-related diseases and its possible therapeutic applications.

What is Ergothioneine (ERG)?
Ergothioneine (ERG) is a sulfur-containing compound derived from a specific amino acid called histidine. It is synthesized by certain bacteria and fungi and is found in various dietary sources, including mushrooms, kidney beans, and meat. ERG acts as an antioxidant, scavenging free radicals and chelating (binding) transition metals that contribute to oxidative stress, which is known to play a role in aging and age-related diseases.

Whole Blood, Urine, and Saliva Metabolomics
Metabolomics is the study of small molecules (metabolites) in biological samples, such as blood, urine, and saliva, to understand physiological and pathological conditions. Researchers have been using metabolomics to investigate the role of ERG and other compounds in aging-related diseases.

In human blood, ERG is primarily found in red blood cells (RBCs) and is much less abundant in urine and saliva. Other biofluids, like urine and saliva, can also provide useful information about health, as they can be easily collected noninvasively and are suitable for daily observation.

Starvation, ERG, and Aging
Studies have shown that calorie restriction (CR) or intermittent fasting (IF) can extend lifespan and reduce oxidative stress in various organisms. These benefits are partially attributed to the activation of specific transcription factors that upregulate antioxidant genes. The fission yeast, S. pombe, serves as an excellent model organism for studying the effects of starvation on metabolism, as it shares many similarities with human cells.

Researchers observed that both glucose and nitrogen starvation led to significant increases of ERG in S. pombe. Similarly, in a small study involving four young, non-obese human volunteers who fasted for 58 hours, researchers found that the levels of ERG and other antioxidants in their blood increased. These findings suggest that the increase in ERG levels might be an adaptive response to fasting stress in both yeast and humans, potentially playing a protective role in aging-related processes.

ERG in Frailty, Dementia, and Sarcopenia
Frailty, dementia, and sarcopenia are common age-related diseases that share clinical features, such as increased dependency on life support. Researchers used whole blood metabolomics to study these diseases and discovered that ERG levels significantly decreased in frailty and dementia but not in sarcopenia (a condition characterized by loss of muscle mass and function). Furthermore, of ERG-related compounds, S-methyl-ERG and hercynine, also decreased in frailty and dementia. This finding suggests that the intake or metabolism of ERG might be affected in these conditions. The decrease in ERG, a potent antioxidant, could contribute to the progression of frailty, dementia, and other aging-related events, as oxidative damage is known to accelerate these disorders.

Researchers also analyzed urine and saliva metabolomics to gain a more comprehensive understanding of aging-related diseases. They found that ERG levels in these biofluids did not show significant age-related differences, indicating that further research is needed to understand the role of ERG in these conditions.

ERG Treatment: A Potential Therapeutic Approach
Previous studies have demonstrated that ERG possesses antioxidative and anti-inflammatory effects that could be beneficial in treating several human diseases, such as rheumatoid arthritis. Additionally, ERG supplementation has been shown to alleviate cognitive impairment and tissue oxidative damage in experimental animal models. As a result, ERG treatment may be a promising therapeutic approach for frailty and dementia.

In conclusion, ERG is an essential antioxidant that plays a vital role in human health and aging-related diseases. This research sheds light on the potential significance of ERG in frailty, dementia, and other aging-related disorders. ERG levels were found to be decreased in frailty and dementia patients, suggesting that a decline in this antioxidant may contribute to the progression of these conditions.

Further studies are needed to better understand the specific mechanisms through which ERG affects aging-related diseases and to determine the potential benefits of ERG supplementation as a therapeutic approach. By investigating the role of ERG in various biofluids and using model organisms like fission yeast, researchers can gain valuable insights into the complex metabolic processes involved in aging and disease.

In the future, it will be crucial to conduct additional research, including larger and more diverse study populations, to validate these findings and explore the potential of ERG as a treatment for frailty, dementia, and other aging-related conditions. By understanding the role of ERG in human health and disease, scientists may be able to develop new therapeutic strategies that can help improve the quality of life for elderly individuals and those suffering from age-related diseases.

References:

1. Kondoh, H., Teruya, T., Kameda, M. and Yanagida, M. (2022), Decline of ergothioneine in frailty and cognition impairment. FEBS Lett, 596: 1270-1278. https://doi.org/10.1002/1873-3468.14299