Healthy aging and edible mushrooms
Ergothioneine, a putative longevity vitamin
Healthy aging and diet
Aging is an inevitable outcome of life, a process of gradual physiological deterioration that all living beings experience with time, characterised by a progressive decline in tissue and organ function and increased risk of mortality. It is a heterogeneous and heterochronic process.
As a heterogeneous process, aging may occur at different rates across diverse organisms, and even organisms of the same species can age at variable rates. Furthermore, the asynchrony by which various cells and tissues age within a single organism highlights the heterochronic nature of aging.
At the biological level, aging is characterised by the accumulation of molecular and cellular damage, which leads to structural and functional aberrancies in cells and tissues, such as loss of mitochondrial homeostasis, impaired intercellular communication, senescence and decreased regenerative capacity (the nine hallmarks of aging).
Many in the classical West saw old age as a disease, but Galen —the Greek physician in the Roman Empire — thought otherwise. In his treatise Hygiene, written around ad 175 and featuring the only surviving classical study of gerontology, he framed aging as a natural process that can be eased or even delayed through preventive measures such as diet.
Galen’s ‘anti-aging’ regime might even be prescribed today. He advocated walking and moderate running, and noted the health benefits of a simple diet involving gruel, raw honey, vegetables and fowl.
Today, it is well known that many vitamins and minerals influence aging by acting as antioxidants to scavenge excessively produced reactive oxygen species (ROS). In particular, many studies have shown that dietary vitamins increase lifespan in various organisms primarily by functioning as antioxidants.
For example, vitamin E/tocopherol, vitamin C/ascorbic acid and vitamin B3 (nicotinic acid and nicotinamide) intake significantly increases the lifespan of rotifers, nematodes and fruit flies: Effects of nutritional components on aging.
But, although vitamins are generally considered to have beneficial effects on health, there is increasing evidence that vitamins also reduce lifespan. For example, the antioxidant functions of vitamin C decrease the long lifespan conferred by mildly increased ROS in C. elegant, and vitamin E intake causes hypertension in patients with type 2 diabetes.
A meta-analysis of 385 publications indicated that overall levels of antioxidant supplementation positively correlated with mortality. In the case of multiple sclerosis, supplementation with vitamin A for 6 months increased the level of C-reactive protein, which is indicative of the level of inflammation.
The reason of all that?
Probably it has to do with the fact that moderate levels of ROS are beneficial for health and longevity, and that antioxidant vitamins may interfere with this beneficial role of ROS.
So, how can we explain these differential effects of vitamin supplementation on lifespan?
One plausible interpretation is hormesis, which is defined as beneficial effects of low doses of substances that are toxic at higher doses. Thus, hormetic effects of vitamins predict that high doses of vitamins have negative effects on the health and aging, while low doses are beneficial for health.
Going back to aging now. The discovery that aging can be ameliorated by dietary, genetic, and pharmacological interventions has opened up the prospect of a broad-spectrum, preventive medicine for aging-related diseases.
For this reason today I am going to talk about Ergothioneine and edible mushrooms used in Traditional Chinese medicine as anti-aging remedies.
So, by screening the literature — and using as criteria clinical trials, epidemiology, Mendelian randomization studies, and medical literature (Prolonging healthy aging: Longevity vitamins and proteins) — the association or causality between various diseases of aging and a number of vitamins, mineral and fatty acids deficiencies has been analysed, and the results indicated ergothioneine as a putative longevity vitamin.
L-ergothioneine (ESH) is a unique sulfur containing amino acid that cannot be synthesised by humans and is only available from certain dietary sources, especially fungi. It is a stable antioxidant, that does not auto-oxidise at physiologic pH (like glutathione), does not promote generation of hydroxyl radicals, so it is considered more stable and may serve as a final defense against oxidation in cells.
In vitro studies have proposed that ergothioneine is a potent antioxidant, similar to glutathione, and may have a role protecting mitochondria.
ESH is synthesised by most mushrooms, cyanobacteria and many types of soil bacteria, but not by plants or animals. Various plant foods contain small amounts of ESH taken up from the soil and animals that eat such plants contain ESH in their flesh. Foods known to synthesise ESH are:
- Edible fungi like king boletus mushrooms (>100 mg/kg wet weight) and the white-button commercial mushrooms (0.5 mg/kg),
- Beef, pork, lamb, and chicken (1 mg/kg wet weight), and
- Oat bran, black turtle bean, and red kidney bean (>3 mg/kg).
So far, ESH has been shown to be present in almost all human cell and tissue types, often at millimolar levels in the brain, bone marrow, lens and cornea of the eye, and erythrocytes, where it appears to play a significant role as an antioxidant.
Its function as a specialised antioxidant is thought to be implicated in:
Cardiovascular disease (CVD) prevention:Ergothioneine antioxidant function: From chemistry to cardiovascular therapeutic potential
Alzheimer’s disease:Ergothioneine Protects Against Neuronal Injury Induced by β-amyloid in Mice
It has been suggested that ESH acts as an adaptive antioxidant for the protection of injured tissues:Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis
In particular, ESH in mammals is taken up by a specialised transporter, the OCTN1 protein, which appears to have been selected for in the European transition from a lifestyle of hunting and gathering to one of agriculture and settlement.
Lack of this transporter results in oxidative damage to proteins, lipids, and DNA, and higher levels of mortality in human cells. Dysfunctional haplotypes of the ESH transporter gene are associated with Crohn’s disease. The ESH transporter is essential because deletion of its gene in mice or zebra fish results in oxidative damage to DNA and lipids. All of these characteristics suggest an involvement in healthy aging.
Another major function of ESH may be to reduce the level of the toxic oxidised ferryl form of heme proteins in vivo, such as myoglobin. One of the problems in Alzheimer’s disease appears to be that the amyloid-β peptide in the brain binds heme very tightly, which leads to a temporary shortage of heme; this causes complex IV in mitochondria to release hydrogen peroxide, which then converts the amyloid-β heme into a toxic ferryl heme peroxidase that damages the cell. In vitro, ESH inhibits the amyloid-β heme peroxidase more effectively than any other antioxidant examined (glutathione and ascorbic acid).
Two cultivated mushrooms rich in ESH:
- Lingzhi (Ganoderma lucidum) and
have been used in folk medicine in China and many Asian countries as anti-aging remedies for centuries now Ergothioneine Concentrations in Selected Foods and Beverages).
Let’s see why.
Edible Mushrooms and ESH
Mushrooms have long been regarded as health-promoting foods worldwide (Potential of Asian Natural Products for Health in Aging). Among cultivated mushrooms, Ganoderma lucidum (Lingzhi) and Hericium erinaceus (Lion’s Mane Mushroom or Hou Tou Gu in Chinese or Yamabushitake in Japanese) are re-emerging as longevity treatments.
Lingzhi (Ganoderma lucidum)
It is believed that Lingzhi (Ganoderma lucidum) is attributed to a range of beneficial effects including enhancing longevity, increasing youthful vigor and vitality and as a remedy for illness:The anti-oxidation and anti-aging effects of Ganoderma lucidum in Caenorhabditis elegans.
In particular, the development of analytical chemistry is reporting that apart from being low in calories, Lingzhi contains many specific biologically active compounds for example L-ergothioneine — known as an effective physiologic cytoprotectant — while polysaccharides and triterpenes are also two major active compounds in Lingzhi.
Researches have shown various health benefits of Lingzhi and its anticancer abilities are widely investigated. The growth of different tumors cells was inhibited in vitro, possibly through its effect on enhancing the body immune system with a broad spectrum of immune-modulation activities.
In fact, a Cochrane review (a Cochrane Review is a peer-reviewed systematic review that has been prepared and supervised by a Cochrane Review Group) concluded that Lingzhi could be administered as an alternative adjunct to the conventional treatment of cancer in consideration of its potential of enhancing tumor response and stimulating host immunity:G. lucidum (Reishi mushroom) for cancer treatment.
In another study, ten healthy Chinese subjects ingested a single dose of Lingzhi powder and showed an increase in plasma FRAP (Ferric Reducing/Antioxidant Power) over the 3 hours monitoring period. Ingestion of a higher concentration of Lingzhi caused a significant post-ingestion increase in plasma antioxidant capacity with a peak at 90 min:Ganoderma Lucidum (‘Lingzhi’); Acute and Short-Term Biomarker Response to Supplementation.
Lingzhi and its extracts exert also hepatoprotective effects by preventing liver damage induced by alcohol and protecting against liver damage in rats. Moreover, one-third of chronic hepatitis B patients returned to normal aminotransferase level after taking Lingzhi extracts for 6 months:Protective Effect of Ganoderma (a Mushroom with Medicinal Properties) Against Various Liver Injuries.
Lingzhi also showed an ability to regulate lipid metabolism.
In a double-blind, placebo-controlled, cross-over study, healthy individuals following an administration of Lingzhi/day for 4 weeks showed a slight trend in the reduction of cholesterol, LDL and triglycerides:Ganoderma lucidum mushroom for the treatment of cardiovascular risk factors.
Moreover, glucans from Lingzhi fruiting bodies lowered postprandial glucose level in diabetes patients:Mushrooms of the Genus Ganoderma Used to Treat Diabetes and Insulin Resistance.
Several studies have also suggested the neuroprotective effects of Lingzhi against oxidative stress in vitro. In a clinical study, Lingzhi attenuated β-amyloid induced synaptotoxicity by preserving a synaptic density protein in cultured neurons and preserved neurons in Alzheimer’s disease:Spore powder of Ganoderma lucidum for the treatment of Alzheimer disease. A pilot study.
To cut a long story short it has been suggested that Lingzhi is a potential candidate for the treatment of aging-related diseases , but of course more clinical studies have to be done to confirm this effect:Emerging Roles of Ganoderma Lucidum in Anti-Aging.
Lion’s Mane Mushroom (Hericium erinaceus)
Another commonly used mushroom in East Asian countries is Hericium erinaceus, an edible mushroom with medicinal value, also known as Lion’s Mane Mushroom or Hou Tou Gu in Chinese or Yamabushitake in Japanese.
It is known that the dried powder of H. erinaceus fruiting body and mycelia consists of protein, carbohydrate, fat, ash, amino acids and water content. The fungal body also contains unsaturated fatty acids, saturated fatty acids, and other elements. Some potential bioactive compounds such as γ-aminobutyric acid (GABA), ergothioneine, and lovastatin were also found to be reported in Lion’s Mane.
Lion’s Mane mushroom polysaccharides extract has significant anticancer and immunomodulation activities.
For example, a single-band protein (HEP3) was isolated from Hericium erinaceus that exhibited immunomodulatory activity, by regulating the composition and metabolism of gut microbiota in vivo:Immunomodulatory Activities of a Fungal Protein Extracted from Hericium erinaceus through Regulating the Gut Microbiota.
Further research revealed that HEP3 improved the immune system via regulating the composition and metabolism of gut microbiota to activate the proliferation and differentiation of T cells, stimulated the intestinal antigen-presenting cells in high-dose cyclophosphamide-induced immunotoxicity in mice, and played a prebiotic role in the case of excessive antibiotics in inflammatory bowel disease model mice.
In other animal studies Lion’s Mane mushroom exerted hypoglycemic and hypolipidemic effects in streptozotocin (STZ)-induced diabetic rats:Antihyperglycemic and antihyperlipidemic activities of aqueous extract of Hericium erinaceus in experimental diabetic rats.
Extracts from Hericium erinaceus may also be beneficial in the treatment of anxiety and depression.
In a 2015 study, mice that consumed Hericium erinaceus extract displayed fewer depressive behaviors and had blood markers that indicated lower depression (probably due to anti-inflammatory effects).
Moreover, in a small Japanese study, women with a variety of health complaints, including menopausal symptoms and poor sleep quality, ate cookies containing Hericium’s erinaceus extracts, and the participants who ate the extract reported lower levels of irritation and anxiety than those in the placebo group.
Moreover, studies with Hericium erinaceus indicated a role related to nerve and brain health. The neuroprotective effect of Lion’s Mane on humans was demonstrated when a double-blind, parallel-group, placebo-controlled trial was performed on 30 Japanese (age 50–80 years old) with mild cognitive impairment. The subjects took four Yamabushitake-containing tablets (each contained 96% of H. erinaceus) three times a day for 16 weeks. The intervention group showed significantly increased scores on the cognitive function scale compared with the placebo group. The scores decreased at week 4 after the termination. This study suggested the effectiveness of H. erinaceus in the prevention or the treatment of dementia and cognitive dysfunction.
Furthermore, Bloomage Biotech — a biotechnology company that provides medical beauty products and services in China — has obtained via multi-fermentation of Hericium erinaceus and Tricholoma matsutake an antiphotoaging and antioxidant active ingredient: the Bioyouth-ergothioneine. Bioyouth-ergothioneine has been proven to protect skin cells from the effects of UVA and reduce the appearance of brown spots.
Finally, researchers in Singapore are conducting a phase 3 clinical trial, where participants will take placebo or 25 mg ergothioneine 3 times weekly for a total of 52 weeks. The trial will be finished in 2021, and should provide more details on the efficacy of this compound. Until then, add to your diet a variety of mushrooms (Porcini, Yellow Oyster, Lion’s Mane, Maitake, Reishi, White Button and others) and non-fungi foods (pork liver, kidney, black, and red beans, and oat bran) and enjoy your life!
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