Elsevier

Experimental Gerontology

Volume 40, Issues 8–9, August–September 2005, Pages 622-633
Experimental Gerontology

Mini-Review
Protein degradation and aging

https://doi.org/10.1016/j.exger.2005.07.005Get rights and content

Abstract

Continuous turnover of intracellular proteins is essential for the maintenance of cellular homeostasis and for the regulation of multiple cellular functions. The first reports showing a decrease in total rates of protein degradation with age are dated more than 50 years ago, when the major players in protein degradation where still to be discovered. The current advances in the molecular characterization of the two main intracellular proteolytic systems, the lysosomal and the ubiquitin proteasome system, offer now the possibility of a systematic search for the defect(s) that lead to the declined activity of these systems in old organisms. We discuss here, in light of the current findings, how malfunctioning of these two proteolytic systems can contribute to different aspects of the phenotype of aging and to the pathogenesis of some age-related diseases.

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)

  • T. Grune et al.

    Selective degradation of oxidatively modified protein substrates by the proteasome

    Biochem. Biophys. Res. Commun.

    (2003)
  • M. Gutierrez et al.

    Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages

    Cell

    (2004)
  • J.N. Keller et al.

    Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain

    Int. J. Biochem. Cell Biol.

    (2004)
  • J.A. Kiel et al.

    Macropexophagy in Hansenula polymorpha: facts and views

    FEBS Lett.

    (2003)
  • J. Lum et al.

    Growth factor regulation of autophagy and cell survival in the absence of apoptosis

    Cell

    (2005)
  • A.E. Majeski et al.

    Mechanisms of chaperone-mediated autophagy

    Int. J. Biochem. Cell Biol.

    (2004)
  • A. Massey et al.

    Pathophysiology of chaperone-mediated autophagy

    Int. J. Biochem. Cell Biol.

    (2004)
  • A.J. Meijer et al.

    Regulation and role of autophagy in mammalian cells

    Int. J. Biochem. Cell Biol.

    (2004)
  • M. Mishto et al.

    Immunoproteasomes and immunosenescence

    Ageing Res. Rev.

    (2003)
  • G. Mortimore et al.

    Regulation of microautophagy and basal protein turnover in rat liver. Effects of short-term starvation

    J. Biol. Chem.

    (1988)
  • E. Ogier-Denis et al.

    Autophagy: a barrier or an adaptive response to cancer

    Biochim. Biophys. Acta

    (2003)
  • Y. Ohsumi et al.

    Two ubiquitin-like conjugation systems essential for autophagy

    Semin. Cell Dev. Biol.

    (2004)
  • S. Rodriguez-Enriquez et al.

    Role of mitochondrial permeability transition pores in mitochondrial autophagy

    Int. J. Biochem. Cell Biol.

    (2004)
  • R. Shringarpure et al.

    Ubiquitin-conjugation is not required for the degradation of oxidized proteins by the proteaseome

    J. Biol. Chem.

    (2003)
  • S. Sooparb et al.

    Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus

    Kidney Int.

    (2004)
  • A. Terman et al.

    Lipofuscin

    Int. J. Biochem. Cell Biol.

    (2004)
  • A. Terman et al.

    Myocyte aging and mitochondrial turnover

    Exp. Gerontol.

    (2004)
  • G. Viteri et al.

    Age-dependent protein modifications and declining proteasome activity in the human lens

    Arch. Biochem. Biophys.

    (2004)
  • D.H. Wolf et al.

    The proteasome: a proteolytic nanomachine of cell regulation and waste disposal

    Biochim. Biophys. Acta

    (2004)
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