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Review
. 2008 Dec;24(12):604-12.
doi: 10.1016/j.tig.2008.10.002. Epub 2008 Nov 5.

Autophagy and aging: keeping that old broom working

Ana Maria Cuervo  1
Affiliations
Review

Autophagy and aging: keeping that old broom working

Ana Maria Cuervo. Trends Genet. 2008 Dec.

Abstract

Autophagy, a highly conserved mechanism of quality control inside cells, is essential for the maintenance of cellular homeostasis and for the orchestration of an efficient cellular response to stress. The decrease in autophagic activity observed in almost all cells and tissues as organisms age was proposed to contribute to different aspects of the aging phenotype and to the aggravation of detrimental age-related diseases. The recent advances in our understanding of the molecular mechanisms underlying autophagy and the identification of the subset of genes involved in this process has enabled the use of genetic manipulations to start testing this hypothesis. Here, I review the recent genetic evidence in support of tight connections between autophagy, health span and aging.

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Figures

Figure 1
Figure 1
Schematic model of the different types of autophagy in mammalian cells. Three different main types of autophagy have been described in mammalian cells. In macroautophagy, entire regions of the cytosol, including proteins and organelles, are sequestered in a double membrane vesicle that then fuses with lysosomes to enable cargo degradation. During microautophagy, the lysosomal membrane invaginates or protrudes to internalize cytosolic components in single membrane vesicles that are then rapidly degraded in the lysosomal lumen. Selective degradation of soluble cytosolic proteins can be attained by chaperone-mediated autophagy, in which candidate substrate proteins (green) are brought to a translocation complex (yellow) at the lysosomal membrane by cytosolic chaperones (red). Substrate proteins can only reach the lysosomal lumen by this pathway after undergoing complete unfolding in the cytosolic side of the lysosomal membrane. The two most important functions of autophagy are also depicted in this model: (i) as an alternative source of energy, by providing essential components - such as amino acids (aa) or free fatty acids (FA) - that can be used for cellular fueling; and (ii) as an essential component of the cellular mechanisms for quality control, by guaranteeing removal of altered proteins and organelles.
Figure 2
Figure 2
Failure of macroautophagy in aging. Possible causes and consequences of the failure of macroautophagy in old organisms are depicted in this schematic model (brown boxes). (a) The accumulation of autophagic vacuoles with age could result from the inability of lipofuscin-loaded lysosomes to fuse with autophagic vacuoles and degrade the sequestered content. (b) In addition, the formation of autophagosomes in old cells might be reduced because of the inability of macroautophagy enhancers (such as glucagon) to induce full activation of this pathway. The stimulatory effect of glucagon is compromised in old cells because of maintained negative signaling through the insulin receptor (IR) even under basal conditions (i.e. in the absence of insulin). Maintained insulin signaling would activate mTOR, a known repressor of macroautophagy. (c) Inadequate turnover of organelles, such as mitochondria, in aging cells could increase levels of free radicals that generate protein damage and (d) could also potentiate the inhibitory signaling through the insulin receptor. (e) An age-dependent decline in macroautophagy can also result in energetic compromise of the aging cells.
Figure 3
Figure 3
Effects of genetic manipulations on autophagy in cellular aging and longevity. Studies in worms (a) have revealed that macroautophagy is upregulated in different long-lived mutants (life span is indicated by green arrows). Blockage of macroautophagy by siRNA against essential autophagy proteins (Atg) in these mutant worms reduces their life-span extension, supporting the view that functional autophagy is required to attain maximal life extension in these worms. (b) Whether or not macroautophagy blockage by similar procedures reduces normal life span in wild-type worms remains controversial (denoted by?). (c) Macroautophagy upregulation in neurons decreases age-dependent neuronal damage and increases life span in flies. (d) Recently, the prevention of the age-related decline in CMA activity in the liver of a transgenic mouse model improved overall hepatic function.
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