December 12, 2007
Chaperones in aging: nothing too shocking
Posted by ouroboros under Gene expression, Protein degradation, Sirtuins
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After yesterday’s feast of autophagy I realized that I have another full meal’s worth of stories regarding chaperones and heat shock proteins (HSPs). Regulation of chaperone genes — which catalyze folding and assembly of proteins, and also help dispose of malfolded proteins — already holds a special place in biogerontologists’ hearts: the life-extending compound resveratrol induces the heat shock response (possibly in an example of hormesis), and stochastic changes in chaperone levels are associated with parallel changes in organismal lifespan.
Without further ado then, here are three recent articles on chaperones and heat shock:
Just as autophagy declines with age, so too does the activity of the proteasome and the expression of the major cytosolic chaperone Hsc70. Bonelli et al. describe how calorie restriction (CR) of rats maintains proteasome activity and Hsc70 expression in the liver, well into old age. In contrast to CR’s effects on autophagy, the boost in proteasome activity does not appear to occur simply as a result of increased expression of proteasome components; the authors argue that something is acting to qualitatively increase the activity of proteasomes while keeping their levels unchanged. (Maybe targeting or delivery is more efficient?)
In humans, several HSPs are upregulated with age, perhaps as a response to increased steady-state levels of oxidatively damaged proteins, which would be expected to fold poorly. Njemini et al. describe an interesting association of increased HSP expression with the increased inflammatory cytokine expression that is a hallmark of frailty in old age.
In budding yeast, daughter cells are protected from inheriting their mother cells’ old age because the mothers keep damaged macromolecules on their side of an asymmetric cell division, a process that requires SIR2, the founding member of the sirtuin family. Erjavec et al. demonstrate that the sequestration of oxidatively altered proteins also requires Hsp104. Overproduction of this chaperone can rescue the accelerated-aging phenotype of sir2 mutants.
December 11, 2007
A feast of autophagy
Posted by ouroboros under Autophagy, Calorie restriction, Protein degradation
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Autophagy is increasingly thought to play an important role in aging, in part because autophagic degradation allows cells to prevent the accumulation of damaged macromolecules such as oxidized proteins and advanced glycation endproducts (AGEs).
I’ve been slowly squirreling away abstracts about the subject, and they’ve been building up — so on this crisp nearly-winter day I figured that it might be time to dig up some of those nuts:
In heart muscle, calorie restriction (CR) boosts autophagy, both by increasing the number of autophagosomes and the expression of autophagy-related proteins. Wohlgemuth et al. suggest that this might provide a mechanism for the beneficial effects of CR on cardiac tissue.
The overall rate of autophagy decreases with age. One specific flavor of degradation that undergoes such a decline is chaperone-mediated autophagy, which directs cytosolic proteins to the lysosome via an interaction with an intracellular receptor. Kiffin et al. have tracked down the cause of this decline, and lay the blame on changes in the processing and stability of the lysosomal receptor LAMP-2.
The benefits of autophagy (and the hazards resulting from its age-related decline) are hinted at in the results of Bergamini et al., who show that an anti-lipolytic drug that stimulates autophagy can reverse at least one biomarker of aging, in this case high levels of altered mitochondrial DNA. The authors also address the relationship between CR and the cellular adaptation to fasting, and argue that autophagy is essential to the anti-aging action of CR.
http://ouroboros.wordpress.com/ un blog interessante.
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