What is Trehalose?
Trehalose is a simple sugar found in nature that has been used extensively in the food and beauty industry for many years. It is a natural, non-reducing disaccharide formed by two glucose molecules held together by an alpha 1-1 bond. Trehalose is found naturally in many plants and animals, such as mushrooms and insects - many of which use trehalose as their primary energy source. In the last decade, much research has been done on trehalose - moving the understanding of its importance from simply another sugar in nature to a potential agent for extending health and longevity.
How does Trehalose work?
Humans convert trehalose to glucose in the body using an enzyme called trehalase. This conversion happens primarily in the gut, prior to entering the bloodstream.
Trehalose is very safe and non-toxic, even at high doses. It has made its way into the consumer market (especially in many Asian and European markets) as a common food sweetener or even in many beauty products. “Data are presented supporting safe human consumption of trehalose in doses up to 50g, and the physiologic ability of humans to digest it. No consistent treatment-related, dose-dependent adverse effects were observed in any of the eight safety studies performed at doses up to 10% of the diets.” [1]
Trehalose has been shown to have numerous health benefits, largely as a result of its unique properties inside the body and more specifically inside the cell. As we’ve come to understand the way trehalose works to protect the cell against outside stressors, it appears trehalose's primary role is in stabilizing protein structures, the root reason why it is of interest for health and longevity.
“Trehalose is synthesized as a stress-responsive factor when cells are exposed to environmental stresses like heat, cold, oxidation, desiccation, and so forth. When unicellular organisms are exposed to stress, they adapt by synthesizing huge amounts of trehalose, which helps them in retaining cellular integrity. This is thought to occur by prevention of denaturation of proteins by trehalose, which would otherwise degrade under stress.” [2]
Furthermore, trehalose plays an important role in the process of “cellular clean-up” known as autophagy. Trehalose induces autophagy independently of mTOR pathway inhibition and acts on the autophagy-lysosomal system - namely as a regulator of lysosome biogenesis.
One suggested mechanism [for how trehalose induces autophagy] is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system.[3]
We demonstrated that trehalose regulates autophagy by inducing rapid and transient lysosomal enlargement and membrane permeabilization (LMP). [4]
Trehalose may also work by inhibiting mTOR and activating AMPK in order to aid in proper protein synthesis and the management and clearing of misfolded proteins.
Figure 1. The molecular link between trehalose and autophagy. Trehalose inhibits cellular import of glucose and fructose through SLC2A (GLUT) transporters, generating a starvation-like (low adenosine triphosphate) state that stimulates autophagy through AMPK and activation of ULK1. This pathway triggers autophagosome biogenesis and autophagic flux, which favors the clearance of pathological protein aggregates and lipid stores. Conversely, autophagy is inhibited by mTOR, a sensor of nutrient availability and recipient of growth factor signaling. AMPK activation may interfere with mTOR-mediated inactivation of ULK1. Trehalose may induce autophagy through additional unidentified mTOR-independent mechanisms.
[5] Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport
Trehalose & Brain Health
Due to its unique properties allowing it to cross over the blood-brain barrier, as well as into the cell to aid in important processes such as autophagy, trehalose shows promise in managing, and even treating neurodegenerative diseases. Currently, trehalose is being looked at as a potential drug for treatment of amyotrophic lateral sclerosis (ALS), and in May 2021 received European Orphan Drug Designation under the name SLS-005. [6] Additionally, trehalose ability to act as a “chemical chaperone” has indicated it as a potential therapeutic for Parkinson’s Disease. [7]
In this review, we briefly summarize the role of aberrant autophagy in PD and the underlying mechanisms that lead to the development of this disease. We also discuss reports that used trehalose to counteract the neurotoxicity in PD, focusing particularly on the autophagy promoting, protein stabilization, and anti-neuroinflammatory effects of trehalose.[8]
An article written by Enzo Emanuele in 2014 and published in Current Drug Targets [9]nicely sums up the role of trehalose in brain health:
Inappropriate protein aggregation is a key mechanism in the pathogenesis of several neurodegenerative disorders. One of the main strategies by which cells deal with abnormal protein aggregates is autophagy, a degradation pathway for intracellular aggregate-prone proteins. Trehalose, a non-reducing disaccharide which has been utilized extensively in the food industry, has been recently demonstrated to have a number of unique properties that point to its potential utility in preventing neurodegeneration. First, trehalose may act as a potent stabilizer of proteins and is able to preserve protein structural integrity. Second, it is a chaperone and reduces aggregation of pathologically misfolded proteins. Third, it improves the clearance of the mutant proteins which act as autophagy substrates when aberrant protein deposition occurs. Notably, trehalose is an mTOR-independent inducer of autophagy, and in animal models of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, has been shown to decrease the levels of toxic protein aggregates, increase autophagy, and improve clinical symptoms and survival. In summary, mounting experimental evidence suggests that trehalose may prevent neurodegenerative disorders by stabilizing proteins and promoting autophagy. Because of the low toxicity profile that allows for administration for extended periods, human studies of trehalose in preventing neurodegeneration are warranted.
Trehalose & Insulin Stability
Research on trehalose also indicates it as a potential intervention option for insulin resistance and management. Despite it being a caloric sugar, trehalose has been shown to mitigate insulin resistance in both mice and humans, as well as help reduce the insulin/IGF-1-like signaling pathway shown to impact aging. It does not cause an “insulin spike” typical of many other sugars likely due to how it works at the lining of the gut, prior to its conversion to glucose inside of the gut. Trehalose demonstrated the ability to suppress adipocyte hypertrophy and increase serum adiponectin [10][11][12], making it a good option for individuals with insulin sensitivity, pre-diabetes, or diabetes. Multiple studies published in the last few years have looked at trehalose as a potential non-pharmaceutical option for management of insulin sensitivity and related diseases.
Our data indicated that a daily intake of 10 g of trehalose improved glucose tolerance and progress to insulin resistance. Furthermore, these results suggested that trehalose can potentially reduce the development of metabolic syndrome and associated lifestyle-related diseases, such as type 2 diabetes.[13]
Trehalose Misunderstanding
Unfortunately, there is some confusion on the benefits and risks of trehalose. When you Google trehalose, you may come across articles referencing a 2018 study published in Nature warning of the risks of trehalose and Clostridium difficile disease (c-diff).
However, another 2018 Nature publication reviewing the literature on trehalose goes so far as to state: “Facts – Trehalose has been shown to be neuroprotective in animal models of various neurodegenerative diseases, such as Parkinson and Huntington diseases.”
Additionally, a 2019 study published by the Lancet disproved the original Nature conclusion, stating “Trehalose supplementation did not increase ribotype-027 virulence in a clinically-validated gut model.”
The likely explanation for the conflicting evidence is that the original study looked at trehalose as a food additive, which is largely found in processed foods. Trehalose occurs naturally in small amounts in mushrooms, honey, lobsters, shrimps, and certain seaweeds (algae). As a food additive, trehalose is artificially produced from corn starch using several bacterial enzymes such as alpha-amylase, obtained from Bacillus licheniformis, and isoamylase from Pseudomonas amyloderamosa.
Trehalose is heat stable and preserves the cell structure of foods after heating and freezing, so it is used as a food texturizer and stabilizer in dried foods, frozen foods, bars, fruit fillings and jams, instant noodles and rice, white chocolate, sugar coating, bakery cream, processed seafood and fruit juices. As you can see, great stuff for the gut microbiome.
So, the more likely explanation for the bump in c-diff at the time artificial trehalose became common as a food additive is because of the increased consumption of processed foods (aka crap)! It may also be related to making it from corn starch, rather than using natural trehalose. Conversely, natural trehalose has been well researched to have many positive health impacts, both for neurocognition and a healthy gut microbiome!
Nature
Dietary trehalose enhances virulence of epidemic Clostridium difficile
Two hypervirulent ribotypes of the enteric pathogen Clostridium difficile, RT027 and RT078, have independently acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose, suggesting a correlation between the emergence of these ribotypes and the widespread adoption of trehalose in the human diet.
Cell Death & Disease
Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction
Trehalose is a non-reducing disaccharide with two glucose molecules linked through an α, α-1,1-glucosidic bond. Trehalose has received attention for the past few decades for its role in neuroprotection especially in animal models of various neurodegenerative diseases, such as Parkinson and Huntington diseases. The mechanism underlying the neuroprotective effects of trehalose remains elusive. The prevailing hypothesis is that trehalose protects neurons by inducing autophagy, thereby clearing protein aggregates. Some of the animal studies showed activation of autophagy and reduced protein aggregates after trehalose administration in neurodegenerative disease models, seemingly supporting the autophagy induction hypothesis. However, results from cell studies have been less certain; although many studies claim that trehalose induces autophagy and reduces protein aggregates, the studies have their weaknesses, failing to provide sufficient evidence for the autophagy induction theory. Furthermore, a recent study with a thorough examination of autophagy flux showed that trehalose interfered with the flux from autophagosome to autolysosome, raising controversy on the direct effects of trehalose on autophagy. This review summarizes the fundamental properties of trehalose and the studies on its effects on neurodegenerative diseases. We also discuss the controversy related to the autophagy induction theory and seek to explain how trehalose works in neuroprotection.
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References
- Richards, A. B., et al. "Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies." Food and chemical toxicology 40.7 (2002): 871-898.
- Jain, Nishant Kumar, and Ipsita Roy. “Effect of trehalose on protein structure.” Protein science : a publication of the Protein Society vol. 18,1 (2009): 24-36. doi:10.1002/pro.3
- Se-Jin Jeong, Jeremiah Stitham, Trent D. Evans, Xiangyu Zhang, Astrid Rodriguez-Velez, Yu-Sheng Yeh, Joan Tao, Koki Takabatake, Slava Epelman, Irfan J. Lodhi, Joel D. Schilling, Brian J. DeBosch, Abhinav Diwan & Babak Razani (2021) Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response, Autophagy, DOI: 10.1080/15548627.2021.1896906
- Paola Rusmini, Katia Cortese, Valeria Crippa, Riccardo Cristofani, Maria Elena Cicardi, Veronica Ferrari, Giulia Vezzoli, Barbara Tedesco, Marco Meroni, Elio Messi, Margherita Piccolella, Mariarita Galbiati, Massimiliano Garrè, Elena Morelli, Thomas Vaccari & Angelo Poletti (2019) Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration, Autophagy, 15:4, 631-651, DOI: 10.1080/15548627.2018.1535292
- Mardones, Pablo, David C. Rubinsztein, and Claudio Hetz. "Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport." Science signaling 9.416 (2016): fs2-fs2.
- https://www.prnewswire.com/news-releases/seelos-therapeutics-receives-european-orphan-drug-designat
- Sarkar, Sumit, et al. "Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-induced Parkinson's disease mouse model." Neurotoxicology 44 (2014): 250-262.
- Khalifeh, Masoomeh, George E. Barreto, and Amirhossein Sahebkar. "Trehalose as a promising therapeutic candidate for the treatment of Parkinson's disease." British journal of pharmacology 176.9 (2019): 1173-1189.
- Emanuele, Enzo. "Can trehalose prevent neurodegeneration? Insights from experimental studies." Current drug targets 15.5 (2014): 551-557.
- Arai, Chikako, et al. "Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in mice with established obesity." Journal of nutritional science and vitaminology 59.5 (2013): 393-401.
- Yoshizane, Chiyo, et al. "Response to: can one teaspoon of trehalose a day mitigate metabolic syndrome and diabetes risks?." Nutrition journal 20.1 (2021): 1-2.
- Arai, Chikako, et al. "Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance." Nutrition research 30.12 (2010): 840-848.
- Mizote, Akiko, et al. "Daily intake of trehalose is effective in the prevention of lifestyle-related diseases in individuals with risk factors for metabolic syndrome." Journal of nutritional science and vitaminology 62.6 (2016): 380-387.