Is the acceptance of new food ingredients for ergot sulfur ushering in a new era of oral anti-aging?

Ergothionein is a high potential ingredient in the skincare industry and a popular raw material in synthetic biology. Market Watch data shows that the market size of ergotamine is expected to reach $171.9 million by 2028, with a compound annual growth rate of 36.2% during the forecast period from 2022 to 2028.

Ergothionein: Super antioxidant C-position
Ergothionine (EGT) is a naturally occurring amino acid. In 1909, Charles Tanret isolated a unique crystalline sulfur-containing compound while studying the ergot fungus that destroys rye grains, and subsequently named the fungus ergothionine. In 1911, Barger and Ewins determined its structure and discovered that ergothionein is a derivative of histidine betaine.

Ergothionein has both thiol and thione forms of tautomers, and thione tautomers dominate at physiological pH, making ergothionein exceptionally strong in antioxidant activity. According to data from Huaxi Biology, ergothionein is produced by Bioyouth ™-EGT The DPPH free radical scavenging ability is 14 times that of glutathione and 30 times that of coenzyme Q10 at the same concentration, making it a well deserved super antioxidant C-site

The structural formulas of two tautomers of ergothionein [1]
Research has shown that the antioxidant mechanism of ergothionein is multifaceted. It can clear reactive oxygen species in the body through various mechanisms, inhibit oxidative stress response, and thus exert antioxidant effects.

1. Direct elimination of free radicals: Ergothionein can directly react with free radicals to eliminate reactive oxygen species in the body, such as hydroxyl radicals, superoxide radicals, hydrogen peroxide, etc. This direct clearance mechanism is the basis of the antioxidant effect of ergothionein.

2. Metal ion chelation: Lysine can form stable chelates with transition metal ions (such as copper ions) in the body, thereby preventing metal ions from catalyzing oxidative stress reactions.

3. Activation of antioxidant enzymes: Ergothionein can activate antioxidant enzymes such as superoxide dismutase, glutathione reductase, and catalase, and the activation of these enzymes helps to clear reactive oxygen species from the body. In addition. It can activate the Nrf2/ARE antioxidant pathway, thereby upregulating the expression of various antioxidant enzymes.

4. Inhibition of oxidase activity: Ergothionein can inhibit the activity of oxidases such as lipid peroxidase and xanthine oxidase, thereby reducing the production of reactive oxygen species.

5. Protecting DNA: Ergothionein can protect DNA from oxidative stress damage, thereby preventing gene mutations and cell death. It can also regulate the expression of cell cycle and apoptosis related genes, affecting oxidative stress damage in cells.

Eye protection, skincare, anti-aging, and the multifunctionality of ergotamine
Based on its strong antioxidant properties, high stability, and non toxicity, more and more studies have confirmed that ergotamine can have a positive impact on human health. Unlike polyphenols, ergothionein is excreted slowly in the body, so ergothionein can be highly retained in human and other animal tissues and red blood cells, fully exerting its effects.

1) Eye protection

Ergothionein is present in high concentrations in eye tissues, including the lens, retina, cornea, and retinal pigment epithelium. It can help protect the eyes by clearing chronic reactive oxygen species (ROS), reducing intracellular ROS production, and inhibiting oxidative induced epithelial mesenchymal transition (EMT).

The L-ergothionein ingredient MitoPrime launched by NNB Nutrition can help improve age-related visual degeneration. MitoPrime is produced through a patented natural fermentation process and can be made into nutritional beverages, food, drinks, sugar, capsules, tablets, powders, and more.

Image source: NNB Nutrition
2) Skin anti-aging

Skin aging is a multifactorial process, which includes epidermal aging caused by ultraviolet radiation, dermal aging caused by collagen loss, and myofascial inflammation caused by cell apoptosis. Ergothionein exhibits significant anti-aging effects on different skin layers through its unique biological activity:

A. Skin layer UV protection:

As an effective antioxidant, ergotamine plays an important role in resisting skin damage caused by UVA and UVB radiation. It protects skin cells from DNA breakage and mutation, as well as mitochondrial damage, by alleviating the inflammatory response caused by UV radiation.

B. Collagen maintenance in the dermis layer:

In the dermis layer, ergothionein enhances collagen synthesis and reduces collagen loss after UV irradiation. Research has shown that ergotamine can significantly enhance the vitality of fibroblasts by reducing the activity of matrix metalloproteinase (MMP-1) and increasing the production of type I collagen [3], thereby inhibiting UV induced photoaging and reducing collagen damage by up to 72.9% [4].

C) Cell charging and repair in the lower layer of muscle:

In the basal layer of the skin, ergotamine has a positive effect on cellular energy metabolism by increasing telomerase activity, prolonging cell lifespan, and promoting rapid renewal and repair of skin tissue.

In response to the potential of ergothionein in skincare, SUPER-SYN, a super ingredient, has proposed the concept of "muscle bottom charging and layered anti-aging", providing comprehensive support for skin health.

Image source: Super Element Material
3) Protecting brain health and improving cognitive function

There is an association between levels of ergothionein and cognitive function and/or neurodegeneration in humans. A randomized, placebo-controlled, double-blind, parallel group study conducted in humans found that continuous oral administration of mushroom extract tablets containing ergothionein for 12 weeks can enhance cognitive function compared to the placebo group.

Starting from 2020, the Japanese market began to launch functional labeled foods containing ergothioneine, with a focus on improving memory function in the elderly. LS Corporation's ergothioneine supplement is a product designed to address memory decline in middle-aged and elderly people.

Image source: Japan Consumer Agency
4) Cardiovascular Health

Research has shown that ergotamine can couple with glutathione to reduce iron-based myoglobin, chelate transition metal iron to clear reactive oxygen species and reactive nitrogen species (ROS/RNS), free radicals produced during ischemia-reperfusion, regulate pro-inflammatory cytokines such as IL-1 β and TNF - α, and ultimately prevent myocardial injury [6], indicating that the inhibition of inflammation related pathways by ergotamine is the main mechanism for alleviating various cardiovascular diseases.

5) Liver protection

Bedirli et al. [7] administered 70 mg/kg ergotamine to liver ischemia-reperfusion rats via gavage, and found that after administration, the HSP70 content in the liver increased, liver injury improved, and the survival rate of rats significantly increased.

6) Improve intestinal health

With the change of contemporary people's eating habits and the increase of life pressure, more and more people are facing intestinal health problems, and the incidence rate of inflammatory bowel disease is rising. Research has found that ergothionein extracted from shiitake mushrooms can downregulate the expression of pro-inflammatory factors, inhibit the TLR4/MyD88/NF - κ B signaling pathway, and significantly alleviate the colon length shortening and colon pathological damage induced by dextran sulfate sodium in mice [8].

7) Sleep improvement

Ergothionein can penetrate the blood-brain barrier through various biological mechanisms, inhibit the formation of peroxynitrite and the nitration of tyrosine residues, and hinder the apoptosis of brain nerve cells [9], thereby reducing stress, relieving depression, and improving sleep difficulties [10].

SUPER-SYN's deep sleep emergency tablets, combined with ingredients such as GABA, L-theanine, and casein peptides, solve the problems of "difficulty falling asleep (long sleep latency)", "difficulty maintaining sleep (frequent awakenings or nighttime awakenings)", and "poor sleep quality (non restorative sleep)", and repair bodily functions during deep sleep.

Image source: Super Element Material
Synthetic biology achieves' ergothionein freedom '
At first, ergothionein was mainly extracted from mushrooms and ergot, which were natural sources with low content, time-consuming purification process, and high cost. The cost of one kilogram of ergothionein was close to $1 million. Later, the American raw material company Barnet used a chemical synthesis route to produce ergotamine. Due to cost constraints, its market price converted to pure powder was about 7000 yuan/g. It can be seen that even with technological advancements, the price of ergotamine remains high. However, with the rapid development of synthetic biology, ergotamine was eventually able to achieve "price freedom".

According to Li Liang et al.'s summary, there are three types of biosynthetic methods [11]:

(1) Using natural microorganisms with the ability to synthesize ergothionein for direct liquid deep fermentation, such as edible mushrooms;

(2) By expressing ergothionein synthase through plasmids and using L-His, L-Cys, and L-Met as substrates, ergothionein is synthesized through biotransformation;

(3) By utilizing engineered strains of ergothionein for fermentation, synthetic biology techniques are introduced into the ergothionein synthesis module to rationally modify key enzymes in the ergothionein synthase and precursor amino acid synthesis metabolic pathways, in order to achieve efficient combination. Combined with metabolic engineering and fermentation engineering to regulate the metabolic flux of precursor substances and fermentation culture conditions, it is expected to achieve efficient production of ergothionein through biosynthetic methods.

Enterprises, universities, and research institutes have all begun to study how to efficiently prepare ergothionein through synthetic biology, improving purity while increasing yield and reducing costs. Japanese research has shown that using engineered microorganisms for fermentation may reduce the production cost of ergothionein by 99%.

Blue California was the first company to produce L-ergothionein through fermentation and launched ErgoActive ingredient in 2015 as an alternative to chemical synthesis and mushroom extraction of ergothionein.

According to the official website of Huaxi Biotechnology, the company currently produces ergothionein, which contains ergothionein pine mushroom extract (Bioyouth) ™-EGT）、Bioyouth ™-EGT Pro Super active ergothionein, Bioyouth ™-EGT Pure Ultra pure ergothionein. Bioyouth ™-EGT It is prepared by fermentation of the mycelium of Hericium erinaceus and Agaricus bisporus.

Image source: Huaxi Biotechnology official website
Zhongke Xinyang has completed the evaluation of tens of thousands of ergothionein synthase enzymes, established a metabolic model for maximum carbon, nitrogen, and sulfur load, combined with innovative total synthesis pathways using green low sugar fermentation technology, to increase the proportion of non grain biomass carbon sources in fermentation and assist in low-carbon manufacturing and carbon cycling. At present, the single tank fermentation scale has reached 100 tons, achieving high purity and strong stability of over 99%. The appearance has been upgraded from yellow powder to white sparkling crystals, with uniform particle size distribution and stable quality. It is not easy to carry impurities or absorb moisture, and has obtained three purification process patents.

The domestic and international compliance path of ergotamine
1) China

In 2014, ergotamine was officially included in the "Catalogue of Used Cosmetics Raw Materials" by the National Medical Products Administration. With its excellent antioxidant properties, ergotamine gradually became the main ingredient in the skincare industry. At present, ergotamine is being applied for as a new food ingredient, indicating that it will achieve cross industry application expansion in the domestic food and functional food fields.

2) The European Union

In July 2017, the European Union approved L-ergothio as a new food ingredient that can be used in dietary supplements. The general population receives 30 milligrams per day, and children over 3 years old receive 20 milligrams per day. It cannot be used in pregnant and lactating women. In 2018, the European Union expanded the scope of use of L-ergothioneine, which can be used not only in dietary supplements but also in ordinary foods such as beverages and cereal bars.

3) United States

In August 2019, ergotamine obtained GRAS certification from the US FDA and can be used in regular food.

4) Japan

Starting from 2020, the Japanese market began to launch functional foods containing ergothionein, with a focus on improving memory function in the elderly.

5) Canada

Health Canada has approved ergotamine as a natural health supplement for both medicinal and non medicinal purposes, and for use as a preservative, antioxidant, and skin conditioner in non medicinal settings. Reference source:

[1] https://pubmed.ncbi.nlm.nih.gov/32051057/

[2] https://www.sciencedirect.com/science/article/abs/pii/S0006295220300678

[3] https://pubmed.ncbi.nlm.nih.gov/32104530/

[4] Data source: "Ergothionein efficacy testing report", third-party experimental institution Huante Biological testing report, project number: 70920223, September 22.

[5] https://pubmed.ncbi.nlm.nih.gov/33287595/

[6] https://www.sciencedirect.com/science/article/abs/pii/S0891584916300314

[7]] https://www.sciencedirect.com/science/article/abs/pii/S0022480404002653

[8] https://pubmed.ncbi.nlm.nih.gov/34873706/

[9] https://pubmed.ncbi.nlm.nih.gov/9070285/

[10] https://doi.org/10.1016/j.jff.2022.105165

[11] Li Liang, Xu Shanshan, Jiang Yanjun Research progress on biosynthetic production of ergothionein [J] Biotechnology Bulletin, 2024, 40 (01): 86-99