Mini-ReviewProtein degradation and aging
Section snippets
Intracellular protein degradation: constant destruction for continuous rejuvenation
All intracellular proteins undergo continuous synthesis and degradation (Mortimore et al., 1989, Schimke, 1970). This constant protein turnover, among other functions, helps reduce, to a minimum, the time a particular protein is exposed to the hazardous cellular environment, and consequently, the probability of being damaged or altered. At a first sight, this constant renewal of cellular components before they lose functionality may appear a tremendous waste of cellular resources. However, it
The lysosomal/autophagic system: the return of the big giant
The term autophagy refers to any process resulting in the degradation of intracellular components inside lysosomes or the vacuole (the equivalent to lysosomes in yeast) (reviewed in Cuervo, 2004a, Cuervo, 2004b, Klionsky, 2005). Lysosomes are single membrane organelles, which contain a large assortment of hydrolases capable of degrading any kind of macromolecules. Extracellular macromolecules can also be internalized and degraded in lysosomes through what is known as heterophagy (details about
The ubiquitin proteasome system
The ubiquitin proteasome system (UPS) is the other major proteolytic system in eukaryotic cells (Ciechanover, 2005, Wolf and Hilt, 2004). Two major steps, the tagging of the substrates for their degradation, and their actual proteolytic cleavage, are attained through the coordinate function of its main components, the ubiquitin conjugating cascade and the proteasome or degradation nano-machine (Fig. 3). The UPS contributes to the maintenance of cellular homeostasis and protein quality control,
Concluding remarks
Alterations in both the lysosomal system and the UPS are common in most tissues of old organisms. The numerous intracellular processes in which these proteolytic systems participate make comprehensible why their failure with age has been proposed as key in the pathogenesis of numerous age-related pathologies. The recent advances in the molecular dissection of autophagy and of the regulatory components of the UPS should help, in the coming years, the identification of the defect(s) responsible
Acknowledgements
We would like to gratefully acknowledge the members of our laboratory for critically reviewing this manuscript and for their valuable suggestions. Research in our laboratory is supported by National Institutes of Health/National Institute of Aging grants AG021904 and AG19834, a Huntington's Disease Society of America Research grant and an Ellison Medical Foundation Award.
References (59)
- et al.
Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation
Mol. Cell
(2005) - et al.
The role of macroautophagy in the ageing process, anti-ageing intervention and age-associated diseases
Int. J. Biochem. Cell Biol.
(2004) - et al.
Pen-2 is sequestered in the endoplasmic reticulum and subjected to ubiquitylation and proteasome-mediated degradation in the absence of presenilin
J. Biol. Chem.
(2004) - et al.
Age-dependent declines in proteasome activity in the heart
Arch. Biochem. Biophys.
(2002) - et al.
Ubiquitin expression is up-regulated in human and rat skeletal muscles during aging
Arch. Biochem. Biophys.
(2004) - et al.
Impairment of proteasome structure and function in aging
Int. J. Biochem. Cell Biol.
(2002) - et al.
Impact of ageing on proteasome structure and function in human lymphocytes
Int. J. Biochem. Cell Biol.
(2003) - et al.
Nuclear proteasome activation and degradation of carboxymethylated histones in human keratinocytes following glyoxal treatment
Free Radic. Biol. Med.
(2005) - et al.
When lysosomes get old
Exp. Gerontol.
(2000) - et al.
Peroxisome turnover by micropexophagy: an autophagy-related process
Trends Cell Biol.
(2004)