Research Article: Glucose delays age-dependent proteotoxicity

Date Published: October , 2012

Publisher: Blackwell Publishing Ltd

Author(s): Arnaud Tauffenberger, Alexandra Vaccaro, Anais Aulas, Christine Vande Velde, J Alex Parker.


Nutrient availability influences an organism’s life history with profound effects on metabolism and lifespan. The association between a healthy lifespan and metabolism is incompletely understood, but a central factor is glucose metabolism. Although glucose is an important cellular energy source, glucose restriction is associated with extended lifespan in simple animals and a reduced incidence of age-dependent pathologies in humans. We report here that glucose enrichment delays mutant polyglutamine, TDP-43, FUS, and amyloid-β toxicity in Caenorhabditis elegans models of neurodegeneration by reducing protein misfolding. Dysregulated metabolism is common to neurodegeneration and we show that glucose enrichment is broadly protective against proteotoxicity.

Partial Text

The accumulation of misfolded proteins in the nervous system is a hallmark of many late-onset neurodegenerative diseases. Cellular mechanisms to combat proteotoxicity decline with age, suggesting that aging may directly impact neurodegenerative disease onset and progression. Proteotoxicity is associated with a number of phenotypes including oxidative stress, transcriptional and metabolic disturbances. Consistently, a number of mechanisms linked to aging and neuroprotection include genes and pathways that regulate metabolism and energy production including dietary restriction (DR; Kenyon, 2005).

Model organisms are providing insights into the links between metabolism, longevity, and age-dependent pathologies. DR is a well-studied lifespan-enhancing phenomenon under examination for its potential to delay age-dependent afflictions. However, DR failed to ameliorate neuronal phenotypes in our polyQ and ALS models leading us to question the role of DR mimetics as therapeutics for neurodegeneration. A major mitigating factor may be the relative effects of DR in different tissues; we observed no benefit from DR in neuronal proteotoxicity models, but we and others have observed the protective effects of DR against proteotoxicity in muscle-based expression systems (Steinkraus et al., 2008). Indeed, there is evidence that C. elegans muscles and neurons are not equivalent in their chaperone activity in handling protein misfolding during aging (Kern et al., 2010).




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