Trehalose

Trehalose is a sugar which, on a cellular level, appears to have therapeutic mechanisms by regulating protein unfolding. Practically, its low oral absorption in its intact form paired with rapid digestion may preclude any benefits of oral intake.

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Summary

All Essential Benefits/Effects/Facts & Information

In Progress


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Trehalose is a disaccharide composed of glucose, differing from the dietary sugar known as maltose which is also comprised of two glucose molecules due to differing bonds. Trehalose is found mostly as a component of mushrooms in the diet, with limited exposure in the human diet otherwise.

It has been investigated for a variety of therapeutic purposes due to its ability to induce apoptosis (controlled cellular death) via an atypical mechanism, and in these therapeutic settings using trehalose injections it appears to be effective.

Unfortunately, not only is trehalose initially poorly absorbed from the intestines but within the intestinal wall there is an enzyme (trehalase) which can rapidly degrade trehalose into glucose. For the trehalose that bypasses this enzyme and gets absorbed, the threhalase present in the liver and the blood appears to finalize the digestion leaving little to no trehalose able to reach a cell and exert its therapeutic effects.

The only way to preserve the effects of trehalose is to avoid oral ingestion by applying the compound topically leading to the promise of trehalose in protecting cellular function being exclusive to the skin, eyes, and hair. It has already shown therapeutic promise for the treatment of dry eye symptoms when used as eye drops, with a potency greater than commercially available products.

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Things To Know

Things to Note

  • Due to rapid digestion via trehalase, it is unlikely that orally ingested trehalose supplements will confer any unique benefits since trehalose would be digested to glucose

Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects trehalose has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
Dry Eyes Strong Very High See 2 studies
The benefits of trehalose containing eye drops appears to be greater than not only placebo (saline) eye drops, but also eye drops containing either hyaluronan (Hyalein) or hydroxyethylcellulose (Mytear) which are proven commercial products for dry eyes.


1Sources and Composition

1.1. Sources and Structure

Trehalose (synonyms ofmycose and tremalose) is a disaccharide (two sugar) comprised of two glucose molecules, named after its sources of trehala manna (from which 'Trehalose' was named from[1]) which is a sugary solution obtained from the nest and/or cocoon of some insects (larinus genera).[2] "Mycose" as a synonym was named after another common source of trehalose, mushrooms.

Trehalose's main biological purpose in mushrooms and bacteria is water regulation, since it seems to form a gel phase during cellular dehydration protecting organelle during this time and then allows rapid rehydration when a proper environment is reintroduced.[3][4] It can serve a hydration function in humans as well as possessing general antioxidant properties, but its major role is as a cellular chaperone regulating intracellular functions such as protein folding and unfolding; it is one of few exogenous chaperones that can be consumed orally similar to the bile acid and chaperone TUDCA.[5]

Trehalose is a dietary sugar found predominately in mushrooms that also appears to have a role in autophagy and protein folding, leading to pharmacological actions atypical of carbohydrates

The structure for trehalose (α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside) differs from the other disaccharide made from two glucose molecules known as maltose (4-O-α-D-Glucopyranosyl-D-glucose) as trehalose has a different bond between the two molecules (a 1,1-glucoside bond rather than an alpha linkage) and trehalose is made of two α-glucose molecules; α-glucose (and β-glucose) referring to the isomerization of the hydroxyl group on carbon 1 in the D-glucose molecule.

Trehalose differs slightly from maltose despite both containing two glucose monosaccharides, as trehalose possesses a different bond and is exclusively comprised of alpha-glucose molecules

1.2. Biological Significance

Despite being synthesized by a wide degree of bacteria, fungi, plants, and insects on an as-needed basis to protect the cells against dessication or states of extreme dryness, trehalose is not reportedly known to be synthesized by mammalian cells[2][6] despite application of trehalose to mammalian cells having a similar protective effect against dessication (200mM).[7]

Trehalose is not synthesized in humans, and any biological effects would either need to be due to oral ingestion (dietary supplements or dietary sources such as mushrooms); trehalose administration secondary to synthesis from intestinal bacteria is plausible but not yet demonstrated


2Molecular Targets

2.1. Autophagy

Trehalose appears to be a disaccharide that can mimic a cellular chaperone, and increases autophagy in a cell via mechanisms independent of mTOR; mTOR is the most well researched regulatory of autophagy and its inhibition (which increases autophagy) the most common mechanism associated with nutraceuticals leading trehalose to be somewhat novel.

The increase in autophagy appears to occur with an increase in FOXO1 translocation and activity[8] (FOXO1 being a positive regulator of autophagy[9]) and in cultured neurons is not related to ATF4 which is unchanged in protein content.Autophagy is increased by an enhancement of FOXO1 activation with no effect on ATF4[8] although protein content of various other autophagy related gene products (Lc3, Becn1, Sqstm1 and Atg5) appear to be increased at the mRNA level.[8]

The inhibition of autophagy is blocked by standard inhibitors 3-methyladenine (Blocks the PtdIns3K initiation complex critical for autophagy[10]) and various lysosomal inhibitors. Due to it being independent of mTOR, combination with mTOR inhibitors such as rapamycin appear to result in additive effects.[11]

Trehalose appears to increase autophagy in a manner independent of mTOR inhibition, which is atypical for nutraceuticals (as most that increase autophagy do so via attenuating mTOR's suppressive actions on this phenomena)

2.2. Protein Aggregation

There appears to be an ability of trehalose to disaggregate proteins in cellular cultures, which is preserved even when autophagy is inhibited[8] suggesting it is a different mechanism.

This has been noted with SOD1 aggregates in vitro[12] and in the spinal fluid of SOD1 mice (model for ALS)[8] which are misfolded proteins that seem to accumulate in pathological conditions (and are decreased by many autophagy interventions[13][14]) and have a pathological role as misfolded monomeric SOD1 is neurotoxic.[15] The protein α-synuclein (relevant to Parkinson's) has also been noted to be degraded with trehalose in vitro[16][11] along with tau protein[17] and huntingtin, a protein involved in the pathology of Huntington's Disease.[18][11]

Various protein aggregates that accumulate during neurodegenerative diseases seen to be disaggregated when trehalose is introduced, suggesting a possible preventative/therapeutic role of trehalose that remains to be investigated


3Pharmacology

3.1. Absorption

Trehalose has a variable absorption rate, but is slightly lesser than pure glucose on average; when measuring the relative absorption of glucose between trehalose and pure glucose in otherwise healthy people given 50 grams of trehalose and measured over the next hour, the relative absorption of trehalose varies between 0.3-1.5 with an average of 0.7 (70% as bioavailable as pure glucose).[19]

In people who can not absorb trehalose normally due to a lack of trehalase it is thought that all absorption that occurs would be via passive diffusion; in regards to disaccharides in general, the amount absorbed by passive diffusion during instances of malabsorption tends to be around 0.5%.[20] Malabsorption of trehalose underlies an intolerance to mushrooms, since the lack of absorption results in diarrhea and intestinal distress.[21]

It should be emphasized that when measuring the bioavailability of trehalose the amount of glucose that appears in the blood is used as the proxy measurement; trehalose itself is not readily absorbed, and must be digested into glucose via trehalase before appreciable absorption. This is similar to lactose, which needs to be digested into its monosaccharides (galactose and glucose) via lactase prior to absorption and a lack of the enzyme causes malabsorption.

At the level of the intestines, trehalose appears to be absorbed to a rate slightly lesser than pure glucose although it is variable. In persons lacking the trehalase enzyme there is next to no absorption, and trehalose is absorbed in the form of glucose (as it is digested first, and then the glucose is absorbed)

3.2. Metabolism

The enzyme that metabolizes trehalose into two alpha-glucose molecules known as trehalse is present in the mammalian intestinal tract[22] and kidneys[23] despite humans not being capable of synthesizing trehalose. Some intestinal bacteria such as saccharomyces boulardii may also release this enzyme into the gut,[24] which was thought to be therapeutic for diarrhea in instances of trehalose deficiency.

The highest estimate of trehalose deficiency (both total and partial) has been estimated to be around 8-10%[24][25]) but is thought to be lower on average, around 3.2-6.0%.[26] Due to low prevalence and minimal dietary sources of trehalose, it is not thought to be a significant nutritional concern like lactose deficiency is.[25]

Humans do not appear to synthesize trehalose, but most people appear to be capable of digesting trehalose into its constituent alpha-glucose molecules as the intestines and kidneys expresses trehalase. An inability to digest trehalose may result in cramping and diarrhea in response to dietary trehalose such as mushrooms

Trehalase also exists in the blood of mammals,[27] which suggests that the low amount of orally absorbed trehalose that escapes intestinal digestion can be eliminated in serum.

Trehalose that reaches the blood can be digested into glucose at this point as well, resulting in glucose


4Peripheral Organ Systems

4.1. Eyes

Trehalose has been hypothesized to have a role in ophthamology related to anti-dessicative properties,[2] and one trial in which mice were placed in an environment conducive to forming symptoms of dry eyes (low-humidity airflow and temperature[28]) for three weeks had less symptoms of dry eyes and apoptosis than did control when they were given eyedrops containing trehalose (concentration of 87.6mM or 30mg/mL).[29]

Eye cells may also experience less damage secondary to UVB radiation when in the presence of trehalose at the aforementioned 30mg/mL concentration[30][31] and can enhance the rate of healing when applied to the eye cell even after UVB-induced damage has occurred.[32] It is thought to be safe for direct application, as trehalose is included in two pharmaceuticals (Avastin and Lucentis) which are administered to the eye via intravitreal injection.[2]

Trehalose appears to have protective effects at the level of the eye in regards to both preventing cellular damage induced by UVB rays and reducing the chance of getting dry eyes, and appears to avoid the problems of oral ingestion (low absorption and rapid digestion) when it is applied directly to the eyes via eye drops

One study using two concentrations of trehalose solution (100mM or 200mM) in saline applied to one eye six times daily for four weeks, while using the other eye as a control, noted that both concentrations appeared to be beneficial to dry eyes with 100mM outperforming the higher dose in prolonging tear film breakup time.[33] These benefits have been noted elsewhere, with trehalose containing eye drops outperforming commercial products containing either hyaluronan (Hyalein) or hydroxyethylcellulose (MyTear).[34]

Eye drops containing trehalose have been demonstrated effective in two trials in humans with dry eye symptoms, and at least one of those trials suggests that its potency is greater than the currently available options of hyaluronan or hydroxyethylcellulose


5Interactions with Medical Conditions

5.1. Amyotrophic Lateral Sclerosis (ALS)

Trehalose has been investigated for delaying the pathology of amyotrophic laterial sclerosis (ALS) due to its ability to increase autophagy.

It appears that in SOD1 mice (mouse model for ALS) that thrice weekly trehalose injections paired with 3% trehalose in the drinking water delayed the onset of ALS symptoms and increased lifespan relative to other sugars.[8]

Administration of trehalose to mice predisposed to ALS appears to attenuate the severity of the disease and increases lifespan relative to other sugars and control

This increase in lifespan seems to correlated with a decrease in spinal SOD1 aggregation and (subsequently) less glial cell activation,[8] this is thought to be secondary to increased rates of microglial autophagy.[8] When tested in vitro (100mM trehalose) SOD1 accumulation is maintained even when autophagy is blocked, suggesting dual mechanisms.[8]

At least in mice, this increase in lifespan may be more pronounced in males[8] despite reduced SOD1 aggregation being similar in both groups.[8]

There may be a reduction in spinal SOD1 aggregation in mice with ALS given trehalose, which is possibly distinct from the enhancement of autophagy

Scientific Support & Reference Citations

References

  1. Tillequin F Trehala, a meeting point between zoology, botany, chemistry, and biochemistry . Rev Hist Pharm (Paris). (2009)
  2. Luyckx J1, Baudouin C Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology . Clin Ophthalmol. (2011)
  3. Sussich F1, et al Reversible dehydration of trehalose and anhydrobiosis: from solution state to an exotic crystal . Carbohydr Res. (2001)
  4. Furuki T1, Oku K, Sakurai M Thermodynamic, hydration and structural characteristics of alpha,alpha-trehalose . Front Biosci (Landmark Ed). (2009)
  5. Lee YY1, et al Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress . Biochem Biophys Res Commun. (2010)
  6. Elbein AD1, et al New insights on trehalose: a multifunctional molecule . Glycobiology. (2003)
  7. Eroglu A1, et al Intracellular trehalose improves the survival of cryopreserved mammalian cells . Nat Biotechnol. (2000)
  8. Castillo K1, et al Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons . Autophagy. (2013)
  9. JNK regulates FoxO-dependent autophagy in neurons
  10. Seglen PO, Gordon PB 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes . Proc Natl Acad Sci U S A. (1982)
  11. Sarkar S1, et al Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein . J Biol Chem. (2007)
  12. Gomes C1, Escrevente C, Costa J Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins . Neurosci Lett. (2010)
  13. Vidal RL1, et al Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy . Hum Mol Genet. (2012)
  14. Harris H1, Rubinsztein DC Control of autophagy as a therapy for neurodegenerative disease . Nat Rev Neurol. (2011)
  15. Brotherton TE1, Li Y, Glass JD Cellular toxicity of mutant SOD1 protein is linked to an easily soluble, non-aggregated form in vitro . Neurobiol Dis. (2012)
  16. Lan DM1, et al Effect of trehalose on PC12 cells overexpressing wild-type or A53T mutant α-synuclein . Neurochem Res. (2012)
  17. Krüger U1, et al Autophagic degradation of tau in primary neurons and its enhancement by trehalose . Neurobiol Aging. (2012)
  18. Tanaka M1, et al Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease . Nat Med. (2004)
  19. Bergoz R, Bolte JP, Meyer zum Bueschenfelde Trehalose tolerance test. Its value as a test for malabsorption . Scand J Gastroenterol. (1973)
  20. van Elburg RM1, et al Repeatability of the sugar-absorption test, using lactulose and mannitol, for measuring intestinal permeability for sugars . J Pediatr Gastroenterol Nutr. (1995)
  21. Bergoz R Trehalose malabsorption causing intolerance to mushrooms. Report of a probable case . Gastroenterology. (1971)
  22. Assay of intestinal disaccharidases
  23. Yoneyama Y, Lever JE Apical trehalase expression associated with cell patterning after inducer treatment of LLC-PK1 monolayers . J Cell Physiol. (1987)
  24. Buts JP1, et al Characterization of alpha,alpha-trehalase released in the intestinal lumen by the probiotic Saccharomyces boulardii . Scand J Gastroenterol. (2008)
  25. Gudmand-Høyer E1, et al Trehalase deficiency in Greenland . Scand J Gastroenterol. (1988)
  26. Gudmand-Høyer E1, Skovbjerg H Disaccharide digestion and maldigestion . Scand J Gastroenterol Suppl. (1996)
  27. Eze LC Plasma trehalase activity and diabetes mellitus . Biochem Genet. (1989)
  28. Chen W1, et al A murine model of dry eye induced by an intelligently controlled environmental system . Invest Ophthalmol Vis Sci. (2008)
  29. Chen W1, et al Trehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosis . Exp Eye Res. (2009)
  30. Cejková J1, et al Reduced UVB-induced corneal damage caused by reactive oxygen and nitrogen species and decreased changes in corneal optics after trehalose treatment . Histol Histopathol. (2010)
  31. Cejková J1, et al Favorable effects of trehalose on the development of UVB-mediated antioxidant/pro-oxidant imbalance in the corneal epithelium, proinflammatory cytokine and matrix metalloproteinase induction, and heat shock protein 70 expression . Graefes Arch Clin Exp Ophthalmol. (2011)
  32. Cejková J1, Cejka C, Luyckx J Trehalose treatment accelerates the healing of UVB-irradiated corneas. Comparative immunohistochemical studies on corneal cryostat sections and corneal impression cytology . Histol Histopathol. (2012)
  33. Matsuo T1, Tsuchida Y, Morimoto N Trehalose eye drops in the treatment of dry eye syndrome . Ophthalmology. (2002)
  34. Matsuo T Trehalose versus hyaluronan or cellulose in eyedrops for the treatment of dry eye . Jpn J Ophthalmol. (2004)

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