Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 5 • September 2012


Housekeeping for a Longer Life: Clearing Unwanted or Toxic Cellular Debris by Inducing Autophagy With the Sugar Trehalose

Autophagy is a natural process in which bulk degradation of cellular cytoplasmic contents takes place, allowing for the removal of unneeded and/or toxic material such as aggregation- prone proteins, including mutant huntingtin (a gene variant associated with Huntington’s disease) and alpha-synuclein (associated with Parkinson disease).1 Other aggregation-prone proteins include amyloid-beta (Alzheimer’s disease) and prions (various prion diseases, such as mad cow disease and possibly Alzheimer’s disease). “Autophagy is an essential process for both the maintenance and the survival of cells, with homeostatic low levels of autophagy being critical for intracellular organelles and proteins.”2 In fact, in a recent paper,3 the researchers concluded that “autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.”

“Autophagy deficiency during aging has been proposed to be the main cause of this biological ‘waste’ accumulation. In support of this theory it has been found that loss-of-function in autophagy genes resulting in intracellular accumulation of damaged proteins and organelles in mice, accelerates aging and life span shortening in Caenorhabditis elegans and Drosophila melanogster. In contrast, elevating autophagy activity increases life span in Drosophila and rescues aged cells from accumulating dysfunctional mitochondria.”3a

Another paper3b found that an autophagy-related protein (beclin 1) was expressed at a reduced level in early Alzheimer disease and that the protein regulates amyloid beta accumulation in mice. Beclin 1 was strongly reduced in the brains of Alzheimer’s disease patients and was also expressed at a lower level in the brains of individuals with mild cognitive impairment as compared to the brains of control patients. Moreover, in an accompanying commentary paper,3c the authors note that in other papers (references given) elimination of basal neuronal autophagy was sufficient to cause neurodegeneration in the absence of other insults. However, other work suggests that autophagosomes in AD patients may be dysfunctional and in a paper using a cell culture model, increased induction of the autophagy pathway through pharmacological manipulation led to elevated amyloid beta accumulation.(3d, paper cited in 3c).

“... recent evidence suggests that autophagy is mostly a cytoprotective mechanism that allow cells to mobilize their energy reserves and to recycle damaged organelles in conditions of lacking nutrients, hypoxia, endoplasmic reticulum stress, accumulation of misfolded proteins, or DNA damage.”3 Misfolded alpha1-antitrypsin, which is a proteinase (the properly folded version functions to break down proteins) is an example of a misfolded protein and evidence indicates that it may be a causative factor in some forms of chronic obstructive pulmonary emphysema and has been found to be eliminated via autophagy.4

A recent paper2 found that in adipose (fat) tissue of insulin resistant mice and hypertrophic (enlarged, insulin resistant) 3T3-L1 adipocytes (fat cells), autophagy was suppressed. Autophagy-related gene expression was also reduced. The suppression of autophagy increased the inflammatory responses in adipocytes (fat cells) via ER (endoplasmic reticulum) stress. The ER is a cellular structure where protein folding takes place and, under conditions of overnutrition (as occurs in obesity and diabetes), results in an accumulation of misfolded proteins; that accumulation and the need to get rid of it (either by destroying the misfolded proteins or refolding them properly) is what causes ER stress. Thus, the researchers conclude that autophagy is “an important regulator of adipocyte inflammation in systemic insulin resistance.”2 Another group reported2a that defective liver autophagy in obesity promotes ER stress and “is a critical component of defective insulin action seen in obesity.”

In an earlier issue of this newsletter (see “The Origami of Aging” in the September 2008 issue of Life Enhancement), we reported on the protective effects of small natural molecules called osmolytes that act as chaperones to help properly fold proteins, a complex process that takes place in the ER. One of these osmolytes, the natural sugar trehalose, has been reported1 to be a novel enhancer of autophagy, which was the mechanism identified in this paper for its ability to accelerate the clearance of aggregation- prone proteins mutant huntingtin and alpha-synuclein. In an earlier paper5 by a different group of scientists, trehalose was also reported to alleviate the pathology induced by insoluble polyglutamine-induced protein aggregates in a mouse model of Huntington disease, though autophagy was not investigated as a potential mechanism; the researchers found trehalose to stabilize the partially unfolded polyglutamine-containing protein. The trehalose was administered to the mice in the Huntington mouse model study in their drinking water, with the protective effect being most prominent in the animals drinking 2% trehalose.5

Trehalose is found naturally in many organisms, including bacteria, yeast, fungi, insects, invertebrates, and plants and is protective against a variety of environmental stimuli, including heat, cold, desiccation, dehydration, and oxidation, by preventing protein denaturation.1 We both take a trehalose containing supplement every day.

References

1. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 282(8):5641-52 (2007).
2. Yoshizaki et al. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun 417:352-7 (2012).
2a. Yang et al. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11:467- 478 (2010).
3. Morselli et al. Caloric restriction and resveratrol promote longevity through Sirtuin-1-dependent induction of autophagy. Cell Death Dis (2010) 1, e10; doi:10.1038/cddis.2009.8
3a. Yen and Klionsky. How to live long and prosper: autophagy, mitochondria, and aging. Physiology 23:248-62 (2008)
3b. Pickford et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 118(6):2190-9 (2008).
3c. Lee and Gao. Regulation of Abeta pathology by beclin 1: a protective role for autophagy? J Clin Invest 118(6):2015-8 (2008).
3d. Yu et al. Macroautophagy —a novel beta amyloid peptide- generating pathway activated in Alzheimer’s disease. J Cell Biol 171:87-98 (2005).
4. Sifers. Clearing conformational disease. Science 329:154-5 (2010).
5. Tanaka et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10(2):148-54 (2004).

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